Table 1.
Recent studies on corneal confocal microscopy for the evaluation of diabetic polyneuropathy
| Authors [Ref.] | n (DM/controls) | Main findings |
|---|---|---|
| Ziegler et al.5 | 86 recently diagnosed T2DM/48 | 1) Reductions in T2DM vs controls: CNFL-MNF (P = 0.001), CNFD-MNF (P < 0.001), CNBD-MNF (P < 0.001), CNCP (P = 0.006), IENFD (P < 0.001), NCS (P < 0.001), QST (P < 0.001) and VR (P = 0.006) |
| 2) CNFD-MNF among T2DM: reduced below the 2.5th percentile in 21% | ||
| 3) IENFD among T2DM: reduced below the 2.5th percentile in 14% | ||
| 4) Vast majority of patients with abnormal CNFD: concomitantly normal IENFD | ||
| 5) Vast majority of patients with abnormal IENFD: concomitantly normal CNFD | ||
| Petropoulos et al.23 | 186/55 | 1) Increasing DSPN severity: significant reduction in manual and automated CNFD (P < 0.0001), CNBD (P < 0.001), and CNFL (P < 0.0001) |
| 2) Manual and automated analysis: correlated for CNFD (r = 0.9, P < 0.0001), CNFL (r = 0.89, P < 0.0001) and CNBD (r = 0.75, P < 0.0001) | ||
| 3) Highest diagnostic performance: manual CNFD and automated CNFL | ||
| Edwards et al.24 | 231/61 | 1) Tortuosity standardized CNFL vs classical CNFL in DM: better in showing differences between DSPN and no DSPN |
| 2) Tortuosity standardized CNFL in DM: 70.5 ± 27.3 (DSPN) vs 84.9 ± 28.7 mm/mm2 (no DSPN), P < 0.001, ROC area under the curve = 0.67 | ||
| 3) Classical CNFL in DM: 15.9 ± 6.9 (DSPN) vs 18.4 ± 6.2 mm/mm2 (no DSPN), P = 0.004, ROC area under the curve = 0.64 | ||
| 4) Tortuosity standardized CNFL vs classical CNFL: 94.3 ± 27.1 (DM without DSPN) vs 84.9 ± 28.7 mm/mm2 (controls) (P = 0.028) | ||
| 5) Classical CNFL: 20.1 ± 6.3 (DM without DSPN) vs 18.4 ± 6.2 mm/mm2 (controls) (P = 0.084) | ||
| 6) Tortuosity standardized CNFL vs classical CNFL in DM: stronger correlations with DSPN attributes | ||
| 7) Tortuosity standardized CNFL vs classical CNFL in DM: stronger correlations with risk factors for DSPN | ||
| Halpern et al.34 | 89 T1DM/0 | 1) Comparable areas under the ROC curve for CNFL against various definitions of DSPN (except for clinical definition) |
| 2) DSPN definitions including NCS: optimal CNFL threshold 14 mm/mm2 | ||
| 3) Clinical DSPN definition: optimal CNFL threshold 15.4 mm/mm2 | ||
| Maddaloni et al.35 | 36 T1DM/20 | 1) T1DM vs controls: 45.4 ± 20.2 vs 92.0 ± 22.7 fibers/mm2 (P < 0.001), more tortuous corneal nerve fibers (P = 0.022), 15.1 ± 3.5 vs 20.6 ± 5.0 beadings (P < 0.001) |
| 2) In T1DM, CAN vs no CAN: CNFD 32.8 ± 16.4 vs 51.7 ± 18.9 fibers/mm2 (P = 0.008); CNFL 5.5 ± 2.4 vs 9.2 ± 3.8 mm/mm2 (P = 0.005) | ||
| 3) In T1DM, NS differences between CAN vs no CAN: branching grade (1.4 ± 0.8 vs 1.9 ± 0.7, P = 0.06), nerve tortuosity (36.4 vs 64%; P = 0.159), nerve beadings (14.8 ± 4.2 vs 15.3 ± 3.2, P = 0.719) | ||
| Zhivov et al.39 | 18 T2DM/20 | 1) Corneal sensation: 59 ± 18 mm in healthy volunteers and 43 ± 11 mm in T2DM (P < 0.001) |
| 2) Reductions in T2DM vs controls: component pixels (P < 0.001), skeleton pixels (P < 0.001), component ratio (P < 0.001), single nerve fibers (P < 0.001), single nerve fibers per component (P < 0.001), total fiber length (P < 0.001), CNFD (P < 0.001), connectivity points (P < 0.001), number of branches (P < 0.001), homogeneity of component pixels (P = 0.001) and average single fiber length (P = 0.08) | ||
| 3) T2DM: NS differences in the aforementioned CCM nerve parameters between patients with DR and those without DR | ||
| Stem et al.43 | 25 T1DM without DSPN and 18 T2DM with DSPN/9 | 1) Severe DSPN: lower CNFL vs controls (12.5 ± 6.1 mm/mm2 vs 20.7 ± 2.2 mm/mm2, P = 0.009) |
| 2) T1DM without DSPN: lower CNFL vs controls (15.1 ± 4.7 mm/mm2 vs 20.7 ± 2.2 mm/mm2, P = 0.033) | ||
| Petropoulos et al.46 | 111/47 | 1) CNFD, CNBD and CNFL: symmetrical pathology (except in patients with severe DSPN) |
| 2) CNFD: significant (P < 0.001) reduction between controls and DM with increasing DSPN severity | ||
| 3) CNBD: significant (P < 0.001) reduction between controls and DM with increasing DSPN severity | ||
| 4) CNFL: significant (P < 0.001) reduction between controls and DM with increasing DSPN severity | ||
| Ishibashi et al.47 | 78 T2DM/28 | 1) DSPN vs no DSPN: reductions in CNFD (P < 0.001), CNFL (P < 0.001) and beading frequency (P < 0.0001) with increased CNFTo (P < 0.0001) |
| 2) Sudomotor function: negative correlations with CNFD (P < 0.002) and CNBD (P < 0.01) | ||
| 3) Sweat gland duct size: correlated with triglycerides (P < 0.02), uric acid (P < 0.01), CNBD (P < 0.03), sudomotor function (P < 0.03) and DSPN severity (P < 0.03) | ||
| Dehghani et al.48 | 147 Τ1DM/60 | 1) DSPN vs controls: significant (P = 0.01) linear decline of CNFD, in association with age (P = 0.04) and T1DM duration (P = 0.03) |
| 2) DSPN: modest correlation between CNBD and peroneal conduction velocity (r = 0.38, P = 0.05) | ||
| 3) DSPN: modest correlation between CNFL and CDT (r = 0.40, P = 0.03) | ||
| Sivaskandarajah et al.49 | 96 T1DM/64 | 1) In T1DM, DSPN vs no DSPN: lower CDT values (P < 0.0001), smaller LDIFLARE areas (P = 0.0002), and lower HRV values (P < 0.0001) |
| 2) In T1DM, reduction of CNFL by every 1 mm/mm2: association with a 0.61°C lower CDT, a 0.07 cm2 lower LDIFLARE area, and a 1.78% lower HRV | ||
| 3) CNFL in T1DM: significant positive correlations with CDT (P = 0.0002), LDIFLARE (P = 0.002) and HRV (P < 0.0001) | ||
| 4) CNFD in T1DM: significant positive correlations with CDT (P = 0.002), LDIFLARE (P = 0.0002) and HRV (P = 0.003) | ||
| 5) CNBD in T1DM: significant positive correlations with CDT (P = 0.0002), LDIFLARE (P = 0.01) and HRV (P = 0.001) | ||
| 6) CNFTo in T1DM: no association with small-fiber function | ||
| Dehghani et al.54 | 0/64 | 1) Age: significant (P = 0.02) linear CNFL reduction by 0.05 mm/mm2 per added year |
| 2) CNFL: NS change in over 36 months (P = 0.41) | ||
| Pritchard et al.51 | 242 T1DM (76 with DSPN, 166 without DSPN)/154 | 1) CNFL: lower in T1DM with DSPN (14.0 ± 6.4 mm/mm2) vs T1DM without DSPN (19.1 ± 5.8 mm/mm2) and controls (23.2 ± 6.3 mm/mm2) (P < 0.001) |
| 2) CNFL: lower in T1DM without DSPN (19.1 ± 5.8 mm/mm2) vs controls (23.2 ± 6.3 mm/mm2) (P < 0.001) | ||
| 3) CNBD: lower in T1DM with DSPN (40.1 ± 32.1 branches/mm2) vs T1DM without DSPN (61.7 ± 37.2 branches/mm2) and controls (83.5 ± 45.8 branches/mm2) (P < 0.001) | ||
| 4) CNBD: lower in T1DM without DSPN (61.7 ± 37.2 branches/mm2) vs controls (83.5 ± 45.8 branches/mm2) (P = 0.001) | ||
| Asghar et al.52 | 37 IGT/20 | 1) IGT vs controls: significantly increased NSP (P < 0.001), McGill pain index (P < 0.001), NDS (P = 0.001), VPT (P = 0.002), WDT (P = 0.006) and CDT (P = 0.03) |
| 2) IGT vs controls: reductions in IENFD (P = 0.03), CNFD (P < 0.001), CNBD (P = 0.002) and CNFL (P = 0.05) | ||
| Pritchard et al.55 | 90 T1DM without DSPN | 1) Development of DSPN after 4 years: associations with lower CNFL (P = 0.041) |
| 2) Development of DSPN after 4 years: associations with longer T1DM duration (P = 0.002), higher triglycerides (P = 0.023), retinopathy (P = 0.008), nephropathy (P = 0.001), higher NDS (P = 0.037), lower CDT (P = 0.001), higher WDT (P = 0.008), higher VPT (P = 0.003), impaired monofilament response (P = 0.003), NCS impairments (P < 0.05) | ||
| 3) CNFL cut-off of 14.1 mm/mm2: 63% sensitivity and 74% specificity for the prediction of DSPN after 4 years | ||
| Azmi et al.56 | 49 T1DM (18 CSII, 31 MDI)/40 | T1DM CSII vs T1DM MDI: increase in CNFD (P = 0.05), CNBD (P = 0.006) and CNFL (P = 0.003), NS difference in VPT, CDT, WDT, NCS or IENFD |
| Brines et al.57 | 48 T2DM/55 | ARA 290 vs placebo: improvement of neuropathic symptoms (P = 0.037), increase in CNFD (P = 0.02) and reduction in HbA1c (P = 0.002) |
| Tavakoli et al.58 | 34/18 | 1) CNFD (best cut-off <23.26 nerves per mm2): 86% sensitivity and 78% specificity for the diagnosis of DAN (AUC = 0.915, P = 0.0001) |
| 2) CNBD (best cut-off <19.53 branches per mm2): 100% sensitivity and 56% specificity for the diagnosis of DAN (AUC = 0.889, P = 0.0001) | ||
| 3) CNFL (best cut-off <4.78 mm/mm2): 86% sensitivity and 78% specificity for the diagnosis of DAN (AUC = 0.907, P = 0.0001) | ||
| 4) CNFD, CNBD, CNFL: significant (P < 0.001) correlations with CASS and COMPASS |
ARA 290, a peptide derived from erythropoietin
AUC, area under the curve
CAN, cardiac autonomic neuropathy
CASS, composite autonomic scoring scale
CCM, corneal confocal microscopy
CDT, cooling detection threshold
CNBD, corneal nerve fiber branch density
CNFD, corneal nerve fiber density
CNFL, corneal nerve fiber length
CNFTo, corneal nerve fiber tortuosity
CNCP, corneal nerve connecting points
COMPASS, composite autonomic symptom scale
CSII, continuous subcutaneous insulin infusion
DAN, diabetic autonomic neuropathy
DR, diabetic retinopathy
DSPN, diabetic polyneuropathy
HbA1c, glycated hemoglobin
HRV, heart rate variability
IENFD, intra-epidermal nerve fiber density
IGT, impaired glucose tolerance
LDIFLARE, laser Doppler imaging flare
MDI, multiple daily insulin injections
MNF, major nerve fibers
NCS, nerve conduction study
NDS, neuropathy disability score
NS, not significant
NSP, neuropathy symptom profile
QST, quantitative sensory testing
T1DM, type 1 diabetes mellitus
T2DM, type 2 diabetes mellitus
VPT, vibration perception threshold
VR, Valsalva ratio
WDT, warm detection threshold.