Neuromuscular disease is a term applied to diseases of nerve roots, plexuses, peripheral
nerves, the neuromuscular junction, and muscle. Disorders of motor and sensory somatic
cell bodies (anterior horn cells, dorsal root ganglia, and cranial nerve nuclei) are generally
considered in this category as well. By exclusion, then, diseases of cerebral cortex, basal
ganglia, cerebellum, and white matter tracts of the brain, brainstem, and spinal cord are not
neuromuscular diseases. Hence, neuromuscular diseases typically present with progressive
weakness and/or sensory symptoms without cognitive or higher cortical dysfunction,
abnormal involuntary movements, bradykinesia, pathologic reflexes, spasticity, or a sensory
level.
The evaluation of patients with suspected neuromuscular disease begins by distinguishing
patients with weakness only (that is, without sensory symptoms or signs) from those with
sensory or sensorimotor symptoms. While neuropathy can spare sensory fibers in certain
specific circumstances, weakness without sensory symptoms or signs usually suggests the
neuromuscular diseases that are not neuropathies: muscle diseases, diseases of the
neuromuscular junction, and motor neuron disorders. Each of these has distinct clinical
features.
Muscle Diseases
Muscle diseases are classified into several categories. Among the most common are:
1.
Muscular dystrophies. Dystrophies are heritable disorders in which the defect is
generally in a gene coding for a structural protein, leading to destruction of muscle
cells and, as a clinical consequence, gradually progressive limb weakness. Many
dystrophies have now been shown to be due to mutations in genes coding for a
complex of proteins that, among other things, anchor the contractile apparatus
within the muscle cell to the cell membrane. Perhaps the best known of these
proteins is dystrophin, which is abnormal in Duchenne muscular dystrophy, an Xlinked dystrophy that causes progressive weakness and early death in boys. Other
common dystrophies include Becker dystrophy, a dystrophinopathy with a milder
phenotype than Duchenne, Facioscapulohumeral dystrophy, an autosomal dominant
condition named for the distribution of weakness and due to a mutation on
chromosome 4, and limb-girdle dystrophy, which is in fact a genetically
heterogeneous syndrome which can result from a variety of described mutations.
Because dystrophies are disorders of structural proteins, they lead to striking
pathologic alterations of muscle cells and, ultimately, cell death, with fibrosis and
atrophy of affected muscles.
2. Inflammatory myopathies. The common inflammatory myopathies are polymyositis,
dermatomyositis, and inclusion body myositis. Polymyositis is a T-cell mediated
autoimmune myopathy characterized histologically by lymphocytic infiltration of
muscle fibers. Polymyositis generally presents in adulthood with progressive,
symmetric, proximal-predominant limb and neck flexion weakness. Dysphagia can
occur due to involvement of the bulbar musculature. Myocarditis occurs rarely as
well and can cause congestive heart failure. Serum CK is nearly always elevated and
1
electromyography of affected muscles demonstrates characteristic myopathic
features. The diagnosis is confirmed histologically, and it is best to biopsy a muscle
that is clinically affected to a moderate degree. Treatment of polymyositis with oral
or intravenous steroids generally results in significant improvement, although
treatment must be continued for months and often years. Because long-term
immunosuppression is commonly needed and results in significant cumulative steroid
side effects, steroid-sparing agents such as azathioprine can be very useful
adjuncts in polymyositis. Like polymyositis, dermatomyositis typically presents with
progressive, symmetric, proximal-predominant weakness of the limbs and trunk, at
times with bulbar and cardiac involvement as well. Nonetheless, dermatomyositis is
distinct from polymyositis in several important respects. In polymyositis the primary
immune attack is against muscle itself, whereas dermatomyositis is an inflammatory
microvasculopathy. Thus, polymyositis is characterized histologically by direct
inflammatory infiltration of muscle fibers, while in dermatomyositis, inflammatory
infiltrates are most prominent in the perviscular spaces and perimysial connective
tissue. Both result in necrosis and regeneration of muscle fibers, but in polymyositis
the distribution of necrotic fibers is relatively diffuse, whereas the histologic
hallmark of dermatomyositis is “perifascicular atrophy,” in which groups of atrophic
fibers are seen, largely on the periphery of muscle fascicles, and presumably due to
infarction. Dermatomyositis is a multisystem disease, and is associated with a
characteristic erythematous rash which is most commonly seen on the dorsum of the
hands, the face, and the eyelids. The relative degree of involvement of skin and
muscle varies considerably among patients. Involvement of other organ systems,
either individually in the context of a specific connective tissue disease, can occur
as well. Dermatomyositis occurs in both children and adults and is associated with an
increased incidence of malignancy in adults. Inclusion body myositis (IBM) is a
progressive myopathy generally presenting in men in mid to late adult life. IBM has
several distinct features. Clinically, it progresses inexorably over many years and
can result in severe disability and, ulltimately, severe dysphagia and ventilatory
failure. Unlike nearly all other neuromuscular disorders, IBM has a predilection for
involvement of the quadriceps muscle. The long finger flexors are also
disproportionately affected in this condition. The diagnosis is confirmed by muscle
biopsy. In addition to variably severe inflammatory infiltrates, IBM demonstrates a
distinct combination of congophilic inclusions and rimmed vacuoles. The inclusions
represent deposition of amyloid. While the cause of IBM is unknown, it is suspected
that the primary pathology is the amyloid deposition and that the inflammatory
infiltrates are secondary. This view is supported by the observation that treatment
with immune modulating therapies results in transient improvement at best but does
not influence the long-term course of the disease.
Other categories of muscle disease include:
3. Toxic myopathies
4. Endocrine myopathies
5. Congenital myopathies
6. Mitochondrial myopathies
2
7. Myotonic dystrophy
Disorders of Neuromuscular Transmission
The neuromuscular junction is a specialized adaptation of both the nerve terminal
and the muscle cell membrane which allows depolarization of a motor axon to result in
depolarization of a muscle cell membrane and, ultimately, contraction of that muscle fiber
via excitation-contraction coupling. The motor nerve terminal is a specialized structore
containing vesicles of the neurotransmitter acetylcholine. The arrival of a wave of
depolarization at the nerve terminal allows voltage gated calcium channels in that region to
open. The resultant influx of calcium results in turn in the fusion of acetylcholine vesicles
with the nerve terminal (the presynaptic membrane) and release of acetylcholine into the
synaptic cleft between the nerve terminal and muscle membrane. The muscle membrane (the
postsynaptic membrane) is a highly redundant structure studded with acetylcholine
receptors. The redundancy of the postsynaptic membrane and the exceedingly high number
of acetylcholine receptors assure effective transmission across the synapse. When a
sufficient quantity of acetylcholine binds to the postsynaptic receptors, sodium channels in
adjacent muscle membrane open, leading to depolarization of the muscle cell and, in turn,
contraction. Disorders of neuromuscular transmission can thus be classified as due to either
presynaptic or postsynaptic pathology.
Myasthenia gravis is the most common disorder of neuromuscular transmission and is
due to postsynaptic pathology. Myasthenia is caused by autoantibodies directed against the
acetylcholine receptor. While antibodies can disrupt neuromuscular transmission by blocking
the receptor site, the primary cause of impaired neuromuscular transmission in myasthenia
is antibody-mediated destruction of the postsynaptic membrane, either due to complementmediated destruction of the membrane, internalization and destruction of acetylcholine
receptors, or both. The result is a simplified postsynaptic membrane and enlarged synaptic
cleft. This reduces the “safety factor” of neuromuscular transmission and, ultimately, leads
to failure of neuromuscular transmission.
Myasthenia presents with muscle weakness and prominent fatiguability. Because
repeated discharges of motor neurons lead to relative depletion of acteylcholine available
for release, fatigue is not only a symptom but can be observed clinically after repeated or
sustained muscle contraction. Extraocular and bulbar muscles are often prominently
affected in addition to limb and trunk musculature. Unlike many myopathies, both proximal
and distal muscles are affected, usually in an asymmetric distribution. Symptoms are often
more prominent towards day’s end. While most patients have some limb or bulbar weakness
(generalized myasthenia), in a significant minority of patients, weakness is restricted to the
extraocular muscles (ocular myasthenia). Neurophysiologic testing will often demonstrate
subclinical involvement of other muscles in patients with ocular myasthenia.
A clinical diagnosis of myasthenia gravis can be confirmed in three ways:
3
1.
2.
3.
Neurophysiologic testing. Repetitive nerve stimulation at 2-3 Hz results in
a characteristic progressive decrement in the amplitude of the evoked
muscle response, as neuromuscular transmission fails in some muscle fibers
due to depletion of available acetylcholine. In single fiber
electromyography, abnormal variation in the relative latency of muscle
fiber contraction can be demonstrated when two fibers innervated by the
same motor neuron are compared. This abnormal variation, called “jitter,”
is also an indication of impaired neuromuscular transmission.
Neurophysiologic studies are highly sensitive when symptomatic muscles
are studied, or in any muscles of patients with clinically significant
generalized myasthenia. They are not specific for myasthenia gravis, but
are strongly supportive of the diagnosis when the clinical presentation is
consistent.
Antibody testing. Serum antibodies that bind to the acetylcholine
receptor are present in at least 80% of patients with generalized
myasthenia gravis and 55% of patients with purely ocular myasthenia.
These antibodies are rarely seen in individuals with other autoimmune
conditions. They are highly specific for myasthenia gravis in patients
whose clinical presentation is typical.
Response to anticholinesterase medications. By inhibiting metabolism of
acetylcholine in the synaptic cleft, edrophonium (Tensilon®) enhances the
availability of acetylcholine. A clinical response to an intravenous bolus of
Tensilon has long been used as a functional diagnostic test for myasthenia
gravis. Unfortunately, the response to Tensilon is often equivocal;
furthermore, any condition in which neuromuscular transmission is
impaired might improve transiently with Tensilon. While still occasionally
used as an adjunctive diagnostic tool, this procedure should not be used as
the sole diagnostic test for myasthenia gravis.
Effective treatment of myasthenia gravis requires immunosuppressive therapy. The
mainstay of treatment is steroid therapy. Prednisone is typically begun at a dose of about 1
mg/kg. Myasthenic weakness often worsens 1 to 2 weeks after starting prednisone, followed
by a striking and sustained improvement in most patients. After a sustained response is
achieved, prednisone is tapered very gradually, generally over a period of months to years.
Unduly rapid tapering commonly leads to relapse, particularly when the prednisone dose
drops below 20-30 mg/day. In order to avoid the weakness commonly associated with
initiation of high dose prednisone, as well as for the purpose of determining the minimum
effective dose, some neurologists begin with relatively low doses and gradually increase
until an adequate response is obtained. Steroid-sparing agents such as azathioprine,
cyclosporine, and mycophenylate mofetil are often used as adjuncts to allow a more rapid
steroid taper and are occasionally used alone. The clinical improvement from these
medications is generally not as immediate as that seen with prednisone.
Myasthenia gravis sometimes worsens abruptly, leading to life-threatening dysphagia
and ventilatory failure. This is referred to as myasthenic crisis, and can occur spontaneously
4
or after a medical illness such as infection. In addition to intensive supportive care and
mechanical ventilation if necessary, rapid improvement in myasthenic weakness can often be
achieved with plasma exchange (PLEX) or intravenous immunoglobulin (IVIg). Unlike steroid
therapy, which generally requires several weeks’ time to take effect, PLEX and IVIg often
provide benefit within days, and are thus ideal treatment modalities in the setting of
myasthenic crisis. Although the benefit of these treatments is short-lived (generally
several weeks), repeated courses of PLEX or IVIg are occasionally used in patients who are
refractory to or intolerant of other immunosuppressant therapies.
Thymectomy is also commonly used as a treatment in myasthenia gravis.
Uncontrolled series suggest that thymectomy enhances the chance for a sustained
remission, with the apparent benefit developing months to years after the procedure. Both
B- and CD4+ T-cells that recognize the acetylcholine receptor have been found in the
thymus in myasthenia gravis. Thymectomy is generally recommended in patients under the
age of 60 with generalized myasthenia; it appears to be less effective in older patients and
its use in patients with ocular myasthenia is controversial. About 10% of patients with
myasthenia have a thymoma, a histologically benign tumor of the thymus gland. Thymectomy
is recommended in all patients with thymoma.
Finally, oral anticholinesterase agents are used for symptomatic relief. Mestinon® is
the most commonly used such drug in North America. While Mestinon is clearly beneficial in
alleviating symptoms in most patients, it is important to emphasize that it has no effect on
the autoimmune pathogenesis of the disease, and should therefore not be used as the sole
treatment modality in patients with clinically significant generalized myasthenia.
Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare acquired presynaptic
disorder of neuromuscular transmission. LEMS is caused by an antibody to the voltage gated
calcium channel (VGCC) and can occur either in isolation or as a paraneoplastic syndrome,
most commonly in association with small cell lung carcinoma. When LEMS presents as a
paraneoplastic phenomenon, it is believed that the pathogenic antibody forms as part of the
immune response to VGCCs on tumor cells. Symptoms of LEMS often develop before the
tumor becomes symptomatic, which may reflect the beneficial effect of the immune
response in suppressing tumor growth. As indicated above, release of acetylcholine from the
nerve terminal is triggered by calcium influx via VGCCs. Thus, blockade of VGCCs leads to
impaired acetylcholine release and, in turn, impaired neuromuscular transmission.
The clinical presentation in LEMS differs from that seen in myasthenia. In LEMS, patients
typically present with mild to moderate bilateral proximal weakness with hypo- or areflexia.
In contrast to myasthenia, extraocular muscles are usually spared. LEMS is also associated
with autonomic findings such as anhidrosis, dry mouth, and erectile dysfunction.
Antibodies to VGCCs are detectable in the serum in most patients with LEMS. The
diagnosis can also be confirmed with neurophysiologic studies. As in myasthenia gravis, 2-3
Hz repetitive nerve stimulation often demonstrates a decremental response in LEMS. In
LEMS, however, routine motor nerve conduction studies demonstrate a low amplitude
response in most if not all muscles. After rapid repetitive stimulation or a sustained
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voluntary contraction, there is a transient but marked increment in the amplitude of the
response. This is not common in myasthenia unless the deficit is very severe. The increment
after exercise in LEMS occurs because sustained or repetitive contraction facilitates
calcium entry through available VGCCs, thus enhancing the chance of effective acetylcholine
release after the subsequent test stimulus.
Treatment of LEMS is generally less satisfactory than treatment of myasthenia.
Perhaps the most important initial intervention is an aggressive search for malignancy.
Treatment of a tumor, when one is found, may result in improvement in neurologic symptoms.
As in myasthenia, LEMS can also be treated with both symptomatic therapy as well as
immunotherapy. Some patients obtain symptomatic relief with mestinon, although the
benefit is usually modest. LEMS is also treated with 3,4 diaminopyridine (3,4-DAP). 3,4-DAP
blocks the potassium channel responsible for restoring the resting membrane potential
after nerve depolarization. This results in prolonged depolarization of the nerve terminal
and, in turn, prolonged opening of the voltage-gated calcium channel.
LEMS can be treated with immunotherapy as well. Steroids, azathioprine, PLEX, and
IVIg have all been used, with less consistent benefit than in myasthenia. Because the
pathogenic antibodies may suppress tumor growth, immunotherapy should probably not be
used in patients with paraneoplastic LEMS without treatment of the tumor itself.
Acetylcholine release can also be inhibited by bacterial toxins, most notably tetanus
and botulinum toxins. Treatment is largely supportive. Antitoxins are available for both.
Motor Neuron Disorders
Voluntary muscle is innervated by motor neurons in the brainstem nuclei and the
anterior horn of the spinal cord. These neurons are in turn innervated by cortical motor
neurons of the primary motor cortex. While motor neurons can be damaged in a wide variety
of pathologic processes, several disorders selectively target motor neurons. These include
amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), spinal muscular atrophy
(SMA), focal motor neuron disease, X-linked spinobulbar muscular atrophy (SBMA, or
Kennedy’s Disease), and poliomyelitis. The following is a review of ALS, the most common of
the motor neuron diseases.
Diagnosis of ALS
ALS is characterized by gradual, progressive loss of both cortical (“upper”) as well
as bulbar and spinal (“lower”) motor neurons. It is this combination of upper and lower motor
neuron disease in the same myotomes that makes ALS unique. Clinically, this is revealed by
the presence of hyperreflexia, pathologic reflexes, loss of abdominal reflexes, or spasticity
6
– all signs of upper motor neuron disease – in myotomes with neurogenic atrophy – a sign of
lower motor neuron disease – in the absence of sensory, cognitive, cerebellar, or
extrapyrimidal symptoms or signs. Fasciculations, which can be seen in a variety of disorders
of anterior horn cells, nerve roots, and peripheral nerve, as well as in some normal
individuals, are often prominent as well. Electromyography and nerve conduction studies
(EMG/NCS) are always needed to confirm lower motor neuron involvement, to determine the
extent of lower motor neuron involvement, and to exclude other neuromuscular causes of
weakness such as polyneuropathy, disorders of neuromuscular transmission, and myopathy.
In some cases, neurogenic atrophy may not be prominent but needle electromyography will
demonstrate widespread evidence of loss of lower motor neurons. Conversely, in some cases
the clinical presentation may be so striking that EMG/NCS hardly seems necessary;
however, the consequences of making a diagnosis of ALS are so profound that a careful
search for other causes of weakness is mandatory. For the same reason, neurologists will
often perform serologic screening for certain metabolic, toxic, or infectious conditions even
though these conditions mimic ALS exceedingly rarely. Such conditions include
hyperthyroidism, hypoparathyroidism, lead toxicity, Lyme disease, and HIV infection. A
progressive disorder of motor neurons has also rarely been described in the setting of
lymphoma and other malignancies, so a general physical examination and appropriate
malignancy screening should be performed in any ALS suspect.
There is a handful of conditions that are particularly likely to be misdiagnosed as
ALS. These include structural lesions of the cervical cord and brainstem, inclusion body
myositis, and multifocal motor neuropathy. There are also other motor neuron diseases
which must be distinguished from ALS and which will be discussed separately.
Any lesion that damages corticospinal tracts as well as nerve roots or cell bodies in
the brainstem or anterior horn will result in a combination of upper and lower motor neuron
findings. The clue, of course, is that the lower motor neuron findings – reflecting injury to
cell bodies at the level of the lesion – will be in myotomes rostral to the upper motor neuron
findings, which reflect injury to the descending corticospinal tracts. For this reason,
whenever lower motor neuron findings exist exclusively rostral to lower motor neuron
findings, imaging (usually MRI) of the relevant level of the central nervous system is
mandatory. Cervical spondylosis, meningioma, and syrinx are among the many lesions that
might result in such a presentation.
Inclusion body myositis (IBM) is a slowly progressive myopathy of older adults
which, because of the presence of atrophy, weakness without sensory findings, and largely
preserved reflexes, is occasionally mistaken for ALS. The distinction is made on the basis
of a distinctive distribution of muscle weakness, absence of pathologic reflexes, myopathic
features on EMG, and characteristic findings on muscle biopsy. IBM is discussed further
above among the inflammatory myopathies.
Multifocal motor neuropathy (MMN) is a pure motor demyelinating neuropathy which
is often associated with prominent cramps and fasciculations, clinical features that are also
common in ALS. In MMN, unlike ALS, pathologic reflexes are rarely, if ever, present;
furthermore, MMN tends to present in the distribution of individual nerves rather than
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spinal cord segments, and is diagnosed on the basis of distinctive electrodiagnostic features
that are usually readily identified. Unlike ALS, MMN responds to immunotherapy, so it is
important not to miss the diagnosis.
ALS typically begins focally and spreads to adjacent regions. Thus, if the initial
symptom is weakness of the left lower limb, it is likely to spread to the left side of the
trunk or right lower limb before affecting the upper limbs or bulbar musculature. Bulbaronset ALS, in which the initial symptoms are in the bulbar musculature, is often
distinguished from limb-onset ALS. Furthermore, in some individuals symptoms and signs of
upper motor neuron dysfunction, such as spasticity and hyperreflexia, predominate, while in
others there is more prominent involvement of lower motor neurons, characterized by
atrophy and fasciculations. The variation in distribution of weakness and degree of upper
motor neuron involvement combine to result in a wide variety of clinical findings, so that any
casual visitor to an ALS clinic might be surprised to learn that all patients carry the same
diagnosis. For example, patients with bulbar ALS commonly walk unaided into the examining
room, with little overt functional disability in the limbs, but with severe dysarthria and
dysphagia. Careful examination will reveal variable degrees of upper motor neuron, or
“pseudobulbar,” findings, such as a spastic dysphonia, slow and awkward tongue movements,
jaw clonus, or a brisk gag reflex despite diminished volitional elevation of the palate. For
unclear reasons, a “pseudobulbar affect,” characterized by exaggerated and socially
embarrassing laughing or crying, is often seen as well. The most striking evidence of lower
motor neuron bulbar involvement in most patents with bulbar ALS is atrophy and
fasciculations in the tongue. By contrast, patients with upper motor neuron-predominant
lower limb-onset ALS develop a spastic gait followed by progressive quadriparesis, usually
with good bulbar function until very late in the disease. These patients often progress
slowly and remain independent for a long period of time because of relatively preserved
strength and hand function. Others present with prominent lower motor neuron findings in
the upper limbs (“brachial amyotrophic diplegia”). And so on. As will be discussed below, the
variety of presentations leads to a variety of functional needs that must be addressed by
the ALS care team.
Etiology
Although a great many hypotheses have been put forward, the cause of ALS remains
unknown. It may be that several mechanisms can cause death of motor neurons. Current
hypotheses include excitotoxicity due to impaired reuptake of glutamate, an excitatory
neurotransmitter, neurofilament dysfunction, leading to impaired protein transport within
the axon, and accelerated apoptosis of motor neurons. Despite numerous clinical trials, only
one drug, riluzole, has been approved for treatment of ALS. Riluzole is a glutamate
antagonist which has been shown to retard progression of ALS to a very modest degree.
Management
8
The management of ALS is largely supportive. Occupational and physical therapists
can be very helpful in devising strategies to maintain function despite disability. Patients
with bulbar symptoms require speech therapy as well as periodic swallowing evaluations
because of the risk of aspiration. As speech and swallowing difficulties progress,
communication devices and gastrostomy become necessary. Pseudobulbar affect can often
be managed successfully with tricyclic agents. Spasticity is managed with lioresal or
tizanidine.
Ventilatory dysfunction poses a special problem in ALS. Mild to moderate ventilatory
insufficiency can often be managed successfully with noninvasive positive pressure
ventilation such as BiPAP (bilevel positive airway pressure). BiPAP is often remarkably
effective even in patients who have severe ventilatory dysfunction and are dependent upon
mechanical ventilation. Invasive mechanical ventilation via tracheostomy and a ventilator has
two significant advantages over BiPAP, however: first, tracheostomy provides airway
protection in patients at risk for aspiration, and second, tracheostomy allows for much more
effective pulmonary toilet. Tracheostomy is usually not necessary until the late stages of
ALS, when patients are entirely dependent in activities of daily living. Because most patients
perceive the quality of life at this point to be poor, few choose invasive mechanical
ventilation.
End of life care
End-stage ALS brings the complications of immobility, such as frozen shoulder, pain, and
constipation. Caregiver burnout is a common problem, as patients require around the clock
care. Hospice care often plays an important role in end-stage ALS by providing respite care,
pain management, and narcotic analgesics to alleviate the anxiety and air hunger due to
ventilatory failure.
Neuropathy
As indicated above, neuropathy (or polyneuropathy; that is, a systemic process affecting
multiple nerves) should be suspected in any patient presenting with sensory and motor
symptoms affecting more than one limb without signs referable to the central nervous
system. To simplify the evaluation of neuropathy, neurologists classify neuropathies
according to four features: the time course, the modalities affected (motor, sensory, and
autonomic), the distribution (diffuse or multifocal), and the nature of the primary pathology
(axonal or demyelinating). Once characterized in this fashion, the differential diagnosis of a
neuropathy is generally reduced to a manageable list of possibilities.
How does one determine these things in clinical practice? The time course is self evident.
The distribution and modalities afffected can also be determined largely from history and
examination, and can be buttressed by EMG/NCS. To reliably determine the nature of the
primary pathology, one needs electrodiagnostic studies and, at times nerve biopsy as well,
9
although experienced clinicians can often make an educated judgement regarding the
pathologic process on the basis of clinical findings.
Most neuropathies are chronic, involve both sensory and motor fibers to some degree, and
conform to one of the following four patterns:
multifocal
vasculiti
sinfiltrative
MMN/LSS
CIDP
metaboli
c
toxic
diffuse
nutritional
CMT II
axona
l
CMT I
demyelinati
ng
1. Symmetric, sensory-predominant, axonal polyneuropathy. This is the pattern seen with
most metabolic, toxic, and nutritional causes of polyneuropathy, and is thus the pattern
most commonly seen by physicians in primary care. These neuropathies are lengthdependent; that is, the longest nerves are affected first. This seems consistent with the
concept that the longest axons, which have the greatest metabolic demand, the greatest
exposure to external stresses, and perhaps the greatest vulnerability to conditions which
compromise transport mechanisms, axonal membrane, or other structures, might be most
vulnerable to systemic toxic, metabolic, or nutritional disorders. These neuropathies are
rarely associated with clinically significant weakness. Thus, the clinical presentation is of
numbness, often accompanied by paresthesias, burning discomfort, and sensitivity to touch,
in the toes and feet. Initial clinical findings are loss of sensation in the distal lower limbs,
followed by loss of Achilles' reflexes and weakness of the intrinsic foot muscles. Examples
of known etiologies of such a presentation include diabetes, alcohol abuse, and vincristine.
The etiology in this syndrome is often unknown, and management generally consists of
treating the causative condition, if known, and treatment of pain. These neuropathies
usually develop gradually over a period of months to years.
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2. Very symmetric sensorimotor axonal or demyelinating neuropathy. The presence of
significant numbness and weakness in a symmetric, length-dependent fashion, generally
manifesting as sensory loss in the feet and ankle dorsiflexion weakness ("foot drop"), should
bring to mind an inherited sensorimotor polyneuropathy, or Charcot-Marie Tooth (CMT).
Though there are some important exceptions, most inherited sensorimotor neuropathies
present in this fashion, and are notable for their exquisite symmetry. Nerve conduction
studies in CMT demonstrate either striking slowing of conduction, indicating a primary
disorder of myelin (CMT I), or low amplitude responses with normal or near-normal
conduction, indicating a primary axonal disorder (CMT II). Regardless of the primary
pathology, disability in CMT develops because of progressive loss of axons. Thus, patients
with CMT I demonstrate very slow nerve conduction velocity throughout life but only
develop disability gradually as axons degenerate. This illustrates two important points: first,
conduction slowing alone does not cause weakness or numbness. Clinical dysfunction due to
disorders of myelin is due to secondary axon loss or conduction block (block of the wave of
depolarization due to focal demyelination, a problem encountered in CIDP (see below) but
not CMT). Second, genetic disorders of myelin lead to axon loss, indicating that normal
myelin plays a role in maintaining normal axons. Symptoms in CMT often develop in
adolescence or early adulthood and progress gradually throughout adult life.
3. Variably asymmetric or multifocal demyelinating neuropathy. When a neuropathy is not
quite as exquisitely symmetric as CMT I or CMT II and the EMG/NCS suggests that
demyelination is the primary pathologic process, one should consider Chronic Inflammatory
Demyelinating Polyradiculoneuropathy, or CIDP. This is a relatively common acquired
neuropathy due to immune mediated demyelination. CIDP is usually bilateral but not quite as
symmetric as CMT I or II, and is occasionally overtly multifocal. CIDP can be sensory or
motor predominant but usually has overt clinical evidence of both. The diagnosis can be
supported by CSF examination, which characteristically demonstrates a high protein without
a cellular infiltrate (albuminocytologic dissociation; see Guillain-Barre Syndrome), and by
evidence of demyelination on nerve biopsy. CIDP is usually treated with corticosteroids,
intravenous immunoglubulin, plasma exchange, or cyclophosphamide. CIDP generally presents
with progressive symptoms over a period of months and, untreated, can run a continuously
progressive or relapsing/remitting course. Although CMT I and II are symmetric, the
differential diagnosis of a slightly asymmetric or multifocal demyelinating polyneuropathy
does include two other inherited neuropathies, Hereditary Neuropathy with Liability to
Pressure Palsies (HNPP) and X-linked CMT (CMTX), which can be identified by genetic
testing.
4. Multifocal axonal neuropathy, often referred to as "mononeuropathy multiplex." In this
pattern, individual nerves are affected in a patchy fashion; for example, such a patient
might present with a left median neuropathy, followed shortly thereafter by a right
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peroneal neuropathy, then a right sixth cranial nerve palsy. Mononeuropathy multiplex can
affect sensory or motor axons but usually involves both. The most common etiologies are
vasculitis and infiltrative disorders, such as sarcoidosis and lymphoma, in which there is
direct infiltration of cells into affected peripheral nerves. Diagnosis usually rests upon
biopsy of a nerve or another affected tissue.
Acute polyneuropathies
Most neuropathies develop gradually over months to years. There are relatively few
conditions which cause an acute polyneuropathy. The most important cause of acute
polyneuropathy is Guillain-Barre Syndrome (GBS). This is a rapidly progressive, motorpredominant, diffuse demyelinating polyradiculoneuropathy. Classically, GBS presents as a
nearly symmetric, progressive hyporeflexic and ultimately areflexic quadriparesis which
nearly always resolves spontaneously but which can lead to sufficient weakness to require
mechanical ventilation at its nadir. GBS is usually accompanied by bothersome sensory
symptoms but rather modest sensory findings. There is often striking autonomic
involvement, leading to a resting tachycardia and dramatic fluctuations in blood pressure.
GBS often follows a systemic infection by several weeks, an observation which is consistent
with the view that it is of autoimmune etiology and is sometimes triggered by an immune
attack upon a foreign antigen which shares an epitope with a component of peripheral nerve.
Pathologically it is characterized by macrophage-mediated segmental demyelination of nerve
and nerve roots, followed by remyelination in the recovery phase. The clinical diagnosis is
confirmed by EMG/NCS confirmation of a demyelinative process and by “albuminocytologic
dissociation;" that is, the finding of an elevated CSF protein, reflective of stripping of
myelin proteins from nerve roots, without a CSF pleocytosis. Though most patients recover
from GBS, the rate of recovery is accelerated by treatment with plasma exchange or
intravenous imunoglobulin. Certain variants of GBS, including an axonal form as well as a
post-infectious pure dysautonomia and post-infectious ataxia and ophthalmoplegia, have
been described as well.
Some toxic neuropathies, including neuropathies due to chemotherapeutic agents, can
develop acutely as well.
Findings isolated to one limb
The discussion so far has focused on systemic neuromuscular disorders that usually affect
more than one limb as well as the trunk or face. Some neuromuscular disorders present with
findings isolated to one limb. In such cases, the differential diagnosis is generally between a
radiculopathy, plexopathy, or mononeuropathy (disease of an individual nerve). The
examiner is therefore obliged to carefully examine the reflexes, distribution of sensory
deficits, and individual muscle groups, all the while thinking carefully about which
neuroanatomic structure is common to all of the abnormal findings.
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Radiculopathy, plexopathy, and mononeuropathy are usually due to extrinsic compression,
trauma, or infiltration. Specifically, the most common causes of radiculopathy are extrinsic
compression from herniated disk or foraminal osteophytes, infiltration from meningeal
processes such as carcinomatous meningitis, lymphomatous meningitis, chronic meningeal
infections, Lyme meningoradiculitis, or meningeal sarcoidosis, and root avulsion due to
trauma. The most common causes of plexopathy are extrinsic compression from mass
lesions, infiltration, trauma, and certain conditions specific to plexuses: neuralgic
amyotrophy, a syndrome of severe proximal upper limb pain followed by weakness and
atrophy, occurring most commonly in young adult men; lumbosacral radiculoplexopathy, a
syndrome of severe proximal lower limb pain followed by weakness and atrophy, occurring
most commonly in diabetics; and postradiation injury.The most common cause of
mononeuropathies is compressive, either repetitive, minor trauma (median entrapment at
the wrist, or carpal tunnel syndrome; ulnar entrapment at the elbow) or single episodes of
prolonged compression (radial neuropathy at the spiral groove; peroneal neurpathy at the
fibular head). Infiltration of malignant or inflammatory cells can also cause
mononeuropathies, particularly of the cranial nerves, as can vasculitis.
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