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ASRA Pain Medicine News, November 2024

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.

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