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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 and myelinated 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 some skin sensations (somatic afferents) 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]

Small fiber neuropathy is a condition characterized by severe pain. Symptoms typically begin in the feet or hands but can start in other parts of the body. Some people initially experience a more generalized, whole-body pain. The pain is often described as stabbing or burning, or abnormal skin sensations such as tingling or itchiness. In some individuals, the pain is more severe during times of rest or at night. The signs and symptoms of small fiber neuropathy can occur at any point in life depending on the underlying cause.

Individuals with small fiber neuropathy often cannot feel pain that is concentrated in a very small area, such as the prick of a pin. However, they have an increased sensitivity to pain in general (hyperalgesia) and experience pain from stimulation that typically does not cause pain (allodynia). People affected with this condition may also have a reduced ability to differentiate between hot and cold.

Sudomotor dysfunction is one of the most common and earliest neurophysiological manifestations of small fiber neuropathies.[3]

In some instances, the small fibers of the autonomic nervous system can be affected, leading to urinary or bowel problems, episodes of rapid heartbeat (palpitations), dry eyes or mouth, or abnormal sweating. They can also experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting.

Small fiber neuropathy is considered a form of peripheral neuropathy because it affects the peripheral nervous system, which connects the brain and spinal cord to muscles and to cells that detect sensations such as touch, smell, and pain. Insensitivity to pain can be particularly problematic. One may be bleeding or have a skin injury without even knowing it.[4]

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.


Mutations in the SCN9A or SCN10A gene can cause small fiber neuropathy. These genes provide instructions for making pieces (the alpha subunits) of sodium channels. The SCN9A gene instructs the production of the alpha subunit for the NaV1.7 sodium channel and the SCN10A gene instructs the production of the alpha subunit for the NaV1.8 sodium channel. Sodium channels transport positively charged sodium atoms (sodium ions) into cells and play a key role in a cell's ability to generate and transmit electrical signals. The NaV1.7 and NaV1.8 sodium channels are found in nerve cells called nociceptors that transmit pain signals to the spinal cord and brain.

The SCN9A gene mutations that cause small fiber neuropathy result in NaV1.7 sodium channels that do not close completely when the channel is turned off. Many SCN10A gene mutations result in NaV1.8 sodium channels that open more easily than usual. The altered channels allow sodium ions to flow abnormally into nociceptors. This increase in sodium ions enhances transmission of pain signals, causing individuals to be more sensitive to stimulation that might otherwise not cause pain. In this condition, the small fibers that extend from the nociceptors through which pain signals are transmitted (axons) degenerate over time. The cause of this degeneration is unknown, but it likely accounts for signs and symptoms such as the loss of temperature differentiation and pinprick sensation. The combination of increased pain signaling and degeneration of pain-transmitting fibers leads to a variable condition with signs and symptoms that can change over time.

SCN9A gene mutations have been found in approximately 30 percent of individuals with small fiber neuropathy; SCN10A gene mutations are responsible for about 5 percent of cases. In some instances, other health conditions cause this disorder. Diabetes mellitus and impaired glucose tolerance are the most common diseases that lead to this disorder, with 6 to 50 percent of diabetics or pre-diabetics developing small fiber neuropathy. Other causes of this condition include a metabolic disorder called Fabry disease, immune disorders such as celiac disease or Sjogren syndrome, an inflammatory condition called sarcoidosis, and human immunodeficiency virus (HIV) infection.[5]

Recently several studies have suggested an association between autonomic small fiber neuropathy and postural orthostatic tachycardia syndrome.[6] Other notable studies have shown a link between erythromelalgia,[7] fibromyalgia,[8] Ehlers–Danlos Syndrome[9] and long covid.[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] Electrochemical skin conductance and quantitative sudomotor axon reflex testing (QSART) measures sweating response at local body sites to evaluate the small nerve fibers that innervate sweat glands.[11]

Electrochemical skin conductance has been evaluated for both early diagnosis of small fiber neuropathy and follow-up of treatment efficacy.[14][15][16][17]

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.[18] 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).[19] 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).[19] Any value measured below the 0.05 Quantile IENFD values per age span, is considered a reliable positive diagnosis for small fiber peripheral neuropathy.[19]

Intraepidermal nerve fiber density (IENFD) normative values for clinical use[19]
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 to reduce progression of the disease and symptoms. For cases without those conditions, there is only symptomatic treatment.[20]

See also[edit]


  1. ^ 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. S2CID 14021390.
  3. ^ Freeman, Roy (April 2005). "Autonomic peripheral neuropathy". The Lancet. 365 (9466): 1259–1270. doi:10.1016/S0140-6736(05)74815-7. PMID 15811460. S2CID 40418387
  4. ^ "Small fiber neuropathy: MedlinePlus Genetics".
  5. ^ "Small fiber neuropathy: MedlinePlus Genetics".
  6. ^ http://www.neurology.org/cgi/content/meeting_abstract/80/1_MeetingAbstracts/S37.005 [dead link]
  7. ^ 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.
  8. ^ McGreevey, Sue (31 July 2013). "Nerve damage and fibromyalgia". The Harvard Gazette. Retrieved 1 June 2018.
  9. ^ 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.
  10. ^ Davis, Hannah E.; McCorkell, Lisa; Vogel, Julia Moore; Topol, Eric J. (13 January 2023). "Long COVID: major findings, mechanisms and recommendations". Nature Reviews Microbiology. 21 (3): 133–146. doi:10.1038/s41579-022-00846-2. ISSN 1740-1534. PMC 9839201. PMID 36639608.
  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. hdl:2434/530580. PMID 20642627. S2CID 205581976.
  13. ^ Lacomis D (August 2002). "Small-fiber neuropathy". Muscle Nerve. 26 (2): 173–88. doi:10.1002/mus.10181. PMID 12210380. S2CID 9689204.
  14. ^ Yajnik, C. S.; Behere, R. V.; Bhat, D. S.; Memane, N.; Raut, D.; Ladkat, R.; ... & Fall, C. H. (2019). "A physiological dose of oral vitamin B-12 improves hematological, biochemical-metabolic indices and peripheral nerve function in B-12 deficient Indian adolescent women". PLOS ONE. 14 (10): e0223000. Bibcode:2019PLoSO..1423000Y. doi:10.1371/journal.pone.0223000. PMC 6786546. PMID 31600243. S2CID 204244441.
  15. ^ Didangelos, T.; Karlafti, E.; Kotzakioulafi, E.; Margariti, E.; Giannoulaki, P.; Batanis, G.; ... & Kantartzis, K. (2021). "Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year, Randomized, Double-Blind, Placebo-Controlled Trial". Nutrients. 13 (2): 395. doi:10.3390/nu13020395. PMC 7912007. PMID 33513879. S2CID 231762127.
  16. ^ Syngle, A.; Chahal, S.; & Vohra, K. (2021). "Efficacy and tolerability of DPP4 inhibitor, teneligliptin, on autonomic and peripheral neuropathy in type 2 diabetes: an open label, pilot study". Neurological Sciences. 42 (4): 1429–1436. doi:10.1007/s10072-020-04681-2. PMID 32803534. S2CID 221129340.
  17. ^ Casellini, C. M.; Parson, H. K.; Hodges, K.; Edwards, J. F.; Lieb, D. C.; Wohlgemuth, S. D.; & Vinik, A. I. (2016). "Bariatric surgery restores cardiac and sudomotor autonomic C-fiber dysfunction towards normal in obese subjects with type 2 diabetes". PLOS ONE. 11 (5): e0154211. Bibcode:2016PLoSO..1154211C. doi:10.1371/journal.pone.0154211. PMC 4854471. PMID 27137224.
  18. ^ 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.
  19. ^ 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. 15 (3): 202–7. doi:10.1111/j.1529-8027.2010.00271.x. PMID 21040142. S2CID 4838905.
  20. ^ 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. S2CID 25227067.
  21. ^ 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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