Office approach to small fiber neuropathy
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.
Inflammatory disease testing
Sjögren syndrome accounts for nearly 10% of cases of small fiber neuropathy. Associated neuropathic symptoms are often non–length-dependent, can precede sicca symptoms for up to 6 years, and in some cases are the sole manifestation of the disease.10 Small fiber neuropathy may also be associated with vasculitis, systemic lupus erythematosus, and other connective tissue disorders.
Testing should include:
- Erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibodies: though these are nonspecific markers of inflammation, they may support an immune-mediated etiology if positive
- Extractable nuclear antigen panel: Sjögren syndrome A and B autoantibodies are the most important components in this setting5,11
- The Schirmer test or salivary gland biopsy should be considered for seronegative patients with sicca or a suspected immune-mediated etiology, as the sensitivity of antibody testing ranges from only 10% to 55%.10
Thyroid function testing
Hypothyroidism, and less commonly hyperthyroidism, are associated with small fiber neuropathy.
Metabolic tests for liver and kidney disease
Renal insufficiency and liver impairment are well-known causes of small nerve fiber dysfunction. Testing should include:
- Comprehensive metabolic panel
- Gamma-glutamyltransferase if alcohol abuse is suspected, since heavy alcohol use is one of the most common causes of both large and small fiber neuropathy.
HIV and hepatitis C testing
For patients with relevant risk factors, HIV and hepatitis C testing should be part of the initial workup (and as second-tier testing for others). Patients who test positive for hepatitis C should undergo further testing for cryoglobulinemia, which can present with painful small fiber neuropathy.26
Serum and urine immunoelectrophoresis
Paraproteinemia, with causes ranging from monoclonal gammopathy of uncertain significance to multiple myeloma, has been associated with small fiber neuropathy. An abnormal serum or urine immunoelectrophoresis test warrants further investigation and possibly referral to a hematology-oncology specialist.
SECOND-TIER TESTING
Less common treatable causes of small fiber neuropathy may also be evaluated.
Copper, vitamin B1 (thiamine), or vitamin B6 (pyridoxine) deficiency testing. Although vitamin B6 toxicity may also result in neuropathy due to its toxic effect on the dorsal root ganglia, the mildly elevated vitamin B6 levels often found in patients being evaluated for neuropathy are unlikely to be the primary cause of symptoms. Many laboratories require fasting samples for accurate vitamin B6 levels.
Angiotensin-converting enzyme levels for sarcoidosis. Small fiber neuropathy is common in sarcoidosis, occurring in more than 30% of patients with systemic disease.27 However, screening for sarcoidosis by measuring serum levels is often falsely positive and is not cost-effective. In a study of 195 patients with idiopathic small fiber neuropathy,11 44% had an elevated serum level, but no evidence of sarcoidosis was seen on further testing, which included computed tomography of the chest in 29 patients.12 Thus, this test is best used for patients with evidence of systemic disease.
Amyloid testing for amyloidosis. Fat pad or bone marrow biopsy should be considered in the appropriate clinical setting.
Paraneoplastic autoantibody panel for occult cancer. Such testing may also be considered if clinically warranted. However, if a patient is found to have low positive titers of paraneoplastic antibodies and suspicion is low for an occult cancer (eg, no weight loss or early satiety), repeat confirmatory testing at another laboratory should be done before embarking on an extensive search for malignancy.
Ganglionic acetylcholine receptor antibody testing for autoimmune autonomic ganglionopathy. This should be ordered for patients with prominent autonomic dysfunction. The antibody test can be ordered separately or as part of an autoantibody panel. The antibody may indicate a primary immune-mediated process or a paraneoplastic disease.28
Genetic mutation testing. Recent discoveries of gene mutations leading to peripheral nerve hyperexcitability of voltage-gated sodium channels have elucidated a hereditary cause of small fiber neuropathy in nearly 30% of cases that were once thought to be idiopathic.29,30 Genetic testing for mutations in SCN9A and SCN10 (which code for the Nav1.7 and Nav1.8 sodium channels, respectively) is commercially available and may be considered for those with a family history of neuropathic pain in the feet or for young, otherwise healthy patients.
Fabry disease is an X-linked lysosomal disorder characterized by angiokeratomas, cardiac and renal impairment, and small fiber neuropathy. Treatment is now available, but screening is not cost-efficient and should only be pursued in patients with other symptoms of the disease.31,32
OTHER POSSIBLE CAUSES
Guillain-Barré syndrome
A Guillain-Barré syndrome variant has been reported that is characterized by ascending limb paresthesias and cerebrospinal fluid albuminocytologic dissociation in the setting of preserved deep tendon reflexes and normal findings on EMG.12 The clinical course is similar to that of typical Guillain-Barré syndrome, in that symptoms follow an upper respiratory or gastrointestinal tract infection, reach their nadir at 4 weeks, and then gradually improve. Some patients respond to intravenous immune globulin.
Vaccine-associated
Postvaccination small fiber neuropathy has also been reported. The nature of the association is unclear.33
Parkinson disease
Small fiber neuropathy is associated with Parkinson disease. It is attributed to a number of proposed factors, including neurodegeneration that occurs parallel to central nervous system decline, as well as intestinal malabsorption with resultant vitamin deficiency.34,35
Rapid glycemic lowering
Aggressive treatment of diabetes, defined as at least a 2-point reduction of serum hemoglobin A1c level over 3 months, may result in acute small fiber neuropathy. It manifests as severe distal extremity pain and dysautonomia.
In a retrospective study,36 104 (10.9%) of 954 patients presenting to a tertiary diabetic clinic developed treatment-induced diabetic neuropathy with symptoms occurring within 8 weeks of rapid glycemic control. The severity of neuropathy correlated with the degree and rate of glycemic lowering. The condition was reversible in some cases.
