Advances in the Diagnosis and Treatment of Painful Diabetic Neuropathy
Mitra Tavakoli, Hassan Fadavi, Rayaz A Malik
2008
European Endocrinology
Symptoms of painful diabetic neuropathy (PDN) occur in 30-40% of patients with diabetic neuropathy. 1 It is most commonly associated with distal symmetrical neuropathy affecting the lower limbs (especially toes and feet), and patients present with burning, stabbing and tingling sensations. PDN is extremely distressing and significantly reduces the quality of life of patients. 2 Hyperglycaemia is clearly important in the genesis of nerve damage, and recent studies suggest that even minimal
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... bations in blood glucose in those with impaired glucose tolerance (IGT) may lead to the development of small nerve fibre damage and neuropathic pain. 3 The causes and consequences of diabetic neuropathy are complex and not well understood. Several hypotheses have been advocated in an attempt to explain the pathophysiology of diabetic neuropathy and include a combination of increased oxidative stress, advanced glycation, polyol accumulation, decreased nitric oxide and impaired sodium + / potassium + (Na + /K + )-adenosine triphosphate (ATPase). 4 Paradoxically, a lack of treatment for underlying nerve damage has improved our understanding of the natural history of PDN because, although nerve damage may initiate PDN, it is clear that as nerve damage progresses pain may diminish. 5 Diagnosis of Painful Diabetic Neuropathy Standard measures of neuropathy such as nerve conduction studies and vibration perception thresholds (VPTs) can be used to detect abnormalities of nerve function, but they focus on large nerve fibres. However, pain is generated and mediated by small c and aδ fibres. Thus, it is no surprise that VPT does not differ between diabetic patients with painful and painless neuropathy. 6 Quantitative sensory testing (QST) including thermal threshold assessment for cold sensation (aδ fibres) and warm sensation (c fibres) can assess small fibre dysfunction, but is highly subjective and lacks precision and accuracy, which makes reproducibility difficult. Gore et al. 7 showed that patients with pain were more likely to have an abnormal cold threshold compared with those without pain; however, the former group also had more severe neuropathy, which was evidenced by a higher VPT and absent reflexes. In general, QST and nerve conduction studies (NCS) cannot distinguish between painful and painless diabetic neuropathy. One of the limitations of QST is the lack of normative data; however, normative data have recently been published for QST 8 and may allow detection and quantification not only of negative symptoms but also of positive sensory symptoms, such as allodynia, both of which are present in patients with PDN. 9 The only techniques that allow direct examination of thinly myelinated and unmyelinated nerve fibre damage and repair are sural nerve biopsy with electron microscopy 10 and skin-punch biopsy, 11 but both are invasive. Intra-epidermal nerve fibre density can be used to evaluate small fibre involvement in diabetic neuropathy. 12 However, there is no clear consensus on the role of intra-epidermal nerve fibre (IENF) loss in patients with painful and painless neuropathy. However, some recent studies do suggest that more refined morphometric evaluation of epidermal nerve fibre morphology, such as axonal swellings 13 and alterations in branching, 14 may be associated with neuropathic pain. A recent study also showed a marked impairment in the cutaneous response to iontophoresed acetylcholine (ACh) in patients with painful neuropathy compared with painless diabetic neuropathy, suggesting that alterations in tissue blood flow may modulate signals generating pain in the periphery. 15 Recently, we have shown that the novel non-invasive technique of corneal confocal microscopy can detect small fibre neuropathy in diabetic patients by visualising small nerve fibres in Bowman's layer of cornea. 15,16 Furthermore, it may be more sensitive than IENF density (IENFD) in detecting early damage 17 and repair after pancreas transplantation. 18 Thus, this may be an ideal technique to accurately quantify small nerve fibre morphology, especially in a reiterative manner following patients with exacerbations and remissions from PDN. We have recently shown that corneal confocal microscopy (CCM) can be used to demonstrate more advanced small nerve fibre damage in patients with Fabry disease, a hereditary condition with pure small fibre neuropathy (unpublished data).
doi:10.17925/ee.2008.04.00.48
fatcat:brfsrqasqzf65e5blc6sozlqiy