Therapath Neuropathology

Small Fiber Neuropathy in Rheumatological Disorders

Patients with rheumatological disorders can present with a variety of syndromes that can result from Small Fiber Neuropathy (SFN). These include musculoskeletal pain (Gemignani, 2014), muscle cramps (Lopate, Streif, Harms, Weihl, & Pestronk, 2013), fasciculations (Tzatha & Chin, 2014), widespread unexplained pain (Oaklander & Klein, 2013), reflex sympathetic dystrophy/complex regional pain syndrome (Oaklander & Fields, 2009), burning paresthesias, and autonomic instability including orthostatic hypotension, postural tachycardia, or gastrointestinal dysmotility (Gibbons, 2014; Haensch, Tosch, Katona, Weis, & Isenmann, 2014).

Several recent studies found that approximately 50% of fibromyalgia patients had reduced Epidermal Nerve Fiber Density (ENFD), consistent with SFN (Caro & Winter, 2014; Gemignani, 2014; Giannoccaro, Donadio, Incensi, Avoni, & Liguori, 2014; Kosmidis et al., 2014; Oaklander, Herzog, Downs, & Klein, 2013; Üçeyler et al., 2013). In the study by Kosmidis et al. (2014), SFN was also found in patients with fibromyalgia and other concomitant rheumatologic disorders.

Biopsy procedure guide

In Sjögren’s syndrome, Fauchais et al. (2011) reported that approximately 40% of patients experienced neuropathic pain with normal electrodiagnostic studies, due to SFN. Chai et al. (Chai, Herrmann, Stanton, Barbano, & Logigian, 2005) reported that 80% of patients with Sjögren’s syndrome and neuropathy presented with burning feet, and 60% had symptoms in a multifocal or non-length dependent pattern. Sene et al. (2013) reported that patients with Sjögren’s syndrome associated neuropathy are characterized by older age at diagnosis and lower frequency of serum B-cell activation markers.

In systemic lupus erythematosus (SLE), Oomatia et al. (Oomatia, Fang, Petri, & Birnbaum, 2014) found that the prevalence of peripheral neuropathy in patients with SLE was 5.9%, with 17% exhibiting a painful SFN in a pattern consistent with dorsal root ganglionopathy and distal axonopathy. Birnbaum et al. (Birnbaum & Bingham, 2014) also reported that SFN can occur in patients with rheumatoid arthritis as a complication of TNF-inhibitor therapy.

SFN can also be associated with sarcoidosis (Bakkers et al., 2010; Hoitsma et al., 2002), and has been implicated in the Gulf War veteran syndrome (Li et al., 2014). Patients with Ehlers-Danlos hypermobility syndrome also have been reported to exhibit symptoms of neuropathic pain (Camerota, Celletti, Castori, Grammatico, & Padua, 2011; Voermans, Knoop, & van Engelen, 2011) or autonomic instability (De Wandele et al., 2014).

Making a diagnosis of SFN is important, as it enables the physician to explain the symptoms to their patients, direct testing for possible contributory causes, and decide on appropriate treatment. Bakkers et al. (Bakkers, Faber, Hoeijmakers, Lauria, & Merkies, 2014) evaluated a total of 265 patients diagnosed with SFN, and found that it was associated with a severe impairment in quality of life. Schaefer et al. (2014), in a study of 100 patients, reported that SFN negatively impacts health status, function, and productivity and leads to substantial direct and indirect costs. Boruchow et al. (Boruchow & Gibbons, 2013) examined the role of skin biopsy in the evaluation and management of patients with suspected SFN. A change in management or diagnosis occurred in 14 of 25 patients with definite SFN, 6 of 9 patients with borderline SFN, and 16 of 35 biopsy negative patients. They concluded that skin biopsy played a valuable role in the workup of these patients.

SFN is diagnosed by punch skin biopsy with enumeration of the density of the small sensory nerve fibers in the epidermis and of the small autonomic fibers in the sweat glands. The standard test is the Epidermal Nerve Fiber Density (ENFD), but in those with normal ENFD, determination of the Sweat Gland Nerve Fiber Density increases the diagnostic yield by 18% to 29% (Hays, Hays, Whitehouse, & Harrington, 2011; Weaver, Kim, Carey, Langsdorf, & Chin, 2013).