Therapath: A Specialty Pathology Laboratory - Overview of Small Fiber Neuropathy

Main Menu

Overview of SFN

Overview of Small Fiber Neuropathy

Small fiber neuropathy most often presents with painful sensations, numbness, or hypersensitivity in the limbs, torso or face. It affects the small, unmyelinated nerve fibers that convey pain and temperature sensations from receptors in the skin, and mediate autonomic functions (Stewart et al, 1992; Novak et al, 2001). The neurological examination may real only minor sensory abnormalities, and EMG and nerve conduction studies, that measure the large fibers, are frequently normal (Lacomis, 2002; Herrmann et al, 2004). Consequently, the diagnosis may be missed, or patients may be misdiagnosed as having other pain syndromes such as RSD (Oaklander et al, 2006), fibromyalgia (Caro et al, 2008) , Erythromelalgia (Patricoff et al, 2007; Kumar and Davis, 2006), restless leg syndrome ( Polysdefkir et al, 2005), or a psychosomatic disorder. The diagnosis of neuropathic pain, however, requires demonstration of the lesion or disease responsible for the symptoms (Treede et al, 2008).

Providing an explanation of their symptoms and reassuring the patients that their evaluation is complete, is as important to patients as treatment of their pain (Petrie et al, 2005; McCraken et al, 2002). Once the diagnosis of small fiber neuropathy is made, the physician can proceed with the appropriate evaluation and treatment.

HOW IS SMALL FIBER NEUROPATHY DIAGNOSED

Small fiber neuropathy is most easily and reliably diagnosed by skin biopsy, demonstrating a reduction in the epidermal nerve fiber density (Periquet et al, 1999; Ebenezer et al, 2007). The sensitivity of skin biopsy in diagnosing small fiber neuropathy is 88.4%, in comparison to 54% for the clinical examination, and 49% for QST, with a specificity of 95 to 97% (Lauria and Devigli, 2007; Devigli et al, 2008).

Skin specimens are routinely obtained by punch biopsy at the calf and thigh, under local anaesthesia. In length dependent neuropathies, such as toxic neuropathies, the epidermal nerve fiber density is more severely reduced distally at the calf, but in sensory neuronopathy or multifocal neuropathies, the nerve fiber density may be preferentially reduced proximally at the thigh (Gorson et al, 2008). The test can also help in distinguishing between sensory radiculopathy and a distal compressive neuropathy, as the distal sensory fibers are spared if the sensory nerve roots are selectively affected. The epidermal nerve fiber density is normal in central nervous system diseases.

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 n 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), scleroderma (Poncelet and Connolly, 2003), mixed connective tissue disease (Olney, 1998), 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), unspecified inflammatory conditions (Dabby et al, 2006), 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.

THE PROCEDURE

Skin biopsy specimens are routinely 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).

The biopsy is done under local anaesthesia, and the site is covered by a band aid. The procedure is easy to perform, takes no more than 5 to 10 minutes, is generally well tolerated, and causes little discomfort.

MANAGEMENT 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, otherwise 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.

In approximately 40% of patients, no cause for the neuropathy could be found on initial evaluation, but in a 2 year follow-up study, a potential cause was identified in 25% of them. 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 to monitor the epidermal nerve fiber density.

Causes of Small Fiber Neuropathy	Evaluation
Diabetes Mellitus and glucose intolerance	Fasting glucose, glycosylated hemoglobin, glucose tolerance test
Sjogren’s syndrome	SSA-Ro and SSB-La antibodies, lacrymal duct biopsy
Lupus erythematosus	ANA, dsDNA antibodies, SCL-70 antibodies, Sm antibodies, RNP antibodies
Vasculitis	Biopsy of skin, nerve, or muscle, ANCA, cryoglobulins, HCV, RF
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, free light chains, transthyretin mutations
Alcohol abuse	History
Toxins	History of exposure, urine or blood toxin levels

Table I: Causes and evaluation of Small Fiber Neuropathy.

References

Lacomis D, Guiliani MJ, Steen V, et al. Small fiber neuropathy and vasculitis. Arthritis Rheumat 1997; 40: 1173-1177.

Lacomis D. Small fiber neuropathy. Muscle Nerve 2002; 26: 173-88.

Lauria G, Majorana A, Borgna M, et al. Trigeminal small fiber sensory neuropathy causes burning mouth syndrome. Pain 2005a; 115: 332-7.

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.

Lauria G, Devigli G. Skin biopsy as a diagnostic tool in peripheral neurpathy. Nat Clin Pract Neurol 2007; 3: 546-57.

Lee JE, Shun CT, Hsieh SC, Hsieh ST. Skin denervation in vasculitic neuropathy. Arch Neurol 2005; 10: 1570-3

McCracken LM, Evon D, Karapas ET. Satisfaction with treatment for chronic pain in a specialty service: preliminary prospective results. Eur J Pain, 2002; 6: 387-93.

Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology 2001; 56: 861-868.

Oaklander AL, Rissmiller JG, Gelman LB, Zheng L, Chang Y, Gott R. Evidence of focal small fiber axonal
denervation in complex regional pain syndrome-1 (reflex sympathetic dystrophy). Pain 2006; 120: 235-43.

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

Onley RK. Neuropathies associated with connective tissue diseases. Semin Neurol 1998; 18: 63-72.

Partricoff J, Valouska A, Nedeljkovic SS, Oaklander AL. Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small fiber axonopathy. Anesth Analg 2007; 104: 438-41.

Periquet MI, Novak V, Collins MP, Nagaraja HN, Erden S, Nash SM, Freimer ML, Sahenk Z, Kissel JT, Mendell JR. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999; 53: 1641-7.

Petrie KJ, Frampton T, Large RG, et al. What do patients expect from their first visit to a pain clinic ?. Clin J Pain 2005: 21:297-301.

Polydefkis M, Yiannoutsos CT, Cohen RA, et al. Reduced intraepidermal nerve fiber density in HIV associated sensory neuropathy. Neurology 2002; 58: 115-9.

Polydefkis M, Griffin JW, McArthur J. New insights into diabetic polyneuropathy. JAMA 2003; 290: 1371-6.

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

Poncelet AN, Connolly MK. Peripheral neuropathy in scleroderma. Muscle Nerve 2003; 28: 330-5.

Seneviratne U, Gunasekera S. Acute small fiber neuropathy; another variant of the Guillain Barre syndrome ? J Neurol Neurosurg Psychiat 2002; 72: 540-542.

Singleton JR. Evaluation and treatment of painful peripheral neuropathies. Semin Neurol 2005; 25: 185-95.

Stewart JD, Low PA, Fealey RD. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve 1992; 15: 661-65.

Treede RD, Jensen TS, Campbell JN, Crucuu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T,
Serra J. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008; 70: 1630-35.

Walk D, Zaretskaya M, Parry GJ. Symptom duration and clinical features in painful sensory neuropathy with and without nerve conduction abnormalities. J Neurol Sci 2003; 214: 3-6.

Zafrir B, Zimmerman M, Felitig Y, et al. Small fiber neuropathy due to vasculitis of the peripheral nervous system. Isr Med Assoc J 2004; 6: 183-4.

Zambelis T, Karandreas N, Tzavellas E, Kokotis P, Liappas J. Large and small fiber neuropathy in chronic alcohol dependent subjects. J Periph Nerve Syst 2005; 10: 375-81.

[ Back ]