Small fiber neuropathy – myths and misconceptions, pt 1

In my first thematic post, I’d like to talk a bit about small fiber neuropathy (or more appropriately — neuropathies — as we will soon find that in reality this is a heterogenous group of disorders of different etiology¹).

SFN is traditionally known as a condition manifesting with cutaneous pain or abnormal skin sensations, such as burning, prickling, tingling, numbness. More recently, this proved to be an extremely limited understanding of a very complex disease, as researchers are recognizing a lot of relatively unspecific symptoms due to involvement of autonomic nerves (in addition to sensory nerves).^2,3,4,5,6

There are multiple types of nerve fibers in the human nervous system.⁷ However, discussing all of them is beyond the scope of this post — for now, we are interested only in thinly myelinated Aδ-fibres and unmyelinated C-fibres, as they are the ones affected by small fiber neuropathy. SFN has been linked to their damage or dysfunction.

There are numerous myths about this condition — presumably because of it being relatively uncommon,⁸ difficult (and unprofitable⁹) to research, diagnose and treat.
Those misconceptions can be roughly grouped into three categories that will sometimes overlap: myths believed by patients, by doctors and by general population.

In the first part of this series of posts, I’ll try to do away with some of the myths perpetuated by the medical community.

“It’s not SFN, because your feet and/or hands don’t hurt“

Symmetrical painful polyneuropathy, starting from the feet (because in the more common, or perhaps just more often diagnosed, length-dependent type the longest nerves are affected first) is considered a classic presentation of SFN.¹⁰ Diabetes is considered the leading cause of this presentation.

Non-length dependent pattern has also been described in multiple studies. Is is best documented in paraneoplastic, immune-mediated and idiopathic cases.^11,12
Patients with mononeuropathy or ganglionopathy may have a variable patchy sensory pattern that may involve the face, tongue, scalp, upper limb, and trunk, before the lower limbs. Patients with
ganglionopathy can present with a proximal pattern, involvement of upper limbs but not lower limbs, or
involvement of the trunk or face. In focal SFN, the symptoms might be localised to the tongue and mouth in primary burning mouth syndrome or it might occur in sensory mononeuropathies such as notalgia and meralgia paraesthetica. ¹³ It may explain pelvic pain, including rectal, perineal and genital pain.¹⁴

“It’s not SFN, because you have no pain”

Diffuse painless degeneration of small nerve fibres has been reported in congenital insensitivity to pain with anhidrosis.¹⁵ SFN has been linked to genital sensory loss.¹⁶ Autonomic fiber involvement may cause symptoms such as: palpitations, nausea, dysphagia, vomiting, dry eyes/mouth, erectile dysfunction, hair loss, sweating, brain fog etc. etc.¹⁷

“Antibiotics wouldn’t give cause it; or just a few days’ worth of antibiotics wouldn’t cause it“

Fluoroquinolones have been linked to small fiber neuropathy in multiple case reports.^18,19,20,21 One nested case-control study of 5357 incident peripheral neuropathy cases and 17 285 matched controls showed that current use of systemic fluoroquinolone antibiotics increased the risk of peripheral neuropathy by 47%.²² In one third of patients, neuropathic symptoms occurred within 24h of treatment initiation,²³ and in more than two-third within 1 week.²⁴

Nitrofurantoin has also been recognized as a potential SFN cause in multiple studies, in one case report with treatment courses as short as 1 week.²⁵

Metronidazole²⁶ and linezolid²⁷ are other potential triggers.

Brief literature search did not yield any results, but there is a lot of convincing anecdotes from Reddit users who developed sudden-onset small fiber neuropathy after short courses of Sulfa/TMP, doxycyclin (and SSRIs), that was often later confirmed by IENFD skin biopsy.

“Skin biopsy was negative, so you don’t have SFN, maybe you have fibromyalgia”

Even though skin biopsy is considered a key method to diagnose SFN,²⁸ it is less than ideal. Specificity* oscillates around 90% in most studies, but sensitivity tends to be lower, with some studies putting it as low as 58%.²⁹ This means that skin biopsy to evaluate IENFD is a test much more likely to correctly identify negative cases (=people who don’t have the disease) rather than the positive ones. Nonetheless, given that it has a fairly high rate of false negative results, it is best coupled with other diagnostic tests to improve accuracy. It is a test that is more appropriate for those presenting with length-dependent pattern, given that the samples are only taken from the leg.

Skin biopsies in small fiber neuropathy. Biopsy from right ankle stained with PGP 9.5 showing marked reduction in IENFD (arrows) of 1.6/mm (a) compared to age-matched control with IENFD of 8.2/mm (b) Skin biopsy from the ankle (c) showing a reduction in IENFD (3.6/mm) and thigh (d) showing the normal density of 11.2/mm with preserved adnexal innervations (e). [magnification = scale bar]

From: Narasimhaiah, Deepti & Mahadevan, Anita. (2022). Role of skin punch biopsy in diagnosis of small fiber neuropathy-A review for the neuropathologist. Indian journal of pathology & microbiology. 65. S329-S336. 10.4103/ijpm.ijpm_92_22.
CC BY-NC-SA 4.0 

Anecdotally, a lot of people who tested negative on first skin biopsy, tested positive on subsequent ones months or years later.
Furthermore, there may be large overlap between SFN and fibromyalgia — in one study 41% of skin biopsies from fibromyalgia subjects vs. 3% of biopsies from control subjects were diagnostic for SFN.³⁰

* If you don’t know what sensitivity and specificity are, please spend some time reading Wikipedia or watching some video on YouTube, as those are easily two most important statistics that will tell you how valuable some medical test is and how much it can be trusted.

In my next post this month, I will try to tackle some other myths. If you have any ideas, questions or requents, please leave a comment!

References:

1. Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol. 2017 Nov;16(11):934-944. doi: 10.1016/S1474-4422(17)30329-0. Erratum in: Lancet Neurol. 2017 Dec;16(12):954. doi: 10.1016/S1474-4422(17)30361-7. PMID: 29029847.
   Term etiology refers to the cause of illness. ↩︎
2. Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol. 2017 Nov;16(11):934-944. doi: 10.1016/S1474-4422(17)30329-0. Erratum in: Lancet Neurol. 2017 Dec;16(12):954. doi: 10.1016/S1474-4422(17)30361-7. PMID: 29029847. ↩︎
3. Novak P. Autonomic Disorders. Am J Med. 2019 Apr;132(4):420-436. doi: 10.1016/j.amjmed.2018.09.027. Epub 2018 Oct 9. PMID: 30308186. ↩︎
4. Oaklander AL, Nolano M. Scientific Advances in and Clinical Approaches to Small-Fiber Polyneuropathy: A Review. JAMA Neurol. 2019 Oct 1;76(10):1240-1251. doi: 10.1001/jamaneurol.2019.2917. Erratum in: JAMA Neurol. 2019 Dec 1;76(12):1520. doi: 10.1001/jamaneurol.2019.3877. PMID: 31498378; PMCID: PMC10021074. ↩︎
5. Wolff DT, Walker SJ. Small Fiber Polyneuropathy May Be a Nexus Between Autonomic Nervous System Dysregulation and Pain in Interstitial Cystitis/Bladder Pain Syndrome. Front Pain Res (Lausanne). 2022 Jan 4;2:810809. doi: 10.3389/fpain.2021.810809. PMID: 35295485; PMCID: PMC8915770. ↩︎
6. Levine TD. Small Fiber Neuropathy: Disease Classification Beyond Pain and Burning. J Cent Nerv Syst Dis. 2018 Apr 18;10:1179573518771703. doi: 10.1177/1179573518771703. PMID: 29706768; PMCID: PMC5912271. ↩︎
7. Full Erlanger-Gasser classification available from: https://www.researchgate.net/figure/Classification-of-the-peripheral-nerve-fibers_tbl1_255952315 [accessed 16 Nov 2024] ↩︎
8. The overall minimum incidence was 11.73 cases/100,000 inhabitants/year. The overall minimum prevalence was 52.95 cases/100,000.
   Simplified figures taken from: Peters MJ, Bakkers M, Merkies IS, Hoeijmakers JG, van Raak EP, Faber CG. Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology. 2013 Oct 8;81(15):1356-60. doi: 10.1212/WNL.0b013e3182a8236e. Epub 2013 Aug 30. PMID: 23997150.
   Note that some researchers like Oaklander and Novak use words such as, respectively, common and very common, although it is not completely clear what they mean by this. ↩︎
9. The whole process of developing and releasing a drug to the market takes about 13-15 years and the cost is estimated to be $2-3 billion. On the other hand, repurposing a drug on average costs $300 million and takes around 6.5 years. In the case of chronic pain, unless you are able to invent a drug that will work substantially better than the competition, it is more profitable to simply repurpose a medication from a different painful condition.
   Figures taken from: Nosengo, N. Can you teach old drugs new tricks?. Nature 534, 314–316 (2016). https://doi.org/10.1038/534314a ↩︎
10. Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol. 2017 Nov;16(11):934-944. doi: 10.1016/S1474-4422(17)30329-0. Erratum in: Lancet Neurol. 2017 Dec;16(12):954. doi: 10.1016/S1474-4422(17)30361-7. PMID: 29029847.  ↩︎
11. Khoshnoodi MA, Truelove S, Burakgazi A, et al. Longitudinal assessment of small fiber neuropathy: evidence of a non-length dependent distal axonopathy. JAMA Neurol 2016; 73: 684–90. ↩︎
12. Waheed W, Boyd J, Khan F, et al. Double trouble: para-neoplastic anti-PCA-2 and CRMP-5-mediated small fibre neuropathy followed by chorea associated with small cell lung cancer and evolving radiological features. BMJ Case Rep 2016; 2016: bcr2016215158. ↩︎
13. Whole paragraph reference:
    Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol. 2017 Nov;16(11):934-944. doi: 10.1016/S1474-4422(17)30329-0. Erratum in: Lancet Neurol. 2017 Dec;16(12):954. doi: 10.1016/S1474-4422(17)30361-7. PMID: 29029847.  ↩︎
14. Chen A, De E, Argoff C. Small Fiber Polyneuropathy Is Prevalent in Patients Experiencing Complex Chronic Pelvic Pain. Pain Med. 2019 Mar 1;20(3):521-527. doi: 10.1093/pm/pny001. PMID: 29447372. ↩︎
15. Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol. 2017 Nov;16(11):934-944. doi: 10.1016/S1474-4422(17)30329-0. Erratum in: Lancet Neurol. 2017 Dec;16(12):954. doi: 10.1016/S1474-4422(17)30361-7. PMID: 29029847. ↩︎
16. AbdelRazek MA, Chwalisz B, Oaklander AL, Venna N. Evidence of small-fiber neuropathy (SFN) in two patients with unexplained genital sensory loss and sensory urinary cystopathy. J Neurol Sci. 2017 Sep 15;380:82-84. doi: 10.1016/j.jns.2017.07.016. Epub 2017 Jul 9. PMID: 28870595; PMCID: PMC5999027. ↩︎
17. Novak P. Autonomic Disorders. Am J Med. 2019 Apr;132(4):420-436. doi: 10.1016/j.amjmed.2018.09.027. Epub 2018 Oct 9. PMID: 30308186. ↩︎
18. Popescu C. Severe Acute Axonal Neuropathy Induced by Ciprofloxacin: A Case Report. Case Rep Neurol. 2018 May 30;10(2):124-129. doi: 10.1159/000489303. PMID: 29928218; PMCID: PMC6006604. ↩︎
19. Francis JK, Higgins E. Permanent Peripheral Neuropathy: A Case Report on a Rare but Serious Debilitating Side-Effect of Fluoroquinolone Administration. Journal of Investigative Medicine High Impact Case Reports. 2014;2(3). doi:10.1177/2324709614545225 ↩︎
20. Estofan LJF, Naydin S, Gliebus G. Quinolone-Induced Painful Peripheral Neuropathy: A Case Report and Literature Review. Journal of Investigative Medicine High Impact Case Reports. 2018;6. doi:10.1177/2324709617752736 ↩︎
21. Oddly, Terkelsen et al (2017) mention antibiotic-related cases of SFN, but call them anecdotal, even though there was a large body of data of SFN linked to antibiotics, often confirmed by quantitative tests, by the time they wrote the article. ↩︎
22. Morales D, Pacurariu A, Slattery J, Pinheiro L, McGettigan P, Kurz X. Association Between Peripheral Neuropathy and Exposure to Oral Fluoroquinolone or Amoxicillin-Clavulanate Therapy. JAMA Neurol. 2019;76(7):827–833. doi:10.1001/jamaneurol.2019.0887 ↩︎
23. Cohen JS. Peripheral Neuropathy Associated with Fluoroquinolones. Annals of Pharmacotherapy. 2001;35(12):1540-1547. doi:10.1345/aph.1Z429 ↩︎
24. Karin Hedenmalm, Olav Spigset, Peripheral sensory disturbances related to treatment with fluoroquinolones, Journal of Antimicrobial Chemotherapy, Volume 37, Issue 4, April 1996, Pages 831–837, https://doi.org/10.1093/jac/37.4.831 ↩︎
25. Tan IL, Polydefkis MJ, Ebenezer GJ, Hauer P, McArthur JC. Peripheral Nerve Toxic Effects of Nitrofurantoin. Arch Neurol. 2012;69(2):265–268. doi:10.1001/archneurol.2011.1120 ↩︎
26. Zivkovic, Sasa A. MD; Lacomis, David MD†; Giuliani, Michael J. MD*. Sensory Neuropathy Associated With Metronidazole: Report of Four Cases and Review of the Literature. Journal of Clinical Neuromuscular Disease 3(1):p 8-12, September 2001. ↩︎
27. Peripheral neuropathy associated with prolonged use of linezolid
    Bressler, Adam M et al.
    The Lancet Infectious Diseases, Volume 4, Issue 8, 528 – 531 ↩︎
28. Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol. 2017 Nov;16(11):934-944. doi: 10.1016/S1474-4422(17)30329-0. Erratum in: Lancet Neurol. 2017 Dec;16(12):954. doi: 10.1016/S1474-4422(17)30361-7. PMID: 29029847. ↩︎
29. Fabry V, Gerdelat A, Acket B, Cintas P, Rousseau V, Uro-Coste E, Evrard SM, Pavy-Le Traon A. Which Method for Diagnosing Small Fiber Neuropathy? Front Neurol. 2020 May 5;11:342. doi: 10.3389/fneur.2020.00342. PMID: 32431663; PMCID: PMC7214721. ↩︎
30. Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain. 2013 Nov;154(11):2310-2316. doi: 10.1016/j.pain.2013.06.001. Epub 2013 Jun 5. PMID: 23748113; PMCID: PMC3845002. ↩︎