Small fibre neuropathy: role in the diagnosis of diabetic sensorimotor polyneuropathy

Small fibres constitute 70-90% of peripheral nerve fibres and regulate several key functions such as tissue blood flow, temperature and pain perception as well as sweating, all of which are highly relevant to the clinical presentation and adverse outcomes associated with foot ulcerations in patients with diabetes. Recent studies demonstrated significant abnormalities in the small fibres in subjects with impaired glucose tolerance and diabetes, despite normal electrophysiology, suggesting that the earliest nerve fibre damage is to the small fibres. Unfortunately, guidelines and consensus statements focus on large fibres and continue to advocate electrophysiology as a diagnostic modality and as a primary end point for the assessment of therapeutic benefit. (In part, this reflects the difficulties in quantifying small fibre dysfunction and damage.) We have therefore critically assessed currently available techniques that measure small fibre dysfunction in diabetic neuropathy, using quantitative sensory and sudomotor testing. We have assessed the role of identifying structural damage by quantifying intraepidermal nerve fibre density in skin biopsies and corneal nerve morphology using corneal confocal microscopy. Finally, we propose a definition for diabetic neuropathy that incorporates small fibre damage.