
Updates & Features
The Many Challenges of Small Fibre Neuropathy – The 4th PainSolve Webinar
April 2019
Challenges around small fibre neuropathy, from the definition to diagnosis
PainSolve Editorial Team
The PainSolve team are delighted to have welcomed Assistant Professor Páll Karlsson of the Danish Pain Research Centre to host his first webinar on the 10th April 2019, titled, ‘The Many Challenges of Small Fibre Neuropathy’. Dr Karlsson based his presentation on a review article that he and his team recently published,1 combined with observations from other research groups to provide a comprehensive overview of the current challenges of small fibre neuropathy (SFN).
Dr Karlsson’s Presentation
Dr Karlsson highlighted the following as the key challenges around SFN:
- Definition – there is disagreement on the current SFN definition
- Dignosis – there is disagreement on which tools to use and the optimal order to use them in
- Idiopathic cases – these still account for 50% of cases
- Complexity of the disease – both the autonomic and somatosensory nervous systems are affected
- Treatment – there are only sparse, symptom-focused treatment options
From Dr Karlsson’s 2017 publication, the proposed definition of SFN is: a disease of, or damage to, the peripheral nervous system affecting small fibres (unmyelinated C-fibres and thinly small Aδ-fibres) in a neuropathic distribution.1 However, this definition is not fully agreed on within the medical community. SFN is further complicated by the clinical presentation being highly heterogenous, with both length- and non-length-dependent clinical patterns being observed (Figure 1). Dr Karlsson further highlighted the difficulties around this disease by presenting a plethora of potential symptom combinations and causes. However, some clarity can be achieved from the fact that 1 in 3 patients with SFN have a metabolic disease, such as diabetes, as the causative factor.
Later in the presentation, Dr Karlsson demonstrated the shortcomings only using clinical examinations in the SFN diagnosis in a diabetic patient population2,3 (Dyck 2010 and 2013). Indeed, the diagnostic accuracy is only around 60%.1 These clinical techniques include both conventional bedside sensory tests and neurophysiological and pathological approaches. Dr Karlsson communicated his concern that the clinical diagnostic tool box could be getting too big for consistently reproducible diagnostic results to be achieved.

Figure 1.1 Adapted from Terkelsen AJ & Karlsson P. 2017. (A) Patients with typical length-dependent polyneuropathy and (B) patchy non-length-dependent neuropathy
Discussion
There were interesting discussion points brought up by the audience in both the morning and afternoon sessions following the presentation. One of these was regarding stained skin biopsy data, which is considered the gold standard in diagnosis, with around 85% diagnostic accuracy. These biopsy stains, taken from diabetic peripheral neuropathy patients, showed stronger signals for pain biomarkers, substance P and calcitonin gene-related peptide positive nerve fibres. Interestingly, these biopsies were collected from the standardised distal lower leg position, independent of whether or not this location had SFN symptoms. Dr Karlsson went onto to explain that his team observed large interpatient variations in these stains as well as in the immunostainings used to measure nerve fibre density. These variations could potentially be explained by differences in the intensity of symptoms seen between patients in the standardised biopsy location, but this cannot be substantiated. This led onto the enquiry of whether it may be more optimal to first screen the patient for the location of the most intense symptom area and then use this area instead for the biopsy. Dr Karlsson mentioned that this could be a beneficial approach, however it could involve taking biopsies from highly varied body parts, which is far from optimal.
A later discussion point was regarding further imagery data showing axonal swelling, which unlike nerve fibre density, is thought be a measure of neuropathic pain. Dr Karlsson mentioned that he believes that their publication that is currently under preparation shows that there is significantly greater axonal swelling in patients with diabetes, irrespective of neuropathic or pain status compared with healthy controls. He goes on to hypothesise that these axonal swellings could therefore be the earliest signs of degenerating or disease in small nerve fibres.
The biggest need for patients with SFN at the current moment was one of the final topics enquired about during the discussion. A need for a diagnosis in these patients was highlighted because without this, patients end up moving around GPs and specialists without recognition of their painful symptoms. Furthermore, the lack of mechanism-based treatment means that there are suboptimal treatment options currently available for patients with SFN. This can force patients to move between treatment options without achieving effective analgesic benefits.
References
- Terkelsen AJ & Karlsson P, et al. Lancet Neurol. 2017;16:423–439
- Dyck PJ, et al. Muscle Nerve. 2010;42(2):157–164
- Dyck PJ, et al. Diabetes. 2013;62(11):3677–3686