title: The Inferior Whorl For Detecting Diabetic Peripheral Neuropathy Using Corneal Confocal Microscopy.
abstract: OBJECTIVE
  In vivo corneal confocal microscopy (CCM) is increasingly used as a surrogate endpoint in studies of diabetic polyneuropathy (DPN). However, it is not clear whether imaging the central cornea provides optimal diagnostic utility for DPN. Therefore, we compared nerve morphology in the central cornea and the inferior whorl, a more distal and densely innervated area located inferior and nasal to the central cornea.
  
  
  METHODS
  A total of 53 subjects with type 1/type 2 diabetes and 15 age-matched control subjects underwent detailed assessment of neuropathic symptoms (NPS), deficits (neuropathy disability score [NDS]), quantitative sensory testing (vibration perception threshold [VPT], cold and warm threshold [CT/WT], and cold- and heat-induced pain [CIP/HIP]), and electrophysiology (sural and peroneal nerve conduction velocity [SSNCV/PMNCV], and sural and peroneal nerve amplitude [SSNA/PMNA]) to diagnose patients with (DPN+) and without (DPN-) neuropathy. Corneal nerve fiber density (CNFD) and length (CNFL) in the central cornea, and inferior whorl length (IWL) were quantified.
  
  
  RESULTS
  Comparing control subjects to DPN- and DPN+ patients, there was a significant increase in NDS (0 vs. 2.6 ± 2.3 vs. 3.3 ± 2.7, P < 0.01), VPT (V; 5.4 ± 3.0 vs. 10.6 ± 10.3 vs. 17.7 ± 11.8, P < 0.01), WT (°C; 37.7 ± 3.5 vs. 39.1 ± 5.1 vs. 41.7 ± 4.7, P < 0.05), and a significant decrease in SSNCV (m/s; 50.2 ± 5.4 vs. 48.4 ± 5.0 vs. 39.5 ± 10.6, P < 0.05), CNFD (fibers/mm2; 37.8 ± 4.9 vs. 29.7 ± 7.7 vs. 27.1 ± 9.9, P < 0.01), CNFL (mm/mm2; 27.5 ± 3.6 vs. 24.4 ± 7.8 vs. 20.7 ± 7.1, P < 0.01), and IWL (mm/mm2; 35.1 ± 6.5 vs. 26.2 ± 10.5 vs. 23.6 ± 11.4, P < 0.05). For the diagnosis of DPN, CNFD, CNFL, and IWL achieved an area under the curve (AUC) of 0.75, 0.74, and 0.70, respectively, and a combination of IWL-CNFD achieved an AUC of 0.76.
  
  
  CONCLUSIONS
  The parameters of CNFD, CNFL, and IWL have a comparable ability to diagnose patients with DPN. However, IWL detects an abnormality even in patients without DPN. Combining IWL with CNFD may improve the diagnostic performance of CCM.
authors.affiliation: Division of Medicine, Weill Cornell Medical College-Qatar, Qatar Foundation, Education City, Doha, Qatar 2Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centr.
authors.forename: Ioannis N
authors.initials: IN
authors.lastname: Petropoulos
authors.affiliation: Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ferdousi
authors.affiliation: Clinical Neurophysiology, Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Marshall
authors.affiliation: Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Uazman
authors.initials: U
authors.lastname: Alam
authors.affiliation: Division of Medicine, Weill Cornell Medical College-Qatar, Qatar Foundation, Education City, Doha, Qatar 2Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centr.
authors.forename: Georgios
authors.initials: G
authors.lastname: Ponirakis
authors.affiliation: Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Shazli
authors.initials: S
authors.lastname: Azmi
authors.affiliation: Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Hassan
authors.initials: H
authors.lastname: Fadavi
authors.affiliation: Queensland University of Technology, School of Optometry and Vision Science, Brisbane, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Efron
authors.affiliation: Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, United Kingdom.
authors.forename: Mitra
authors.initials: M
authors.lastname: Tavakoli
authors.affiliation: Division of Medicine, Weill Cornell Medical College-Qatar, Qatar Foundation, Education City, Doha, Qatar 2Centre for Endocrinology and Diabetes, University of Manchester and Central Manchester NHS Foundation Trust, Manchester Academic Health Science Centr.
authors.forename: Rayaz A
authors.initials: RA
authors.lastname: Malik
mesh_terms: D000328:Adult; D000368:Aged; D003315:Cornea / Q000294:innervation / Q000473:pathology*; D003929:Diabetic Neuropathies / Q000175:diagnosis*; D005260:Female; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods*; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology*; D012372:ROC Curve; D015203:Reproducibility of Results; D012720:Severity of Illness Index