Nerve Fiber Tortuosity Research Articles

Comparative quantitative assessment of the human corneal sub-basal nerve plexus by in vivo confocal microscopy and histological staining.

PurposeThis study was designed to compare and contrast quantitative data of the human corneal sub-basal nerve plexus (SBP) evaluated by two different methods: in vivo confocal microscopy (IVCM), and immunohistochemical staining of ex vivo donor corneas.MethodsSeven parameters of the SBP in large-scale IVCM mosaicking images from healthy subjects were compared with the identical parameters in ex vivo donor corneas stained by β-III-tubulin immunohistochemistry. Corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), average weighted corneal nerve fiber tortuosity (CNFTo), corneal nerve connection points (CNCP), average corneal nerve single-fiber length (CNSFL), and average weighted corneal nerve fiber thickness (CNFTh) were calculated using a dedicated, published algorithm and compared.ResultsOur experiments showed significantly higher values for CNFL (50.2 vs 21.4 mm/mm2), CNFD (1358.8 vs 277.3 nerve fibers/mm2), CNBD (847.6 vs 163.5 branches/mm2), CNFTo (0.095 vs 0.081 μm-1), and CNCP (49.4 vs 21.6 connections/mm2) in histologically staining specimens compared with IVCM images. In contrast, CNSFL values were higher in IVCM images than in histological specimens (32.1 vs 74.1 μm). No significant difference was observed in CNFTh (2.22 vs 2.20 μm) between the two groups.ConclusionsThe results of this study have shown that IVCM has an inherently lower resolution compared with ex vivo immunohistochemical staining of the corneal SBP and that this limitation leads to a systematic underestimation of several SBP parameters. Despite this shortcoming, IVCM is a vital clinical tool for in vivo characterization, quantitative clinical imaging, and evaluation of the human corneal SBP.

In vivo corneal confocal microscopy as a novel non-invasive tool to investigate cardiac autonomic neuropathy in Type 1 diabetes.

To investigate whether small nerve fibre degeneration detected using corneal confocal microscopy is associated with cardiac autonomic neuropathy in people with Type 1 diabetes. Thirty-six people with Type 1 diabetes and 20 age- and sex-matched healthy control subjects were enrolled. Tests to determine heart rate response to deep-breathing (expiratory-to-inspiratory ratio), heart rate response to lying-to-stand test (30:15 ratio) and blood pressure response to standing were performed to detect cardiac autonomic neuropathy. Corneal confocal microscopy was performed to assess: corneal nerve density and corneal nerve beadings; branching pattern; and nerve fibre tortuosity. Compared with control participants, participants with Type 1 diabetes had fewer (mean ± SD 45.4 ± 20.2 vs 92.0 ± 22.7 fibres/mm²; P < 0.001) and more tortuous corneal nerve fibres (20 participants with Type 1 diabetes vs four control participants had nerve tortuosity grade 2/3; P = 0.022) and fewer beadings (mean ± SD 15.1 ± 3.5 vs 20.6 ± 5.0; P < 0.001). Of the participants with Type 1 diabetes, 11 met the criteria for the diagnosis of cardiac autonomic neuropathy. Corneal nerve density was significantly lower in participants with cardiac autonomic neuropathy than in those without (mean ± SD 32.8 ± 16.4 vs 51.7 ± 18.9 fibres/mm²; P = 0.008). This difference remained significant after adjustment for age (P = 0.02), gender (P = 0.04), disease duration (P = 0.005), insulin requirement (P = 0.02) and neuropathy disability score (P = 0.04). This study suggests that corneal confocal microscopy could represent a new and non-invasive tool to investigate cardiac autonomic neuropathy in people with Type 1 diabetes. Larger studies are required to define the role of corneal confocal microscopy in the assessment of cardiac autonomic neuropathy.

Peripheral neuropathy in Parkinson disease: An in vivo confocal microscopy study

AbstractPurpose To assess whether corneal confocal microscopy (CCM) can detect alterations in corneal nerve morphology in patients with Parkinson disease.Methods Twenty‐five patients with Parkinson disease and 25 control subjects were examined. Patients underwent neurological and complete ophthalmological evaluation. Corneal sensitivity testing was performed with a Cochet‐Bonnet esthesiometer and corneal sub‐basal nerve morphology assessment with confocal microscopy (Heidelberg Retina Tomograph II/Rostock Cornea Module). CCM was used to quantify corneal nerve fibre density, tortuosity, length and branch density.Results Patients with Parkinson disease had decreased corneal sensation in comparison with controls. Corneal nerve fiber morphology differed in both groups, with a lower global fiber density, branch density and higher tortuosity in Parksinson patients (p&lt;0,05). These parameters were found to be related to dopaminergic medication exposure.Conclusion We found a decreased corneal sensation and corneal nerve fiber changes in patients with Parkinson disease. CCM may be used to detect signs of peripheral neuropathy and follow patients in dopaminergic therapy.

Structure-Function Relationship Between Corneal Nerves and Conventional Small-Fiber Tests in Type 1 Diabetes

OBJECTIVEIn vivo corneal confocal microscopy (IVCCM) has been proposed as a noninvasive technique to assess small nerve fiber structural morphology. We investigated the structure-function relationship of small fibers in diabetic sensorimotor polyneuropathy (DSP).RESEARCH DESIGN AND METHODSNinety-six type 1 diabetic subjects with a spectrum of clinical DSP and 64 healthy volunteers underwent IVCCM examinations to determine corneal nerve structure, including corneal nerve fiber length (CNFL), fiber density (CNFD), branch density (CNBD), and fiber tortuosity (CNFT). Small nerve fiber function was assessed by cooling detection thresholds (CDTs), axon reflex–mediated neurogenic vasodilatation in response to cutaneous heating by laser Doppler imaging flare technique (LDIFLARE), and heart rate variability (HRV). Linear associations between structural and functional measures in type 1 diabetic subjects were determined using Spearman correlation coefficients and linear regression analysis.RESULTSOf the type 1 diabetic subjects, with a mean age of 38.2 ± 15.5 years and a mean HbA1c of 7.9 ± 1.4%, 33 (34%) had DSP according to the consensus definition. Modest correlations were observed between CNFL, CNFD, and CNBD and all functional small-fiber tests (rs = 0.25 to 0.41; P ≤ 0.01 for all comparisons). For example, quantitatively every 1 mm/mm2 lower CNFL was associated with a 0.61°C lower CDT, a 0.07 cm2 lower LDIFLARE area, and a 1.78% lower HRV. No significant associations were observed for CNFT and the functional small-fiber measures.CONCLUSIONSSmall nerve fiber structural morphology assessed by IVCCM correlated well with functional measures of small nerve fiber injury. In particular, CNFL, CNFD, and CNBD demonstrated clear structure-function relationships.

Corneal confocal microscopy is efficient, well‐tolerated, and reproducible

In order to develop an efficient, reproducible, and well-tolerated protocol for assessing corneal innervation, 11 normal subjects underwent corneal confocal microscopy (CCM) using a Heidelberg Retinal Tomography III microscope. Five standardized locations were sampled in the left eye and one centrally in the right. The protocol was repeated 1-4 weeks later. A blinded technician measured nerve fiber length (NFL) and tortuosity coefficient (TC). The relationship between image location and NFL and TC was assessed using one-way analysis of variance, and reproducibility determined using relative intertrial variability and intraclass correlation coefficients. NFL reproducibility was maximized by averaging four or more images from the left eye, or one central image from both eyes. TC was less reproducible. CCM is a rapid, well-tolerated, and reproducible method for assessing corneal innervation.

Corneal confocal microscopy detects small‐fiber neuropathy in Charcot–Marie–Tooth disease type 1A patients

Although unmyelinated nerve fibers are affected in Charcot-Marie-Tooth type 1A (CMT1A) disease, they have not been studied in detail due to the invasive nature of the techniques needed to study them. We established alterations in C-fiber bundles of the cornea in patients with CMT1A using non-invasive corneal confocal microscopy (CCM). Twelve patients with CMT1A and 12 healthy control subjects underwent assessment of neuropathic symptoms and deficits, electrophysiology, quantitative sensory testing, corneal sensitivity, and corneal confocal microscopy. Corneal sensitivity, corneal nerve fiber density, corneal nerve branch density, corneal nerve fiber length, and corneal nerve fiber tortuosity were significantly reduced in CMT1A patients compared with controls. There was a significant correlation between corneal sensation and CCM parameters with the severity of painful neuropathic symptoms, cold and warm thresholds, and median nerve CMAP amplitude. CCM demonstrates significant damage to C-fiber bundles, which relates to some measures of neuropathy in CMT1A patients.

Variables associated with corneal confocal microscopy parameters in healthy volunteers: implications for diabetic neuropathy screening

Corneal confocal microscopy is a promising screening method for diabetic neuropathy. Although much research in this field has been accomplished, we aimed to determine and confirm the known clinical and eyewear variables associated with the parameters of corneal confocal microscopy specifically in healthy volunteers, in particular associations with corneal nerve fibre length. Clinical characteristics, electrophysiological examination and a general clinical eye history were collected from 64 healthy volunteers. Corneal confocal microscopy was performed to determine corneal nerve fibre length, corneal nerve branch density, corneal nerve fibre density and tortuosity coefficient. Univariate and multivariate linear regression analysis was used to determine clinical variables associated with corneal nerve fibre length parameters. We observed that corneal nerve fibre length has a broad distribution in healthy volunteers (18 ± 4 mm/mm(2), 95% confidence interval, 12.3-25.7 mm/mm(2)). Multivariate regression analysis demonstrated that HbA(1c) was the only independent clinical factor to account for variations in corneal nerve fibre length, independent of age and status of contact lens wear. This study does not provide convincing evidence that corneal nerve fibre length is independently associated with age or the wearing of contact lenses, and that these factors are therefore unlikely to hinder valid screening for polyneuropathies such as diabetic neuropathy. Furthermore, the strong inverse association of corneal nerve fibre length with glycaemic exposure may support the use of this parameter to detect subclinical pre-diabetic nerve injury.

Correlation of Diabetic Retinopathy and Corneal Neuropathy Using Confocal Microscopy

Purpose/Aim: To employ corneal confocal microscopy to assess differences in the extent of corneal nerve fiber alterations between diabetic patients classed according to retinopathy status and nondiabetic patients.Materials and Methods: Two hundred seventy-eight corneas of 139 patients with type 2 diabetes mellitus and 94 corneas of 47 age-matched control participants were scanned using corneal confocal microscopy. Images of the subbasal nerve plexus were collected and analyzed for nerve fiber density (NFD), nerve branch density (NBD), nerve fiber length (NFL), and nerve fiber tortuosity (NFT). Diabetic patients were categorized into three groups according to the classification of diabetic retinopathy (DR) proposed in the Early Treatment of Diabetic Retinopathy Study, based on indirect fundoscopy, fundus photography, and fluorescein angiography findings. A separate classification into four groups according to the severity of peripheral diabetic neuropathy (DN) was also used, based on the results of clinical and electrodiagnostic examinations.Results: Average NFD, NBD, and NFL differed significantly according to DR status and were found to be lower, whereas NFT was found to be higher in diabetic patients than control participants. A positive correlation between diabetic corneal neuropathy and peripheral DN was also found.Conclusions: Nerve fiber alterations of the subbasal nerve plexus of diabetic corneas appear to progress in parallel with DR and peripheral DN. Corneal confocal microscopy could possibly represent a promising adjuvant technique for the early diagnosis and assessment of human DN.

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.

Detection of Diabetic Sensorimotor Polyneuropathy by Corneal Confocal Microscopy in Type 1 Diabetes

OBJECTIVEWe aimed to determine the corneal confocal microscopy (CCM) parameter that best identifies diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes and to describe its performance characteristics.RESEARCH DESIGN AND METHODSConcurrent with clinical and electrophysiological examination for classification of DSP, CCM was performed on 89 type 1 diabetic and 64 healthy subjects to determine corneal nerve fiber length (CNFL), density, tortuosity, and branch density. Area under the curve (AUC) and optimal thresholds for DSP identification in those with diabetes were determined by receiver operating characteristic (ROC) curve analysis.RESULTSDSP was present in 33 (37%) subjects. With the exception of tortuosity, CCM parameters were significantly lower in DSP case subjects. In ROC curve analysis, AUC was greatest for CNFL (0.88) compared with fiber density (0.84, P = 0.0001), branch density (0.73, P < 0.0001), and tortuosity (0.55, P < 0.0001). The threshold value that optimized sensitivity and specificity for ruling in DSP was a CNFL of ≤14.0 mm/mm2 (sensitivity 85%, specificity 84%), associated with positive and negative likelihood ratios of 5.3 and 0.18. An alternate approach that used separate threshold values maximized sensitivity (threshold value ≥15.8 mm/mm2, sensitivity 91%, negative likelihood ratio 0.16) and specificity (≤11.5 mm/mm2, specificity 93%, positive likelihood ratio 8.5).CONCLUSIONSAmong CCM parameters, CNFL best discriminated DSP cases from control subjects. A single threshold offers clinically acceptable operating characteristics, although a strategy that uses separate thresholds to respectively rule in and rule out DSP has excellent performance while minimizing unclassified subjects. We hypothesize that values between these thresholds indicate incipient nerve injury that represents those individuals at future neuropathy risk.

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.

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: 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.

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.

Corneal nerve tortuosity in diabetic patients with neuropathy.

Corneal confocal microscopy is a reiterative, rapid, noninvasive in vivo clinical examination technique capable of imaging corneal nerve fibers. Nerve fiber tortuosity may indicate a degenerative and attempted regenerative response of nerve fibers to diabetes. The purpose of this study was to define alterations in the tortuosity of corneal nerve fibers in relation to age, duration of diabetes, glycemic control, and neuropathic severity. The cornea and collected images of the subbasal nerve plexus of 18 diabetic patients (stratified into mild, moderate, and severe neuropathic groups using conventional clinical measures of neuropathy) and 18 age-matched nondiabetic control subjects were scanned, and a novel mathematical paradigm was applied to quantify the extent of nerve tortuosity, which was termed the tortuosity coefficient (TC). TC was significantly different between the four clinical groups (F(3) = 12.2, P < 0.001). It was significantly greater in the severe neuropathic group than in control subjects (P < 0.003) and in the mild (P < 0.004) and moderate (P < 0.01) neuropathic groups. TC did not correlate significantly with the age (r = -0.003, P > 0.05), duration of diabetes (r = -0.219, P > 0.05), or hemoglobin A1c (HbA1c; r = 0.155, P > 0.05) of diabetic patients. Corneal confocal microscopy allows rapid, noninvasive in vivo evaluation of corneal nerve tortuosity. This morphologic abnormality relates to the severity of somatic neuropathy and may reflect an alteration in the degree of degeneration and regeneration in diabetes.