Reviews

Small fiber neuropathy: A burning problem

Cleveland Clinic Journal of Medicine. 2009 May;76(5):297-305 | 10.3949/ccjm.76a.08070

ABSTRACTSmall fiber neuropathy is increasingly being recognized as a major cause of painful burning sensations in the feet, especially in the elderly. Although strength remains preserved throughout the course of the disease, the pain and paresthesias are often disabling. Diabetes mellitus is the most common identifiable cause of small fiber neuropathy, and impaired oral glucose tolerance and individual components of the metabolic syndrome are often associated with it. Some cases, however, are idiopathic. Skin biopsy (with an evaluation of the density of intraepidermal nerve fibers) and tests of autonomic nerve function are useful for the diagnosis. Management involves controlling pain and identifying and aggressively treating the underlying cause.

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KEY POINTS

Symptoms of small fiber neuropathy typically start with burning feet and numb toes.
Causes and associated conditions can be found in over 50% of cases. These include glucose dysmetabolism, connective tissue diseases, sarcoidosis, dysthyroidism, vitamin B₁₂ deficiency, paraproteinemia, human immunodeficiency virus infection, celiac disease, neurotoxic drug exposure, and paraneoplastic syndrome.
Findings on routine nerve conduction studies and electromyography are typically normal in this disease.
Management includes aggressively identifying and treating the underlying cause, advising lifestyle modifications, and alleviating pain.

References

Gregg EW, Gu Q, Williams D, et al. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract 2007; 77:485–488.
Lacomis D. Small fiber neuropathy. Muscle Nerve 2002; 26:173–188.
Smith AG, Singleton JR. Impaired glucose tolerance and neuropathy. Neurologist 2008; 14:23–29.
Chai J, Herrmann DN, Stanton M, Barbano RL, Logigian EL. Painful small-fiber neuropathy in Sjogren syndrome. Neurology 2005; 65:925–927.
Goransson LG, Tjensvoll AB, Herigstad A, Mellgren SI, Omdal R. Small-diameter nerve fiber neuropathy in systemic lupus erythematosus. Arch Neurol 2006; 63:401–404.
Orstavik K, Norheim I, Jorum E. Pain and small-fiber neuropathy in patients with hypothyroidism. Neurology 2006; 67:786–791.
McArthur JC, Brew BJ, Nath A. Neurological complications of HIV infection. Lancet Neurol 2005; 4:543–555.
Brannagan TH, Hays AP, Chin SS, et al. Small-fiber neuropathy/neuronopathy associated with celiac disease: skin biopsy findings. Arch Neurol 2005; 62:1574–1578.
Polydefkis M, Allen RP, Hauer P, Earley CJ, Griffin JW, McArthur JC. Subclinical sensory neuropathy in late-onset restless legs syndrome. Neurology 2000; 55:1115–1121.
Gorson KC, Herrmann DN, Thiagarajan R, et al. Non-length dependent small fibre neuropathy/ganglionopathy. J Neurol Neurosurg Psychiatry 2008; 79:163–169.
Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 2001; 24:1448–1453.
Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001; 24:1229–1231.
Smith AG, Singleton JR. The diagnostic yield of a standardized approach to idiopathic sensory-predominant neuropathy. Arch Intern Med 2004; 164:1021–1025.
Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003; 60:108–111.
Gregg EW, Sorlie P, Paulose-Ram R, et al. Prevalence of lower-extremity disease in the US adult population >=40 years of age with and without diabetes: 1999–2000 National Health and Nutrition Examination Survey. Diabetes Care 2004; 27:1591–1597.
Boulton A. What causes neuropathic pain? J Diabetes Complications 1992; 6:58–63.
Russell JW, Sullivan KA, Windebank AJ, Herrmann DN, Feldman EL. Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis 1999; 6:347–363.
Costa LA, Canani LH, Lisboa HR, Tres GS, Gross JL. Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complications in type 2 diabetes. Diabet Med 2004; 21:252–255.
Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005; 352:341–350.
Smith A, Rose K, Singleton J. Idiopathic neuropathy patients are at high risk for metabolic syndrome. J Neurol Sci 2008; 273:25–28.
Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008; 131:1912– 1925.
Low VA, Sandroni P, Fealey RD, Low PA. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 2006; 34:57–61.
McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol 1998; 55:1513–1520.
Gibbons CH, Griffin JW, Polydefkis M, et al. The utility of skin biopsy for prediction of progression in suspected small fiber neuropathy. Neurology 2006; 66:256–258.
Polydefkis M, Yiannoutsos CT, Cohen BA, et al. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology 2002; 58:115–119.
Herrmann DN, Griffin JW, Hauer P, Cornblath DR, McArthur JC. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology 1999; 53:1634–1640.
Zhou L, Kitch DW, Evans SR, et al. Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy. Neurology 2007; 68:2113–2119.
Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology 2001; 56:861–868.
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393–403.
Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for prediabetic neuropathy. Diabetes Care 2006; 29:1294–1299.
Hoitsma E, Faber CG, van Santen-Hoeufft M, De Vries J, Reulen JP, Drent M. Improvement of small fiber neuropathy in a sarcoidosis patient after treatment with infliximab. Sarcoidosis Vasc Diffuse Lung Dis 2006; 23:73–77.
Chen H, Lamer TJ, Rho RH, et al. Contemporary management of neuropathic pain for the primary care physician. Mayo Clin Proc 2004; 79:1533–1545.
Galluzzi KE. Managing neuropathic pain. J Am Osteopath Assoc 2007; 107( suppl 6):ES39–ES48.
Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology 1998; 51:1682–1688.

Figure 1. Symptoms are pain, burning, numbness, and autonomic dysfunction (lack of sweating) in the hands and feet in a stocking-glove distribution. Strength is not affected. Tendon reflexes are normal, as are nerve conduction studies.

An estimated 15 to 20 million people in the United States over age 40 have some type of peripheral neuropathy.¹ In many, the impairment is purely or predominantly in small nerve fibers, and the clinical presentation consists of pain, burning, tingling, and numbness in a length-dependent or stocking-glove distribution. (“Length” refers to distance from the trunk; distal fibers are affected first.) Symptoms typically begin in the feet and slowly ascend to the distal legs, at which point the hands may also be affected (Figure 1).

In many of these patients, the findings on neurologic examination, nerve conduction studies, and electromyography are normal, although some may show signs of mild distal sensory loss on physical examination. The lack of objective findings on routine nerve conduction studies and electromyography may lead many physicians to attribute the symptoms to other disorders such as plantar fasciitis, vascular insufficiency, or degenerative lumbosacral spine disease.

The past 2 decades have seen the development of specialized tests that have greatly facilitated the diagnosis of small fiber neuropathy; these include skin biopsy to evaluate the density of nerve fibers in the epidermis and studies of autonomic nerve function. Common etiologies have been identified for small fiber neuropathy and can be specifically treated, which is critical for controlling progression of the disease. Pain management is becoming easier with more available options but is still quite challenging.

WHAT IS SMALL FIBER NEUROPATHY?

Figure 2.

Small fiber neuropathy is a disorder of the peripheral nerves that primarily or exclusively affects small somatic fibers, autonomic fibers, or both, resulting in sensory changes and autonomic dysfunction when both types are involved (Figure 2).²

Peripheral nerve fibers can be classified according to size, which correlates with the degree of myelination.

Large nerve fibers are heavily myelinated and include A-alpha fibers, which mediate motor strength, and A-beta fibers, which mediate vibratory and touch sensation.
Medium-sized fibers, known as A-gamma fibers, are also myelinated and carry information to muscle spindles.
Small fibers include myelinated A-delta fibers and unmyelinated C fibers, which innervate skin (somatic fibers) and involuntary muscles, including cardiac and smooth muscles (autonomic fibers). Together, they mediate pain, thermal sensation, and autonomic function.

Small fiber neuropathy results from selective impairment of small myelinated A-delta and unmyelinated C fibers.

Sensory symptoms: Pain, burning, tingling, numbness

Damage to or loss of small somatic nerve fibers results in pain, burning, tingling, or numbness that typically affects the limbs in a distal-to-proximal gradient. In rare cases, small fiber neuropathy follows a non-length-dependent distribution in which symptoms may be manifested predominantly in the arms, face, or trunk.

Symptoms may be mild initially, with some patients complaining of vague discomfort in one or both feet similar to the sensation of a sock gathering at the end of a shoe. Others report a wooden quality in their feet, numbness in their toes, or a feeling as if they are walking on pebbles, sand, or golf balls. The most bothersome and fairly typical symptom is burning pain in the feet that extends proximally in a stocking-glove distribution and is often accompanied by stabbing or aching pains, electric shock-like or pins-and-needles sensations, or cramping of the feet and calves.

Symptoms are usually worse at night and often affect sleep. Some patients say that their feet have become so exquisitely tender that they cannot bear having the bed sheets touch them, and so they sleep with their feet uncovered. A small number of patients do not have pain but report a feeling of tightness and swelling in their feet (even though the feet appear normal).

Examination often reveals allodynia (perception of nonpainful stimuli as being painful), hyperalgesia (perception of painful stimuli as being more painful than expected), or reduced pinprick and thermal sensation in the affected area. Vibratory sensation can be mildly reduced at the toes. Motor strength, tendon reflexes, and proprioception, however, are preserved because they are functions of large nerve fibers.

Autonomic symptoms

When autonomic fibers are affected, patients may experience dry eyes, dry mouth, orthostatic dizziness, constipation, bladder incontinence, sexual dysfunction, trouble sweating, or red or white skin discoloration.² Examination may show orthostatic hypotension and skin changes. The skin over the affected area may appear atrophic, dry, shiny, discolored, or mildly edematous as the result of sudomotor and vasomotor abnormalities.

References

Gregg EW, Gu Q, Williams D, et al. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract 2007; 77:485–488.
Lacomis D. Small fiber neuropathy. Muscle Nerve 2002; 26:173–188.
Smith AG, Singleton JR. Impaired glucose tolerance and neuropathy. Neurologist 2008; 14:23–29.
Chai J, Herrmann DN, Stanton M, Barbano RL, Logigian EL. Painful small-fiber neuropathy in Sjogren syndrome. Neurology 2005; 65:925–927.
Goransson LG, Tjensvoll AB, Herigstad A, Mellgren SI, Omdal R. Small-diameter nerve fiber neuropathy in systemic lupus erythematosus. Arch Neurol 2006; 63:401–404.
Orstavik K, Norheim I, Jorum E. Pain and small-fiber neuropathy in patients with hypothyroidism. Neurology 2006; 67:786–791.
McArthur JC, Brew BJ, Nath A. Neurological complications of HIV infection. Lancet Neurol 2005; 4:543–555.
Brannagan TH, Hays AP, Chin SS, et al. Small-fiber neuropathy/neuronopathy associated with celiac disease: skin biopsy findings. Arch Neurol 2005; 62:1574–1578.
Polydefkis M, Allen RP, Hauer P, Earley CJ, Griffin JW, McArthur JC. Subclinical sensory neuropathy in late-onset restless legs syndrome. Neurology 2000; 55:1115–1121.
Gorson KC, Herrmann DN, Thiagarajan R, et al. Non-length dependent small fibre neuropathy/ganglionopathy. J Neurol Neurosurg Psychiatry 2008; 79:163–169.
Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care 2001; 24:1448–1453.
Novella SP, Inzucchi SE, Goldstein JM. The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy. Muscle Nerve 2001; 24:1229–1231.
Smith AG, Singleton JR. The diagnostic yield of a standardized approach to idiopathic sensory-predominant neuropathy. Arch Intern Med 2004; 164:1021–1025.
Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003; 60:108–111.
Gregg EW, Sorlie P, Paulose-Ram R, et al. Prevalence of lower-extremity disease in the US adult population >=40 years of age with and without diabetes: 1999–2000 National Health and Nutrition Examination Survey. Diabetes Care 2004; 27:1591–1597.
Boulton A. What causes neuropathic pain? J Diabetes Complications 1992; 6:58–63.
Russell JW, Sullivan KA, Windebank AJ, Herrmann DN, Feldman EL. Neurons undergo apoptosis in animal and cell culture models of diabetes. Neurobiol Dis 1999; 6:347–363.
Costa LA, Canani LH, Lisboa HR, Tres GS, Gross JL. Aggregation of features of the metabolic syndrome is associated with increased prevalence of chronic complications in type 2 diabetes. Diabet Med 2004; 21:252–255.
Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005; 352:341–350.
Smith A, Rose K, Singleton J. Idiopathic neuropathy patients are at high risk for metabolic syndrome. J Neurol Sci 2008; 273:25–28.
Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008; 131:1912– 1925.
Low VA, Sandroni P, Fealey RD, Low PA. Detection of small-fiber neuropathy by sudomotor testing. Muscle Nerve 2006; 34:57–61.
McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol 1998; 55:1513–1520.
Gibbons CH, Griffin JW, Polydefkis M, et al. The utility of skin biopsy for prediction of progression in suspected small fiber neuropathy. Neurology 2006; 66:256–258.
Polydefkis M, Yiannoutsos CT, Cohen BA, et al. Reduced intraepidermal nerve fiber density in HIV-associated sensory neuropathy. Neurology 2002; 58:115–119.
Herrmann DN, Griffin JW, Hauer P, Cornblath DR, McArthur JC. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology 1999; 53:1634–1640.
Zhou L, Kitch DW, Evans SR, et al. Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy. Neurology 2007; 68:2113–2119.
Novak V, Freimer ML, Kissel JT, et al. Autonomic impairment in painful neuropathy. Neurology 2001; 56:861–868.
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393–403.
Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for prediabetic neuropathy. Diabetes Care 2006; 29:1294–1299.
Hoitsma E, Faber CG, van Santen-Hoeufft M, De Vries J, Reulen JP, Drent M. Improvement of small fiber neuropathy in a sarcoidosis patient after treatment with infliximab. Sarcoidosis Vasc Diffuse Lung Dis 2006; 23:73–77.
Chen H, Lamer TJ, Rho RH, et al. Contemporary management of neuropathic pain for the primary care physician. Mayo Clin Proc 2004; 79:1533–1545.
Galluzzi KE. Managing neuropathic pain. J Am Osteopath Assoc 2007; 107( suppl 6):ES39–ES48.
Kieburtz K, Simpson D, Yiannoutsos C, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology 1998; 51:1682–1688.

Small fiber neuropathy: A burning problem

References

Sensory symptoms: Pain, burning, tingling, numbness

Autonomic symptoms

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