Small fiber peripheral neuropathy

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Small fiber peripheral neuropathy

Small fiber peripheral neuropathy is a type of peripheral neuropathy that occurs from damage to the small unmyelinated peripheral nerve fibers. These fibers, categorized as C fibers and small Aδ fibers, are present in skin, peripheral nerves, and organs.[1] The role of these nerves is to innervate the skin (somatic fibers) and help control autonomic function (autonomic fibers). It is estimated that 15-20 million people in the United States have some form of peripheral neuropathy.[2]

Signs and symptoms[edit]

Sensory symptoms of small fiber neuropathy are highly variable. Common complaints include paresthesias, dysesthesias, and insensitivity to pain. Paresthesias are abnormal sensations. They are often described as numbness, burning, cold, prickling, pins and needles along with other symptoms. Dysesthesias are unpleasant sensations, either spontaneous or evoked. A light breeze, the feeling of clothes, or even a soft touch can cause pain.[3] Insensitivity to pain can be particularly problematic. One may be bleeding or have a skin injury without even knowing it.

Topographic pattern[edit]

Like many polyneuropathies, the symptoms are typically length-dependent, starting in the longer nerves and progressively attacking shorter nerves. This means that symptoms often start in the hands and feet before progressing upwards, and that symptoms are usually more severe in the extremities. Some patients have a widespread, non-length dependent, or "patchy", presentation which is sporadic and can affect many nerves.

Patients with Fabry disease have isolated small fiber engagement, and can have a more widespread small fiber disruption.


There are many possible causes of small fiber neuropathy. The most common causes are diabetes mellitus or impaired glucose intolerance.[4] Other possible causes include hypothyroidism, Sjögren's syndrome, systemic lupus erythematosus, vasculitis, sarcoidosis, Vitamin B12 deficiency, celiac disease, Lyme disease, HIV, Fabry disease, Charcot-Marie-Tooth Disease, amyloidosis, Ehlers-Danlos Syndrome, and alcohol use disorder.[1] A 2008 study reported that in approximately 40% of patients no cause could be determined after initial evaluation.[5] When no cause can be identified, the neuropathy is called idiopathic. A recent study revealed dysfunction of a particular sodium channel (Nav1.7) in a significant portion of the patient population with an idiopathic small fiber neuropathy.[6]

Recently several studies have suggested an association between autonomic small fiber neuropathy and postural orthostatic tachycardia syndrome.[7] Other notable studies have shown a link between erythromelalgia,[8] fibromyalgia,[9] and Ehlers-Danlos Syndrome.[10]


The diagnosis of small fiber neuropathy often requires ancillary testing.[11] Nerve conduction studies and electromyography are commonly used to evaluate large myelinated sensory and motor nerve fibers, but are ineffective in diagnosing small fiber neuropathies.[12]

Quantitative sensory testing (QST) assesses small fiber function by measuring temperature and vibratory sensation. Abnormal QST results can be attributed to dysfunction in the central nervous system. Furthermore, QST is limited by a patient’s subjective experience of pain sensation.[13] Quantitative sudomotor axon reflex testing (QSART) measures sweating response at local body sites to evaluate the small nerve fibers that innervate sweat glands.[11]

Skin biopsy[edit]

A skin biopsy for the measurement of epidermal nerve fiber density is an increasingly common technique for the diagnosis of small fiber peripheral neuropathy.[11] Physicians can biopsy the skin with a 3-mm circular punch tool and immediately fix the specimen in 2% paraformaldehyde lysine-periodate or Zamboni's fixative.[14] Specimens are sent to a specialized laboratory for processing and analysis where the small nerve fibers are quantified by a neuropathologist to obtain a diagnostic result.[12]

This skin punch biopsy measurement technique is called intraepidermal nerve fiber density (IENFD).[15] The following table describes the IENFD values in males and females of a 3 mm biopsy 10-cm above the lateral malleolus (above ankle outer side of leg).[15] Any value measured below the 0.05 Quantile IENFD values per age span, is considered a reliable positive diagnosis for Small Fiber Peripheral Neuropathy.[15]

Intraepidermal nerve fiber density (IENFD) normative values for clinical use[15]
Females Males
Age in years 0.05 Quantile IENFD values per age span Median IENFD values per age span 0.05 Quantile IENFD values per age span Median IENFD values per age span
20-29 8.4 13.5 6.1 10.9
30-39 7.1 12.4 5.2 10.3
40-49 5.7 11.2 4.4 9.6
50-59 4.3 9.8 3.5 8.9
60-69 3.2 8.7 2.8 8.3
70-79 2.2 7.6 2.1 7.7
≥80 1.6 6.7 1.7 7.2


Treatment is based on the underlying cause, if any. Where the likely underlying condition is known, treatment of this condition is indicated treated to reduce progression of the disease and symptoms. For cases without those conditions, there is only symptomatic treatment.[16]

See also[edit]


  1. ^ a b Overview of Small Fiber Neuropathy. Therapath Neuropathology.
  2. ^ Tavee, Jinny; Zhou, Lan (May 2009). "Small fiber neuropathy: A burning problem". Cleveland Clinic Journal of Medicine. 76 (5): 297–305. doi:10.3949/ccjm.76a.08070. ISSN 0891-1150. PMID 19414545.
  3. ^ Latov, Norman (2007). Peripheral Neuropathy: When the Numbness, Weakness and Pain Won't Stop. American Academy of Neurology (AAN) quality of life guides. Demos Medical Publishing. p. 8. ISBN 9781932603590.
  4. ^ Polydefkis, M; et al. (2003). "New insights into diabetic polyneuropathy". JAMA. 290 (10): 1371–6. doi:10.1001/jama.290.10.1371. PMID 12966130.
  5. ^ Devigili, G; et al. (2008). "The diagnostic criteria for small fiber neuropathy; from symptoms of neuropathology". Brain. 131 (7): 1912–1925. doi:10.1093/brain/awn093. PMC 2442424. PMID 18524793.
  6. ^ Faber, C; et al. (2011). "Gain of function Na(V) 1.7 mutations in idiopathic small fiber neuropathy". Annals of Neurology. 71 (1): 26–39. doi:10.1002/ana.22485. PMID 21698661.
  7. ^
  8. ^ Davis, Mark DP; Weenig, Roger H; Genebriera, Joseph; Wendelschafer-Crabb, Gwen; Kennedy, William R; Sandroni, Paola (September 2006). "Histopathologic findings in primary erythromelalgia are nonspecific: special studies show a decrease in small nerve fiber density". Journal of the American Academy of Dermatology. 55 (3): 519–522. doi:10.1016/j.jaad.2006.04.067. ISSN 0190-9622. PMID 16908366.
  9. ^ McGreevey, Sue (31 July 2013). "Nerve damage and fibromyalgia". The Harvard Gazette. Retrieved 1 June 2018.
  10. ^ Cazzato, Daniele; Castori, Marco; Lombardi, Raffaella; Caravello, Francesca; Bella, Eleonora Dalla; et al. (July 2016). "Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes". Neurology. 87 (2): 155–159. doi:10.1212/WNL.0000000000002847. eISSN 1526-632X. PMC 4940063. PMID 27306637.
  11. ^ a b c Hovaguimian A, Gibbons CH (June 2011). "Diagnosis and treatment of pain in small-fiber neuropathy". Curr Pain Headache Rep. 15 (3): 193–200. doi:10.1007/s11916-011-0181-7. PMC 3086960. PMID 21286866.
  12. ^ a b Lauria G, Hsieh ST, Johansson O, et al. (July 2010). "European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy". Eur. J. Neurol. 17 (7): 903–12, e44–9. doi:10.1111/j.1468-1331.2010.03023.x. PMID 20642627.
  13. ^ Lacomis D (August 2002). "Small-fiber neuropathy". Muscle Nerve. 26 (2): 173–88. doi:10.1002/mus.10181. PMID 12210380.
  14. ^ Hays, AP; et al. (January 2016). "Fixation of skin biopsies for determination of epidermal nerve fiber density". Clinical Neuropathology. 35 (1): 44–45. doi:10.5414/NP300891. ISSN 0722-5091. PMID 26365464.
  15. ^ a b c d Lauria, G; Bakkers, M; Schmitz, C; Lombardi, R; Penza, P; Devigili, G; Smith, AG; Hsieh, ST; Mellgren, SI; Umapathi, T; Ziegler, D; Faber, CG; Merkies, IS (September 2010). "Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study". Journal of the Peripheral Nervous System : JPNS. 15 (3): 202–7. doi:10.1111/j.1529-8027.2010.00271.x. PMID 21040142.
  16. ^ Chan, Amanda C. Y.; Wilder-Smith, Einar P. (May 2016). "Small fiber neuropathy: Getting bigger!". Muscle & Nerve. 53 (5): 671–682. doi:10.1002/mus.25082. ISSN 1097-4598. PMID 26872938.
  17. ^ Levine, Todd D; Saperstein, David S (March 2015). "Routine use of punch biopsy to diagnose small fiber neuropathy in fibromyalgia patients". Clinical Rheumatology. 34 (3): 413–417. doi:10.1007/s10067-014-2850-5. ISSN 0770-3198. PMC 4348533. PMID 25535201.

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