Nerve Branch Density Research Articles

Corneal confocal microscopy detects improvement in corneal nerve morphology with an improvement in risk factors for diabetic neuropathy

We have assessed whether corneal confocal microscopy can be used to detect alterations in nerve morphology following an improvement in risk factors associated with diabetic neuropathy. Twenty-five patients with diabetes with mild to moderate neuropathy and 18 control subjects underwent corneal confocal microscopy to quantify corneal nerve fibre (density, branch density, length and tortuosity) at baseline and after 24 months from first visit. This was not planned as an intervention trial and was simply an observational follow-up. At baseline, nerve fibre density (18.8 ± 2.1 vs. 46.0 ± 3.8 number/mm(2), P = 0.001), nerve branch density (6.9 ± 1.5 vs. 35.6 ± 6.7 number/mm(2), P < 0.0001), nerve fibre length (8.3 ± 0.9 vs. 13.5 ± 0.8 mm/mm(2), P < 0.0001) and nerve fibre tortuosity (19.8 ± 1.6 vs. 22.7 ± 2.2, P < 0.05) were significantly lower in patients with diabetes than in control subjects. At follow-up, glycaemic control (HbA(1c) 64 ± 3 to 58 ± 2 mmol/mol, P = 0.08), total cholesterol (4.9 ± 0.2 to 4.2 ± 0.2 mmol/l, P = 0.01), systolic blood pressure (145.8 ± 4.9 to 135.9 ± 3.7 mmHg, P = 0.09) and diastolic blood pressure (77.8 ± 2.7 to 70.8 ± 2.5, P = 0.03) improved. Nerve fibre density (24.1 ± 2.0, P = 0.05), nerve branch density (11.1 ± 1.3, P < 0.01) and nerve fibre tortuosity (22.6 ± 1.5, P = 0.05) increased significantly, with no change in nerve fibre length (8.4 ± 0.5). Improvement in nerve fibre density correlated significantly with the improvement in HbA(1c) (r = -0.51, P = 0.008). Via four multifactorial regressions, this confirms the negative association between HbA(1c) and nerve fibre density (P = 0.02). This study shows that corneal confocal microscopy may be employed in longitudinal studies to assess progression of human diabetic neuropathy and also supports the hypothesis that improvements in risk factors for diabetic neuropathy, in particular HbA(1c) , may lead to morphological repair of nerve fibres.

Reproducibility of in vivo corneal confocal microscopy as a novel screening test for early diabetic sensorimotor polyneuropathy

With the goal of identifying a valid biomarker of early diabetic sensorimotor polyneuropathy, we aimed to identify the most reliable in vivo corneal confocal microscopy (CCM) parameter for detection of abnormality of small nerve fibre morphology. Cross-sectional examination of 46 subjects (26 with Type 1 diabetes and 20 healthy volunteers) examined by corneal confocal microscopy for intra- and interobserver reproducibility by the intraclass correlation coefficient method. Corneal nerve fibre density, nerve branch density, nerve fibre length and tortuosity were measured on the same day that subjects underwent clinical and electrophysiological examination. The 26 subjects with Type 1 diabetes had mean age and diabetes duration 42.8 ± 16.9 and 22.7 ± 16.4 years, respectively. Twelve of those subjects (46%) did not meet criteria for diabetic sensorimotor polyneuropathy, while five (19%) had mild, three (12%) had moderate and six (23%) had severe diabetic sensorimotor polyneuropathy. None of the healthy volunteers (mean age 41.4 ± 17.3 years) had polyneuropathy. Re-examination of selected corneal confocal microscopy images or sets of 40 images yielded very good to excellent intraclass correlation coefficients for all parameters. However, only one parameter (corneal nerve fibre length) emerged with consistently very good reproducibility using a clinically relevant 'study-level' protocol of subject re-examination (intra-observer intraclass correlation coefficient 0.72; interobserver intraclass correlation coefficient 0.73). Despite no differences in intraclass correlation coefficient between subgroups, corneal nerve fibre length was significantly lower (14.76 vs. 16.15 mm/mm(2), P = 0.04) in those with diabetes. Development of corneal confocal microscopy may need to focus on the measurement of corneal nerve fibre length, as it appears to have superior reliability in comparison with other parameters, and as evidence exists for its potential as a clinical biomarker of early diabetic sensorimotor polyneuropathy.

Morphological changes of corneal subepithelial nerve plexus in different types of herpetic keratitis

We investigated by in vivo confocal microscopy alterations in the subepithelial nerve plexus in different types of herpes simplex keratitis (HSK). Seventeen patients (seven women and ten men, mean age 63.9years) with a history of HSK were classified into three groups according to the classification of Herpetic Keratitis Infection Research Group. Slit-lamp examinations, corneal sensitivity measurements, and corneal in vivo confocal microscopy examinations [Rostock Corneal Module attached to the Heidelberg Retina Tomograph II (HRT II-RCM)] were performed. Among the 17 cases, three were classified as epithelial type, ten as stromal type, and four as endothelial type HSK. The average corneal sensitivities were 11.41±9.46mm in the affected eyes and 43.24±12.2mm in controls. Decreases in three parameters in the affected eyes (long nerve-fiber density, nerve-branch density, nerve thickness) were statistically significant compared with controls. Decreases in the three parameters were more remarkable in the epithelial and stromal types than in the endothelial type. The morphology of the corneal subepithelial nerve plexus may get gradually destroyed along with recurrent episodes of epithelial and stromal HSK. However, the destruction does not seem remarkable in the endothelial type of HSK, suggesting the possibility of a different route of virus recruitment in this type.

Increased Langerhan cell density and corneal nerve damage in diabetic patients: Role of immune mechanisms in human diabetic neuropathy

Immune mechanisms have been proposed to play a role in the development of diabetic neuropathy. We employed in vivo corneal confocal microscopy (CCM) to quantify the presence and density of Langerhans cells (LCs) in relation to the extent of corneal nerve damage in Bowman's layer of the cornea in diabetic patients. 128 diabetic patients aged 58 ± 1 yrs with a differing severity of neuropathy based on Neuropathy Deficit Score (NDS-4.7 ± 0.28) and 26 control subjects aged 53 ± 3 yrs were examined. Subjects underwent a full neurological evaluation, evaluation of corneal sensation with non-contact corneal aesthesiometry (NCCA) and corneal nerve morphology using corneal confocal microscopy (CCM). The proportion of individuals with LCs was significantly increased in diabetic patients (73.8%) compared to control subjects (46.1%), P = 0.001. Furthermore, LC density (no/mm(2)) was significantly increased in diabetic patients (17.73 ± 1.45) compared to control subjects (6.94 ± 1.58), P = 0.001 and there was a significant correlation with age (r = 0.162, P = 0.047) and severity of neuropathy (r = -0.202, P = 0.02). There was a progressive decrease in corneal sensation with increasing severity of neuropathy assessed using NDS in the diabetic patients (r = 0.414, P = 0.000). Corneal nerve fibre density (P < 0.001), branch density (P < 0.001) and length (P < 0.001) were significantly decreased whilst tortuosity (P < 0.01) was increased in diabetic patients with increasing severity of diabetic neuropathy. Utilising in vivo corneal confocal microscopy we have demonstrated increased LCs in diabetic patients particularly in the earlier phases of corneal nerve damage suggestive of an immune mediated contribution to corneal nerve damage in diabetes.

Correlation of diabetic corneal neuropathy and retinopathy

Abstract Purpose Corneal confocal microscopy is a rapid, non‐invasive and reiterative technique, suitable for the accurate detection and quantification of corneal subbasal nerve plexus. The aim of this study is to correlate corneal nerve fibre alterations with the abnormalities in the retina of diabetic patients and compare them with those of nondiabetic people Methods 278 diabetic corneas and 94 corneas of age‐matched control subjects were included in the study. Diabetic patients were further classified with respect to the stage of retinopathy, according to indirect fundoscopy, fundus photography and fluorescein angiography. The central corneas were scanned with HRT II and we estimated nerve fibre density (NFB) nerve branch density (NBD), nerve fibre length (NFL) and nerve fibre tortuosity (NFT). Finally, we made out the glycemic and lipidemic profile of patients. Results NFD values for control, NDR, NPDR and PDR groups were 31.27 ± 0.99, 27.35 ± 0.77, 23.67 ± 0.83 and 18.77 ± 0.77 respectively and NBD values were 45.12± 2.85, 39.86 ± 3, 30.56 ± 2.71 and 24.98 ± 2.08 respectively. NFL values for control, NDR, NPDR and PDR were 16.58 ± 0.55, 14.82 ± 0.56, 12.27 ± 0.49 and 10.41± 0.45 respectively and NFT values were 5.78 ± 0.28, 6.6 ± 0.52, 6.57 ± 0.22 and 7.02 ± 0.39 respectively. NFD, NBD, NFL were significantly reduced and NFT appeared to be higher in diabetic patients, according to the stage of diabetic retinopathy. The glycemic profile was analogue to the retina status, but the lipidemic one appeared to vary. Conclusion Alterations in corneal nerve plexus are apparent in diabetic patients and more pronounced in PDR.Corneal confocal microscopy could be a promising technique for the early diagnosis and treatment of diabetic neuropathy.

Corneal Confocal Microscopy

OBJECTIVEThe accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies.RESEARCH DESIGN AND METHODSA 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).RESULTSCorneal 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).CONCLUSIONSCCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity.

Nerve growth factor and expression of its receptors in patients with diabetic neuropathy

Low serum nerve growth factor (NGF) levels have been reported in patients with diabetic peripheral neuropathy (DPN), but the role of NGF in the development of neuropathy is unclear. Thus, we investigated the associations of serum NGF level and NGF receptor activity with the presence and severity of DPN. One hundred and thirty-six patients with Type 2 diabetes were included in this cross-sectional study. Serum NGF levels were measured by ELISA. Expressions of NGF receptors (TrkA and p75(NTR)) were measured by immunohistochemical staining. The presence and severity of DPN were assessed by neuropathy disability score (NDS) and by corneal nerve fibre length (cNFL) and nerve branch density (cNBD) using in vivo confocal microscopy. Patients with DPN had higher serum NGF levels (56-451 pg/ml) than patients without DPN (4-54 pg/ml). However, in DPN patients, serum NGF was negatively associated with neuropathy severity (mild 222 +/- 64 pg/ml; moderate 114 +/- 17 pg/ml; severe 89 +/- 20 pg/ml). This negative association was consistent in all severity indices (NDS, P < 0.001; cNFL, P < 0.001; cNBD P = 0.010) even after adjustment for age, sex, diabetes duration, insulin use, fasting glucose and glycated haemoglobin. Although NGF receptor activities had significantly (P < 0.05) negative associations with the presence and severity of neuropathy, these associations were not significant when adjusted for other factors. Serum NGF level was positively associated with the presence of DPN but negatively associated with neuropathy severity in DPN patients. The change in serum NGF might be a consequence of, rather than a contributor to, the early development of DPN.

Corneal confocal microscopy: A novel noninvasive means to diagnose neuropathy in patients with fabry disease

Neuropathy is a cause of significant disability in patients with Fabry disease, yet its diagnosis is difficult. In this study we compared the novel noninvasive techniques of corneal confocal microscopy (CCM) to quantify small-fiber pathology, and non-contact corneal aesthesiometry (NCCA) to quantify loss of corneal sensation, with established tests of neuropathy in patients with Fabry disease. Ten heterozygous females with Fabry disease not on enzyme replacement therapy (ERT), 6 heterozygous females, 6 hemizygous males on ERT, and 14 age-matched, healthy volunteers underwent detailed quantification of neuropathic symptoms, neurological deficits, neurophysiology, quantitative sensory testing (QST), NCCA, and CCM. All patients with Fabry disease had significant neuropathic symptoms and an elevated Mainz score. Peroneal nerve amplitude was reduced in all patients and vibration perception threshold was elevated in both male and female patients on ERT. Cold sensation (CS) threshold was significantly reduced in both male and female patients on ERT (P < 0.02), but warm sensation (WS) and heat-induced pain (HIP) were only significantly increased in males on ERT (P < 0.01). However, corneal sensation assessed with NCCA was significantly reduced in female (P < 0.02) and male (P < 0.04) patients on ERT compared with control subjects. According to CCM, corneal nerve fiber and branch density was significantly reduced in female (P < 0.03) and male (P < 0.02) patients on ERT compared with control subjects. Furthermore, the severity of neuropathic symptoms and the neurological component of the Mainz Severity Score Index correlated significantly with QST and CCM. This study shows that CCM and NCCA provide a novel means to detect early nerve fiber damage and dysfunction, respectively, in patients with Fabry disease.

Corneal confocal microscopy: A novel means to detect nerve fibre damage in idiopathic small fibre neuropathy

Patients with idiopathic small fibre neuropathy (ISFN) have been shown to have significant intraepidermal nerve fibre loss and an increased prevalence of impaired glucose tolerance (IGT). It has been suggested that the dysglycemia of IGT and additional metabolic risk factors may contribute to small nerve fibre damage in these patients.Twenty-five patients with ISFN and 12 aged-matched control subjects underwent a detailed evaluation of neuropathic symptoms, neurological deficits (Neuropathy deficit score (NDS); Nerve Conduction Studies (NCS); Quantitative Sensory Testing (QST) and Corneal Confocal Microscopy (CCM)) to quantify small nerve fibre pathology.Eight (32%) patients had IGT. Whilst all patients with ISFN had significant neuropathic symptoms, NDS, NCS and QST except for warm thresholds were normal. Corneal sensitivity was reduced and CCM demonstrated a significant reduction in corneal nerve fibre density (NFD) (P<0.0001), nerve branch density (NBD) (P<0.0001), nerve fibre length (NFL) (P<0.0001) and an increase in nerve fibre tortuosity (NFT) (P<0.0001). However these parameters did not differ between ISFN patients with and without IGT, nor did they correlate with BMI, lipids and blood pressure.Corneal confocal microscopy provides a sensitive non-invasive means to detect small nerve fibre damage in patients with ISFN and metabolic abnormalities do not relate to nerve damage.

Distribution and morphological changes of subbasal nerve fiber after different excimer laser operation

目的 观察准分子激光原位角膜磨镶术(LASIK)和准分子激光上皮下角膜磨镶术(LASEK)术后角膜上皮基底膜下神经分布及形态学特征.方法 共焦显微镜观察低、中度近视LASIK及LASEK 27例(54眼),术前、术后1、3、6月的角膜上皮基底膜下神经纤维分布和形态学特征,并测定泪膜破裂时间(BUT)和泪液分泌量(Schirmer I值).结果 LASIK(12例,24眼)与LASEK(15例,30眼)术后角膜上皮基底膜下神经纤维的再生和形态学在各时间点差异均无统计学意义.两组中BUT有统计学意义(P 0.05).结论 对于低、中度近视而言,LASIK与LASEK术后角膜上皮基底膜下神经纤维的再生未显示形态学上的差异。

Corneal Nerves Alterations in Various Types of Systemic Polyneuropathy, Identified by In Vivo Confocal Microscopy

In vivo confocal microscopy (IVCM) is a newly developed application to assess corneal nerve morphology. The purpose of the study is to evaluate the role of IVCM in the assessment of various types of polyneuropathy, and to define alterations of corneal nerves in such conditions. Eighteen patients with various types of polyneuropathy were characterized by clinical neurological and ophthalmic examinations, as well as by electroneuromyography (ENMG). Full thickness IVCM of corneal nerves was carried out on all patients and 15 age-matched eyes using Heidelberg Retina Tomograph II (HRT II). The subbasal nerve plexus were statistically analysed regarding long nerve fiber density, nerve branch density, nerve thickness, nerve bead number and nerve tortuosity. In subbasal nerve plexus, the following three parameters were significantly reduced in patients with polyneuropathy compared to controls: long nerve fibre density (p < 0.01), nerve branch density (p < 0.001), and nerve bead number (p = 0.001). In addition, the average grade of nerve tortuosity was 2.87 +/- 0.97 in the polyneuropathic group and 1.17 +/- 0.68 in the control group (p < 0.0001). IVCM allows a non-invasive, in vivo study of corneal nerves with high resolution. It therefore appears invaluable in clinical investigations. IVCM appears to be valuable in a large variety of polyneuropathic conditions.

Subbasal Nerve Regeneration After LASEK Measured by Confocal Microscopy

To determine the relationship between the degree of subbasal nerve regeneration and corneal sensation and tear film functions after LASEK using corneal confocal microscopy. This prospective, observational, and longitudinal study included 35 LASEK patients who underwent tear breakup time assessment, phenol red thread test, corneal esthesiometry, and confocal microscopy preoperatively and 1, 3, and 6 months postoperatively. Subbasal nerve images were analyzed to assess nerve regeneration. Postoperatively, tear breakup time decreased significantly and had not returned to the preoperative level by 6 months after surgery. There were no significant differences in the phenol red thread test results before and after LASEK. Central corneal sensation decreased significantly 1 month after LASEK and returned to normal levels 3 months after surgery. Nerve fiber density, nerve branch density, and nerve fiber length and width decreased significantly after LASEK and had not returned to preoperative levels 6 months after surgery. Subbasal nerve fibers retained their vertical orientation after LASEK. There were no significant correlations between the length and density of subbasal nerve fibers and central corneal sensitivity, tear volume, or breakup time after surgery. Subbasal nerves were injured by LASEK and had not returned to preoperative levels 6 months after surgery. Corneal sensitivity was reduced after LASEK and returned to normal levels 3 months after surgery.

Subbasal nerve fiber regeneration after LASIK and LASEK assessed by noncontact esthesiometry and in vivo confocal microscopy: Prospective study

To evaluate recovery of the corneal subbasal nerve plexus and corneal sensitivity after myopic laser in situ keratomileusis (LASIK) and laser-assisted subepithelial keratectomy (LASEK). Manchester Centre for Vision, Royal Eye Hospital, Manchester, United Kingdom. Thirty LASEK patients and 20 LASIK patients had slit-scanning confocal microscopy and noncontact corneal esthesiometry preoperatively and 1, 3, and 6 months after surgery. Images of the subbasal nerve plexus were analyzed using customized software to evaluate nerve regeneration. Central corneal sensitivity decreased significantly 1 month after LASEK and LASIK and returned to normal levels after 3 months. Corneal subbasal nerve fiber density, nerve branch density, nerve fiber length, and nerve fiber width decreased significantly 1 month after LASIK and had not returned to the preoperative levels by 6 months. Nerve fiber tortuosity decreased significantly 1 month after LASEK and returned to the preoperative levels 3 months after surgery. There were no significant differences in nerve fiber tortuosity before and after LASIK. Neither corneal sensitivity nor nerve fiber morphology was different between the 2 groups at any postoperative visit. Corneal sensitivity and subbasal nerve morphology were adversely affected by LASEK and LASIK. Corneal sensitivity recovered 3 months after the procedure, but subbasal nerves were still abnormal after 6 months. Despite the different forms of surgical trauma to corneal nerves with LASIK and LASEK, there was no apparent difference in the time course of recovery of corneal structure and function.

Corneal Confocal Microscopy Detects Early Nerve Regeneration After Pancreas Transplantation in Patients With Type 1 Diabetes

Corneal confocal microscopy (CCM) is a rapid, noninvasive, clinical examination technique that quantifies small nerve fiber pathology. We have used it to assess the neurological benefits of pancreas transplantation in type 1 diabetic patients. In 20 patients with type 1 diabetes undergoing simultaneous pancreas and kidney transplantation (SPK) and 15 control subjects, corneal sensitivity was evaluated using noncontact corneal esthesiometry, and small nerve fiber morphology was assessed using CCM. Corneal sensitivity (1.54 +/- 0.28 vs. 0.77 +/- 0.02, P < 0.0001), nerve fiber density (NFD) (13.8 +/- 2.1 vs. 42 +/- 3.2, P < 0.0001), nerve branch density (NBD) (4.04 +/- 1.5 vs. 26.7 +/- 2.5, P < 0.0001), and nerve fiber length (NFL) (2.23 +/- 0.2 vs. 9.69 +/- 0.7, P < 0.0001) were significantly reduced, and nerve fiber tortuosity (NFT) (15.7 +/- 1.02 vs. 19.56 +/- 1.34, P = 0.04) was increased in diabetic patients before pancreas transplantation. Six months after SPK, 15 patients underwent a second assessment and showed a significant improvement in NFD (18.04 +/- 10.48 vs. 9.25 +/- 1.87, P = 0.001) and NFL (3.60 +/- 0.33 vs. 1.84 +/- 0.33, P = 0.002) with no change in NBD (1.38 +/- 0.74 vs. 1.38 +/- 1.00, P = 1.0), NFT (15.58 +/- 1.20 vs. 16.30 +/- 1.19, P = 0.67), or corneal sensitivity (1.23 +/- 0.39 vs. 1.54 +/- 00.42, P = 0.59). Despite marked nerve fiber damage in type 1 diabetic patients undergoing pancreas transplantation, small fiber repair can be detected within 6 months of pancreas transplantation using CCM. CCM is a novel noninvasive clinical technique to assess the benefits of therapeutic intervention in human diabetic neuropathy.

Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy

Surrogate markers of diabetic neuropathy are being actively sought to facilitate the diagnosis, measure the progression, and assess the benefits of therapeutic intervention in patients with diabetic neuropathy. We have quantified small nerve fiber pathological changes using the technique of intraepidermal nerve fiber (IENF) assessment and the novel in vivo technique of corneal confocal microscopy (CCM). Fifty-four diabetic patients stratified for neuropathy, using neurological evaluation, neurophysiology, and quantitative sensory testing, and 15 control subjects were studied. They underwent a punch skin biopsy to quantify IENFs and CCM to quantify corneal nerve fibers. IENF density (IENFD), branch density, and branch length showed a progressive reduction with increasing severity of neuropathy, which was significant in patients with mild, moderate, and severe neuropathy. CCM also showed a progressive reduction in corneal nerve fiber density (CNFD) and branch density, but the latter was significantly reduced even in diabetic patients without neuropathy. Both IENFD and CNFD correlated significantly with cold detection and heat as pain thresholds. Intraepidermal and corneal nerve fiber lengths were reduced in patients with painful compared with painless diabetic neuropathy. Both IENF and CCM assessment accurately quantify small nerve fiber damage in diabetic patients. However, CCM quantifies small fiber damage rapidly and noninvasively and detects earlier stages of nerve damage compared with IENF pathology. This may make it an ideal technique to accurately diagnose and assess progression of human diabetic neuropathy.

Decreased Density of Corneal Basal Epithelium and Subbasal Corneal Nerve Bundle Changes in Patients with Diabetic Retinopathy

To define alterations in the density of corneal basal epithelium in relation to diabetic retinopathic severity and the alteration of corneal innervation using confocal microscopy. Prospective case-control study. Forty-two type II diabetic patients stratified into nondiabetic (NDR), nonproliferative diabetic (NPDR), and proliferative diabetic (PDR) retinopathy and 14 age-matched healthy control subjects were studied. Epithelial and stromal cell densities and subbasal nerves were investigated by confocal microscopy. Corneal basal epithelial cell density (P = .0001), nerve fiber density (NFD) (P < .0001), nerve branch density (NBD) (P = .0003), and tortuosity coefficient (Tc) (P < .0001) were significantly different among the four groups. Basal epithelial density was significantly correlated with NFD (r = 0.43, P = .0009), NBD (r = 0.36, P = .007), and TC (r = -0.58, P < .0001). Patients with diabetes show alterations in corneal innervations and basal epithelial cell density in different retinopathic stages. We demonstrate that reduced density in basal epithelial cell is correlated with changes in innervation.