Early Detection of Nerve Fiber Loss by Corneal Confocal Microscopy and Skin Biopsy in Recently Diagnosed Type 2 Diabetes

Dan Ziegler; Nikolaos Papanas; Andrey Zhivov; Stephan Allgeier; Karsten Winter; Iris Ziegler; Jutta Brüggemann; Alexander Strom; Sabine Peschel; Bernd Köhler; Oliver Stachs; Rudolf F. Guthoff; Michael Roden


Diabetes. 2014;63(7):2454-2463. 

In This Article


The demographic and clinical characteristics of the patients and control subjects are reported in Table 1. Mean BMI and the percentage of clinical DSPN were higher in the diabetic group compared with the control subjects (P < 0.05). No significant differences between the groups were noted for sex, age, percentage of smokers, and systolic and diastolic blood pressure. The percentages of patients on diet-only, oral glucose–lowering drugs, and insulin were 39.5, 53.5, and 5.8%, respectively. Diabetes duration until CCM measurement was 2.1 ± 1.8 years. Laboratory parameters in the diabetic group included: HbA1c, 6.8 ± 1.1% or 50.8 ± 12.0 mmol/mol; fasting blood glucose, 138 ± 37 mg/dL; fasting C-peptide, 3.3 ± 1.8 ng/mL; creatinine, 0.88 ± 0.17 mg/dL; triglycerides, 176 ± 100 mg/dL; total cholesterol, 212 ± 39 mg/dL; HDL cholesterol, 49 ± 12 mg/dL; and LDL cholesterol, 136 ± 36 mg/dL. Prevalence of microalbuminuria and macroalbuminuria was 15.1 and 3.5%, respectively, whereas nonproliferative (background) retinopathy was present in 2.3% of the patients. Treated hypertension was observed in 47.7% of the patients. The percentages of patients who were physically active to a moderate and high degree were 30.2 and 26.7%.

CCM measures, corneal sensation, IENFD, and peripheral and cardiovascular autonomic nerve function tests in the diabetic and control groups studied are presented in Table 2. Among the CCM measures, CNFL, CNFD, CNBD, CNCP, and CNFTh, and the corresponding MNF variables, were significantly reduced in the diabetic group compared with the control group (all P < 0.05), except for CNCP-MNF (P = 0.107). CNFTo-MNF tended to be higher in the diabetic group than in the control group (P = 0.096). No differences between the groups were found for CNFTh, CNFTh-MNF, and CNFTo. The CCM image area tended to be smaller in the diabetic group than in the control group (P = 0.091). Corneal sensation did not differ significantly between the groups. IENFD and median, ulnar, and peroneal motor NCV and median and sural sensory NCV and median, ulnar, and sural SNAP, cold TDT on the foot, expiration-to-inspiration ratio, and the Valsalva ratio were significantly lower, and metacarpal and malleolar VPT were significantly higher, in subjects with versus those without diabetes (all P < 0.05). No differences between the groups were noted for ulnar sensory NCV, warm and cold TDT on the thenar eminence, warm TDT on the foot, coefficient of R-R interval variation at rest, high-frequency and low-frequency power spectrum, and maximum-to-minimum 30:15 ratio.

Typical examples of CCM showing normal SNP appearance in a healthy subject and CNF loss in a patient with recently diagnosed T2D are shown in Fig. 1.

Figure 1.

CCM showing the SNP. A: Normal SNP appearance in a healthy subject. B: CNF loss in a patient with recently diagnosed T2D. A single image frame with the commonly used size of 400 μm × 400 μm is displayed for comparison.

The percentages of values below the 2.5th percentile limit of normal were significantly higher for CNFL, CNFD-MNF, CNBD-MNF, IENFD, peroneal MNCV, sural SNCV, sural SNAP, and cold TDT, whereas the percentages of values above the 97.5th percentile were significantly higher for malleolar VPT and tended to be higher for warm TDT in subjects with T2D than in control subjects (Table 3). No significant differences between the groups were noted for the remaining parameters listed in Table 3. Only 2.7% (95% CI 0.5–8.4) of the patients had both abnormal CNFD and IENFD, whereas 65.8% (95% CI 55.6–74.9) had both normal CNFD and IENFD. Abnormal CNFD with concomitantly normal IENFD was noted in 20.5% (95% CI 13.1–29.9) of the diabetic group, whereas the opposite (i.e., normal CNFD and concomitantly abnormal IENFD) was found in 11.0% (95% CI 5.6–18.9) of the patients.

Correlation analysis in the control group showed no association between CCM measures and age, except for CNCP (r = −0.323; P = 0.025) and BMI. In the diabetic group, no correlation was observed between the CCM measures and IENFD (data not shown). The correlation analysis for the highest correlations (r > 0.2) for CCM measures with measures of peripheral nerve structure and function in the entire study population are reported in Table 4. The CCM measures correlated most consistently with median MNCV, median SNCV, and sural SNAP. IENFD correlated with each of the four CCM measures listed but was not associated with the CCM-MNF parameters. IENFD was correlated with each of the nerve conduction measures listed, except for ulnar SNCV.