Continuing Education Activity
Small fiber neuropathy presents with burning pain, often beginning in the extremities, most notably in the feet. It is due to the involvement of A-delta and C nerve fibers. It may occur idiopathically or due to metabolic, hereditary, infectious, immune-mediated, or toxic etiologies. It must be promptly diagnosed and treated to avoid pain, debility, or possible large nerve fiber involvement. This activity reviews the evaluation and treatment of small fiber neuropathy and highlights the role of the interprofessional team in evaluating and treating patients with this condition.
- Identify the different etiologies of small fiber neuropathy.
- Review the proper evaluation of small fiber neuropathy, including patient history and examination findings.
- Outline the management options available for small fiber neuropathy.
- Describe interprofessional team strategies useful for enhancing care coordination and communication to improve outcomes in small fiber neuropathy.
Peripheral neuropathy is a prevalent problem, affecting an estimated 15 to 20 million people in the United States above the age of 40. It is the most common cause of outpatient neurology appointments in the United States and accounts for healthcare spending of over $10 billion each year.
In many affected individuals, such neuropathies involve the small nerve fibers, including the peripheral thinly myelinated Aδ fibers as well as unmyelinated C nerve fibers. Involvement of these small nerve fibers, referred to as small fiber neuropathy (SFN), typically presents with pain, burning, numbness, and tingling, often in a stocking-glove distribution, with symptoms typically starting in the feet and ascending superiorly.
Small fiber neuropathy affects the small myelinated Aδ-fibers as well as the unmyelinated C-fibers. SFN may affect both sensory and autonomic fibers, leading to sensory changes, autonomic dysfunction, or a combination of symptoms.
The autonomic small nerve fibers transmit thermoregulatory, cardiovascular, gastrointestinal, sudomotor, urogenital, and other autonomic signals, while the somatic small nerve fibers transmit information regarding pain, temperature, and itch.
General symptoms of SFN include fatigue, cognitive disturbances, headache, and widespread musculoskeletal pain, and thus may negatively impact their quality of life. SFN is associated with a multitude of diseases; however, it may also present idiopathic. The etiologies of SFN can be broken down into six categories.
- Fabry's disease
- Mutation in sodium channels
- Wilsons disease
- Familial amyloidosis
- Neurotoxic drugs
- Ehlers- Danlos
- Monoclonal gammopathy
- Acute inflammatory small fiber neuropathy
- Connective tissue disease
- Chronic inflammatory demyelinating polyneuropathy
- Rheumatic diseases (undifferentiated connective tissue disorders, rheumatoid arthritis, psoriatic arthropathy)
- Sjögren syndrome, Primary systemic amyloidosis
- Diabetes mellitus
- Impaired glucose tolerance
- Vitamin B12 deficiency
- Copper deficiency
- Abnormal thyroid function
A cross-sectional epidemiological retrospective study of SFN conducted in the Netherlands found an incidence of 12 cases per 100,000/year, with a prevalence of 53 cases per 100,000. This study found SFN to be more commonly seen in men and more frequently diagnosed in patients over the age of 65.
These disease rates are likely underestimated due to a lack of awareness and lack of standardized diagnostic criteria, with rates expected to increase in the coming years with increased awareness of SFN.
The nerves of the peripheral nervous system are classified into different types based on a multitude of factors, including diameter, myelination, and conduction velocity, see Table 1. Aα- and Aβ-fibers are considered large nerve fibers, while Aδ- and C-fibers are considered small nerve fibers. Amongst small fibers, myelinated Aδ-fibers demonstrate faster conduction velocities (4 to 36 m/s) than unmyelinated C-fibers (0.4 to 2.8 m/s). This difference is due to the larger diameter and presence of myelin.
SFN is defined as a dysfunction of these small Aδ and C fibers, which occurs by an unclear mechanism. Demyelinating processes are unlikely to be the underlying pathogenesis as demyelinating processes do not solely affect small fibers. Thus it is believed that distal axonal loss or neuronal degeneration is the most likely underlying etiology for SFN.
|Aα- and Aβ-fibers
Aα: 12-20 μm
Aβ: 6-12 μm
Aα: 72-120 m/s
Aβ: 36-72 m/s
Proprioception, light touch
Nocioception (mechanical, chemical, thermal)
Temperature, itch, Nocioception (mechanical, chemical, thermal)
History and Physical
A thorough history and physical exam are crucial in the evaluation of SFN. Patients with SFN often present initially with sensory symptoms, including pain, burning, numbness, and tingling. While most cases of SFN present in a length-dependent pattern (symptoms beginning in the feet and advancing proximally), some cases have followed either a non-length-dependent (proximal, diffuse, or patchy distribution involving different body parts including the mouth, face, trunk, scalp, or upper limbs before or simultaneously with lower limb involvement) or an asymmetric mono/multiplex neuropathy (involvement of one or more sensory peripheral nerve, often with burning mouth syndrome, vulvodynia, or notalgia and meralgia parasthetica).
Length-dependent SFN often occurs due to metabolic causes, including diabetes or neurotoxic exposure, while non-length-dependent SFN often occurs due to paraneoplastic disorders and immune-mediated pathologies such as Sjögren syndrome.
Patients with SFN often present initially with neuropathic foot pain. Symptoms may be mild at onset, with some patients noting a vague discomfort in the feet. Reported descriptions may include numbness in the toes, a wooden quality in the feet, or a feeling that the patient describes as walking on sand, golf balls, or pebbles. Burning pain in the feet expending proximally in a stocking-glove distribution is often the most bothersome and typical symptom.
This burning is often accompanied by aching or stabbing pains, pins and needles sensation, electric shock, or cramping in the feet and calves. Patients with SFN typically experience the worst of their symptoms at night, often complaining of restless legs, bed sheet intolerance, and clothes causing allodynia or dysesthesia. Some patients do not report pain but note a feeling of swelling and tightness in their feet. Autonomic fiber involvement may lead to additional symptoms, including dry mouth, dry eyes, constipation, bladder incontinence, orthostatic dizziness, sexual dysfunction, red or white skin discoloration, or trouble sweating.
Upon initial presentation, a detailed history should be obtained, including medical history, family history, alcohol use, and use of neurotoxic medications such as colchicine, metronidazole, and chemotherapeutics.
Given the known association between SFN and conditions such as hepatitis C and Human immunodeficiency virus (HIV), the examiner should inquire about relevant risk factors such as sexual history, intravenous drug use, and blood transfusions. A thorough neurologic physical exam can differentiate small fiber from large fiber neuropathy.
Examination often demonstrates allodynia, hyperalgesia, or reduced thermal and pinprick sensation in the affected area. Findings such as weakness, reduced proprioception, and absent deep tendon reflexes should not be seen in SFN, as they instead indicate large fiber involvement. When history is suspicious for autonomic fiber involvement, vitals should be checked to screen for orthostatic hypotension, and skin should be checked, which may appear dry, shiny, atrophic, discolored, or mildly edematous due to vasomotor or sudomotor abnormalities. A physical exam should also evaluate any previously mentioned systemic disorders known to be associated with SFN.
Diagnostic evaluation for suspected SFN often involves a multitude of tests. While nerve conduction studies and needle EMG demonstrate only large fiber involvement leading to normal results in patients with isolated small fiber involvement, these tests may be useful in evaluating subclinical large nerve fiber involvement and alternative diagnoses, including alternative diagnoses lumbosacral radiculopathy.
Small fibers travel too slowly, and their conduction responses cannot be captured by a nerve conduction study, which is a routine test performed to evaluate large sensory and motor nerve fibers. Therefore, a skin biopsy is often used to assess small sensory nerve fibers in the skin. Skin biopsy is a minimally invasive procedure that may also be used to evaluate intraepidermal nerve fiber density. Skin specimens are typically obtained by a 3 mm punch biopsy at the distal leg and thigh and are then sent for laboratory analysis. SFN may be diagnosed if the intraepidermal nerve fiber density is less than normal. Skin biopsy testing has an 88% sensitivity in the diagnosis of SFN.
An additional test that may be performed is quantitative sudomotor axon reflex testing (QSART), a noninvasive autonomic study used to assess the volume of sweat produced in the limbs in response to acetylcholine. QSART can measure postganglionic sympathetic sudomotor nerve function and may provide a sensitivity of up to 80% in the diagnosis of SFN.
Additional useful diagnostic tests may include tilt-table and cardiovagal testing for patients with palpitations and orthostasis and thermoregulatory sweat testing for patients with abnormal sweating patterns.
The diagnosis of SFN remains difficult as there is not yet an available gold standard test. While some sources have suggested that the presence of at least two abnormal findings, including clinical presentation, quantitative sensory testing (QST), and skin biopsy are the best diagnostic criteria for SFN, other sources have included the inclusion of QSART instead of skin biopsy for diagnosis.
While as many as half of cases of SFN are considered idiopathic, it is important to attempt to find the underlying cause to find a possible treatment. Testing may include the following:
First Tier Studies
- Complete blood cell count to evaluate for hematologic abnormalities
- Complete metabolic panel to assess for renal or hepatic impairment
- Lipid panel to evaluate for hyperlipidemia
- Erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibody to evaluate for inflammatory disease
- Thyroid-stimulating hormone, free T4, and T3 levels to assess for hypothyroidism
- 2-hour oral glucose tolerance test and hemoglobin A1C to evaluate for diabetes and impaired glucose tolerance
- Extractable nuclear antigen testing for Sjögren syndrome A and B antibodies
- Vitamin B12, methylmalonic acid, and homocysteine levels to assess for vitamin B12 deficiency
- Tissue transglutaminase and antigliadin antibodies to evaluate for Celiac disease
- Human immunodeficiency virus (HIV) and hepatitis C virus antibodies to evaluate for HIV and hepatitis
Second Tier Studies
- Angiotensin-converting enzyme to evaluate for sarcoidosis
- Thiamine (vitamin B1) to evaluate for vitamin B1 deficiency
- Pyridoxine (vitamin B6) to assess for vitamin B6 deficiency
- Copper level to evaluate for copper deficiency
- Serum and urine monoclonal protein analysis, nerve biopsy, and fat pad analysis to evaluate for systemic amyloidosis
- Paraneoplastic autoantibody panel to evaluate for paraneoplastic disease
- Ganglionic acetylcholine receptor antibodies to evaluate for autoimmune autonomic ganglionopathy
- SCN9A and SCN10A genes to evaluate for hereditary small fiber neuropathy
- GLA gene to evaluate for Fabry disease
- Transthyretin gene to evaluate for familial amyloidosis
- ABCA1 gene to evaluate for Tangier disease
Treatment / Management
The management of SFN should involve treatment of the underlying etiology in patients with an identified cause of neuropathy. Diabetes should be managed not only with glycemic and lipid-lowering agents but also with lifestyle modifications focusing specifically on nutrition and exercise. Since walking and running may be difficult for SFN patients due to pain, alternative exercises, including aqua therapy, swimming, and stationary cycling, may be pursued.
In cases of Vitamin B12 deficiency, parenteral rather than oral supplementation is often recommended as the deficiency is more often due to reduced absorption rather than low dietary intake. A suggested regimen may consist of intramuscular or subcutaneous methylcobalamin 1,000 μg injection given once daily for one week, followed by once weekly for one month, followed by a monthly maintenance dose for the next 6 to 12 months.
As per anecdotal case reports, painful SFN and dysautonomia secondary to Sjögren syndrome have been treated successfully with corticosteroids, intravenous immune globulin (IVIG), and other immunosuppressants.
SFN associated with sarcoidosis may also be treated with IVIG as well as with infliximab and combination therapy. Patients with SFN secondary to celiac disease may find relief from SFN symptoms with a gluten-free diet.
Pain management is important in the treatment of SFN, as neuropathic pain may be debilitating and cause a decrease in function and depression. Pain secondary to SFN is often best managed with a multidisciplinary team, which may involve a primary care physician, a pain management specialist, a neurologist, as well as a psychiatrist. Medications used in the treatment of SFN include anticonvulsants, antidepressants, topical anesthetics, narcotics, non-narcotic analgesics, and antiarrhythmics, while nonpharmacologic treatments such as heat, ice, massage of painful areas, and transcutaneous electrical nerve stimulation (TENS) may also be used.
First-line medications are the anticonvulsant medications gabapentin and pregabalin, the tricyclic antidepressants amitriptyline and nortriptyline, the semisynthetic opioid analgesic tramadol, and a 5% topical lidocaine patch. These medications may be used either alone or in combination. Nonsteroidal anti-inflammatory medications and selective serotonin reuptake inhibitors may also be used; however, they are often less effective than the previously mentioned drugs. The voltage-gated sodium channel blocker Mexiletine, typically used as an antiarrhythmic medication, may help with refractory pain related to sodium channel dysfunction.
Opioid medications should be reserved only for refractory cases; given the potential for addiction, however, they may sometimes be necessary for patients with debilitating pain who do not respond to other medications. Regimens that combine medications with different mechanisms may be most effective. A study that evaluated a treatment regimen combining gabapentin and nortriptyline found such treatment to be more effective than either drug alone in treating neuropathic pain.
Treatment with inhaled cannabis was found to reduce pain in patients with diabetic neuropathy and HIV; however, side effects including somnolence, euphoria, and cognitive impairment were noted. Holistic therapies such as yoga, tai chi, and meditation may help pain, quality of life, and balance in patients with neuropathy.
In many cases, neuromodulation has proven effective in treating the painful symptoms of SFN. Treatments include traditional dorsal column stimulation, dorsal horn stimulation, and dorsal root ganglion stimulation.
As previously mentioned, it is imperative to differentiate small fiber from large fiber neuropathy. Findings such as weakness, reduced proprioception, and absent deep tendon reflexes indicate large fiber (Aα- and Aβ) involvement and may differentiate large fiber neuropathy from small fiber neuropathy.
EMG and nerve conduction studies are also helpful in this differentiation, as these studies will be normal with small fiber involvement and abnormal with large fiber involvement. EMG may also differentiate from lumbar radiculopathy, which may also present with lower extremity burning and numbness. Differentiation between these conditions is imperative for implementing a proper treatment regimen, as management of these conditions varies.
|Treatment (medication Category)
||Dosage (per day)
||Common Adverse Effects
||sedation, dizziness, weight gain, peripheral edema
||sedation, dizziness, weight gain, peripheral edema
||weight loss, cognitive slowing, sedation, renal stones, paresthesias, glaucoma, depression with suicidal ideation
||sedation, anticholinergic effects, weight gain, arrhythmia, sexual dysfunction
||sedation, anticholinergic effects, weight gain, arrhythmia, sexual dysfunction
|Lidocaine 5% patch (topical anesthetic)
||3 patches for 12 hours
||local edema, erythema, burning
|Capsaicin 0.75% (topical anesthetic)
||apply up to 4 times per day
|Tramadol (semisynthetic opioid analgesic)
||sedation, seizures, dizziness, constipation, nausea
|Mexiletine (voltage-gated sodium channel blocker)
||nausea, vomiting, dry mouth, abdominal pain
Table 2 
Most patients with SFN experience a slowly progressive course, with a clinical plateau reached following years of symptom development. One study showed only 13% of 124 patients with SFN had developed signs of large-fiber involvement over a two-year period.
This same study found that none of the patients developed Charcot joints, weakness, sensory ataxia, or foot ulcers, which are symptoms typically seen in patients with chronic or severe large fiber neuropathy. It additionally found that over half of the patients either improved or remained stable over the two years. Further studies would be useful in evaluating symptomatic progression over a period longer than two years.
The risk for complications in patients with SFN often varies based on the underlying etiology. Proper treatment should be sought out and implemented to prevent disease progression related to underlying medical conditions. The pain brought about by SFN may also cause dysfunction and inactivity in patients. For this reason, proper pain control is imperative for the continuation of physical activity to prevent complications of inactivity, including weight gain and depression.
Deterrence and Patient Education
Patients diagnosed with SFN should be educated regarding strategies to lessen the burden of their neuropathic pain and the proper management of any possible underlying condition.
- Patients with diabetes should be educated regarding diet, exercise, and insulin (if necessary). Regular outpatient follow-up should be arranged with primary care, podiatry, ophthalmology, endocrinology, and cardiology.
- Patients with SFN secondary to alcohol should be provided with resources for alcohol abstinence.
- Patients with nutritional deficiencies such as vitamin B12 deficiency should be educated on proper supplementation.
- Patients with SFN in infectious etiologies such as HIV, Lyme, and hepatitis C should be educated regarding proper antiviral treatment for their underlying infection.
- Patients with immune-mediated and hereditary etiologies of their SFN should be educated regarding treatment strategies and other possible complications related to their underlying condition.
In addition to education regarding the proper management of underlying conditions related to SFN, an emphasis should be placed on the continuation of physical activity.
Enhancing Healthcare Team Outcomes
A strong relationship between the clinician and the patient is imperative for improving healthcare outcomes. Good communication amongst an interprofessional team is key, which may include a neurologist, pain medicine physician, physiatrist, primary care clinician, dietician, and nurse.
SFN may cause debilitating pain without proper management, often leading to deconditioning and depression. Cause-specific treatment, pain control, and lifestyle modification are key elements in the team approach to managing small fiber neuropathy.