Corneal Confocal Microscopy Detects Neuropathy in Subjects With Impaired Glucose Tolerance

Omar Asghar; Ioannis N. Petropoulos; Uazman Alam; Wendy Jones; Maria Jeziorska; Andrew Marshall; Georgios Ponirakis; Hassan Fadavi; Andrew J.M. Boulton; Mitra Tavakoli; Rayaz A. Malik


Diabetes Care. 2014;37(9):2643-2646. 

In This Article

Abstract and Introduction


Objective Impaired glucose tolerance (IGT) represents one of the earliest stages of glucose dysregulation and is associated with macrovascular disease, retinopathy, and microalbuminuria, but whether IGT causes neuropathy is unclear.

Research Design and Methods Thirty-seven subjects with IGT and 20 age-matched control subjects underwent a comprehensive evaluation of neuropathy by assessing symptoms, neurological deficits, nerve conduction studies, quantitative sensory testing, heart rate variability deep breathing (HRVdb), skin biopsy, and corneal confocal microscopy (CCM).

Results Subjects with IGT had a significantly increased neuropathy symptom profile (P < 0.001), McGill pain index (P < 0.001), neuropathy disability score (P = 0.001), vibration perception threshold (P = 0.002), warm threshold (P = 0.006), and cool threshold (P = 0.03), with a reduction in intraepidermal nerve fiber density (P = 0.03), corneal nerve fiber density (P < 0.001), corneal nerve branch density (P = 0.002), and corneal nerve fiber length (P = 0.05). No significant difference was found in sensory and motor nerve amplitude and conduction velocity or HRVdb.

Conclusions Subjects with IGT have evidence of neuropathy, particularly small-fiber damage, which can be detected using skin biopsy and CCM.


The association between impaired glucose tolerance (IGT) and peripheral neuropathy was first highlighted when subjects with idiopathic small-fiber neuropathy were found to have an unexpectedly high prevalence of IGT.[1] Subsequently in the population-based San Luis Valley[2] and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA)/Cooperative Health Research in the Region Augsburg (KORA)[3] studies, neuropathy occurred in 26–28% of patients with diabetes, in 11–13% of those with IGT, and in 4–8% of control subjects. In contrast, Dyck et al.[4] did not find an increased prevalence of neuropathy among subjects with impaired glycemia.

Establishing neuropathy in IGT is important because it may provide insights into the early pathogenetic components of diabetic neuropathy and highlights that neuropathy may occur with minimal metabolic derangement. The detection of peripheral neuropathy in IGT remains challenging, especially because most of the studies have used a combination of symptoms and neurologic signs that are large-fiber weighted. An increasing body of evidence suggests a predominantly small-fiber neuropathy, with a significant reduction in intraepidermal nerve fiber density (IENFD) and minimal large-fiber involvement in subjects with IGT.[5]

Corneal confocal microscopy (CCM), a novel surrogate measure of small-fiber neuropathy, has been shown to detect early small-fiber damage in diabetic patients.[6,7] The purpose of this study was to undertake a comprehensive assessment of neuropathy in subjects with IGT using symptoms and neurological deficits, neurophysiology, quantitative sensory testing, and in particular, skin biopsy and CCM, as sensitive measures of small-fiber neuropathy.