ADVERTISEMENT

Office approach to small fiber neuropathy

Cleveland Clinic Journal of Medicine. 2018 October;85(10):801-812 | 10.3949/ccjm.85a.17124
October 1, 2018|Cleveland Clinic Journal of Medicine
Jinny O. Tavee, MD
Author and Disclosure Information

Jinny O. Tavee, MD
Medical Director, Neuromuscular Division, Associate Professor, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL

Address: Jinny O. Tavee, MD, Department of Neurology, Northwestern University Feinberg School of Medicine, 710 N Lakeshore Drive, Abbott Hall, Suite 1114, Chicago, IL 60611; jinny.tavee@nm.org; htavee@hotmail.com

ABSTRACT

Small fiber neuropathy is often characterized by neuropathic pain in the feet with normal nerve conduction studies and neurologic examination. Diagnosis requires specialized nerve tests, including autonomic studies and a skin biopsy study showing reduced intraepidermal nerve fiber density. Small fiber neuropathy has numerous causes but is often idiopathic. A practical approach to identifying an underlying cause is to first screen for common ones and then proceed with further testing as needed. Treatment consists of correcting the underlying cause, managing pain, and modifying lifestyle.

KEY POINTS

  • Patients typically develop a symmetric “stocking-glove” pattern of sensory loss in the feet and hands.
  • The diagnosis may be confirmed with skin biopsy for nerve fiber density, which can easily be done in a clinic setting with commercially available kits.
  • Diabetes is the most common identifiable cause of small fiber neuropathy.
  • Serologic testing can help uncover a vitamin deficiency or other potentially treatable condition.
  • Antiepileptics, antidepressants, and topical agents are first-line drugs for managing pain.

DIAGNOSTIC TESTING

Although patients with either large or small fiber neuropathy may have subjective hyperesthesia or numbness of the distal lower extremities, the absence of significant abnormalities on neurologic examination should prompt consideration of small fiber neuropathy.

Electromyography worthwhile

Nerve conduction studies and needle electrode examination evaluate only large nerve fiber conditions. While electromyographic results are normal in patients with isolated small fiber neuropathy, the test can help evaluate subclinical large nerve fiber involvement and alternative diagnoses such as bilateral S1 radiculopathy. Nerve conduction studies may be less useful in patients over age 75, as they may lack sural sensory responses because of aging changes.13

Skin biopsy easy to do

Skin biopsy for evaluating intraepidermal nerve fiber density is one of the most widely used tests for small fiber neuropathy. This minimally invasive procedure can now be performed in a primary care office using readily available tools or prepackaged kits and analyzed by several commercial laboratories.

Figure 1.
Skin specimens are obtained by 3-mm punch biopsy of the distal leg and thigh and are sent to a laboratory for analysis. The sample is immunostained against a panaxonal marker nerve, and fiber densities are calculated (Figure 1).14 The results are compared with normative data for age and sex, and a formal report with the diagnosis is sent to the ordering physician. The test has a sensitivity of 88%.5,15

Reduced intraepidermal nerve fiber density on skin biopsy has been described in various other conditions such as fibromyalgia and chronic pain syndromes.16,17 The clinical significance of these findings remains uncertain.

Quantitative sudomotor axon reflex testing

Quantitative sudomotor axon reflex testing (QSART) is a noninvasive autonomic study that assesses the volume of sweat produced by the limbs in response to acetylcholine. A measure of postganglionic sympathetic sudomotor nerve function, QSART has a sensitivity of up to 80% and can be used to diagnose small fiber neuropathy.18 In a series of 115 patients with sarcoidosis small fiber neuropathy,9 the QSART and skin biopsy findings were concordant in 17 cases and complementary in 29, allowing for confirmation of small fiber neuropathy in patients whose condition would have remained undiagnosed had only one test been performed. QSART can also be considered in cases where skin biopsy may be contraindicated (eg, patient use of anticoagulation).  Of note, the study may be affected by a number of external factors, including caffeine, tobacco, antihistamines, and tricyclic antidepressants; these should be held before testing.

Other diagnostic studies

Other tests may be helpful, as follows:

Tilt-table and cardiovagal testing may be useful for patients with orthostasis and palpitations.

Thermoregulatory sweat testing can be used to evaluate patients with abnormal patterns of sweating, eg, hyperhidrosis of the face and head.

Figure 2. Corneal confocal microscopy in small fiber neuropathy: A, normal corneal nerve fibers and branching; B, marked reduction of corneal nerve fibers.
Corneal confocal microscopy is a promising new noninvasive diagnostic tool that provides objective quantification of small nerve fibers in the subbasal layer of the cornea, which holds the densest concentration of these fibers (Figure 2).19 Routine corneal confocal microscopy is currently limited to ophthalmology, but the growing use of the corneal findings as a marker for therapeutic interventions in neuropathy studies may prompt more widespread availability soon.

INITIAL TESTING FOR AN UNDERLYING CAUSE

Although up to half of cases of small fiber neuropathy are idiopathic, it is important to search for an identifiable underlying cause amenable to treatment.5,20 A cost-effective approach is to start with a battery of blood tests that cover the most common causes, and then proceed with second-tier testing as needed (Table 2).

Glucose tolerance test for diabetes

Diabetes is the most common identifiable cause of small fiber neuropathy and accounts for about a third of all cases.5 Impaired glucose tolerance is also thought to be a risk factor and has been found in up to 50% of idiopathic cases, but the association is still being debated.21

While testing for hemoglobin A1c is more convenient for the patient, especially because it does not require fasting, a 2-hour oral glucose tolerance test is more sensitive for detecting glucose dysmetabolism.22

Lipid panel for metabolic syndrome

Small fiber neuropathy is associated with individual components of the metabolic syndrome, which include obesity, hyperglycemia, and dyslipidemia. Of these, dyslipidemia has emerged as the primary factor involved in the development of small fiber neuropathy, via an inflammatory pathway or oxidative stress mechanism.23,24

Vitamin B12 deficiency testing

Vitamin B12 deficiency, a potentially correctable cause of small fiber neuropathy, may be underdiagnosed, especially as values obtained by blood testing may not reflect tissue uptake. Causes of vitamin B12 deficiency include reduced intake, pernicious anemia, and medications that can affect absorption of vitamin B12 (eg, proton pump inhibitors, histamine 2 receptor antagonists, metformin).

Testing should include:

  • Complete blood cell count to evaluate for vitamin B12-related macrocytic anemia and other hematologic abnormalities
  • Serum vitamin B12 level
  • Methylmalonic acid or homocysteine level in patients with subclinical or mild vitamin B12 deficiency, manifested as low to normal vitamin B12 levels (< 400 pg/mL); methylmalonic acid and homocysteine require vitamin B12 as a cofactor for enzymatic conversion, and either or both may be elevated in early vitamin B12 deficiency.

Celiac antibody panel

Celiac disease, a T-cell mediated enteropathy characterized by gluten intolerance and a herpetiform-like rash, can be associated with small fiber neuropathy.25 In some cases, neuropathy symptoms are preceded by the onset of gastrointestinal symptoms, or they may occur in isolation.25

ADVERTISEMENT
ADVERTISEMENT
ADVERTISEMENT