New diagnostic approach to the identification of small fibre neuropathy

New diagnostic approach to the identification of small fibre neuropathy -

A recent review by Danish Diabetes Academy Post Doc Páll Karlsson is picked out as editor's choice in the November 2017 issue of the Lancet Neurology. The review describes the clinical presentations of small fibre neuropathy and its causes, and presents a strategy for clinical examination.

Up to 50% of diabetic patients develop distal sensory neuropathy, where both myelinated and small unmyelinated nerve fibres are affected. In this comprehensive review, the authors focus on small nerve fibres, which include peripheral afferent unmyelinated C-fibres and thinly myelinated small Aδ-fibres. In the somatosensory nervous system, these fibres transmit information about temperature, pain, and itch, and in the autonomic nervous system, they mediate sudomotor, thermoregulatory, cardiovascular, gastrointestinal, urogenital, and other autonomic functions. Damage to the peripheral nervous system affecting small fibres in a neuropathic distribution is termed small fibre neuropathy (SFN); however, there is no gold standard for the diagnosis of SFN. 


The clinical presentation of SFN is heterogeneous, with no single clinical pattern fitting all presentations. However, one of the most common presentations is a length-dependent polyneuropathy, which can either be painful (neuropathic pain in the feet, e.g. burning pain) or pain free, with absent or reduced pain and temperature sensation. Signs and symptoms ascend from the distal extremities (toes and feet) to the ankles and even above the knees. Once symptoms reach the knee, the upper limbs can become involved. This distal-to-proximal gradient is often seen in patients with impaired glucose intolerance or diabetes. 

This comprehensive review touches many important aspects of SFN, including clinical assessment (questionnaires and clinical examination tools), pathological examination (nerve and skin biopsy), test of sudomotor function and corneal confocal microscopy, as well as the many causes of SFN (where diabetes is the most common cause, responsible for 1/3 of all SFN cases), biochemical markers and last but not least, diagnostic criteria. 


The review aims to help clinicians in assessing the small fibres and proposes a diagnostic approach to the identification of SFN. The diagnostic approach should be systematic; thus, clinical history and examination are the essential first steps in the process. The patient´s history may lead to “possible neuropathy” and different examination may lead to “probable neuropathy” or “clinically confirmed SFN” or “clinically confirmed large fibre neuropathy”. The review proposes that at least one abnormal neurophysiological or structural measure (ie, abnormal intraepidermal nerve fibre density) is required for a clinically confirmed diagnosis of SFN. 


Lastly, the review suggests different important research priorities for SFN. These include a gold standard for the diagnosis of SFN, identification of diagnostic biomarkers and a better understanding of how and why some patients develop neuropathic pain. 


Astrid Terkelsen1,2*, Pall Karlsson1,2*, Giuseppe Lauria3,4, Roy Freeman5, Nanna Finnerup,1,2 Troels Staehelin Jensen1,2
* = Shared first authorship 

1Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
2Danish Pain Research Center, Aarhus University, Aarhus, Denmark
33rd Neurology Unit and Skin Biopsy Peripheral Neuropathy and Neuropathic Pain Centre, Carlo Besta Neurological Institute, IRCCS Foundation, Milan, Italy
4Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, Milan, Italy
5Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Harvard Medical School, MA, USA

Source: The Lancet Neurology