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
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
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
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
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.
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
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.
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