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Clinical Issues
in Polyneuropathy: Introduction
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The first step in developing a rational approach to patient management
is obtaining a working knowledge of the underlying disorders that
fall under the category of neuropathy. Although it is often used
loosely to refer to polyneuropathy, the term neuropathy is actually
not specific and implies any peripheral nerve lesion, focal or diffuse.
Classification schemes used widely among peripheral neurologists
are based on anatomic and physiologic characteristics of the various
disorders affecting peripheral nerves. The use of these classifications
is not just an academic exercise but creates a basis for rational
decision making in the evaluation and management of patients. The workup
and treatment of individual patients with neuropathy must be approached
with a basic understanding of the clinical behavior, including the
anatomic and pathophysiologic characteristics, of the various neuropathic
disorders.
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Classification
and Clinical Course
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The term polyneuropathy is used to describe a condition that
is fairly symmetric and generalized, as opposed to focal neuropathy
(mononeuropathy) or multifocal neuropathy (mononeuropathy multiplex).
This chapter focuses on the diffuse disorders, including polyneuropathy
and multifocal mononeuropathies. These two groups of disorders may
be indistinguishable clinically and are frequently accompanied by
severe and disabling pain.
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Once a disorder of peripheral nerves is suspected, an attempt
should be made to characterize the clinical features based on the
time course, anatomic distribution, and physiology. Using this information,
a reasonable differential diagnosis can be developed, which will
determine appropriate further workup and management. This section
further discusses the clinical and physiologic features of the diffuse
neuropathies; their diagnostic evaluation is covered in the next
section.
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An important clue as to the etiology of a particular polyneuropathy
(PN) is its time course. Generally accepted guidelines would classify
a neuropathy as acute (< 3 weeks), subacute (weeks
to months), or chronic (> 4–6 months).
Notably, neuropathies in each of these categories may be associated
with debilitating pain. The typical clinic patient presenting with
chronic, insidious PN is probably the most easily diagnosed; the
more acute neuropathies may be difficult to differentiate from central
nervous system disease, particularly spinal cord compression.
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Fiber Type and
Distribution
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PN may involve motor, sensory, or autonomic fibers. There is
a tendency in some neuropathies for selective involvement of fibers
of the same general size distribution. Thus, a neuropathy may involve
predominantly large-diameter sensory fibers (mediating vibration
and proprioception) in addition to intermediate-sized motor fibers.
Conversely, PN may primarily involve small-diameter sensory fibers
(mediating pain and temperature) with or without involvement of
autonomic fibers. Typically, pain is a prominent feature of these
so-called small-fiber neuropathies. Certainly, a neuropathy may
be generalized in terms of the fiber type involvement (as commonly
seen in diabetes); however, careful examination often reveals a
predominance of one group of fibers over another.
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A detailed description of the pathophysiologic mechanisms underlying
PN in various disorders is beyond the scope of this chapter; instead,
we focus on the relevant clinical-pathologic correlates as well
as the electrodiagnostic characteristics of the different neuropathies,
depending on the primary site of pathologic change.
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The two primary sites of pathologic involvement in neuropathy
are the axon and the myelin sheath, or Schwann cell; the former
being more common in PN. In general, in axonopathies, the longest
and larger diameter fibers tend to be involved first, with degeneration
originating in distal portions of individual axons and proceeding
proximally. This creates a length-dependent pattern, which can be
demonstrated both clinically and electrophysiologically. This generalized “dying-back” is
theorized to result from metabolic derangement in the cell bodies
or diffusely within axons. Axonopathies tend to be quite symmetric
in terms of side-to-side involvement, a feature that distinguishes
them from the multiple mononeuropathies. These are the most common
type of PN; almost all toxic and metabolic insults to the peripheral
nervous system result in axonal degeneration.
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Less frequently, the axon is largely spared and demyelination
is the primary pathologic change. Although myelinopathies may be
the result of abnormal Schwann cell development or metabolism, these
situations are rare and the most frequent clinical situation is
one in which segmental demyelination, or loss of myelin between
the nodes of Ranvier, occurs. Segmental demyelination usually is
the result of an autoimmune attack on peripheral nerves and nerve
roots (as in Guillain-Barré syndrome), with the clinical
pattern being somewhat variable; the limbs are involved proximally
as well as distally, although usually fairly symmetrically side-to-side.
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Etiology and
Prognosis
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Tables 37-1 and 37-2 list the most common causes of PN, based
on their physiology (axonal versus demyelinating) and time course.
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Although the clinical course of various neuropathies is highly
variable, depending on etiology, there are a few generalizable rules
regarding prognosis. Any disorder involving significant axonal injury
will be less likely to recover than one in which the primary physiology
is segmental demyelination. Thus, the differentiation between these
two is of practical importance for the clinician. In a disorder
characterized purely by the latter, recovery occurs by remyelination
and usually occurs over 6 to 8 weeks. In generalized neuropathies,
even of primary demyelinating type (e.g., Guillain-Barré syndrome),
there is nearly always some accompanying axonal injury and, ultimately,
prognosis is dependent on its severity. Thus, recovery may be complete
but take months or even years.
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In primary axonal neuropathies, the prognosis is dependent on
the nature and severity of the axonal injury. For example, in typical
mononeuropathy multiplex, in which nerve injury results from ischemic
insult, recovery occurs largely through axonal regrowth. Individual
regrowth of axons occurs from the proximal nerve stump, at a rate
of about 1 inch per month. This form of recovery is very slow and
nearly always incomplete. In neuropathies characterized by a dying-back
type of physiologic change, there usually is very little regrowth
of individual axons. Instead, functional recovery occurs through
reinnervation of muscle fibers by nearby healthy axons, a mechanism
that probably only limits the severity of the deficit related to
axonal loss, rather than allowing any improvement in function.
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Mononeuropathy
Multiplex
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Mononeuropathy multiplex (MM) is a diffuse neuropathic disorder,
similar to PN, but it is distinguished by involvement of multiple
individual nerves. MM may be impossible to distinguish from PN based
on history and examination alone, as the cumulative involvement
of multiple nerves can produce a generalized and fairly symmetric
picture. A high index of suspicion for MM is important in the appropriate
clinical setting. MM is almost invariably the result of ischemic
insult to nerves, the most common etiology being small- and medium-vessel
vasculitis. MM occurs in the majority of cases of systemic vasculitis
and may be its presenting symptom; in rare cases, vasculitis is
restricted to the peripheral nervous system (nonsystemic vasculitic
neuropathy).1
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Regardless of etiology, MM typically presents with the acute
onset of severe pain and numbness in the involved limb; motor and
sensory deficit develop over days. Nerves that are often involved early
are those at so-called watershed zones of the vascular tree (e.g.,
the sciatic nerve in the thigh, the ulnar nerve in the forearm).
Progression to other nerves eventually produces a picture suggestive
of severe, axonal PN; the progression may be subacute or, rarely,
chronic. In all cases, pain remains a prominent feature of the disorder.
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The prognosis is dependent on the underlying etiology of the
MM. In vasculitic neuropathy, aggressive treatment of the underlying
disease is aimed at preventing further ischemia. Recovery of existing
lesions occurs by means of axonal regrowth, at a pace of about 1
inch per month from the site of the injury. An aggressive therapeutic
approach to pain is appropriate, particularly early in the course
of the disorder, when immunosuppressive therapy has not reached
maximum effectiveness. Over time, if the vasculitis can be adequately
treated, it may be possible to reduce or withdraw pain therapies.
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Table 37-3 lists the most common etiologies of MM, based on time
course.
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Diagnostic Evaluation
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History and
Physical Examination
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The first step in the diagnostic evaluation of any neuropathy
is the history and physical examination of the patient. Several
important historical points should be reviewed. One should determine the
time course of the illness—acute, subacute, or chronic.
Next, involvement of nerve fiber types should be ascertained—sensory,
motor, and autonomic, with regard to both positive and negative symptoms.
Specific inquiry should be made regarding the presence or absence
of pain. Positive symptoms refer to abnormal spontaneous sensory
or motor phenomena (e.g., pins and needles, fasciculations), whereas
negative symptoms describe a loss of function (e.g., weakness, numbness).
Inquiry should be made regarding the symptom distribution and symmetry
(i.e., stocking glove versus individual nerve territories), as well
as the progression (i.e., slow and insidious versus acute-onset
deficits with plateaus). Finally, one should obtain a family history,
with an eye to excluding a congenital form of neuropathy.
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Characteristic features of neuropathic pain are useful in differentiating
it from pain from any other source. It is vital that these symptoms
and signs are sought during the history and physical examination
as they are often primary evidence for a diagnosis of PN. In some
neuropathies, such as those limited to involvement of small fibers,
normal laboratory studies are the rule, and diagnosis is based on
clinical grounds alone. The presence of positive symptoms is typical
of the neuropathic disorders.
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Positive symptoms that are typical of PN include (1) paresthesias—nonpainful,
spontaneous sensory phenomena such as pins and needles or tingling;
(2) dysesthesias—unpleasant spontaneous or evoked sensory
phenomena such as burning; (3) hyperesthesia—increased
sensitivity to stimuli, often with an unpleasant quality; (4) allodynia—pain
created by a normally nonpainful stimulus, such as the bedcovers;
and (5) hyperpathia or hyperalgesia—exaggerated pain response created
by a normally painful stimulus.
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The presence of these symptoms should be sought specifically,
in addition to allowing the patient to describe the precise nature
of his or her pain. Also, the effect of pain on quality of life
and functional status is extremely important. Specific pain measures,
such as the Neuropathic Pain Scale,2 may be used
to quantify the patient’s pain as well as its effect on
the quality of life. Such scales are particularly helpful for patients
involved in clinical therapeutic trials and may be used to assess
efficacy of treatment regimens outside of experimental trials.
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The physical examination should be guided by the patient history.
For example, the suggestion of asymmetric onset of symptoms should
prompt a careful search for evidence of individual nerve involvement,
as opposed to a stocking-glove distribution of sensory loss.
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A complete neurologic examination is required. One cannot adequately
localize the problem to the peripheral nerve without a careful physical
examination to rule out myelopathy, polyradiculopathy, or myopathy,
which may mimic or complicate PN. The details of the neurologic
examination are not reviewed here, but a few points are worth emphasizing.
The goal of the physical examination is to characterize the pattern,
symmetry, and distribution of abnormalities and to determine which
modalities are involved (motor, sensory, autonomic); the distribution
with regard to fiber type should also be demonstrable. The typical
pattern to look for is bilaterally symmetric, usually distally predominant.
The proximal lower extremities tend to be involved before the distal
upper extremities, although this is variable; the anterior thoracic
region is often involved in more severe cases. However, there may
be proximal predominance, and upper extremities may be involved
disproportionately. In MM, the pattern is usually multiple nerve
involvement, although it may likely be impossible to differentiate
from PN, other than subtle asymmetry in an otherwise stocking-glove
distribution. The deep tendon reflexes are part of the overall pattern,
as well, and are typically reduced or absent in a distribution consistent
with the underlying pathophysiology. For example, patients with
distal axonopathies typically have absent ankle jerks, whereas those
with chronic demyelinating neuropathies are areflexic.
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In patients with painful positive symptoms, there often are correlative
signs on the physical examination. Allodynia may be elicited by
lightly stroking the involved area (mechanical stimulus) or by testing
with a cold instrument (thermal stimulus). Hyperalgesia or hyperpathia
may be elicited during pinprick testing. A single, painful stimulus
may be reported as a sensory deficit, whereas repeated stimuli in
the same area produce an exaggerated pain; this phenomenon is called
summation.3 Abnormal sensations may last for several
seconds or minutes after discontinuation of the stimulus, a phenomenon
called after sensations.3 These examination findings
are important, because they are unique to patients with neuropathic pain.
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Clinical Neurophysiology
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Electrophysiologic
Studies
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The second logical step in the diagnostic evaluation is the electrodiagnostic
examination, specifically, nerve conduction studies (NCS) and electromyography
(EMG). The utility of these studies is several. Firstly, they usually
clarify the diagnosis of PN. Although important, there is a limit
to the localizing value of physical examination, even when carefully
performed. For example, a detailed physical examination cannot differentiate
multiple root involvement from PN or MM in most cases; coexisting
neurologic problems may also significantly alter the physical examination. It
is important to note that NCS cannot assess the integrity of small-diameter
sensory fibers (i.e., those mediating pain and temperature) and
so will be normal in patients with pure small-fiber neuropathies.
However, these neuropathies are rare, and in those patients with
involvement of larger fibers, NCS are more sensitive than physical
examination for diagnosing PN.
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In addition to establishing a diagnosis with accuracy, electrodiagnostic
studies provide several other types of information—the
predominant pathophysiology (i.e., axonal or demyelinating), time
course and severity of the disorder, and whether motor or sensory
fibers, or both, are involved. NCS can differentiate hereditary
from acquired forms of PN and is much more sensitive than physical
examination for identifying MM. Chapter 9 discusses the use of electrodiagnostic testing
in detail. Once the underlying pathophysiology and the time course
are understood, the differential diagnostic possibilities are narrowed
considerably.
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Quantitative
Sensory Testing
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Quantitative sensory testing (QST) is a specialized technique
for measuring the intensity of a given stimulus required to elicit
specific sensory perceptions.4 Specifically, QST
assesses a sensory detection threshold to various stimuli, including
touch-pressure, vibration, heat, and coolness. QST, when properly
performed, provides a quantitative, noninvasive means of assessing
sensory function. One major advantage is that QST for thermal thresholds
allows some quantifiable measure of small-fiber function, which
is not possible with routine NCS. Several commercial systems exist
for QST. However, a major problem with QST is that it is not widely
available for clinical use, and its reliability is highly operator
dependent. Notably, its sensitivity in patients with pure small-fiber
neuropathies, the group in whom it is potentially of the greatest
diagnostic importance, has been reported in several studies to be
around 60%.5,6 Nonetheless, it can be
quite helpful in confirming the physical examination findings and substantiating
the clinical suspicion of neuropathy. In small-fiber neuropathies,
in particular, QST is recommended, as it may provide the only objective
means for establishing a diagnosis and can be used to measure efficacy
of various therapeutic modalities.4 QST is typically
pursued in the evaluation of PN if the routine NCS are nondiagnostic.
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The differential diagnostic considerations in any given neuropathy
are dependent on the physiologic characteristics and time course
of the underlying disorder (see Tables 37-1, 37-2, and 37-3). Thus,
the diagnostic evaluation should proceed initially with electrophysiologic
studies, as discussed earlier, and laboratory workup should be guided
by the differential diagnostic considerations raised by these findings.
The laboratory workup will nearly always include blood studies and
occasionally urine studies. Cerebrospinal fluid evaluation is no
longer routinely necessary; it is most commonly obtained in fairly
acute neuropathies in which Guillain-Barré is suspected.
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Table 37-4 outlines the appropriate laboratory workup for PN
and MM based on time course and electrophysiology.
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Nerve biopsy is required in a small proportion of patients with
neuropathy, and should be performed only in situations in which
the indication is clearly defined. Only rarely is biopsy necessary
to establish a diagnosis of PN. Nerve biopsy is most useful in patients
with MM, as a means of determining the causative disorder, which
is usually inflammatory in nature and has a high morbidity and mortality
if untreated. Other disorders appropriately diagnosed by nerve biopsy include
sarcoidosis, amyloidosis, and, rarely, leprosy. In the cases of
vasculitis and sarcoidosis, a muscle biopsy is usually obtained
simultaneously. Nerve biopsy is infrequently performed in cases
of progressive PN in which exhaustive workup has failed to reveal
an underlying diagnosis. In these cases, the aim of the biopsy is
to determine the presence or absence of a potentially treatable
disorder.
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In recent years, a technique has been developed for quantitative
assessment of cutaneous innervation in punch biopsies of the skin.
The epidermis contains free nerve endings, which are the terminals
of small-caliber, unmyelinated fibers. Using control values obtained
from a healthy cohort, investigators have been able to identify
abnormal patterns of intraepidermal nerve fiber (IENF) density in
patients with small-fiber sensory neuropathies (SFSNs).5,7 Examination
of patients with idiopathic, human immunodeficiency virus (HIV)—associated,
and diabetic painful sensory neuropathies indicates a correlation
between IENF density and clinical estimates of small-fiber sensory
dysfunction.7 Studies of patients with idiopathic
SFSNs suggest that IENF is a more sensitive diagnostic indicator
of pure, small-fiber neuropathies than either QST or sural nerve
biopsy.5 Although IENF is still available only
in specialized centers, it holds promise as an important tool for
routine use in patients with painful sensory neuropathies, whose
routine workup may be entirely normal, especially when small-fiber
involvement predominates.