Small fiber neuropathy: a common and important clinical disorder

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Abstract

Small fiber neuropathy (SFN) is a neuropathy selectively involving small diameter myelinated and unmyelinated nerve fibers. Interest in this disorder has considerably increased during the past few years. It is often idiopathic and typically presents with peripheral pain and/or symptoms of autonomic dysfunction. Diagnosis is made on the basis of the clinical features, normal nerve conduction studies (NCS) and abnormal specialized tests of small nerve fibers. Among others, these tests include assessment of epidermal nerve fiber density, temperature sensation tests for sensory fibers and sudomotor and cardiovagal testing (QSART) for autonomic fibers. Unless an underlying disease is identified, treatment is usually symptomatic and directed towards alleviation of neuropathic pain.

Introduction

Peripheral neuropathy can be categorized based on the function of the involved nerve fibers or on their diameter and conduction velocity. Regarding the functions of different nerve fibers, three types of peripheral nerve fibers can be distinguished: somatic motor fibers, somatic sensory fibers and autonomic fibers. Sensory functions include sensation for touch, vibration, temperature and pain. Autonomic functions include sweating, bowel movements, lacrimation, sexual functions, blood pressure and heart rate variability. Based on size, large diameter myelinated (A-alpha and A-beta), medium size myelinated (A-gamma), small diameter myelinated (A-delta) and unmyelinated (C) nerve fibers can be distinguished. A-alpha and A-beta nerve fibers carry motor functions, vibration sense and touch. A-gamma fibers carry motor function to muscle spindles. A-delta fibers and C-fibers carry temperature and pain sensation and autonomic functions. Small fiber neuropathies (SFN) preferentially affect small-calibre myelinated and unmyelinated fibers, leaving the larger myelinated fibers relatively unaffected.

Routine electrodiagnostic studies, which primarily test large myelinated fiber function, are mostly normal in these patients [1], [2], [3]. Therefore, the syndrome of SFN has been an enigma to practitioners because of the unexplained contrast between severe pain in the extremities and a paucity of neurological and electrophysiological findings. Recent advantages in diagnostic techniques (temperature threshold testing (TTT), intra-epidermal nerve fiber density (IENFD) assessment in skin biopsy) facilitate objective confirmation of clinical diagnosis and the characterization of fiber type involvement in SFN [4], [5]. This paper reviews clinical features, diagnostic tests and underlying diseases. Furthermore, opportunities for future therapeutic as well as pathogenesis studies are discussed.

Section snippets

Clinical features

Though relatively few detailed descriptions of the clinical features have been published [1], [2], [3], [6], [7], the clinical syndrome is a relatively stereotypical distinctive syndrome (Table 1). Small fiber dysfunction can be defined as a generalised peripheral neuropathy in which the small diameter myelinated and unmyelinated nerve fibers are affected, either exclusively or to a much greater degree than the large diameter myelinated fibers [8]. Although this definition is adequate for a

Diagnostic tests

NCS and EMG, which are key in the evaluation of other (large fiber) neuropathies, are generally normal in patients with SFN [15]. However, recent advantages in diagnostic tests have facilitated confirmation of the clinical diagnosis of SFN. Nevertheless, a fundamental problem in evaluating diagnostic tests for SFN is that a gold standard for the disorder is lacking. Furthermore, in many patients, functionally different small fiber systems are affected selectively. In order to diagnose SFN and

Pathogenesis and etiology

In some cases SFN is part of an underlying disease (Table 2). However, no specific etiology is identified for the majority of SFN patients encountered in neurology practice, especially in the elderly (in up to 93%) [22]. Only case reports are published of most causes; therefore, the frequencies of the different causes are not known. The neuropathology has remained largely unexplored. However, there is some support for a role of ischaemia, cytokines and oxidative stress:

Natural course and prognosis

Longitudinal natural history studies are not available to date. From follow-up, it is known that at least some patients evolve from a strict SFN to large fiber sensory neuropathy [22], [104]. In our experience, the progression of SFN seems to be slow, and although pain and autonomic dysfunction are troublesome symptoms, patients seem not to become physically disabled. Spontaneous remission sometimes occurs [1]. Tobin et al. [23] found that about one-third of their patients with idiopathic SFN

Therapy

Unless an identifiable treatable cause (see Table 2) is found, the management of SFN usually centers upon the treatment of neuropathic pain [7], [114]. Literature regarding painful neuropathies can be divided into three groups: diabetic neuropathies (the most extensively studied pathological condition), HIV-related neuropathies and remaining neuropathies. There appears to be an important difference in HIV-related neuropathy on one hand and diabetic and remaining neuropathies on the other hand;

Conclusions

SFN is a relatively common disorder resulting in severe and troublesome symptoms, which may be difficult to control. Standard electrophysiological tests such as nerve conduction studies and EMG remain normal in SFN. Therefore, the syndrome may easily be overlooked. Whether patients with SFN are at risk for sudden life threatening arrhythmias when they develop cardiac denervation is unknown and needs further study. Future studies regarding pathophysiology and treatment are warranted as well. As

Acknowledgements

We thank I.N. van Schaik and N.R. Rosenberg for providing data of the diagnostic value of skin biopsy in small fiber neuropathy.

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