|
The definition of peripheral neuropathy can range from a condition in
which there is damage to nerve fibers within the peripheral nervous system
to the more traditional distal symmetric polyneuropathy.1 Likewise,
the causes of peripheral neuropathy are diverse and include metabolic,
infectious, paraneoplastic, toxic, drug-induced, nutritional, hereditary,
traumatic, immune-mediated or inflammatory, and idiopathic etiologies.
Diagnosing the cause of a patient's peripheral neuropathy can therefore be a
challenging and complex task, oftentimes with no specific etiology
identified. There are, however, useful diagnostic tools and clinical
approaches that can simplify this process and successfully lead to a
treatable and potentially reversible cause of the neuropathy since, unlike
the CNS, the peripheral nervous system can regenerate, leading to a
satisfactory outcome for patient and diagnostician alike.
Peripheral Neuropathy. In this review, peripheral neuropathy will
refer to a polyneuropathy in which multiple and usually bilateral large
fiber peripheral nerves are involved. Typical symptoms of peripheral
neuropathy are numbness and tingling in the feet and hands that may progress
proximally with varying degrees of muscle weakness, atrophy, ataxia, painful
paresthesias, and autonomic dysfunction. There are different types of
peripheral neuropathies that can affect primarily sensory, motor, autonomic,
or mixed fibers. The pathologic process can produce injury or dysfunction at
the level of the axon, often resulting in Wallerian degeneration, which
histologically results in degeneration of the terminal portion of the
intramuscular nerve at a time when the proximal parts of the same fibers are
relatively intact.2 The process can also or alternatively cause injury at
the level of the Schwann cell, which produces the myelin in which axons are
sheathed for more efficient conduction of nerve impulses along the length of
the nerve fiber. Demyelination can be focal, multifocal or diffuse. Any of
these processes can cause acute or chronic, focal or diffuse, axonal or
demyelinating patterns of neuropathic dysfunction which are associated with
different etiologies. Therefore, characterizing the pathophysiology of any
particular neuropathy can be helpful in determining etiology as well as
prognosis, since remyelination occurs faster and more completely than does
regeneration of nerve fibers.2
It is important to make sure that a peripheral neuropathy is present,
rather than other disorders that can produce similar symptoms. Other
conditions that can simulate peripheral neuropathy are disorders of the
spinal cord, such as syringomyelia, cervical stenosis, low grade compressive
tumors, as well as multiple sclerosis, tabes dorsalis, and lumbar stenosis
producing polyradiculopathy. In the case of a possible motor neuropathy,
consideration must be given to amyotrophic lateral sclerosis, myasthenia
gravis, or polymyopathy. There may be a history of localized pain, trauma,
or associated central neurologic symptoms that may be helpful in suggesting
one of these etiologies. Careful clinical examination usually points toward
one of these etiologies, particularly the sensory and reflex examinations.
For instance, the sensory exam may be in a stocking glove distribution of
sensory loss, but the reflexes are not diminished, or are increased, raising
the suspicion of a myelopathy. Nerve conduction and electomyography studies
are used to confirm the diagnosis of a peripheral neuropathy, though X-rays
and MRI's may also be needed to exclude the presence of any of these other
disorders. Despite the desire to be parsimonious in diagnosis, more than one
potential cause of a patient's neuropathic symptoms can often be found.
Electrophysiologic Diagnosis of Peripheral Neuropathies. Nerve conduction
velocity (NCV) and electromyographic (EMG) testing can confirm the presence
of a peripheral neuropathy as well as localize and characterize a number of
useful features that can generate a list of specific etiologies. The
accuracy in focusing on a specific group of diagnostic possibilities is
related to the appropriate application of electrodiagnostic techniques and
the thoroughness of the study. In most cases, evaluating one upper and lower
extremity and a few select nerves in contralateral limbs will be sufficient.3
In addition, there are technical limitations of this testing, which includes
tester experience and training, inaccessible nerves or muscles, and the
recording of small fiber potentials that are primarily involved in painful
small fiber polyneuropathies. Nerve conduction testing involves measuring
the amplitude and conduction velocities of motor and sensory nerve
potentials along segments of different peripheral nerves, with attention to
the pattern and distribution of abnormalities as well as the severity. An
axonal neuropathy is indicated by low amplitude compound muscle action
potentials (CMAP's) or sensory nerve action potentials (SNAP's) in the
setting of relatively normal conduction velocities. Conversely,
demyelinating neuropathies cause significantly slowed nerve conduction
velocities with relatively normal CMAP and SNAP amplitudes with distal
stimulation. The presence of conduction block, as well as the extent of
focal, diffuse, symmetric, proximal, distal, sensory or motor involvement is
also routinely evaluated. Needle electromyography can also differentiate
between axonal and demyelinative processes by the presence of spontaneous
activity and patterns of recruitment. Positive sharp waves, fibrillation
potentials, and complex repetitive discharges usually appear within 7 to 10
days after axonal injury.3 These characteristic signs of axonal
denervation are not present in primarily demyelinating neuropathies, which
show decreased interference patterns. EMG can also distinguish between
myopathic and neuropathic, as well as, acute and chronic processes.
The polyneuropathy can then be classified based on the predominant
electrodiagnostic abnormalities described by a combination of the following
features; axonal, demyelinating, diffuse, multifocal, sensory, and motor.
Lists of specific polyneuropathies classified by similar electrodiagnostic
characteristics can then be referred to for further investigations to
establish an etiologic diagnosis. This approach would be expected to avoid
unnecessary testing, for example, in multifocal axonal neuropathy, measuring
serum B12 level or evaluating other family members in search for an
inherited neuropathy would be fruitless.4 However, it is not always
possible to make these distinctions based solely on clinical or
electrophysiologic grounds, especially when the neuropathy is advanced.
Furthermore, exceptions to these general rules occur, and an all inclusive
approach may be necessary to establish an etiological diagnosis.4 For
example, diabetes can produce distal symmetric axonal, multifocal
demyelinating, proximal, or autonomic neuropathy, so that serum glucose and
hemoglobin A1c should be tested in all peripheral neuropathies.
Clinical Diagnosis of Peripheral Neuropathies. Two basic
approaches to the evaluation of peripheral neuropathy are seen quite
frequently. One is to test minimally for an etiology, ie, to check glucose
and thyroid-stimulating hormone (TSH), since a treatable cause of the
neuropathy is not expected to be found. The other is to order a full battery
of tests at the onset including antibody studies and nerve biopsies, which
can be quite expensive and produce results that can be confusing or of low
yield. After a few patients, this approach discourages further attempts to
evaluate for etiology and testing is then done minimally.
A stepwise and directed approach to the evaluation of peripheral
neuropathy, however, can increase the yield on finding a treatable cause of
neuropathy, yet keep unjustified testing to a minimum.
Once the presence of a peripheral neuropathy is confirmed with
examination and EMG testing, and obvious causes are excluded in the history,
ie, traumatic injury or toxic exposure, initial screening blood work to look
for any associated metabolic or medical conditions is performed. This should
include complete blood cell count (CBC), chemistry panel with serum glucose,
Hgb A1c, TSH, B12, folate, erythrocyte sedimentation rate (ESR), antinuclear
antibody (ANA), rheumatoid factor (RF), serum protein electropheresis (SPEP),
immuno-fixation (IFE), hepatitis panel, and any other specific blood tests
that are suggested by the medical history or exam.
If abnormalities are found, further medical evaluation as well as
treatment should be initiated and observation for improvement or
stabilization of symptoms should occur for the next few months.
If there is a family history of peripheral neuropathy, or an undiagnosed
disorder of abnormal appearing feet or gait, a hereditary neuropathy is
suggested. A carefully obtained pedigree to determine the pattern of
inheritance as autosomal dominant, recessive or X-linked, in combination
with the electrophysiologic type of neuropathy and associated features has
been traditionally used to classify the type of hereditary neuropathy.
Advances in molecular diagnostic testing have made the definitive diagnosis
of a growing list of specific genetic neuropathies possible. However,
because inherited peripheral neuropathies have no specific therapy at
present, the clinical value of knowing the exact cause of a neuropathy may
not be clear and the cost of a full screening evaluation may be expensive.
In most cases, however, a focused laboratory examination for the genetic
causes of neuropathy can directly affect the present and future treatment of
the patient and may have important implications for prognostic counseling.6
Even if no family history is obtained, testing in sporadic cases may be
clinically more useful than in those cases with a strong family history,
since those with a treatable acquired neuropathy in which further testing
should be pursued, can be separated from those in which an untreatable
genetic neuropathy has been identified.
The largest category of hereditary peripheral neuropathies falls under
Charcot- Marie-Tooth (CMT), or also known as HMSN. CMT 1 is the most
commonly seen with a prevalence of approximately 1 in 2500.6 It is an
autosomal dominant demyelinating neuropathy with uniformly slow conduction
velocities. A duplication on chromosome 17 accounts for probably over 80% of
CMT 1 neuropathies and over 60% of all hereditary sensorimotor neuropathies.5
Genetic testing can also be done to identify CMT X, hereditary neuropathy
with liability to pressure palsies (HNPP), familial amyloid polyneuropathy (FAP),
CMT 3 (Dejerine-Sottas disease), and CMT 2 (axonal HMSN). In patients with
no family history of neuropathy and nerve conduction velocities with 30% or
greater slowing, genetic testing for CMT1A, HNPP if focal features are
present, and CMT X should be obtained. In patients with acute, painless
mononeuropathy, brachial plexopathy, or transient recurrent entrapment
syndromes, HNPP gene testing should be performed. These common presenting
features are present in up to 75% of patients with HNPP neuropathy.7
There are a number of other hereditary neuropathies that present in
childhood or are associated with other distinct clinical features (ie, acute
intermittent porphyria, adrenoleukodystrophy) in which genetic testing can
be obtained, but will not be discussed here.
Assuming that polyneuropathy associated with known medical conditions or
drug toxicity, such as renal failure, alcohol abuse, chemotherapy, or
critical illness polyneuropathy have been identified and treated
appropriately, the remaining causes fall into the inflammatory,
immune-mediated, infectious, paraneoplastic, and idiopathic categories of
neuropathy. Treatment of many of these neuropathies, such as Guillain-Barre
syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP), can
be very gratifying to treat since they respond well to immunosuppressant or
IVIG therapy.8 Clinical course and EMG characterization of the
polyneuropathy is most useful at this stage to direct further evaluation and
treatment.
Rapid onset polyneuropathy that causes progressive weakness and areflexia
that reaches its nadir within 4 weeks after onset is acute inflammatory
demyelinating polyneuropathy (AIDP) and is the most common form of
Guillain-Barre syndrome, which can also present with a number of variants.
The hallmark of this neuropathy is its rapid onset and self-limited course.
EMG shows typical demyelinating features though axonal involvement can occur
in cases associated with Campylobacter jejuni infection. Lumbar puncture
shows elevated protein. Serum antibodies to a variety of gangliosides, such
as Anti-GD1a, GD1b, GM2, GM1, and GQ1b antibodies, if present, can suggest
associated infections, such as cytomegaloviru (CMV), or prognosis (high
titers of Anti-GM1 is associated with more severe neuropathy and worse
recovery).9 Evaluation for other causes, such as human
immunodeficiency virus (HIV) neuropathy, poliomyelitis syndromes, botulism,
tick paralysis, acute intermittent porphyria, acute toxic neuropathies, and
myelopathies, with appropriate testing should be obtained.8 Therapy
consists of IVIG or plasmapheresis as well as supportive medical,
respiratory and critical care.
CIDP is often considered to represent "chronic Guillain-Barre syndrome",
but it increasingly appears to be a discrete disorder from the standpoint of
immunopathogenesis and probably etiology.8 It is a sensorimotor
demyelinating polyneuropathy with duration of progression beyond 2 months.
Because treatment with immunosuppression, IVIG, or plasmapheresis is
longterm, detailed evaluation should be completed before instituting a
"therapeutic trial." This evaluation should include spinal fluid evaluation
to look for other causes (ie, Lyme disease, HIV, CMV), detailed
electrodiagnostic evaluation in some cases nerve biopsy to exclude
infiltrative processes (ie, lymphoma, granulomas).8 Autoantibody
testing for anti-MAG, anti-GM1, anti-SGPG, and anti-Hu antibodies should
also be obtained to look for these specific demyelinating forms of
polyneuropathy.
Paraneoplastic peripheral neuropathies usually produce sensorimotor,
axonal or mononeuritis multiplex neuropathies. Small cell carcinoma of the
lung has been the neoplasm most commonly associated with peripheral
neuropathy, but neuropathies have been seen with a wide variety of other
tumors, and polyneuropathy occurring secondary to cancer chemotherapy may
sometimes be mistakenly considered to be paraneoplastic. Three groups of
neuropathies have been described in association with solid tumors: a
progressive, often painful peripheral neuropathy associated with lung and
other neoplasms, a predominantly axonal neuropathy, and a mononeuritis
multiplex which represents a vasculitis of nerve, usually seen in
association with small cell carcinoma of the lung.10 A second group
of paraneoplastic sensory and motor neuropathies has been described in
patients with paraproteinemic syndromes accompanying plasma cell dyscrasias.11
While several new paraneoplastic antibodies have been identified in the past
few years, most are associated with CNS clinical syndromes and anti-Hu and
anti- amphiphysin (motor neuron syndrome) remain the only testable
antibodies associated with peripheral nerve syndrome. Anti-Hu antibodies are
otherwise known as anti- neuronal nuclear antibodies, type 1 (ANNA-1) and
are most closely associated with small cell lung carcinomas. In patients
with sensory polyneuropathy and positive anti-Hu antibodies, 80% to 90% are
found to have small cell lung carcinoma.9 Other associated neoplasms include
prostate cancer, small cell adrenal cancer, lung adenocarcinoma,
neuroblastoma, and chondrosarcoma. The neurological syndrome and
seropositivity precedes diagnosis of the tumor in nearly all cases and
additional symptoms of limbic encephalopathy, cerebellar ataxia, brainstem
involvement, or autonomic dysfunction can occur in one-half of these
patients.9
Reports of treatment of paraneoplastic neurological syndromes with
immunosuppresants, plasmapheresis, or IVIG are anecdotal and generally
disappointing. Delay in instituting therapy very early in the course of
disease may be a major factor in treatment failure. Remission of these
syndromes following tumor removal or successful chemotherapy has been
reported with small cell cancer of the lung, testicle, breast, and Hodgkin's
disease, but in general has resulted in little to no neurologic improvement.
IVIG therapy has been reported to improve or stabilize the course, usually
in cerebellar syndromes, however.10
There are a number of other autoimmune peripheral neuropathies that are
associated with specific antibodies and produce characteristic clinical
syndromes.
The "antibody" test of greatest utility is assaying for the presence of a
monoclonal gammopathy. Detection of monoclonal gammopathies has become
increasingly important as the spectrum of paraprotein-emic neuropathies has
broadened. These monoclonal proteins can be missed by serum protein
electropheresis because they do not usually increase the total amount of
gammaglobulin. Immunofixation electropheresis is the most sensitive assay,
and monoclonal spikes may be detectable only by this method.12
Detection of a monoclonal immunoglobulin requires subsequent evaluation for
multiple myeloma, solitary plasmacytoma, and amyloidosis with skeletal
surveys, urine immunofixation, and bone marrow biopsy. Otherwise, the
neuropathies that are associated with monoclonal gammopathies of
undetermined significance (MGUS) are of the IgA, IgG, or IgM class with a
subset of the IgM antibody associated neuropathies having anti-MAG
antibodies (50%).13 The monoclonal IgG and IgA associated
neuropathies are usually axonal and treatment is similar to the anti-MAG
associated neuropathy described next.
The anti-MAG associated peripheral neuropathies first described by Latov
and colleagues14 is a slowly progressive large fiber sensory
neuropathy with ataxia, mild distal weakness, and tremor, presenting in men
more commonly in the 6th to 8th decades. Symptoms can be present for several
months to years before a definitive diagnosis can be made. Markedly slow
conduction velocities without conduction block and mild axonal involvement
are seen on electrophysiologic studies. Anti-MAG antibodies bind to small
peripheral nerve proteins and glycolipids, such as myelin associated
glycoprotein (MAG), and sulfated glucuronyl paragloboside (SGPG). Since 25%
of all cases with anti-MAG antibodies did not fit the typical clinical
picture and 6% did not have IgM monoclonal proteins, it is recommended to
test for anti-MAG Abs in patients with monoclonal IgM gammopathy and
neuropathy, and with demyelinating neuropathy without monoclonal gammopathy
but without other defined causes.13 Treatment is with plasmapheresis,
immunosuppression, or IVIG.
Anti-GM1 antibodies have been identified in multifocal motor neuropathy (MMN)
and Guillain-Barre syndrome, previously described. High titers of these IgM
antibodies are found in approximately 70% of patients with the typical
clinical and electrophysiologic picture of MMN, with titers suggestive of
MMN even if the features are not typical.12 Clinically, there is a
gradual asymmetric weakness of the distal limbs without sensory symptoms or
signs. Proximal conduction block on electrophysiologic testing is present
and distinguishes this disorder from motor neuron disease (ALS or spinal
muscular atrophy). Treatment can be quite successful in improving function
with IVIG, followed by plasmapheresis and steroid therapy.13
Antisulfatide antibodies described by Pestronk and colleagues 15 are
associated with a predominantly sensory axonal peripheral neuropathy, some
with monoclonal proteins as well. These patients tend to present with
chronic, painful, symmetric, distal, slowly progressive sensory loss with
involvement of both large and small nerve fibers. Although clinical
experience is limited due to the small number of reported cases, testing for
antisulfatide antibodies in idiopathic sensory neuropathies may yield a
positive result that could be considered for immunomodulating therapy.9
Another peripheral neuropathy syndrome described by Pestronk 16 is the
gait disorder, autoantibody, late-age onset, polyneuropathy (GALOP) syndrome
that resembles anti-MAG neuropathies with distal sensory loss, ataxia, and
demyelinating features on NCV. High titer IgM antibodies bind to a central
nervous system myelin antigen preparation that copurifies with MAG. IVIG and
cyclophosphamide has shown improvement in these neuropathies.9
The remaining peripheral neuropathies may require nerve biopsy for
diagnosis. Screening for lupus or other rheumatologic conditions should have
been done initially, but vasculitis, granulomatous diseases, sarcoid,
lymphoma, and amyloidosis may not have been apparent. If these disorders are
suspected to be the cause of neuropathy and have not been diagnosed by other
means, nerve biopsy should be performed. The sural nerve is used for biopsy
and permanent neuropathic pain and discomfort in addition to numbness can be
a complication, so that this procedure is reserved for progressive
neuropathies that remain undiagnosed by the previously outlined evaluations.
Special comment should be made about a group of patients with purely
sensory neuropathies and gait ataxia who have elevated ANA titers but few
other laboratory abnormalities. These patients often prove to have sensory
ganglionitis associated with features of Sjogren syndrome. They constitute a
discrete patient population and are noteworthy in part because they present
initially to neurologists rather than to rheumatologists. In most, there is
little evidence of other extraglandular effects of their Sjogren syndrome. A
lip biopsy, showing the typical inflammation of minor salivary glands, can
be a useful confirmatory test.12
Finally, it has been estimated that up to one third of peripheral
neuropathies are idiopathic. These neuropathies are classified by their
clinical syndrome, which include sensory axonal polyneuropathy with large
and small fiber involvement, small-fiber sensory neuropathy, large-fiber
sensory neuropathy, sensorimotor neuropathy, and autonomic neuropathy (Shy-Drager
syndrome). Treatment is usually symptomatic, although some patients may
respond to a trial of immunotherapy. More research into their causes and to
develop better diagnostic tests and treatments are needed.17
|
References
1. Thomas PK. Symptomotology and
differential diagnosis of peripheral neuropathy. Peripheral
Neuropathy. Eds. Peter J. Dyck, et al. 1984;2:1169-1170.
2. Kimura, Jun. Electrodiagnosis
in Diseases of Nerve and Muscle: Principles and Practice, Ed. 2.
1989:67.
3. Donofrio Peter D. Diagnostic
evaluation of polyneuropathy. AAEM Course D: Problem Solving in
Electrodiagnostic Medicine. 1992:33-46.
4. Parry Gareth J. An approach to the
patient with peripheral neuropathy. Update in Neuromuscular Disease.
American Academy of Neurology Education Program Syllabus.
2000;8AC.003:94-103.
5. Shy Michael E. Inherited
peripheral neuropathies. Peripheral Neuropathy. AAN Education
Program Syllabus. 2000;7FC.002:144-187.
6. Lynch DR, Chance PF. Inherited
peripheral neuropathies. The Neurologist. 1997; 3(5):277-292.
7. Pareyson D. Detection of
hereditary neuropathy with liability to pressure palsies among
patients with acute painless mononeuropathy or plexopathy. Muscle
and Nerve. 1998;21:1686-1691.
8. Griffin JW. The Guillain-Barre
syndrome and CIDP. Clinical Neuroimmunology. AAN Education
Program Syllabus. 2000;7FC.003:56-71.
9. Wolfe GI. Peripheral neuropathies
and inflammatory myopathies. Autoantibody Testing in Neuromuscular
Disease. AAN Education Program Syllabus. 2000;8BS.002:1-26.
10. Greenlee JE. Paraneoplastic
neurological syndromes. Clinical Neuroimmunology. AAN Education
Program Syllabus. 2000;7FC.003:124-148.
11. Latov N. Neuropathic syndromes
associated with autoreactive IgM antibodies. Autoimmunity Forum.
1989;1:2-4.
12. Griffin JW. Antibody testing in
peripheral nerve diseases. Clinical Neuroimmunology. AAN
Education Program Syllabus. 2000;7FC.003:47-71.
13. Hayes MT. Immune-mediated
peripheral neuropathies. Athena Diagnostics slide presentation based
on Analyzing new strategies to diagnose and treat autoimmune
neuropathies. Advances in Neuroimmunology. 1995;2(2).
14. Latov N. Plasma cell dyscrasia
and peripheral neuropathy with a monoclonal antibody to peripheral
nerve myelin. N Engl J Med. 980;303:618-621.
15. Pestronk A. Antibodies to myelin
associated glycoprotein and sulfatide in predominantly sensory
polyneuropathies. Ann Neurol. 1990;28:239.
16. Pestronk A. Treatable gait
disorder and polyneuropathy associated with high serum IgM binding
to antigens that copurify with myelin-associated glycoprotein.
Muscle and Nerve. 1994;17:1293-1300.
17. Olney R. A guide to the
peripheral neuropathies by The Neuropathy Association, 1999.
|
|
