Abstract
Accurately quantifying the progression of diabetic peripheral neuropathy is key to identify individuals who will progress to foot ulceration and to power clinical intervention trials. We have undertaken detailed neuropathy phenotyping to assess the longitudinal utility of different measures of neuropathy in patients with diabetes. Nineteen patients with diabetes (age 52.5 ± 14.7 years, duration of diabetes 26.0 ± 13.8 years) and 19 healthy controls underwent assessment of symptoms and signs of neuropathy, quantitative sensory testing, autonomic nerve function, neurophysiology, intra-epidermal nerve fibre density (IENFD) and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), branch density (CNBD) and fibre length (CNFL). Mean follow-up was 6.5 years. Glycated haemoglobin (p = 0.04), low-density lipoprotein-cholesterol (LDL-C) (p = 0.0009) and urinary albumin creatinine ratio (p < 0.0001) improved. Neuropathy symptom profile (p = 0.03), neuropathy disability score (p = 0.04), vibration perception threshold (p = 0.02), cold perception threshold (p = 0.006), CNFD (p = 0.03), CNBD (p < 0.0001), CNFL (p < 0.0001), IENFD (p = 0.04), sural (p = 0.02) and peroneal motor nerve conduction velocity (p = 0.03) deteriorated significantly. Change (∆) in CNFL correlated with ∆CPT (p = 0.006) and ∆Expiration/Inspiration ratio (p = 0.002) and ∆IENFD correlated with ∆CNFD (p = 0.005), ∆CNBD (p = 0.02) and ∆CNFL (p = 0.01). This study shows worsening of diabetic neuropathy across a range of neuropathy measures, especially CCM, despite an improvement in HbA1c and LDL-C. It further supports the utility of CCM as a rapid, non-invasive surrogate measure of diabetic neuropathy.
Highlights
Quantifying the progression of diabetic peripheral neuropathy is key to identify individuals who will progress to foot ulceration and to power clinical intervention trials
Whilst the DCCT in patients with T1DM showed that intensive glycaemic control reduced the incidence of clinical diabetic peripheral neuropathy (DPN) and nerve conduction abnormalities by 60%3; in patients with T2DM, the U KPDS4 and VA-CSDM trial[5] reported no effect on DPN and cardiac autonomic neuropathy and whilst the Kumamoto s tudy[6] showed a prevention of nerve conduction slowing, the ACCORD t rial[7] showed no effect on Vibration perception threshold (VPT) over 6-years
Low density lipoprotein cholesterol (LDL-C) was significantly lower in diabetic patients compared to controls at baseline (p = 0.05) and decreased further at follow up (p = 0.0009), whilst triglycerides did not differ between patients and controls at baseline (p = 0.9) and did not change at follow up (p = 0.9). Estimated glomerular filtration rate (eGFR) did not differ significantly between diabetic patients and controls at baseline and decreased at follow up (p = 0.004)
Summary
Quantifying the progression of diabetic peripheral neuropathy is key to identify individuals who will progress to foot ulceration and to power clinical intervention trials. Nineteen patients with diabetes (age 52.5 ± 14.7 years, duration of diabetes 26.0 ± 13.8 years) and 19 healthy controls underwent assessment of symptoms and signs of neuropathy, quantitative sensory testing, autonomic nerve function, neurophysiology, intraepidermal nerve fibre density (IENFD) and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), branch density (CNBD) and fibre length (CNFL). This study shows worsening of diabetic neuropathy across a range of neuropathy measures, especially CCM, despite an improvement in HbA1c and LDL-C. It further supports the utility of CCM as a rapid, non-invasive surrogate measure of diabetic neuropathy. Corneal confocal microscopy (CCM) is a rapid non-invasive imaging technique for the quantitative assessment of small fibre damage. Automated quantification of corneal nerve parameters allows rapid, unbiased and objective assessment of small fibre damage[17] with comparable diagnostic capability to I ENFD18,19
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