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Dr Nurcan Üçeyler, from Germany, gave a plenary lecture on small fibre pathology at the recent Neuropathic Pain Congress in Nice, France. We thought it was pretty interesting, so we thought we’d write a summary for you…

By Tory Madden, University of South Australia, Adelaide, Australia

There are a number of neuropathic conditions in which small fibre pathology has been found. This group of conditions includes those that are defined by their painfulness - e.g. fibromyalgia and complex regional pain syndrome - and others that are not, e.g. polyneuropathies. Small fibre pathology manifests as a reduction in the density of small nerve fibres in the skin, and after it is first detected with non-invasive clinical tests like Quantitative Sensory Testing or conduction studies, it is often confirmed using more invasive procedures like skin biopsy or corneal confocal microscopy.

Now, a 'dying back' of nerve fibres sounds pretty serious, and we all know that some of these small (A and C) fibres are nociceptors. Indeed, numerous studies have investigated various mechanisms by which small fibre die-back could lead to pain. But the interesting thing is that small fibre pathology does not seem to be a reliable predictor of pain: small fibre density does not seem to differ between people who have painful polyneuropathies and people who have painless polyneuropathies, although both groups have reduced small fibre density in comparison with healthy controls.

Dr Üçeyler pointed out that small fibre pathology may not be a driver of pain - or even a major contributor to pain - but may just be a feature that is common to many different clinical entities. If that is so, it might not be sensible to focus treatment directly on reversing or limiting the small fibre pathology, because doing so might not help with pain. In contrast, each clinical entity may require a different therapeutic approach, and identifying and addressing the processes that actually drive the pain will be an important component of that approach.

There has been a fair amount of research focussed on small fibre pathology recently - hence the knowledge I have just outlined. But Dr Üçeyler succinctly explained three questions that have not yet been answered, but that will be important questions for the work to come.

First, what causes the loss of density of small fibres? Could the actual problem be a ganglionopathy - a problem with the nerve cell body that prompts die-back from the terminal portion of the axon? Or perhaps, in some conditions, it is just one consequence of an entirely different process. We need to work this out.

Second, exactly which fibres are lost in small fibre pathology? The classification of 'small' and 'large' remains pretty crude, and we need to know more about the characteristics of the fibres that are affected.

Third, how is the loss of small fibre density related to pain? Is it a driver of pain, a consequence of pain, or merely a concurrent event? The poor association between painfulness and small fibre pathology implies that this relationship is unlikely to be causative.

It is clear that more mechanistic research is needed. In the meantime, perhaps we should all be cautious about assuming that small fibre pathology is the mechanism behind the pain experienced by people with painful neuropathies. If the content of this plenary lecture is anything to go by, it seems that recent research places the small fibre system as a victim, rather than a culprit.

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