Home
Menu

ASRA Pain Medicine Update

A Review of Small Fiber Neuropathy

Nov 6, 2024, 04:15 AM by Joseph Levinson, MD, Reid Collis, MD, and Priyanka Singla, MD

Cite as: Levinson J, Collis R, Singla P. Small fiber neuropathy review. ASRA Pain Medicine News 2024;49. https://doi.org/10.52211/asra110124.008.

Introduction

Peripheral neuropathy is one of the most common causes of outpatient neurology appointments in the United States.1,2 Small fiber neuropathy (SFN) is a peripheral sensory neuropathy. In a population-based retrospective study, the prevalence of SFN was found to be 13.3 per 100,000.3

Pathophysiology

SFN predominantly affects the small, myelinated A(delta) fibers and the unmyelinated C-fibers.4 It affects both sensory and autonomic nerve fibers.5

SFN may be idiopathic or occur in association with other diseases. Diabetes mellitus is the most common identifiable cause.6 A number of conditions that can lead to SFN include dyslipidemia (particularly with elevated low-density lipoprotein LDL and triglyceride levels), chronic kidney disease, both non-alcoholic fatty liver disease and alcohol-associated cirrhosis, vitamin B deficiencies, hypo- and hyperthyroid dysfunction, connective tissue disorder, sarcoidosis, paraproteinemia, celiac disease, infectious etiologies (eg hepatitis C, HIV, Lyme disease, herpes zoster, and long COVID), familial amyloid, sodium channel gene variants, Fabry’s disease, paraneoplastic syndrome, and copper deficiency.4,6-17

Although the exact mechanism remains unclear, probable pathological processes include demyelination, distal axonal loss, and neuronal degeneration.5,9,18

Presentation

SFN typically presents with sensory symptoms, including burning, tingling, and numbness. The symptoms can be in “glove and stocking” distribution as seen in length-dependent processes and most seen in metabolic etiologies. It can also present as length-independent processes with patchy, proximal, or diffuse patterns, as seen in immune-mediated and paraneoplastic disorders.5,18,19 Less common presentations include mono/multiplex neuropathy, including meralgia paresthetica, vulvodynia, Wartenberg neuropathy, and burning mouth syndrome.19–22 Chronic itch and muscle cramps have been recognized as symptoms of SFN.8

Autonomic nervous system involvement can lead to dry mouth, dry eyes, constipation, bladder incontinence, orthostasis, skin discoloration, or sexual dysfunction.5

Testing and Diagnosis

The diagnostic criteria for SFN are largely based on the Besta criteria and the NEURODIAB expert panel.19,23

The Besta criteria include two of three of the following: clinical signs of SFN, an abnormal thermal threshold of the foot by quantitative sensory testing (QST), and decreased intraepidermal nerve fiber density (IENFD) at the distal leg.23 In a recent reappraisal study, Devigili et al concluded that the combination of clinical signs and abnormal QST and/or IENFD findings can more reliably lead to the diagnosis of SFN than the combination of abnormal QST and IENFD findings in the absence of clinical signs.24

The expert panel at NEURODIAB categorized SFN as19,25

  • possible SFN with length-dependent symptoms and/or clinical signs of small fiber damage; 
  • probable SFN with symptoms, clinical signs, and normal sural nerve conduction (NC) study; and 
  • definite SFN with symptoms and signs, normal sural NC study, and altered IENFD at the ankle and/or abnormal QST thermal thresholds at the foot. 

Diagnostic workup includes detailed history, a physical exam, laboratory studies, electrodiagnostic studies, skin biopsy, and QST. Sudomotor testing such as quantitative sudomotor axon reflex testing (QSART) and cardiovascular autonomic tests can support the diagnosis if applicable.5,11,26 

A diagnostic workup starts with a detailed history and a thorough physical exam. Multiple questionnaires have been validated for screening for SFN.26 Physical examination may reveal positive signs (allodynia, hyperalgesia) or negative sensory signs (decreased sensitivity to noxious stimuli).26 Small fiber function is examined by testing the patient’s response to heat, cold, and pain evoked by pinprick.26

Laboratory workup should be guided by history and physical, but consider lab evaluation for metabolic, infectious, toxic, immune-mediated, rheumatic, and hereditary disease as noted above.5,27

In pure SFN, nerve conduction studies are unremarkable but can be used to identify large fiber neuropathy or lumbar radiculopathy.27 Skin biopsy is the most reliable tool for diagnosis and is considered positive if there is decreased intraepidermal nerve fiber density (IENFD).24 QST is a set of psychosocial tests assessing somatic sensory input using testing algorithms, but it is limited by the time required and risk of bias, given that patient participation is required.24,28 If applicable, autonomic testing can supplement the diagnosis of SFN as small fibers are involved in the autonomic response. Tests include QSART and other sudomotor tests.29–31 Cardiovascular autonomic tests can be used but are expensive and take time to perform.29 Finally, corneal confocal microscopy detects a decrease of corneal nerve fiber density and is associated with SFN.32

In individuals with suspected SFN but in whom a diagnosis cannot clearly be made via these diagnostic tests and criteria, care should be taken to exclude common conditions that mimic SFN, including venous insufficiency, spinal stenosis, myelopathy, and psychosomatic disturbances.24

Current Therapeutic Modalities

Treatment for SFN should aim to control symptom neuropathic pain and treat underlying conditions.5 Treatment options include oral and topical pharmacological treatments, non-pharmacological therapies, and neuromodulation. Recommendations are largely based on guidelines for the treatment of neuropathic pain.

Pharmacological Treatment

According to neuropathic pain guidelines, gabapentin, pregabalin, tricyclic antidepressants, duloxetine, and venlafaxine are recommended as first-line options for neuropathic pain.33–36 Second-line options include tramadol, lidocaine patches, and capsaicin cream (in post-herpetic neuralgia and HIV neuropathies).35,36 Second- to third-line options include stronger opioids given the risk profile (abuse, lack of long-term safety trials).34,36 Stronger opioids can be considered as a first-line option for those with acute neuropathic pain or neuropathic cancer pain.33,36 Additional third- to fourth-line medications include antidepressants, such as bupropion, citalopram, and paroxetine and antiepileptics, such as carbamazepine, lamotrigine, and lacosamide as well as dextromethorphan, memantine, and mexiletine.33,36 More recently updated guidelines state many of these third-line medications have inconclusive evidence.35 Sodium channel-blocking anticonvulsants, including lacosamide, are showing promise in the treatment of SFN due to sodium channel gene mutations.37-39

Non-pharmacological Treatment

Exercise and diet interventions can be helpful for both neuropathic pain and autonomic symptoms in patients with diabetic neuropathy, HIV/AIDS, and chemotherapy-induced peripheral neuropathy (CIPN).40-42 Acupuncture for neuropathic pain has insufficient evidence to make a firm recommendation.43 Cognitive behavioral therapy, behavioral therapy, and mindfulness have mixed evidence for treating neuropathic pain but may be considered in concert with pharmacological therapy. 44-47

Neuromodulation

The FDA approved spinal cord stimulation (SCS) for use in painful diabetic neuropathy.48 Case reports have noted improved pain with SCS in patients with HIV-induced peripheral neuropathy, CIPN, and SFN with anhidrosis.49-51The benefits of SCS in these conditions are limited to the dermatomal region covered by the SCS implant, where further progression of the disease may lead to pain in dermatomes not covered by the previously implanted device. 

Conclusion

Small fiber neuropathy is a painful sensory neuropathy that causes a huge healthcare burden. Most of the treatment modalities are aimed at controlling neuropathic pain symptoms. There is a need to develop specific treatment guidelines for this debilitating disease.

Joe Levinson
Joseph Levinson, MD, is a resident physician in the department of physical medicine and rehabilitation at the University of Virginia in Charlottesville.
Reid Collins
Reid Collis, MD, is a resident physician in the department of physical medicine and rehabilitation at the University of Virginia in Charlottesville.
Priyanka Singla
Priyanka Singla, MD, is an assistant professor in the department of anesthesiology at the University of Virginia in Charlottesville.

References

  1. Burke JF, Skolarus LE, Callaghan BC, et al. Choosing wisely: highest-cost tests in outpatient neurology. Ann Neurol2013;73(5):679-83. https://doi.org/10.1002/ana.23865
  2. Tavee J. Office approach to small fiber neuropathy. Cleve Clin J Med2018;85(10):801-12. https://doi.org/10.3949/ccjm.85a.17124
  3. Johnson SA, Shouman K, Shelly S, et al. Small fiber neuropathy incidence, prevalence, longitudinal impairments, and disability. Neurology2021;97(22):e2236-47. https://doi.org/10.1212/WNL.0000000000012894
  4. Hovaguimian A, Gibbons CH. Diagnosis and treatment of pain in small-fiber neuropathy. Curr Pain Headache Rep2011;15(3):193-200. https://doi.org/10.1007/s11916-011-0181-7
  5. Cascio MA, Mukhdomi T. Small fiber neuropathy. In: StatPearlsStat Pearls Publishing; 2022.
  6. Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med2009;76(5):297-305. https://doi.org/10.3949/ccjm.76a.08070
  7. Oaklander AL. Increasing associations of long-COVID with small-fiber neuropathy. Pain2024;165(9):e93-5. https://doi.org/10.1097/j.pain.0000000000003260
  8. Sopacua M, Hoeijmakers JGJ, Merkies ISJ, et al. Small-fiber neuropathy: expanding the clinical pain universe. J Peripher Nerv Syst2019;24(1):19-33. https://doi.org/10.1111/jns.12298
  9. Lacomis D. Small-fiber neuropathy. Muscle Nerve2002;26(2):173-88. https://doi.org/10.1002/mus.10181
  10. Raasing LRM, Vogels OJM, Veltkamp M, et al. Current view of diagnosing small fiber neuropathy. J Neuromuscul Dis2021;8(2):185-207. https://doi.org/10.3233/JND-200490
  11. Strand N, Wie C, Peck J, et al. Correction to: small fiber neuropathy. Curr Pain Headache Rep2022;26(6):439. https://doi.org/10.1007/s11916-022-01050-w
  12. Gu X, Tang D, Xuan Y, et al. Association between non-alcoholic fatty liver disease and peripheral neuropathy in US population, a cross-sectional study. Sci Rep2023;13(1):5304. https://doi.org/10.1038/s41598-023-32115-4
  13. Jain J, Singh R, Banait S, et al. Magnitude of peripheral neuropathy in cirrhosis of liver patients from central rural India. Ann Indian Acad Neurol2014;17(4):409-15. https://doi.org/10.4103/0972-2327.144012
  14. Sène D. Small fiber neuropathy: diagnosis, causes, and treatment. Joint Bone Spine2018;85(5):553-9. https://doi.org/10.1016/j.jbspin.2017.11.002
  15. Ørstavik K, Norheim I, Jørum E. Pain and small-fiber neuropathy in patients with hypothyroidism. Neurology2006;67(5):786-91. https://doi.org/10.1212/01.wnl.0000234035.13779.4a
  16. Sahni V, Gupta N, Anuradha S, et al. Thyrotoxic neuropathy- an underdiagnosed condition. Med J Malaysia2007;62(1):76-7.
  17. Morkavuk G, Leventoglu A. Small fiber neuropathy associated with hyperlipidemia: utility of cutaneous silent periods and autonomic tests. ISRN Neurol2014;2014:579242. https://doi.org/10.1155/2014/579242
  18. Khoshnoodi MA, Truelove S, Burakgazi A, et al. Longitudinal assessment of small fiber neuropathy: evidence of a non-length-dependent distal axonopathy. JAMA Neurol2016;73(6):684-90. https://doi.org/10.1001/jamaneurol.2016.0057
  19. Devigili G, Cazzato D, Lauria G. Clinical diagnosis and management of small fiber neuropathy: an update on best practice. Expert Rev Neurother2020;20(9):967-80. https://doi.org/10.1080/14737175.2020.1794825
  20. Bohm-Starke N, Hilliges M, Falconer C, et al. Increased intraepithelial innervation in women with vulvar vestibulitis syndrome. Gynecol Obstet Invest1998;46(4):256-60. https://doi.org/10.1159/000010045
  21. Collins MP, Hadden RD. The nonsystemic vasculitic neuropathies. Nat Rev Neurol2017;13(5):302-16. https://doi.org/10.1038/nrneurol.2017.42
  22. Puhakka A, Forssell H, Soinila S, et al. Peripheral nervous system involvement in primary burning mouth syndrome—results of a pilot study. Oral Dis2016;22(4):338-44. https://doi.org/10.1111/odi.12454
  23. Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain2008;131(Pt 7):1912-25. https://doi.org/10.1093/brain/awn093
  24. Devigili G, Rinaldo S, Lombardi R, et al. Diagnostic criteria for small fibre neuropathy in clinical practice and research. Brain2019;142(12):3728-36. https://doi.org/10.1093/brain/awz333
  25. Tesfaye S, Boulton AJM, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care2010;33(10):2285-93. https://doi.org/10.2337/dc10-1303
  26. Terkelsen AJ, Karlsson P, Lauria G, et al. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol2017;16(11):934-44. https://doi.org/10.1016/S1474-4422(17)30329-0
  27. Strand N, Wie C, Peck J, et al. Small fiber neuropathy. Curr Pain Headache Rep2022;26(6):429-38.https://doi.org/10.1007/s11916-022-01044-8
  28. Backonja MM, Attal N, Baron R, et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain2013;154(9):1807-19. https://doi.org/10.1016/j.pain.2013.05.047
  29. Lefaucheur JP. Assessment of autonomic nervous system dysfunction associated with peripheral neuropathies in the context of clinical neurophysiology practice. Neurophysiol Clin2023;53(2):102858. https://doi.org/10.1016/j.neucli.2023.102858
  30. Fealey RD, Low PA, Thomas JE. Thermoregulatory sweating abnormalities in diabetes mellitus. Mayo Clin Proc1989;64(6):617-28. https://doi.org/10.1016/s0025-6196(12)65338-5
  31. Abraham A, Alabdali M, Alsulaiman A, et al. Laser doppler flare imaging and quantitative thermal thresholds testing performance in small and mixed fiber neuropathies. PLoS One2016;11(11):e0165731. https://doi.org/10.1371/journal.pone.0165731
  32. Brines M, Culver DA, Ferdousi M, et al. Corneal nerve fiber size adds utility to the diagnosis and assessment of therapeutic response in patients with small fiber neuropathy. Sci Rep2018;8(1):4734. https://doi.org/10.1038/s41598-018-23107-w
  33. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc2010;85(3 Suppl):S3-14. https://doi.org/10.4065/mcp.2009.0649
  34. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol2010;17(9):1113-e88. https://doi.org/10.1111/j.1468-1331.2010.02999.x
  35. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol2015;14(2):162-73. https://doi.org/10.1016/S1474-4422(14)70251-0
  36. Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag2007;12(1):13-21. https://doi.org/10.1155/2007/730785
  37. de Greef BTA, Hoeijmakers JGJ, Geerts M, et al. Lacosamide in patients with Nav1.7 mutations-related small fibre neuropathy: a randomized controlled trial. Brain2019;142(2):263-75.https://doi.org/10.1093/brain/awy329
  38. Dormer A, Narayanan M, Schentag J, et al. A Review of the therapeutic targeting of SCN9A and Nav1.7 for pain relief in current human clinical trials. J Pain Res2023;16:1487-98. https://doi.org/10.2147/JPR.S388896
  39. Faber CG, Hoeijmakers JGJ, Ahn HS, et al. Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol2012;71(1):26-39. https://doi.org/10.1002/ana.22485
  40. Zilliox LA, Russell JW. Physical activity and dietary interventions in diabetic neuropathy: a systematic review. Clin Auton Res2019;29(4):443-55. https://doi.org/10.1007/s10286-019-00607-x
  41. Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care2006;29(6):1294-9. https://doi.org/10.2337/dc06-0224
  42. Zhang YH, Hu HY, Xiong YC, et al. Exercise for neuropathic pain: a systematic review and expert consensus. Front Med2021;8:756940. https://doi.org/10.3389/fmed.2021.756940
  43. Ju ZY, Wang K, Cui HS, et al. Acupuncture for neuropathic pain in adults. Cochrane Database Syst Rev2017;12(12):CD012057. https://doi.org/10.1002/14651858.CD012057.pub2
  44. Evans S, Fishman B, Spielman L, et al. Randomized trial of cognitive behavior therapy versus supportive psychotherapy for HIV-related peripheral neuropathic pain. Psychosomatics2003;44(1):44-50. https://doi.org/10.1176/appi.psy.44.1.44
  45. Li C, Hou W, Ding D, et al. Evidence mapping based on systematic reviews of cognitive behavioral therapy for neuropathic pain. Neural Plast2023;2023:2680620. https://doi.org/10.1155/2023/2680620
  46. Eccleston C, Hearn L, Williams AC de C. Psychological therapies for the management of chronic neuropathic pain in adults. Cochrane Database Syst Rev2015;2015(10):CD011259.https://doi.org/10.1002/14651858.CD011259.pub2
  47. Castelnuovo G, Giusti EM, Manzoni GM, et al. Psychological treatments and psychotherapies in the neurorehabilitation of pain: evidences and recommendations from the Italian Consensus Conference on Pain in Neurorehabilitation. Front Psychol2016;7:115. https://doi.org/10.3389/fpsyg.2016.00115
  48. Yeung AM, Huang J, Nguyen KT, et al. Spinal cord stimulation for painful diabetic neuropathy. J Diabetes Sci Technol2024;18(1):168-92. https://doi.org/10.1177/19322968221133795
  49. Eckmann M, Papanastassiou A, Awad M. A unique case for spinal cord stimulation: successful treatment of small fiber neuropathy pain using multiple spinal cord stimulators. Case Rep Med2017;2017:6969285. https://doi.org/10.1155/2017/6969285
  50. D’Souza RS, Her YF, Jin MY, et al. Neuromodulation therapy for chemotherapy-induced peripheral neuropathy: a systematic review. Biomedicines2022;10(8). https://doi.org/3390/biomedicines10081909
  51. Abd-Elsayed A, Schiavoni N, Sachdeva H. Efficacy of spinal cord stimulators in treating peripheral neuropathy: a case series. J Clin Anesth2016;28:74-7. https://doi.org/10.1016/j.jclinane.2015.08.011
Close Nav