European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society

Abstract

Revision of the guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy, published in 2005, has become appropriate due to publication of more relevant papers. Most of the new studies focused on small fiber neuropathy (SFN), a subtype of neuropathy for which the diagnosis was first developed through skin biopsy examination. This revision focuses on the use of this technique to diagnose SFN. Task force members searched the Medline database from 2005, the year of the publication of the first EFNS guideline, to June 30(th), 2009. All pertinent papers were rated according to the EFNS and PNS guidance. After a consensus meeting, the task force members created a manuscript that was subsequently revised by two experts (JML and JVS) in the field of peripheral neuropathy and clinical neurophysiology, who were not previously involved in the use of skin biopsy. Distal leg skin biopsy with quantification of the linear density of intraepidermal nerve fibers (IENF), using generally agreed upon counting rules, is a reliable and efficient technique to assess the diagnosis of SFN (level A recommendation). Normative reference values are available for bright-field immunohistochemistry (level A recommendation) but not yet for confocal immunofluorescence or the blister technique. The morphometric analysis of IENF density, either performed with bright-field or immunofluorescence microscopy, should always refer to normative values matched for age (level A recommendation). Newly established laboratories should undergo adequate training in a well established skin biopsy laboratory and provide their own stratified age and gender-matched normative values, intra- and interobserver reliability, and interlaboratory agreement. Quality control of the procedure at all levels is mandatory (Good Practice Point). Procedures to quantify subepidermal nerve fibers and autonomic innervated structures, including erector pili muscles, and skin vessels are under development but need to be confirmed by further studies. Sweat gland innervation can be examined using an unbiased stereologic technique recently proposed (level B recommendation). A reduced IENF density is associated with the risk of developing neuropathic pain (level B recommendation), but it does not correlate with its intensity. Serial skin biopsies might be useful for detecting early changes of IENF density, which predict the progression of neuropathy, and to assess degeneration and regeneration of IENF (level C recommendation). However, further studies are warranted to confirm the potential usefulness of skin biopsy with measurement of IENF density as an outcome measure in clinical practice and research. Skin biopsy has not so far been useful for identifying the etiology of SFN. Finally, we emphasize that 3-mm skin biopsy at the ankle is a safe procedure based on the experience of 10 laboratories reporting absence of serious side effects in approximately 35,000 biopsies and a mere 0.19% incidence of non-serious side effects in about 15 years of practice (Good Practice P...

Impairment of small somatic and autonomic nerve fibres in intensive care unit patients with severe sepsis and critical illness polyneuropathy – a single center controlled observational study

“…Skin biopsies have become a valuable tool in the evaluation of patients with neuropathy [19] with good evidence of reliable normative data [25]. Detection of an impairment of small nerve fibers in sepsis may give further insights into the pathophysiological role of autonomic neuropathy in patients with severe sepsis/septic shock [12].…”

“…Its minimal invasiveness makes skin biopsy a useful tool in clinical practice for diagnosing and monitoring the progression of peripheral nerve damage. Intraepidermal nerve fibres (IENFs) can be labelled with antibodies against protein gene product (PGP) 9.5 [18,19]. The innervation of dermal autonomic structures (sweat glands, blood vessels, hair follicles) can be detected using antibodies against adrenergic, noradrenergic, cholinergic, and vasodilatatory peptidergic fibres [20].…”

“…Quantification of IENF density closely correlates with clinical symptoms and is more sensitive than sensory nerve conduction studies and sural nerve biopsies in diagnosing small fibre neuropathy. Diagnostic efficiency and predictive values of this technique are very high (level A recommendation) [18,19]. …”

Influence of Mitochondrial Genetics on the Mitochondrial Toxicity of Linezolid in Blood Cells and Skin Nerve Fibers

“…Intraepidermal nerve fiber density (IENFD) was measured, and axonal swellings were counted (magnification, ϫ40) (BristolMyers-Squibb, Germany) by bright-light microscopy after staining with the panaxonal antibody PGP 9.5 (diluted 1:800; AbD Serotec, Oxford, United Kingdom), by following the free-floating protocol (40)(41)(42). Three random skin sections (43) were analyzed, and a 1.5-m-long marker was used to check the swelling diameters (30).…”

Tracking Epidermal Nerve Fiber Changes in Asian Macaques

“…Similarly, morphologic examination of peripheral nerve tissue, such as the sural or sciatic nerves, may not reflect early changes to small fibers that may begin in distal regions (Herrmann et al , 1999). In recent years, visualization and assessment of epidermal nerve fibers (ENF) in skin biopsies has become a standard clinical tool to diagnose SFN caused by a wide variety of conditions (Ebenezer et al , 2007, Lauria et al , 2010). Unlike quantitative sensory testing that relies on patient responses and is subject to bias (Hlubocky et al , 2009), ENF analysis is objective and can be applied to animal models (Lauria et al , 2005).…”