Peripheral Neuropathies

Fall 2002
Volume 13, Number 2

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Small fiber neuropathy is a relatively common disorder often associated with systemic conditions, such as diabetes, HIV, and vasculitis. Painful burning feet with diminished pain and temperature perception, and in some cases autonomic dysfunction, characterize this syndrome. Despite the magnitude of the symptoms there are few objective measures to identify and quantify these neuropathies. Skin biopsy and new immunohistochemical staining techniques have facilitated the evaluation of this syndrome.

Introduction. Peripheral neuropathies involve different populations of nerve fibers. Most patients present with large fiber neuropathies characterized by numbness, tingling, weakness, loss of deep tendon reflexes, and abnormal electrophysiologic studies. A more enigmatic group of patients present with severe pain and a paucity of findings on clinical examination and electrophysiologic studies. Many of these patients have small fiber neuropathies. The disparity of subjective sensory complaints to objective signs sometimes leads to an erroneous diagnosis of psychogenic pain. Patients with these syndromes are often difficult to treat. Thus, prompt evaluation and accurate identification of these syndromes is important.

Clinical Presentation. The majority of patients with peripheral neuropathy exhibit evidence of large fiber involvement. Large or IA fibers subserve motor function, position, and vibration sensation. Patients with large fiber neuropathies, such as demyelinating hereditary sensory motor neuropathies complain of numbness, tingling, and weakness. Examination classically reveals diminished deep tendon reflexes, reduced vibratory and position senses, and distal weakness. The clinical impression is confirmed by electrophysiologic abnormalities, such as slowed motor and sensory conduction velocities, reduced motor and sensory action potential amplitudes, and denervation on the electromyogram.

In contrast, patients with small myelinated A delta and unmyelinated fiber C fiber involvement complain of severe pain and diminished thermal and pain perception. Due to difficulty characterizing the discomfort, orthopedists, podiatrists, and rheumatologists may initially evaluate patients for arthritic disorders. Pain is described as burning, prickling, stabbing, jabbing, or tight band-like pressure. Dysesthesias are initially localized to the toes, but may spread to the legs and even the hands and arms. The examination can be normal and reveal a stocking-glove distribution sensory loss with preserved strength. Achilles reflexes may be slightly reduced, but significantly diminished reflexes implicate large fiber co-involvement. These patients do not develop ulcers or Charcot joints.

Small Fiber Disorders. Systemic conditions associated with small fiber neuropathies include HIV, antiretroviral therapy for HIV1, Fabry's disease2, Hereditary Sensory Autonomic Neuropathy3, Friedrich ataxia4, systemic amyloid5, vasculitis6, and diabetes7. For many patients no specific etiology is defined.

Clinical Evaluation. For the patient with suspected small fiber neuropathy a thorough history and examination are essential. The history should contain a review of medical conditions, family history, medications, and toxic exposures. The comprehensive neurologic exam includes evaluation for orthostatic blood pressure and altered cutaneous sensation.

Laboratory Studies. Laboratory studies should include complete blood counts, serum urea nitrogen, BUN, creatinine, electrolytes, liver enzymes, thyroid function studies, fasting glucose, gylycosalated hemoglobin, B12, Vitamin E, fluorescent treponemal antibody test (FTA), erythrocyte sedimentation rate (ESR), human immunodeficiency virus (HIV), antinuclear antibody (ANA), anti Hu, immunofixation, and immunoglobulin electrophoresis.

Electrodiagnostic Studies. Electromyography and nerve conduction studies assess large fiber involvement, but are of only exclusive value for following the small fiber syndromes. Reduced sensory nerve action potential may be the earliest signs of large fiber co-involvement in mixed disorders. The large fiber component may become evident as the neuropathy progresses.

Sensory Threshold and Autonomic Studies. Sensory and autonomic function has been studied in patients with small fiber neuropathies. Thermal sensitivity in the feet was reported as abnormal in 86% of patients with diabetic neuropathy. The impairment was prominent in patients with clinical evidence of small fiber neuropathy and painful feet. Sweating mediated by unmyelinated axons was also abnormal in studies of diabetic patients.8, 9 Stewart, in 40 patients with distal small fiber neuropathy found sweat testing abnormal in 80% and minor heart rate abnormalities in 28%..10 Novak evaluated autonomic involvement in painful neuropathies and identified preferential involvement of cholinergic and skin vasomotor fibers.11 Sensory and autonomic testing are important tools for evaluating painful neuropathies.

Neuropathologic Techniques. Epidermal nerves identified by Langerhans in 1868, are the terminal fibers of dorsal root ganglia orgin.12 Prior attempts to quantify small fibers on skin biopsy utilizing silver and cholinesterase staining yielded inconsistent results.13, 14 Sural nerve biopsy is useful for assessment of large myelinated fibers, but its sensitivity for small fibers is diminished by the inclusion of proximal non-end organ trunks and small fiber autonomic nerves. Sural nerve study also requires electron microscopy.

Several authors describe the application of a new technique utilizing a neuronal antibody to protein gene product 9.5(PGP 9.5). This method provides reproducible staining of small nerve fibers in the dermis and epidermis. Fiber loss and degeneration are readily identified and quantified. Specimens are obtained by skin or skin blister biopsy. Compared to sural nerve biopsy these techniques are relatively painless and noninvasive. Serial biopsies are particularly advantageous for staging neuropathies and determining the effectiveness of neurotrophic therapy. Biopsies are usually obtained from the dorsum of the foot or hand. The spatial distribution of a neuropathy may be determined by obtaining additional samples from proximal sites, such as the thigh and trunk.15-17

The function of epidermal nerve fibers has not been well understood. Recent studies seem to correlate nociceptor function with intraepidermal nerve fiber (IENF) density. For example, treatment with capsaicin reduces cutaneous pain sensitivity and is associated with small epidermal nerve fiber loss. As sensation recovers serial biopsies reveal increased fiber density.18 Kennedy and Wendelschafer-Crabb found this technique to be valuable for following small fiber function in diabetes. Clinical estimates of severity correlated with the severity of small fiber loss.19 McCarthy reported decreased IENF density in untreated and treated (antiviral therapy) HIV patients with sensory neuropathy. In a third group of HIV patients without clinical manifestation of neuropathy, diminished IENF density suggested subclinical disease.1 Holland et al, evaluated patients with no specific cause for painful feet and found fiber loss in the subpapillary plexus beneath the epidermis. Biopsies also demonstrated increased branching and swelling, probably reflecting a pre-degenerative phase of neuropathy.

Two distinct clinical patterns emerge based on the spatial distribution of symptoms and the IENF studies. The majority of patients present with progressive peripheral dysesthesias and distal fiber loss consistent with a length dependent or dying back process. A second smaller group of patients experience a monophasic illness characterized by the acute onset of generalized cutaneous burning of the limbs and trunk followed by slow recovery. In this group, IENF studies reveal generalized small fiber loss without the proximal-distal gradient. These findings suggest direct involvement at the dorsal root ganglia.20, 21

Restless Leg Syndrome. Restless Leg Syndrome (RLS) may occur without apparent cause or may be associated with medical conditions. Peripheral neuropathy has been associated with RLS.22-24 IENF studies demonstrated a subclinical small fiber neuropathy in a subset of RLS patients without dysesthesias. This may explain the response to pain medication in some patients with RLS.25

Treatment. Treatment options for neuropathic pain include anticonvulsants, antidepressants, anti-inflammatory medications, immunosuppressants, lidocaine, mexilitene, opioids, topical agents, nerve blocks, nerve stimulators, physical therapy, acupuncture, relaxation, and meditation techniques. A host of over-the-counter remedies have also been tried. In our experience a variable degree of pain relief is achieved with one or a combination of these medications or techniques. Adverse effects, such as drowsiness, confusion, and anorexia limit the effective dose of many medications. The initial drugs of choice are tricyclic antidepressants and anticonvulsants.26

Conclusion. Many individuals suffer from burning feet due to small fiber neuropathies. The development of immunohistochemical staining of small epidermal nerve fibers has increased our understanding of these disorders. Application of this technique allows us to identify these syndromes and follow the effectiveness of new therapies.

Address comments and questions to:

Marc M. Treihaft, MD, FAAN
3535 S. Lafayette, #204
Englewood, CO 80113

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