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Epidermal Nerve Fiber Evaluation for Small Fiber Neuropathy

Small fiber neuropathy affect the small, unmyelinated nerve fibers in the sensory nerves. These fibers convey pain and temperature sensations from the skin, as well as maintain autonomic functions (Stewart et al, 1992; Novak et al, 2001). The diagnosis can easily be missed, as the neurological examination may reveal only minor sensory abnormalities, and EMG and nerve conduction studies, that measure the large fibers, are frequently normal. Consequently, the diagnosis may be missed, or patients may be misdiagnosed as having a psychosomatic disorder, RSD, fibromyalgia, or restless leg syndrome . (Lacomis, 2002; Herrmann et al, 2004; Polysdefkir et al, 2005).

Symptoms of Small Fiber Neuropathy

Symptoms of small fiber neuropathy include numbness, and annoying or painful sensations, called paresthesias, that are variably described as tingling, stinging, burning, freezing, itching, aching, pulling, squeezing, or electric shock-like. . Innocuous stimuli can provoke unpleasant sensations, called dysesthesias; Clothes can feel like sandpaper against the skin, the hands may become hypersensitive to touch, or pressure from shoes or socks can causes severe pain in the feet. Symptoms of small fiber neuropathy can occur anywhere in the body, including the arms, legs, torso, face, or even the mouth (Walk et al, 2003; Lauria et al, 2005a)

Causes of Small Fiber Neuropathy

Small fiber neuropathy be caused by many different conditions, 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 Sjogren’s syndrome (Chai et al, 2005), lupus (Omdal et al, 2002; Goransson et al, 2006), sarcoid (Hoitsman et al, 2005), vasculitis (Lacomis et al, 1997; Zafrir et al, 2004; Lee et al, 2005), inflammatory bowel disease (Gondim et al, 2005), a variant of the Guillain-Barre syndrome (Seneviratne and Gunasekera, 2002), nutritional deficiencies, celiac disease (Brannagan et al, 2005), Lyme disease, HIV-1 infection (polydifkis et al, 2002), hereditary conditions including Fabry disease (Dyck et al, 1985; Dutsch et al, 2003), amyloid, alcohol abuse (Zambelis et al, 2005) or toxins (Kuo et al, 2005). In cases where no cause can be found, the neuropathy is called idiopathic. In some cases, progressive neuropathies that affect both the small and large nerve fibers can present as small fiber neuropathies before they can be detected by electrodiagnostic studies. A listing of the known causes of small fiber neuropathy, and the corresponding diagnostic tests, is provided in Table I.

How is Small Fiber Neuropathy diagnosed?

The diagnosis of small fiber neuropathy can be made with certainty, by demonstrating a reduction in the density of small nerve fibers in the skin. EMG and nerve conduction studies are usually normal in this condition, as they mostly measure the large nerve fibers in the motor or sensory nerves. The epidermal nerve fiber density is normal in patients with central nervous system disease.

A skin specimen is obtained for analysis, using a 3 mm punch biopsy. The small nerve fibers in the epidermis are visualized by immunocytochemistry, using an antibody to an axonal protein. The number and structural integrity of the small fibers is then evaluated by a pathologist. Patients with small fiber neuropathy exhibit a reduction is the epidermal nerve fiber density, or structural abnormalities that are indicative of neuropathy. All procedures are done according to international standards and guidelines (Lauriae et al, 2005b).

Skin specimens are routinely obtained by punch biopsy at the calf and thigh, under local anaesthesia. In length dependent neuropathies the epidermal nerve fiber density is more severely reduced distally at the calf, but in ganglioneuritis or multifocal neuropathies, the nerve fiber density may be preferentially reduced at the thigh. The procedure is easy to perform, takes no more than 5 to 10 minutes, and causes little discomfort. The biopsy site is routinely covered by a band aid for several days until the skin heals.

Treatment of Small Fiber Neuropathy

Therapy in patients with small fiber neuropathy is directed at both the underlying cause, once it is identified, and at ameliorating the symptoms. Some acute onset, idiopathic small fiber neuropathies respond to prednisone (Dabby et al, 2006). Painful paresthesias are routinely treated using oral medications such as Lyrica or Cymbalta, or by topical applications such as the Lidoderm patch.

Causes of Small Fiber Neuropathy	Evaluation
Diabetes Mellitus and glucose intolerance	Blood glucose, glycosylated hemoglobin, glucose tolerance test
Sjogren’s syndrome	SSA-Ro and SSB-La antibodies, lacrymal duct biopsy
Lupus erythematosus	ANA, dsDNA antibodies
Vasculitis	Skin, nerve, or muscle biopsy
Sarcoid	Chest radiogram, biopsy
Inflammatory bowel disease	History, small or large bowel biopsy
Nutritional deficiency	Serum B12, B6, or B1 vitamins
Celiac disease	Gliadin and transglutaminase antibodies, duodenal biopsy
Lyme disease	Serological tests for Lyme antibodies
HIV-1 infection	Serological tests for HIV-1 antibodies
Fabry disease	Alpha-galactosidase A activity
Amyloidosis	Biopsy
Alcohol abuse	Alcohol abuse
Toxins	History, toxin levels

Table I: Causes and evaluation of Small Fiber Neuropathy.

References

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Chai J, Herrmann DN, Stanton M, Barbano RL, Logigian EL. Painful small-fiber neuropathy in Sjogren syndrome. Neurology 2005; 65: 925-7.

Dabby R, Gilad R, Sadeh M, Lampi Y, Watenberg N. Acute steroid responsive small fiber neuropathy; a new entity ? J Periphe Nerv Syst 2006; 11: 47-52.

De Sousa EA, Hays AP, Chin RL, Sander HW, Brannagan TH 3rd. Characteristics of patients with sensory neuropathy diagnosed with abnormal small nerve fibers on skin biopsy. J Neurol Neurosurg Psychiat 2006; 77: 983-5.

Dyck PJ, Low PA, Stevens JC. Hereditary burning feet as the only manifestation of
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Dutsch M, Marhol H, Stemper B, Brys M, Haendl T, Hiltz MJ. Small fiber dysfunction predominates in Fabry neuropathy. J Clin Neurophysiol 2002; 19: 575-86.

Gondolin FA, Brannagan TH, Sander HW, Chin RL, Latov N. Peripheral neuropathy in patients with inflammatory bowel disease. Brain 005; 128: 867-79.

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Lauria G, Cornblath DR, Johansson O, et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neurol 2005b; 12: 747-58.

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Omdal R, Mellgren SI, Goransson L, et al. Small fiber involvement in systemic lupus erythematosus: a controlled study. Arthritis Rheum 2002; 46: 1228-32.

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Polydefkis M, Allen RP, Haver CJ, et al. Subclinical sensory neuropathy in late onset restless leg syndrome. Neurology 2005; 55: 1115-1121.

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