Skin Test for Small Fiber Neuropathy



Small fiber neuropathy (SFN) is caused by damage to the small, unmyelinated fibers in the peripheral nerves that innervate the skin and internal organs, including the cardiovascular system, gastrointestinal tract, and bladder, among others. These fibers convey pain and temperature sensations from the skin, and mediate autonomic functions (Stewart et al, 1992; Novak et al, 2001). Dysfunction of the small nerve fibers can cause sensory or autonomic symptoms. The neurological examination and EMG and nerve conduction studies that measure the large nerve fibers are usually normal (Lacomis, 2002; Herrmann et al, 2004), so that the diagnosis requires examination of the small nerve fibers in the skin.

Skin samples are routinely obtained by punch skin biopsy at standard sites, and the density of the small nerve fibers is determined by morphometry after immunostaining with an antibody to the axonal marker PGP- 9.5. Two standardized tests are available; the Epidermal Nerve Fiber Density (ENFD) test measures the density of the small sensory nerve fibers in the skin, and the Sweat Gland Nerve Fiber Density (SGNFD) test measures the density of the small autonomic nerve fibers in the sweat glands. (Lauria et al, 2010; Gibbons et al, 2009). The SGNFD test may also show a decrease in nerve fiber density in some patients with small fiber neuropathy whose ENFD test is normal (Hays et al, 2011).

Making the diagnosis of SFN provides an explanation for the symptoms, and helps direct further testing for potentially reversible causes, whose treatment can result in amelioration of the neuropathy. Outcome studies have also found that providing an explanation of their symptoms and reassuring the patients that their evaluation is complete, is as important to patients as treatment of their neuropathic pain (Petrie et al, 2005; McCraken et al, 2002). Understanding the cause of their symptoms helps the patient accept their illness, cope with their symptoms, and be more receptive to their physician's recommendations and treatments.

Sensory And Autonomic Small Fiber Neuropathies; Symptoms And Differential Diagnosis

Symptoms of sensory small fiber neuropathy include numbness, hypersensitivity, and spontaneous painful or annoying sensations called paresthesias. The latter can present as tingling, burning, freezing, stinging, stabbing, itching, squeezing, tearing, buzzing, aching, or electric sensations that fluctuate in severity. The skin can be hypersensitive to pressure or touch, and innocuous stimuli can provoke unpleasant sensations, called dysesthesias; clothes can feel like sandpaper against the skin, and the pressure from wearing shoes or socks can cause pain and limit walking. These sensations can occur anywhere in the body, including the feet, arms, legs, torso, scalp, face, or even the mouth (Walk et al, 2003; Lauria et al, 2005). At the same time, however, patients can experience a loss of sensation, and inability to feel painful stimuli, as when stepping on a sharp nail or burning the fingers on a hot stove, without being aware of the injury.

Symptoms of autonomic small fiber neuropathy include abnormal sweating or temperature regulation, lightheadedness or fainting when standing up from hypotension or tachycardia, gastroparesis with bloating and constipation or diarrhea, incomplete bladder emptying or difficulty initiating a stream, sexual dysfunction from hypo or hypersensitivity, dryness and thinning of the skin, hair loss in the legs, and ridged or brittle nails (Low et al, 2003; Freeman 2007; Waldinger et al, 2009).

The differential diagnosis includes other conditions that can cause pain including multiple sclerosis or myelopathy (Herrmann et al, 2010), Reflex Sympathetic Dystrophy, Regional Pain Syndrome (RSD) (Oaklander et al, 2006), polymyalgia rheumatica, fibromyalgia (Caro et al, 2008; Uceyler et al, 2010; Gupta and Harney, 2010), Erythromelalgia (Patricoff et al, 2007; Kumar and Davis, 2006), Raynaud syndrome (Manek et al, 2009) restless leg syndrome (Polysdefkir et al, 2005; Gemignai et al, 2009), neuroma, fasciitis, or somatic pains resulting from anxiety or depression. Patients are sometimes diagnosed as having neuropathic pain, although that requires demonstration of the underlying disease or lesion (Treede et al, 2008). Autonomic symptoms can be misdiagnosed as being due to cardiac arrhythmia, colitis or irritable bowel syndrome, chronic bladder infections, skin allergies, or emotional stress.

Underlying Causes, Treatmant And Prognosis

The causes of small fiber neuropathy are diverse, and in some cases, the neuropathy is the first manifestation of an underlying systemic disease. The most common cause is diabetes mellitus or glucose intolerance (Polydefkis and McArthur, 2005). Other causes include metabolic syndrome (Zhou et al, 2011), hypothyroidism (Devigli et al, 2008; Penza et al, 2009; Magri et al, 2010), Sjögren’s syndrome (Chai et al, 2005; Chai and Logigian 2010), lupus (Omdal et al, 2002; Goransson et al, 2006), scleroderma (Poncelet and Connolly, 2003), mixed connective tissue disease (Olney, 1998), sarcoid (Holtzman et al, 2005; Bakkers et al, 2010), vasculitis (Lacomis et al, 1997; Zafrir et al, 2004; Lee et al, 2005), inflammatory bowel disease (Gondim et al, 2005), psoriasis (Narayanaswami et al, 2007), unspecified inflammatory conditions (Dabby et al, 2006), Guillain-Barre syndrome (Seneviratne and Gunasekera, 2002), nutritional deficiencies such as B12 deficiency, celiac disease (Brannagan et al, 2005), Lyme disease, HIV-1 infection (polydifkis et al, 2002), Hepatitis C infection (Tembl et al 1999), Fabry disease including in female carriers (Dutsch et al, 2003; Torvin Moller et al, 2009; Liquori et al, 2010), amyloid, alcohol abuse (Zambelis et al, 2005), neurotoxic drugs including statins (Lo et al, 2003), toxins (Kuo et al, 2005), or vaccinations (Souayah et al, 2009).

In cases where no cause can be found, the neuropathy is called idiopathic. In some cases, a progressive neuropathy that affects both the small and large nerve fibers can first present as small fiber neuropathies before progressing to involve the large fibers, at which point it can also cause electrodiagnostic abnormalities. A listing of the known causes of small fiber neuropathy, and the corresponding diagnostic tests, is provided in Table I.

One large study reported that in approximately 40% of patients, no cause for the neuropathy was found on initial evaluation, but in a 2 year follow-up study, a potential cause was identified in 25% of these patients. Thirteen percent of patients went on to develop a large fiber neuropathy (Devigili et al, 2008). Progression of the underlying neuropathy can be evaluated by repeating the biopsy and monitoring the ENFD.

Therapy in patients with small fiber neuropathy is directed at both the underlying cause, if one can be identified, and at ameliorating the symptoms. Some acute onset, otherwise idiopathic small fiber neuropathies were reported to respond to prednisone, presumably because they were caused by inflammatory mechanisms (Dabby et al, 2006). Painful paresthesias can be treated using oral medications for neuropathic pain such as Lyrica or Cymbalta, or with topical medications such as Lidoderm.

Causes of Small Fiber NeuropathyEvaluation
Diabetes Mellitus,  glucose intolerance, hypothyroidism, chronic renal disease Fasting glucose, glycosylated hemoglobin, glucose tolerance test, thyroid functions, renal functions
Sjogren’s syndrome SSA-Ro and SSB-La antibodies, salivary or lacrymal duct biopsy
Lupus erythematosus, scleroderma, mixed connective tissue disease, psoriasis ANA, dsDNA antibodies, SCL-70 antibodies, Sm antibodies, RNP antibodies, biopsy
Vasculitis Biopsy of skin, nerve, or muscle, ANCA, cryoglobulins, HCV, RF
Sarcoid Chest radiogram, biopsy
Autoimmune autonomic ganglionopathy Anti-ganglionic nicotinic AChR antibodies
Inflammatory bowel disease History, small or large bowel biopsy
Nutritional deficiency or B6 toxicity Serum B12, B6, or B1 vitamins
Celiac disease Gliadin and transglutaminase antibodies, duodenal biopsy
Lyme disease Serological tests for Lyme antibodies
HIV-1 infection, HCV infection Serological tests for HIV-1 or HCV antibodies
Fabry disease Alpha-galactosidase A activity
Amyloidosis; primary or hereditary Biopsy, free light chains, transthyretin mutations
Alcohol abuse History
Drugs, toxins History of exposure, urine or blood levels

Table I : Causes and evaluation of Small Fiber Neuropathy.

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