title: Standardizing corneal nerve fibre length for nerve tortuosity increases its association with measures of diabetic neuropathy.
abstract: OBJECTIVE
  Recent studies on corneal markers have advocated corneal nerve fibre length as the most important measure of diabetic peripheral neuropathy. The aim of this study was to determine if standardizing corneal nerve fibre length for tortuosity increases its association with other measures of diabetic peripheral neuropathy.
  
  
  METHODS
  Two hundred and thirty-one individuals with diabetes with either predominantly mild or absent neuropathic changes and 61 control subjects 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 and corneal nerve fibre tortuosity were measured using corneal confocal microscopy. A tortuosity-standardised corneal nerve fibre length variable was generated by dividing corneal nerve fibre length by corneal nerve fibre tortuosity. Differences in corneal nerve morphology between individuals with and without diabetic peripheral neuropathy and control subjects were determined and associations were estimated between corneal morphology and established tests of, and risk factors for, diabetic peripheral neuropathy.
  
  
  RESULTS
  The tortuosity-standardised corneal nerve fibre length variable was better than corneal nerve fibre length in demonstrating differences between individuals with diabetes, with and without neuropathy (tortuosity-standardised corneal nerve fibre length variable: 70.5 ± 27.3 vs. 84.9 ± 28.7, P < 0.001, receiver operating characteristic area under the curve = 0.67; corneal nerve fibre length: 15.9 ± 6.9 vs. 18.4 ± 6.2 mm/mm², P = 0.004, receiver operating characteristic area under the curve = 0.64). Furthermore, the tortuosity-standardised corneal nerve fibre length variable demonstrated a significant difference between the control subjects and individuals with diabetes, without neuropathy, while corneal nerve fibre length did not (tortuosity-standardised corneal nerve fibre length variable: 94.3 ± 27.1 vs. 84.9 ± 28.7, P = 0.028; corneal nerve fibre length: 20.1 ± 6.3 vs. 18.4 ± 6.2 mm/mm², P = 0.084). Correlations between corneal nerve fibre length and established measures of neuropathy and risk factors for neuropathy were higher when a correction was made for the nerve tortuosity.
  
  
  CONCLUSIONS
  Standardizing corneal nerve fibre length for tortuosity enhances the ability to differentiate individuals with diabetes, with and without neuropathy.
authors.affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology, Woolloongabba, Qld, Australia.
authors.forename: K
authors.initials: K
authors.lastname: Edwards
authors.forename: N
authors.initials: N
authors.lastname: Pritchard
authors.forename: D
authors.initials: D
authors.lastname: Vagenas
authors.forename: A
authors.initials: A
authors.lastname: Russell
authors.forename: R A
authors.initials: RA
authors.lastname: Malik
authors.forename: N
authors.initials: N
authors.lastname: Efron
mesh_terms: D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003315:Cornea / Q000294:innervation* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000150:complications*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003929:Diabetic Neuropathies / Q000150:complications / Q000453:epidemiology / Q000473:pathology* / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000150:complications / Q000175:diagnosis / Q000473:pathology* / Q000503:physiopathology; D003941:Diagnostic Techniques, Ophthalmological; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology*; D009431:Neural Conduction; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000453:epidemiology / Q000473:pathology* / Q000503:physiopathology; D011793:Queensland / Q000453:epidemiology; D012372:ROC Curve; D012307:Risk Factors; D012720:Severity of Illness Index; D012984:Software