Corneal nerve tortuosity in diabetic patients with neuropathy.

PURPOSE 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. METHODS 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). RESULTS 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. CONCLUSIONS 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.

[1]  E. Syková,et al.  Glial diffusion barriers during aging and pathological states. , 2001, Progress in brain research.

[2]  H. Gröne,et al.  Small proteoglycans in human diabetic nephropathy: discrepancy between glomerular expression and protein accumulation of decorin, biglycan, lumican, and fibromodulin , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[3]  T. Tervo,et al.  Histochemical demonstration of adrenergic nerves in the stroma of human cornea. , 1987, Investigative ophthalmology & visual science.

[4]  B. Schimmelpfennig,et al.  Sensory denervation of the rabbit cornea affects epithelial properties , 1980, Experimental Neurology.

[5]  N Efron,et al.  Morphology of Corneal Nerves Using Confocal Microscopy , 2001, Cornea.

[6]  T. Doetschman,et al.  TGFβ2 in corneal morphogenesis during mouse embryonic development , 2001 .

[7]  T. Doetschman,et al.  TGFbeta2 in corneal morphogenesis during mouse embryonic development. , 2001, Developmental biology.

[8]  J. McLaren,et al.  Reinnervation in the cornea after LASIK. , 2002, Investigative ophthalmology & visual science.

[9]  M. Inatani,et al.  Proteoglycans in the Eye , 2002, Cornea.

[10]  M. B. Brown,et al.  Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy , 1999, Neurology.

[11]  N. Fullwood,et al.  Corneal and scleral collagens--a microscopist's perspective. , 2001, Micron.

[12]  M. Kawabuchi,et al.  The effect of aging on the morphological nerve changes during muscle reinnervation after nerve crush. , 1998, Restorative neurology and neuroscience.

[13]  M. Nugent,et al.  Nuclear localization of basic fibroblast growth factor is mediated by heparan sulfate proteoglycans through protein kinase C signaling , 2003, Journal of cellular biochemistry.

[14]  G. Vrensen,et al.  Ultrastructural organization of human corneal nerves. , 1996, Investigative ophthalmology & visual science.

[15]  W. Litchy,et al.  Individual attributes versus composite scores of nerve conduction abnormality: Sensitivity, reproducibility, and concordance with impairment , 2003, Muscle & nerve.

[16]  P. Dyck,et al.  A standard test of heat-pain responses using CASE IV , 1996, Journal of the Neurological Sciences.

[17]  W. Litchy,et al.  Use of percentiles and normal deviates to express nerve conduction and other test abnormalities , 2001, Muscle & nerve.

[18]  G. Dougherty,et al.  A quantitative index for the measurement of the tortuosity of blood vessels. , 2000, Medical engineering & physics.

[19]  R. U. Margolis,et al.  Functional characterization of chondroitin sulfate proteoglycans of brain: interactions with neurons and neural cell adhesion molecules , 1993, The Journal of cell biology.

[20]  N. Ohba,et al.  Capsaicin-induced corneal changes associated with sensory denervation in neonatal rat. , 1987, Japanese journal of ophthalmology.

[21]  M. Cerro,et al.  Peptidergic and catecholaminergic fibers in the human corneal epithelium , 1989, Acta ophthalmologica. Supplement.

[22]  I. Immonen,et al.  Corneal structure and sensitivity in type 1 diabetes mellitus. , 2000, Investigative ophthalmology & visual science.

[23]  P. Sönksen,et al.  A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population , 1993, Diabetologia.

[24]  R. A. Malik,et al.  Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients , 2003, Diabetologia.

[25]  A. Cuello,et al.  Substance P-immunoreactive nerves in the human cornea and iris. , 1982, Investigative ophthalmology & visual science.

[26]  J. Baum Topical treatment with nerve growth factor for corneal neurotrophic ulcers. , 1999, Survey of ophthalmology.

[27]  T. Tervo Consecutive demonstration of nerves containing catecholamine and acetylcholinesterase in the rat cornea , 1977, Histochemistry.

[28]  J. Griffiths,et al.  The North‐West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community‐based patient cohort , 2002, Diabetic medicine : a journal of the British Diabetic Association.

[29]  Frederick W. Fraunfelder,et al.  Laser-Assisted In Situ Keratomileusis Complications in Diabetes Mellitus , 2002, Cornea.

[30]  J. McArthur,et al.  Intraepidermal nerve fiber density in patients with painful sensory neuropathy , 1997, Neurology.

[31]  J. Arezzo New developments in the diagnosis of diabetic neuropathy. , 1999, The American journal of medicine.

[32]  W. Schady,et al.  Sural nerve fibre pathology in diabetic patients with mild neuropathy: relationship to pain, quantitative sensory testing and peripheral nerve electrophysiology , 2001, Acta Neuropathologica.

[33]  M. Barbacid,et al.  Corneal innervation and sensitivity to noxious stimuli in trkA knockout mice , 1998, The European journal of neuroscience.

[34]  G F Vrensen,et al.  Architecture of human corneal nerves. , 1997, Investigative ophthalmology & visual science.

[35]  C. McGhee,et al.  Assessing the sub‐basal nerve plexus of the living healthy human cornea by in vivo confocal microscopy , 2002, Clinical & experimental ophthalmology.