Corneal Confocal Microscopy Detects Small Fibre Neuropathy in Patients with Upper Gastrointestinal Cancer and Nerve Regeneration in Chemotherapy Induced Peripheral Neuropathy.

Published onlineThere are multiple neurological complications of cancer and its treatment. This study assessed the utility of the novel non-invasive ophthalmic technique of corneal confocal microscopy in identifying neuropathy in patients with upper gastrointestinal cancer before and after platinum based chemotherapy. In this study, 21 subjects with upper gastrointestinal (oesophageal or gastric) cancer and 21 healthy control subjects underwent assessment of neuropathy using the neuropathy disability score, quantitative sensory testing for vibration perception threshold, warm and cold sensation thresholds, cold and heat induced pain thresholds, nerve conduction studies and corneal confocal microscopy. Patients with gastro-oesophageal cancer had higher heat induced pain (P = 0.04) and warm sensation (P = 0.03) thresholds with a significantly reduced sural sensory (P<0.01) and peroneal motor (P<0.01) nerve conduction velocity, corneal nerve fibre density (CNFD), nerve branch density (CNBD) and nerve fibre length (CNFL) (P<0.0001). Furthermore, CNFD correlated significantly with the time from presentation with symptoms to commencing chemotherapy (r = -0.54, P = 0.02), and CNFL (r = -0.8, P<0.0001) and CNBD (r = 0.63, P = 0.003) were related to the severity of lymph node involvement. After the 3rd cycle of chemotherapy, there was no change in any measure of neuropathy, except for a significant increase in CNFL (P = 0.003). Corneal confocal microscopy detects a small fibre neuropathy in this cohort of patients with upper gastrointestinal cancer, which was related to disease severity. Furthermore, the increase in CNFL after the chemotherapy may indicate nerve regeneration

Automated Quantification of Neuropad Improves Its Diagnostic Ability in Patients with Diabetic Neuropathy.

PublishedResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tNeuropad is currently a categorical visual screening test that identifies diabetic patients at risk of foot ulceration. The diagnostic performance of Neuropad was compared between the categorical and continuous (image-analysis (Sudometrics)) outputs to diagnose diabetic peripheral neuropathy (DPN). 110 subjects with type 1 and 2 diabetes underwent assessment with Neuropad, Neuropathy Disability Score (NDS), peroneal motor nerve conduction velocity (PMNCV), sural nerve action potential (SNAP), Deep Breathing-Heart Rate Variability (DB-HRV), intraepidermal nerve fibre density (IENFD), and corneal confocal microscopy (CCM). 46/110 patients had DPN according to the Toronto consensus. The continuous output displayed high sensitivity and specificity for DB-HRV (91%, 83%), CNFD (88%, 78%), and SNAP (88%, 83%), whereas the categorical output showed high sensitivity but low specificity. The optimal cut-off points were 90% for the detection of autonomic dysfunction (DB-HRV) and 80% for small fibre neuropathy (CNFD). The diagnostic efficacy of the continuous Neuropad output for abnormal DB-HRV (AUC: 91%, P = 0.0003) and CNFD (AUC: 82%, P = 0.01) was better than for PMNCV (AUC: 60%). The categorical output showed no significant difference in diagnostic efficacy for these same measures. An image analysis algorithm generating a continuous output (Sudometrics) improved the diagnostic ability of Neuropad, particularly in detecting autonomic and small fibre neuropathy.National Institute of Health (NIH)Juvenile Diabetes Research Foundation (JDRF

Early Detection of Diabetic Peripheral Neuropathy: A Focus on Small Nerve Fibres

Diabetic peripheral neuropathy (DPN) is the most common complication of both type 1 and 2 diabetes. As a result, neuropathic pain, diabetic foot ulcers and lower-limb amputations impact drastically on quality of life, contributing to the individual, societal, financial and healthcare burden of diabetes. DPN is diagnosed at a late, often pre-ulcerative stage due to a lack of early systematic screening and the endorsement of monofilament testing which identifies advanced neuropathy only. Compared to the success of the diabetic eye and kidney screening programmes there is clearly an unmet need for an objective reliable biomarker for the detection of early DPN. This article critically appraises research and clinical methods for the diagnosis or screening of early DPN. In brief, functional measures are subjective and are difficult to implement due to technical complexity. Moreover, skin biopsy is invasive, expensive and lacks diagnostic laboratory capacity. Indeed, point-of-care nerve conduction tests are convenient and easy to implement however questions are raised regarding their suitability for use in screening due to the lack of small nerve fibre evaluation. Corneal confocal microscopy (CCM) is a rapid, non-invasive, and reproducible technique to quantify small nerve fibre damage and repair which can be conducted alongside retinopathy screening. CCM identifies early sub-clinical DPN, predicts the development and allows staging of DPN severity. Automated quantification of CCM with AI has enabled enhanced unbiased quantification of small nerve fibres and potentially early diagnosis of DPN. Improved screening tools will prevent and reduce the burden of foot ulceration and amputations with the primary aim of reducing the prevalence of this common microvascular complication

Translation and cultural adaptation of the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale into Arabic for use with patients with diabetes in Libya.

In Libya neuropathic pain is rarely assessed in patients with diabetes. The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale is used worldwide to screen for neuropathic pain. There is no Arabic version of LANSS for use in Libya. The aim of this study was to develop an Arabic version of LANSS and to assess its validity and reliability in diabetic patients in Benghazi, Libya. LANSS was translated into Arabic by four bilingual translators and back translated to English by a university academic. Validity and reliability of the Arabic LANSS was assessed on 110 patients attending a Diabetes Centre in Benghazi. Concurrent validity was tested and compared with the Self-completed Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS). Test-retest reliability was conducted 1-2 weeks later. Internal consistency and inter-class correlation (ICC) between LANSS and S-LANSS was also tested. Internal consistency within first completion of the Arabic LANSS was acceptable (Cronbach's alpha = 0.793) and similar to the Arabic S-LANSS (0.796) and the second completion of the Arabic LANSS (0.795). ICC between the Arabic LANSS and the Arabic S-LANSS was 0.999 (p 0.95, p < 0.0001). We concluded that the Arabic version of LANSS pain scale was valid and reliable for use on Libyan diabetic patients. This study provided results suggesting that the S-LANSS could also be used on diabetic patients

Small-fibre neuropathy in men with type 1 diabetes and erectile dysfunction: a cross-sectional study

Aims/hypothesis: The aim of this study was to identify the contribution of small- and large-fibre neuropathy to erectile dysfunction in men with type 1 diabetes mellitus. Methods: A total of 70 participants (29 without and 41 with erectile dysfunction) with type 1 diabetes and 34 age-matched control participants underwent a comprehensive assessment of large- and small-fibre neuropathy. Results: The prevalence of erectile dysfunction in participants with type 1 diabetes was 58.6%. After adjusting for age, participants with type 1 diabetes and erectile dysfunction had a significantly higher score on the Neuropathy Symptom Profile (mean ± SEM 5.3 ± 0.9 vs 1.8 ± 1.2, p = 0.03), a higher vibration perception threshold (18.3 ± 1.9 vs 10.7 ± 2.4 V, p = 0.02), and a lower sural nerve amplitude (5.0 ± 1.1 vs 11.7 ± 1.5 mV, p = 0.002), peroneal nerve amplitude (2.1 ± 0.4 vs 4.7 ± 0.5 mV, p < 0.001) and peroneal nerve conduction velocity (34.8 ± 1.5 vs 41.9 ± 2.0 m/s, p = 0.01) compared with those without erectile dysfunction. There was also evidence of a marked small-fibre neuropathy with an impaired cold threshold (19.7 ± 1.4°C vs 27.3 ± 1.8°C, p = 0.003), warm threshold (42.9 ± 0.8°C vs 39.0 ± 0.9°C, p = 0.005) and heart rate variability (21.5 ± 3.1 vs 30.0 ± 3.7 beats/min, p = 0.001) and reduced intraepidermal nerve fibre density (2.8 ± 0.7 vs 5.9 ± 0.7/mm, p = 0.008), corneal nerve fibre density (12.6 ± 1.5 vs 23.9 ± 2.0/mm2, p < 0.001), corneal nerve branch density (12.7 ± 2.5 vs 31.6 ± 3.3/mm2, p < 0.001) and corneal nerve fibre length (8.3 ± 0.7 vs 14.5 ± 1.0 mm/mm2, p < 0.001) in participants with type 1 diabetes and erectile dysfunction. Erectile dysfunction correlated significantly with measures of both large- and small-fibre neuropathy. Conclusions/interpretation: Small-fibre neuropathy is prominent in patients with type 1 diabetes, and is associated with erectile dysfunction and can be objectively quantified using corneal confocal microscopy. This may allow the identification of patients who are less likely to respond to conventional therapies such as phosphodiesterase type 5 inhibitors

Brain alterations in regions associated with end‐organ diabetic microvascular disease in diabetes mellitus: A UK Biobank study

Background Diabetes mellitus (DM) is associated with structural grey matter alterations in the brain, including changes in the somatosensory and pain processing regions seen in association with diabetic peripheral neuropathy. In this case-controlled biobank study, we aimed to ascertain differences in grey and white matter anatomy in people with DM compared with non-diabetic controls (NDC). Methods This study utilises the UK Biobank prospective, population-based, multicentre study of UK residents. Participants with diabetes and age/gender-matched controls without diabetes were selected in a three-to-one ratio. We excluded people with underlying neurological/neurodegenerative disease. Whole brain, cortical, and subcortical volumes (188 regions) were compared between participants with diabetes against NDC corrected for age, sex, and intracranial volume using univariate regression models, with adjustment for multiple comparisons. Diffusion tensor imaging analysis of fractional anisotropy (FA) was performed along the length of 50 white matter tracts. Results We included 2404 eligible participants who underwent brain magnetic resonance imaging (NDC, n = 1803 and DM, n = 601). Participants with DM had a mean (±standard deviation) diagnostic duration of 18 ± 11 years, with adequate glycaemic control (HbA1C 52 ± 13 mmol/mol), low prevalence of microvascular complications (diabetic retinopathy prevalence, 5.8%), comparable cognitive function to controls but greater self-reported pain. Univariate volumetric analyses revealed significant reductions in grey matter volume (whole brain, total, and subcortical grey matter), with mean percentage differences ranging from 2.2% to 7% in people with DM relative to NDC (all p < 0.0002). The subcortical (bilateral cerebellar cortex, brainstem, thalamus, central corpus callosum, putamen, and pallidum) and cortical regions linked to sensorimotor (bilateral superior frontal, middle frontal, precentral, and postcentral gyri) and visual functions (bilateral middle and superior occipital gyri), all had lower grey matter volumes in people with DM relative to NDC. People with DM had significantly reduced FA along the length of the thalamocortical radiations, thalamostriatal projections, and commissural fibres of the corpus callosum (all; p < 0·001). Interpretation This analysis suggests that anatomic differences in brain regions are present in a cohort with adequately controlled glycaemia without prevalent microvascular disease when compared with volunteers without diabetes. We hypothesise that these differences may predate overt end-organ damage and complications such as diabetic neuropathy and retinopathy. Central nervous system alterations/neuroplasticity may occur early in the natural history of microvascular complications; therefore, brain imaging should be considered in future mechanistic and interventional studies of DM

Diagnosis of neuropathy and risk factors for corneal nerve loss in type 1 and type 2 diabetes: A corneal confocal microscopy study

© 2020 by the American Diabetes Association. OBJECTIVE To assess the diagnostic utility of corneal confocal microscopy (CCM) for diabetic peripheral neuropathy (DPN) and the risk factors for corneal nerve loss. RESEARCH DESIGN AND METHODS A total of 490 participants, including 72 healthy control subjects, 149 with type 1 diabetes, and 269 with type 2 diabetes, underwent detailed assessment of peripheral neuropathy and CCM in relation to risk factors. RESULTS Corneal nerve fiber density (CNFD) (P < 0.0001 and P < 0.0001), corneal nerve fiber branch density (CNBD) (P < 0.0001 and P < 0.0001), and corneal nerve fiber length (CNFL) (P < 0.0001 and P = 0.02) were significantly lower in patients with type 1 and type 2 diabetes compared with control subjects. CNFD (P < 0.0001), CNBD (P < 0.0001), and CNFL (P < 0.0001) were lower in type 1 diabetes compared with type 2 diabetes. Receiver operating characteristic curve analysis for the diagnosis of DPN demonstrated a good area under the curve for CNFD of 0.81, CNBD of 0.74, and CNFL of 0.73. Multivariable regression analysis showed a significant association among reduced CNFL with age (b =-0.27, P = 0.007), HbA1c (b=-1.1; P = 0.01), and weight (b=-0.14; P = 0.03) in patients with type 2 diabetes and with duration of diabetes (b=-0.13; P = 0.02), LDL cholesterol (b=1.8, P = 0.04), and triglycerides (b =-2.87; P = 0.009) in patients with type 1 diabetes. CONCLUSIONS CCM identifies more severe corneal nerve loss in patients with type 1 diabetes compared with type 2 diabetes and shows good diagnostic accuracy for DPN. Furthermore, the risk factors for a reduction in corneal nerve fiber length differ between type 1 and type 2 diabetes

The utility of corneal nerve fractal dimension analysis in peripheral neuropathies of different etiology

Purpose: Quantification of corneal confocal microscopy (CCM) images has shown a significant reduction in corneal nerve fiber length (CNFL) in a range of peripheral neuropathies. We assessed whether corneal nerve fractal dimension (CNFrD) analysis, a novel metric to quantify the topological complexity of corneal subbasal nerves, can differentiate peripheral neuropathies of different etiology. Methods: Ninety patients with peripheral neuropathy, including 29 with diabetic peripheral neuropathy (DPN), 34 with chronic inflammatory demyelinating polyneuropathy (CIDP), 13 with chemotherapy-induced peripheral neuropathy (CIPN), 14 with human immunodeficiency virus-associated sensory neuropathy (HIV-SN), and 20 healthy controls (HCs), underwent CCM for estimation of corneal nerve fiber density (CNFD), CNFL, corneal nerve branch density (CNBD), CNFrD, and CNFrD adjusted for CNFL (ACNFrD). Results: In patients with DPN, CIDP, CIPN, or HIV-SN compared to HCs, CNFD (P = 0.004–0.0001) and CNFL (P = 0.05–0.0001) were significantly lower, with a further significant reduction among subgroups. CNFrD was significantly lower in patients with CIDP compared to HCs and patients with HIV-SN (P = 0.02–0.0009) and in patients with DPN compared to HCs and patients with HIV-SN, CIPN, or CIDP (P = 0.001–0.0001). ACNFrD was lower in patients with CIPN, CIDP, or DPN compared to HCs (P = 0.03–0.0001) and in patients with DPN compared to those with HIV-SN, CIPN, or CIDP (P = 0.01–0.005). Conclusions: CNFrD can detect a distinct pattern of corneal nerve loss in patients with DPN or CIDP compared to those with CIPN or HIV-SN and controls. Translational Relevance: Various peripheral neuropathies are characterized by a comparable degree of corneal nerve loss. Assessment of corneal nerve topology by CNFrD could be useful in differentiating neuropathies based on the pattern of loss

Corneal confocal microscopy detects a reduction in corneal endothelial cells and nerve fibres in patients with acute ischemic stroke

YesEndothelial dysfunction and damage underlie cerebrovascular disease and ischemic stroke. We undertook corneal confocal microscopy (CCM) to quantify corneal endothelial cell and nerve morphology in 146 patients with an acute ischemic stroke and 18 age-matched healthy control participants. Corneal endothelial cell density was lower (P<0.001) and endothelial cell area (P<0.001) and perimeter (P<0.001) were higher, whilst corneal nerve fbre density (P<0.001), corneal nerve branch density (P<0.001) and corneal nerve fbre length (P=0.001) were lower in patients with acute ischemic stroke compared to controls. Corneal endothelial cell density, cell area and cell perimeter correlated with corneal nerve fber density (P=0.033, P=0.014, P=0.011) and length (P=0.017, P=0.013, P=0.008), respectively. Multiple linear regression analysis showed a signifcant independent association between corneal endothelial cell density, area and perimeter with acute ischemic stroke and triglycerides. CCM is a rapid non-invasive ophthalmic imaging technique, which could be used to identify patients at risk of acute ischemic stroke.Qatar National Research Fund Grant BMRP2003865