Does the Prevailing Hypothesis That Small-Fiber Dysfunction Precedes Large-Fiber Dysfunction Apply to Type 1 Diabetic Patients?

Abstract

OBJECTIVEThe prevailing hypothesis that early subclinical small-fiber injury precedes largefiber damage in diabetic sensorimotor polyneuropathy (DSP) is based on lower intraepithelial nerve fiber density in type 2 prediabetic patients despite normal nerve conduction studies (NCSs). We aimed to confirm the same hypothesis in type 1 diabetic patients by examining whether: 1) subjects without DSP include a spectrum with both normal and abnormal small-fiber measures and 2) subjects with DSP have concurrent evidence of abnormal small-fiber measures. RESEARCH DESIGN AND METHODSA healthy control population (n = 53) was used to generate threshold values for four small-fiber tests: cooling detection thresholds (CDTs), laser Doppler imaging of heat-evoked flare (LDI flare ), heart rate variability (HRV), and corneal confocal microscopy. Based on NCS results, type 1 diabetic patients (n = 131) were dichotomized according to the presence or absence of DSP. RESULTSThreshold values derived from healthy control subjects were 26.58C, 1.4 cm 2 , 13%, and 12.9 mm/mm 2 for CDT, LDI flare , HRV, and corneal nerve fiber length, respectively. Among type 1 diabetic patients, 57 of 131 had evidence of DSP, and 74 of 133 did not. Using abnormality of any small-fiber test to define small-fiber dysfunction, 55 of 57 (96.5%) DSP patients and 39 of 74 (52.7%) control subjects without DSP had concurrent small-fiber damage. The severity of small-fiber abnormalities worsened with an increasing number of NCS abnormalities (ANOVA, P < 0.01). CONCLUSIONSOur findings in type 1 diabetes support the prevailing hypothesis that small-fiber dysfunction occurs early in DSP. However, further research is required to determine which combination of small-fiber tests is most suitable as a surrogate marker in clinical trials.Diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes, affecting 28-55% of patients (1). A prospective Finnish study found evidence of probable or definite neuropathy in 8.3% of diabetic patients at the time of diagnosis, 16.7% after 5 years, and 41.9% after 10 years (2). Diabetes-related peripheral neuropathy results in serious morbidity, including chronic neuropathic pain, leg

Comment on Breiner et al. Does the Prevailing Hypothesis That Small-Fiber Dysfunction Precedes Large-Fiber Dysfunction Apply to Type 1 Diabetic Patients? Diabetes Care 2014;37:1418–1424

“…It would be helpful to know the coefficient of variation for the methodology used in their study. The mean values reported by Breiner et al (1) are quite different to those we have obtained.…”

“…We read with great interest the article by Breiner et al (1) demonstrating the presence of small-fiber dysfunction in type 1 diabetes of significant duration in the absence of perceptible abnormalities in large-fiber function, and we congratulate the authors for their simple, clear, and elegant study design. We also agree with the authors that this study "has made an important contribution to the literature" in understanding the development of early neuropathy in type 1 diabetes.…”

Corneal confocal microscopy in chronic inflammatory demyelinating polyneuropathy

“…It has also been widely used to evaluate diabetic neuropathy in multiple studies10 demonstrating that this technique is a viable surrogate endpoint for early diagnosis,11 stratification of neuropathy severity,12 and assessing the response to treatment 13. This technique is highly reproducible14, 15 and well‐tolerated 16.…”

Corneal Confocal Microscopy Predicts 4-Year Incident Peripheral Neuropathy in Type 1 Diabetes

“…CCM is able to track the recovery of DPN after interventions such as improving risk factors for DPN (10), simultaneous pancreas and kidney transplantation (11), and continuous subcutaneous insulin infusion (12). Nerve parameters assessed using CCM correlate significantly with structural (skin punch biopsy) (13) and functional (14) measures of small-nerve fiber injury, and abnormalities in the corneal nerve plexus have been shown to precede neurophysiological abnormalities in patients with type 1 diabetes (15). However, the capacity for CCM to predict future onset of DPN is unknown.…”