Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain?

Abstract

The different neuropathic pain types (e.g., ongoing burning pain and allodynia) are frequent and disabling complaints in patients with peripheral neuropathies. Although the reference standard technique for diagnosing painful small-fibre neuropathies is nerve fibre density assessment by skin biopsy, the relationship between the epidermal nerve fibre (ENF) density and neuropathic pain is still unclear. In a clinical and skin biopsy study designed to investigate whether changes in ENF density are directly related to pain, we enrolled 139 consecutive patients with distal symmetric peripheral neuropathy. All patients underwent clinical examination. The Neuropathic Pain Symptom Inventory was used to distinguish the different neuropathic pain types. A skin biopsy was conducted, and ENFs were immunostained with the antiprotein gene product 9.5, and their linear density was quantified with bright-field microscopy. No difference was found in ENF density between patients with and without neuropathic pain, nor between patients with and without ongoing burning pain. Conversely, ENF density was higher in patients with provoked pains (including mechanical dynamic allodynia) than in those without. The variable association between ENF density and symptoms of neuropathic pain supports the idea that neuropathic pain symptoms arise through distinct underlying mechanisms. The lack of relationship between ongoing burning pain and ENF density suggests that this type of pain reflects factors other than loss of nociceptive afferents. The association between ENF density and provoked pain (including mechanical dynamic allodynia) suggests that this type of pain might be mediated by spared and sensitised nociceptive afferents.

Neuropathic pain assessment

“…Interestingly, the decreased IENFD recovered after causal treatment of the neuropathy (hormone replacement in hypothyroidism [42], steroidsensitive neuropathy [43] and metabolic improvement in prediabetic neuropathy [44], as well as because of exercise programs in diabetic patients without neuropathy symptoms and in metabolic syndrome neuropathy [45,46]). A recent study demonstrated no difference in the IENFD between patients with and without neuropathic pain, or between patients with and without ongoing burning pain, confirming previous results [47]. The IENFD was, however, higher in patients with provoked pain than in those without [47], suggesting that this type of pain might be mediated by spared and sensitized nociceptive afferents, which might have implications for treatment approaches.…”

“…A recent study demonstrated no difference in the IENFD between patients with and without neuropathic pain, or between patients with and without ongoing burning pain, confirming previous results [47]. The IENFD was, however, higher in patients with provoked pain than in those without [47], suggesting that this type of pain might be mediated by spared and sensitized nociceptive afferents, which might have implications for treatment approaches.…”

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…This localization implies that aldose reductase dysfunction does not only alter vascular function, although this observation has led to something of a conundrum with regard to the pathogenic role of the enzyme: demyelination can be a feature of human diabetic neuropathy 28,43 , but diabetic rodents rarely exhibit marked Schwann cell pathology Diabetic neuropathy classically presents as a sensory neuropathy that results from damage to both large and small fibres, which can cause negative symptoms, such as loss of sensation to touch, vibration, pinprick, hot and cold 177,178 , and positive symptoms, such as paradoxical pain and hypersensitivity [179][180][181][182][183] . Negative and positive symptoms are both most pronounced distally, with a characteristic stocking-glove pattern (see the figure).…”

How to diagnose neuropathic pain? The contribution from clinical examination, pain questionnaires and diagnostic tests

“…Whereas some studies have reported a possible relationship between IENF density and the severity pain [53], most investigators could not replicate these data [54]. IENF density is correlated with cold and warm thresholds, but not with the presence and severity of neuropathic pain, supporting the idea that neuropathic pain symptoms do not merely reflect axonal loss but arise through distinct underlying mechanisms [51,52].…”

“…These studies, however, indicate that the diagnostic yield of skin biopsy strongly depends on the reference cut-off values [48,50,51]. Although skin biopsy selectively assesses epidermal nerve fibre density and reliably diagnoses smallfibre neuropathy, published studies report contradictory results on the relationship between skin biopsy data and pain [52]. Whereas some studies have reported a possible relationship between IENF density and the severity pain [53], most investigators could not replicate these data [54].…”