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We sought to determine whether early nerve damage may be detected by corneal confocal microscopy (CCM), skin biopsy, and neurophysiological tests in 86 recently diagnosed type 2 diabetic patients compared with 48 control subjects. CCM analysis using novel algorithms to reconstruct nerve fiber images was performed for all fibers and major nerve fibers (MNF) only. Intraepidermal nerve fiber density (IENFD) was assessed in skin specimens. Neurophysiological measures included nerve conduction studies (NCS), quantitative sensory testing (QST), and cardiovascular autonomic function tests (AFTs). Compared with control subjects, diabetic patients exhibited significantly reduced corneal nerve fiber length (CNFL-MNF), fiber density (CNFD-MNF), branch density (CNBD-MNF), connecting points (CNCP), IENFD, NCS, QST, and AFTs. CNFD-MNF and IENFD were reduced below the 2.5th percentile in 21% and 14% of the diabetic patients, respectively. However, the vast majority of patients with abnormal CNFD showed concomitantly normal IENFD and vice versa. In conclusion, CCM and skin biopsy both detect nerve fiber loss in recently diagnosed type 2 diabetes, but largely in different patients, suggesting a patchy manifestation pattern of small fiber neuropathy. Concomitant NCS impairment points to an early parallel involvement of small and large fibers, but the precise temporal sequence should be clarified in prospective studies.

Bidimensional regression is a method for comparing the degree of resemblance between 2 planar configurations of points and, more generally, for assessing the nature of the geometry (Euclidean and non-Euclidean) between 2-dimensional independent and dependent variables. For example, it can assess the similarity between location estimates from different tasks or participant groups, measure the fidelity between cognitive maps and actual locations, and provide parameters for psychological process models. The authors detail the formal similarity between uni- and bidimensional regression, provide computational methods and a new index of spatial distortion, outline the advantages of bidimensional regression over other techniques, and provide guidelines for its use. The authors conclude by describing substantive areas in psychology for which the method would be appropriate and uniquely illuminating.

The key advances embodied in the proposed technique are its high degree of integration and automation (both for image acquisition and image processing) and the resulting short duration of CCM. By providing an easy-to-use tool for obtaining large-scale mosaic images of the SNP, this technique has the potential to facilitate larger clinical trials where SNP morphology is used as a surrogate marker for peripheral neuropathy.

Citation: Lagali NS, Allgeier S, Guimarães P, et al. Reduced corneal nerve fiber density in type 2 diabetes by wide-area mosaic analysis. Invest Ophthalmol Vis Sci. 2017;58:6318-6327. DOI:10.1167/iovs.17-22257 PURPOSE. To determine if corneal subbasal nerve plexus (SBP) parameters derived from widearea depth-corrected mosaic images are associated with type 2 diabetes. METHODS.One hundred sixty-three mosaics were produced from eyes of 82 subjects by laserscanning in vivo confocal microscopy (IVCM). Subjects were of the same age, without (43 subjects) or with type 2 diabetes (39 subjects). Mosaic corneal nerve fiber length density (mCNFL) and apical whorl corneal nerve fiber length density (wCNFL) were quantified and related to the presence and duration of diabetes (short duration < 10 years and long duration ‡ 10 years).RESULTS. In mosaics with a mean size of 6 mm 2 in subjects aged 69.1 6 1.2 years, mCNFL in type 2 diabetes was reduced relative to nondiabetic subjects (13.1 6 4.2 vs. 15.0 6 3.2 mm/ mm 2 , P ¼ 0.018). Also reduced relative to nondiabetic subjects was mCNFL in both shortduration (14.0 6 4.0 mm/mm 2 , 3.2 6 3.9 years since diagnosis) and long-duration diabetes (12.7 6 4.2 mm/mm 2 , 15.4 6 4.2 years since diagnosis; ANOVA P ¼ 0.023). Lower mCNFL was associated with presence of diabetes (P ¼ 0.032) and increased hemoglobin A1c (HbA1c) levels (P ¼ 0.047). By contrast, wCNFL was unaffected by diabetes or HbA1c (P > 0.05). Global SBP patterns revealed marked degeneration of secondary nerve fiber branches outside the whorl region in long-duration diabetes.CONCLUSIONS. Wide-area mosaic images provide reference values for mCNFL and wCNFL and reveal a progressive degeneration of the SBP with increasing duration of type 2 diabetes.