Diagnostic Criteria for Small Fibre Neuropathy in Clinical Practice and Research

Grazia Devigili; Sara Rinaldo; Raffaella Lombardi; Daniele Cazzato; Margherita Marchi; Erika Salvi; Roberto Eleopra; Giuseppe Lauria


Brain. 2019;142(12):3728-3736. 

In This Article

Abstract and Introduction


The diagnostic criteria for small fibre neuropathy are not established, influencing the approach to patients in clinical practice, their access to disease-modifying and symptomatic treatments, the use of healthcare resources, and the design of clinical trials. To address these issues, we performed a reappraisal study of 150 patients with sensory neuropathy and a prospective and follow-up validation study of 352 new subjects with suspected sensory neuropathy. Small fibre neuropathy diagnostic criteria were based on deep clinical phenotyping, quantitative sensory testing (QST) and intraepidermal nerve fibre density (IENFD). Small fibre neuropathy was ruled out in 5 of 150 patients (3.3%) of the reappraisal study. Small fibre neuropathy was diagnosed at baseline of the validation study in 149 of 352 patients (42.4%) based on the combination between two clinical signs and abnormal QST and IENFD (69.1%), abnormal QST alone (5.4%), or abnormal IENFD alone (20.1%). Eight patients (5.4%) had abnormal QST and IENFD but no clinical signs. Further, 38 patients complained of sensory symptoms but showed no clinical signs. Of those, 34 (89.4%) had normal QST and IENFD, 4 (10.5%) had abnormal QST and normal IENFD, and none had abnormal IENFD alone. At 18-month follow-up, 19 of them (56%) reported the complete recovery of symptoms and showed normal clinical, QST and IENFD findings. None of those with one single abnormal test (QST or IENFD) developed clinical signs or showed abnormal findings on the other test. Conversely, all eight patients with abnormal QST and IENFD at baseline developed clinical signs at follow-up. The combination of clinical signs and abnormal QST and/or IENFD findings can more reliably lead to the diagnosis of small fibre neuropathy than the combination of abnormal QST and IENFD findings in the absence of clinical signs. Sensory symptoms alone should not be considered a reliable screening feature. Our findings demonstrate that the combined clinical, functional and structural approach to the diagnosis of small fibre neuropathy is reliable and relevant both for clinical practice and clinical trial design.


Small fibre neuropathy (SFN) is a sensory, typically painful, disease of thin myelinated and unmyelinated nerve fibres. It occurs early in the course of several systemic illnesses such as diabetes, amyloidosis and connective tissue disorders, can be genetically determined or idiopathic (Cazzato and Lauria, 2017), and is a model to investigate the efficacy of new targeted analgesics (Eijkenboom et al., 2019b). The somatic compartment of this class of fibres conveys thermosensation, nociception and itch from cutaneous fields through sensory peripheral nerves to the dorsal horns in a hierarchical fashion determined by molecular-driven coding of sensory neurons (Lallemend and Ernfors, 2012; LaMotte et al., 2014; Lou et al., 2015). Distinct molecular profiles have been identified as key for the neurogenesis of nociceptors (Bartesaghi et al., 2019) and axon ending targeting to the ectodermic or mesodermic/endodermic tissues (Yang et al., 2013). Thus, phylogenetically conserved peripheral signalling such as thermosensation and nociception are conveyed towards the integrative brain areas through a complex class of nerve fibres whose function is driven by precise molecular ontogenesis.

Somatic and autonomic functional assessment of small nerve fibres is achieved by assaying the psychophysical sensory thresholds (e.g. cold, heat) by quantitative sensory testing (QST), pain-related and laser evoked potential recording, single axon recording using microneurography and tests encompassing sympathetic and parasympathetic autonomic functions (Terkelsen et al., 2017). Their structural assessment relies on skin biopsy and corneal confocal microscopy. The first combines quantification of intraepidermal nerve fibre density (IENFD), dermal nerve bundles, and autonomic organ innervation with analysis of pain-related receptors and myelin protein expression, and has become a routine method (Lauria et al., 2004, 2006, 2011; Lauria and Lombardi, 2007; Provitera et al., 2007; Zhao et al., 2008; Gibbons et al., 2009; Nolano et al., 2010). The second provides various morphometric parameters to quantify corneal nociceptors and their changes over time, and is currently mostly applied in research (Kalteniece et al., 2018; Petropoulos et al., 2019). Overall, these techniques have replaced sensory nerve biopsy that, although it allows identification of small nerve fibres enwrapped into Remak bundles in semi-thin sections, and their ultrastructural quantification, it cannot differentiate afferent and efferent autonomic from somatic axons and is much more invasive (Sommer, 2018).

Despite the advances allowed by new techniques, the diagnostic criteria for SFN are yet to be fully established (Terkelsen et al., 2017). This limitation has several implications both for clinical practice in terms of correct access of patients to treatments and research for the definition of entry criteria in trials. However, it does not arise from the lack of knowledge on the diagnostic performance of tests for small nerve fibre functioning or morphometric assay, but rather from how their combination meets the diagnostic requirements for individual patients at the clinical level. Indeed, abnormal findings in some small nerve fibre-related tests, such as skin biopsy, QST or laser-evoked potentials can occur in painful clinical conditions irrespective of the localization, nature and aetiology of pain (Devigili et al., 2008; Backonja et al., 2013; Terkelsen et al., 2017; Uceyler et al., 2018) and even in painless neuropathies or systemic diseases (Nolano et al., 2001, 2008; Bennett and Woods, 2014; Dalla Bella et al., 2016; Marchi et al., 2018). In such a frame, patients' symptoms and signs of small nerve fibre dysfunction are crucial to the reliable interpretation of the findings obtained by the diagnostic tests.

In the past decade, two sets of diagnostic criteria have been proposed. The first (Besta criteria) (Devigili et al., 2008) is based on the combination of at least two abnormal findings of the following: (i) clinical signs of small fibre impairment (pinprick and thermal sensory loss and/or allodynia and/or hyperalgesia); (ii) abnormal warm or cold thresholds, or both, at the foot as assessed by QST; and (iii) reduced IENFD at the distal leg. Exclusion criteria were any clinical sign of large fibre impairment (e.g. light touch and vibratory sensation, deep tendon reflexes, limb or gait ataxia) and any abnormality at nerve conduction studies (NCSs). The second, within the revised guideline of the Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) (Tesfaye et al., 2010) based on a grading as: (i) possible, if symptoms or clinical signs of small fibre damage, or both; (ii) probable, if clinical signs of small fibre damage, and normal sural NCS; and (iii) definite, if clinical signs of small fibre damage, normal sural NCS, and abnormal QST thresholds at the foot or reduced IENFD at the ankle, or both. The NEURODIAB criteria do not require specification of the clinical signs of small fibre damage.

Our study aimed to address three key questions: (i) the agreement between the two proposed criteria; (ii) the weight of each of the three main components of the proposed criteria, i.e. symptoms and signs (clinical), QST (functional), and IENFD (structural); and (iii) the most reliable approach to individual patients suspected to have SFN. To this end, based on the comparison between the NEURODIAB and Besta criteria, we performed a reappraisal study of a cohort of sensory neuropathy patients (Devigili et al., 2008), analysed how patients were reclassified, and conducted a prospective and follow-up validation study on a new large cohort of patients to confirm the reliability of the diagnostic criteria.