There is no consensus on a gold standard test to diagnose small fiber sensory peripheral neuropathy. Diagnostic criteria have been proposed (Botez and Herrmann 2008; Devigili et al 2008). When there is reasonable suspicion for peripheral sensory dysfunction, electrodiagnostic studies can exclude large fiber sensory neuropathy. Electrodiagnostic testing assesses large nerve fibers and is typically normal in isolated small fiber sensory peripheral neuropathy. Some patients and clinicians are unsettled by a presumptive small fiber sensory peripheral neuropathy diagnosis based solely on history, clinical examination, and normal laboratory studies. Further confirmation is possible using skin biopsy for intraepidermal nerve fiber density evaluation. Normative reference values are available stratified by decade of life (Lauria et al 2010).
The concept of diabetic small fiber sensory peripheral neuropathy is not new (Brown et al 1976), and it was further advanced with the advent of pan-axonal marker PGP 9.5, which allows for staining and quantification of intraepidermal nerve fiber density on skin biopsies (Levy et al 1992). A minimally invasive procedure, punch skin biopsy may confirm small fiber sensory peripheral neuropathy when electrodiagnostic testing is normal (England et al 2009). Two or 3 standardized biopsy sites may reveal reduced intraepidermal nerve fiber density and/or morphological changes such as axonal swellings and increased branching/sprouting (Wendelschafer-Crabb et al 2006; Lauria and Devigili 2007). Reduced intraepidermal nerve fiber density is not exclusive to small fiber sensory peripheral neuropathy, and, in fact, most large fiber peripheral neuropathy patients have both small and large diameter nerve fiber involvement. Therefore, skin biopsies for patients with large fiber peripheral neuropathy identified on electrodiagnostic testing may not be clinically necessary. Some genetic disorders with large nerve fiber dysfunction such as Charcot-Marie-Tooth disease and spinobulbar muscular atrophy (Kennedy disease) also reveal reduced intraepidermal nerve fiber density, but these patients have overt large fiber dysfunction. Occasionally Congo red staining may demonstrate amyloid deposits in skin biopsy samples.
Thermal and vibratory thresholds obtained with quantitative sensory testing can be useful, but they cannot distinguish sensory dysfunction of CNS origin from peripheral nervous system localization and are usually secondary forms of testing. Furthermore, quantitative sensory testing is a psychophysical test that hampers routine clinical use; however, the test is helpful in tracking individuals over time for research purposes (Freeman et al 2003). Quantitative sensory testing should not be used as the sole diagnostic test for small fiber sensory peripheral neuropathy, although it may be useful in conjunction with other tests, particularly in research settings.
A more objective ancillary test with thermal stimulation is the promising, but still experimental, contact heat evoked potential stimulation (CHEPS) (Wong and Chung 2011). CHEPS may be as good as or better than epidermal nerve fiber density in patients with small fiber neuropathy (Smith 2012, abstract presented at the AAN 2012 Annual Meeting).
Autonomic testing may be abnormal in small fiber sensory peripheral neuropathy patients, even in the absence of overt autonomic dysfunction. A battery of autonomic tests may be considered in patients with small fiber sensory peripheral neuropathy (England et al 2009). The most sensitive tests are the thermoregulatory sweat test and the quantitative sudomotor axon reflex test (QSART). The thermoregulatory sweat test is only available in a few specialized centers. The test requires patients to be sprinkled with alizarin red powder and warmed up in a temperature-controlled room to induce sweating, which changes the marker powder color, identifying sweating patterns. QSART testing correlates moderately well with skin biopsy measures in this patient population. Sympathetic skin response and heart rate variability with deep breathing are simple tests that can be performed using routine electrodiagnostic testing equipment, but both have lower sensitivity.
Cutaneous silent period, a relatively simple neurophysiologic test, may be more sensitive to detect small fiber neuropathy than sympathetic skin response and heart rate variability (Koytak et al 2011).
Other autonomic tests such as the axon reflex flare test and laser evoked potentials may correlate with intraepidermal nerve fiber density, but are less reliable. The use of stimulated skin wrinkling tests with water immersion or with topical anesthetics procaine and lidocaine are interesting, but not established alternatives to intraepidermal nerve fiber density assessment (Wilder-Smith et al 2009). The silastic mold sweat imprint test allows quantification of skin sweat (Kennedy and Navarro 1989) and has similar sensitivity to QSART. In vivo quantification of sweat glands using optical coherence tomography was recently described by our group. Additional diagnostic tests used in research and academic settings include laser Doppler imager flare technique, acetylcholine iontophoresis, and in vivo imaging of corneal small nerve fibers with confocal microscopy (Messmer et al 2010). There has been recent interest in in vivo confocal microscopy for assessment of corneal nerve fibers in patients with diabetic peripheral neuropathy (Smith et al 2012, abstract presented at the AAN 2012 Annual Meeting).
Associated conditions may be identified in up to 50% of small fiber sensory peripheral neuropathy cases, with important treatment implications; however, identification of an underlying cause is lower than with other forms of peripheral neuropathy. A significant number of patients remain idiopathic, but diabetes mellitus is common (De Sousa et al 2006). The American Diabetes Association recommends laboratory screening for diabetes mellitus or prediabetes (relabeled “at risk for diabetes”) with fasting glucose, hemoglobin A1C (glycohemoglobin), or a 2-hour oral glucose tolerance test (American Diabetes Association 2010). Other lab work includes evaluation for hypothyroidism (TSH with reflex free T4); nutritional factors (serum vitamins B1, B6, B12); inflammatory, rheumatological, or vasculitic causes (antinuclear antibody and extractible nuclear antigen panel); sarcoidosis (serum angiotensin converting enzyme level); M-protein (serum immunoelectrophoresis with immunofixation); serum cryoglobulins; and Sjogren antibodies anti-Ro/SSA and anti-La/SSB, which are part of the extractible nuclear antigen antibody panel.
In the appropriate clinical context, evaluation for hanseniasis with search for acid-fast bacilli may be conducted in suspected tissues. Other tests for infectious causes include serum HIV ELISA with reflex western blot, hepatitis C viral antibody with reflex polymerase chain reaction, and Lyme disease.
Hereditary conditions such as Fabry disease, HSAN 4, and HSAN5 can be tested in specialty labs. See http://www.ncbi.nlm.nih.gov/sites/GeneTests for further information.
Small fiber sensory peripheral neuropathy is associated with both acquired and familial amyloidosis. Tissue demonstration of amyloid deposits in abdominal fat pad aspirates or rectal biopsies can confirm the diagnosis of amyloidosis. Acquired amyloidosis may occur in isolation or as part of the POEMS syndrome. Familial amyloid polyneuropathy is usually caused by a mutation in the transthyretin gene.
A subgroup of patients formerly characterized as idiopathic small fiber neuropathy may have functional variants of Nav1.7 that impair slow-inactivation producing dorsal root ganglion neuronal hyperexcitability associated with pain, as noted in the voltage clamp analysis of a single patient (Han et al 2012). This test is not yet commercially available.
In patients with idiopathic small fiber sensory peripheral neuropathy, testing may include screening for celiac-associated antibodies (gliadin and tissue transglutaminase). When suspected, celiac disease warrants gastrointestinal evaluation with upper endoscopy and duodenal mucosal biopsy.
MRI of the lumbar spine may help evaluate for spinal stenosis and lumbosacral radiculopathy. Musculoskeletal ultrasound may help diagnose plantar fasciitis. It can also help diagnose tarsal tunnel syndrome, which is commonly caused by ganglia, varicose veins, or talocalcaneal coalition (Nagaoka and Matsuzaki 2005).