Laser Doppler Imager Flare (LDIflare) small fibre function

Distal sensorimotor peripheral neuropathy (DSPN), the classical length dependent symmetrical neuropathy of diabetes, can affect up to 50% of those with diabetes leading to significant morbidity, mortality and healthcare costs. There is increasing recognition that small nerve fibres, mediating pain, temperature and autonomic function, are involved early in the course of diabetic neuropathy, preceding large fibre involvement. However, assessment small fibre neuropathy (SFN), continues to be a significant challenge. The currently available options are either invasive, subjective with poor reproducibility, may not directly assess the region of interest or are still in a research phase. Thus, there is an ongoing need for simple, non-invasive and reproducible techniques for the evaluation of SFN. The laser Doppler imager flare (LDIflare) is one such novel, non-invasive technique of assessing small fibre function. It has been shown to be a reliable indicator of small fibre neuropathy, even when other SFN markers are either inconclusive or normal. However, the original methodology, took over an hour to complete, which limited its use as a clinical tool. The LDIflare methodology was therefore modified to overcome this limitation by incorporating an accelerated acclimatisation phase and a shorter duration of skin heating but at a higher final temperature reducing the total procedure time to under 30 minutes. The size of the resultant flares was nearly twice as large compared to the older method while demonstrating similar group differences in those with and without clinical neuropathy. Assessment of the LDIflare in healthy volunteers (n=94) demonstrated significant inverse relationship of LDIflare size to age (r=-0.42, p<0.0001) but not with other anthropometric or metabolic factors except for fasting triglycerides (r=-0.36, p<0.0001). Furthermore, the LDIflare possessed a sensitivity of 77%, specificity of 90%, positive predictive value (PPV) of 82% and negative predictive value of (NPV) 87% for the detection of clinical neuropathy. Recent observations, exploring into the aetiopathogenesis of diabetic neuropathy, have suggested that triggers for neuropathy development in the two main forms of diabetes may be different. Small fibre function (SFF) in individuals with type 1 diabetes with (MV+, n=24) and without (MV-, n=24) renal and retinal microvascular disease, but all without clinical neuropathy was assessed using the LDIflare. The finding of abnormal SFF only in the MV- group suggests that direct microvascular damage is an early aetiopathogenic factor in type 1 diabetes. Furthermore, in another study of normal glucose tolerant individuals not meeting the criteria for metabolic syndrome, SFF was observed to be abnormal with increasing fasting triglyceride concentrations. This is suggestive that hypertriglyceridaemia may play a pathogenic role in the development of neural dysfunction, and may partly explain the presence of neuropathy early in the course of type 2 diabetes, when significant hyperglycaemia is not a factor. The LDIflare in its current modification is a novel, reliable, non-invasive measure and objective method of detecting small fibre neuropathy. It has good reproducibility and offers excellent accuracy for the detection of clinical neuropathy. The age based normative values allow for a clear distinction of abnormal results. While further comparative studies between the LDIflare and modern markers of SFN are desired, the studies included in this submission support the use of the LDIflare technique to investigate abnormalities in the peripheral nervous system, in particular small nerve fibres, in research but also in clinical domains.