Updates & Features
Diagnostic Challenges of Small Fibre Neuropathy
What current research is being conducted to overcome the diagnostic challenges of small fibre neuropathy?
Prof. Páll Karlsson, Aarhus University Hospital
Small fibre neuropathy (SFN) has until recently been a neglected subgroup among patients with neuropathy. SFN has a major impact on quality of life because of the underlying disease and the symptoms. SFN constitutes a heterogeneous group of neuropathies in which there is a selective or predominant damage or dysfunction of the thinly myelinated Aδ-fibres and/or unmyelinated C-fibres. Clinically, the patient usually presents with positive and negative symptoms due to small fibre dysfunction and in some cases cardiovascular, gastrointestinal and urogenital dysfunction due to affection of small fibres innervating these organs.
Causes of SFN
There are multiple possible causes of SFN: metabolic, exposure to neurotoxins, vitamin intoxication, infections, immunological and hereditary.1 However, in up to 50% of cases the underlying cause is unknown.1,2 There have been advances in our understanding of SFN, but classification is difficult due to its features and natural history; larger nerve fibres may also be involved, several of the tests used to identify SFN are time-consuming, require specific expertise, and are limited to specialist centres, loss of all fibres are not specific to SFN and may be due to causes other than neuropathy.
No gold standard for diagnosis of SFN
The diagnosis of SFN is a challenge because there is no clinically established gold standard to demonstrate such nerve fibre involvement. The diagnostic process of patients with suspected SFN involves questionnaires, clinical features and examination and a series of diagnostic tests. Not all the diagnostic method results are abnormal in each patient, which makes it difficult to construct clear guidelines for a diagnostic algorithm for SFN. Nevertheless, diagnostic criteria for SFN have previously been proposed, using a combination of intraepidermal nerve fibre density (IENFD) by skin punch biopsy, quantitative sensory testing and clinical examination.3
Recently, a new diagnostic approach for the investigation of distal polyneuropathy and SFN was proposed (Figure 1).1 The proposal starts with a clinical history to support the diagnosis of possible distal neuropathy, followed by a bedside examination to reveal presence of sensory dysfunction and finally nerve conduction studies (NCS) to examine the large nerve fibres. If the NCS is abnormal, the patient has clinically confirmed large fibre neuropathy (LFN) and no further examination is needed. If, however, the NCS is normal, examination of the small nerve fibres by taking a skin biopsy and/or performing a functional test of the small fibres is required. If these tests are abnormal the patient has clinically confirmed SFN, but if these also are normal, the patient does not have neuropathy.
Figure 1.1 Proposed diagnostic approach to the investigation of distal polyneuropathy. IENFD: Intraepidermal nerve fibre density; QSART: Quantitative sudomotor axon reflex testing; QDIRT: Quantitative direct and indirect testing of sudomotor function; QST: Quantitative sensory testing. *If structural and functional tests for an SFN are abnormal, the diagnosis is a clinically confirmed mixed large and small fibre neuropathy
Large vs small fibre neuropathy
In the peripheral nervous system, different nerve fibres subserve somatic, autonomic, and motor functions. Normally, these fibres are classified by their degree of myelination and the sensory nerve fibres include small fibres, that are thinly myelinated (Aδ) or unmyelinated (C) and myelinated large fibres (Aβ). Table 1 summarises the main function, perception, and velocity of each subtype. SFN is a condition that selectively affects fibres of small calibre, namely the C- and Aδ fibres, while large fibres are damaged in LFN. However, it is common that both fibre types are involved, and neuropathy can either be pain-free or painful, thus making diagnosis difficult.
|Fibre (type)||Properties||Velocity (m/s)||Function||Perception|
|Aδ (small)||Myelinated||5-30||Pain (pinprick)
Temperature (cold threshold)
|C (small)||Unmyelinated||<1||Pain (Temperature/ pressure/chemical)||Dull
Table 1. Major classification of nerve fibres and their properties, velocity, function and perception.
Small and large fibres have different functions, making the signs and symptoms of SFN and LFN distinct. SFN is dominated by pain (often described as burning, pricking or electric), loss of temperature, touch and pressure sensation and in some cases autonomic dysfunction. Whilst LFN manifests with weakness, muscle wasting, loss of joint position and vibration sense, poorly localizable numbness and sensory ataxia. Abnormal deep-tendon reflexes and large-fibre sensory function are also signs of LFN. Patients with diseased small fibres typically complain of deep-localised pain and numbness, spontaneous pain, allodynia (pain due to a stimulus that does not normally provoke pain), and/or hyperalgesia (increased pain from a stimulus that normally provokes pain).
Distal vs non-length-dependent generalised SFN
The clinical presentation of SFN is heterogeneous, but the two distinct clinical entities are a distal length-dependent4 and a generalised non-length-dependent type5. Length-dependent SFN classically presents with neuropathic pain in the feet (burning feet). Damage to distal autonomic nerve fibres may induce distal anhidrosis, changes in skin color and temperature and trophic changes with dry, shiny, atrophic, or discolored hands and feet. The patients usually develop symptoms in the toes and feet gradually progressing to involve the distal legs, fingertips, and hands. This traditional distal pattern is often associated with a decreased IENFD of unmyelinated nerves at the distal leg in approximately 85% of the cases3. In contrast, the second entity that has been termed as a non-length-dependent SFN, patients experience atypical patterns of sensory disturbances in a patchy pattern that can affect the face, tongue, scalp, upper limb or trunk before the lower limb or the latter may be affected simultaneously. Patients may experience: abdominal pain, early satiety, bloating, nausea, vomiting and alternating constipation with diarrhea as evidence of gastric and bowel paresis.
Painful vs pain-free SFN
While all SFN patients have symptoms, such as sensory disturbances, not all patients suffer from neuropathic pain. Neuropathic pain is a major clinical problem, but the underlying mechanisms are not known in details and it remains unclear why some neuropathic patients develop pain while others do not.6 Therefore, it is not surprising that the literature reports that treatment of neuropathic pain remains unsatisfactory; on average there is a minimum 50% pain reduction.
SFN Research priorities
As suggested by Terkelsen and colleagues, there is an urgent need for a gold standard for the diagnosis of SFN and development of diagnostic biomarkers.1 Additionally, it is unknown how sensory neurons or small fibres develop or maintain neuropathic pain. An important research field for SFN is for example the study of molecular changes in ion channels and receptors expressed on sensory nerve fibres.
- Terkelsen A, et al. Lancet Neurology 2017; 16: 934-944
- Farhad K, et al. Muscle Nerve 2016; 53: 856–61
- Devigili G, et al. Brain 2008; 131: 1912–25
- Stewart JD, et al. Muscle Nerve 1992; 15: 661-5
- Khan S, et al. Muscle Nerve 2012; 45: 86–91
- Jensen TS, et al. Curr Opin Support Palliat Care 2007; 1: 126-31