Advances in Screening, Early Diagnosis and Accurate Staging of Diabetic Neuropathy

Abstract

The incidence of both type 1 and type 2 diabetes is increasing worldwide. Diabetic peripheral neuropathy (DPN) is among the most distressing and costly of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life. This incurs a significant burden on health care costs and society, especially as these young people enter their peak working and earning capacity at the time when diabetes-related complications most often first occur. DPN is often asymptomatic during the early stages; however, once symptoms and overt deficits have developed, it cannot be reversed. Therefore, early diagnosis and timely intervention are essential to prevent the development and progression of diabetic neuropathy. The diagnosis of DPN, the determination of the global prevalence, and incidence rates of DPN remain challenging. The opinions vary about the effectiveness of the expansion of screenings to enable early diagnosis and treatment initiation before disease onset and progression. Although research has evolved over the years, DPN still represents an enormous burden for clinicians and health systems worldwide due to its difficult diagnosis, high costs related to treatment, and the multidisciplinary approach required for effective management. Therefore, there is an unmet need for reliable surrogate biomarkers to monitor the onset and progression of early neuropathic changes in DPN and facilitate drug discovery. In this review paper, the aim was to assess the currently available tests for DPN's sensitivity and performance.

Keywords: Diabetic Neuropathy; Diagnosis; Early Detection; Screening; microvascular complications; neuropathy biomarkers.

Figure 1

Examples of nine different tests for diabetic peripheral neuropathy (DPN), (A) Physical examination and Neuropathy disability score (NDS), (B) Nerve Conduction studies being performed on the lower leg, (C) DPNcheck device to test sural nerve conduction performed on the lower leg, (D) Monofilament screening test sights and procedure, (E) Vibration perception threshold testing, (F) Medoc TSAII quantitative sensory testing device for thermal perception threshold, (G) Sudoscan equipment. Hand and feet sensor plates with displaying test results, (H) Neuropad test demonstrated original blue color, (I) A punch skin biopsy to collect samples needed for IENFD measurement, (J) An image of the corneal sub-basal nerves using corneal confocal microscopy and the CCM probe positioning during corneal scanning.

Figure 2

Images from Bowman’s layer of the cornea at (A) T2DM with mild neuropathy; (B) moderate neuropathy; (C) Healthy Control Subject (yellow arrows show LCs and red arrows indicates main corneal nerve c nerve fibers).

Figure 3

Corneal confocal microscopy images of the corneal, sub-basal nerves (A–C). Healthy control (A) shows numerous corneal main nerve fibers (green arrowheads) with branching nerves (blue asterisks). CCM images of patients with diabetes and mild (B) or severe (C) neuropathy demonstrate reduced corneal nerves and branches. Skin biopsies (E, F) immunostained. Healthy control (E) shows numerous intraepidermal nerve fibers (red arrowheads) with a well-developed subepidermal nerve plexus (yellow arrowheads). A diabetic patient (F) demonstrates reduced subepidermal and minimal intraepidermal nerve fibers. Scale bar = 100 mm. (E, F) adapted from (186).