studentsyllabus-neuromuscular_000

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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 notneuromuscular 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 theneuromuscular diseases that are not neuropathies: muscle diseases, diseases of the

neuromuscular junction, and motor neuron disorders. Each of these has distinct clinicalfeatures.

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 musclecells 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 apparatuswithin the muscle cell to the cell membrane. Perhaps the best known of theseproteins is dystrophin, which is abnormal in Duchenne muscular dystrophy, an X-

linked 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 dominantcondition named for the distribution of weakness and due to a mutation on

chromosome 4, and limb-girdle dystrophy, which is in fact a geneticallyheterogeneous 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 aswell and can cause congestive heart failure. Serum CK is nearly always elevated and

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7. Myotonic dystrophy

Disorders of Neuromuscular Transmission

The neuromuscular junction is a specialized adaptation of both the nerve terminaland 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 structorecontaining 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 thesynaptic cleft between the nerve terminal and muscle membrane. The muscle membrane (the

postsynaptic membrane) is a highly redundant structure studded with acetylcholinereceptors. The redundancy of the postsynaptic membrane and the exceedingly high number

of acetylcholine receptors assure effective transmission across the synapse. When asufficient 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 isdue to postsynaptic pathology. Myasthenia is caused by autoantibodies directed against the

acetylcholine receptor. While antibodies can disrupt neuromuscular transmission by blockingthe receptor site, the primary cause of impaired neuromuscular transmission in myasthenia

is antibody-mediated destruction of the postsynaptic membrane, either due to complement-

mediated destruction of the membrane, internalization and destruction of acetylcholinereceptors, or both. The result is a simplified postsynaptic membrane and enlarged synapticcleft. This reduces the safety factor of neuromuscular transmission and, ultimately, leads

to failure of neuromuscular transmission.

Myasthenia presents with muscle weakness and prominent fatiguability. Becauserepeated 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 orsustained 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 days 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:

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1. Neurophysiologic testing. Repetitive nerve stimulation at 2-3 Hz results in

a characteristic progressive decrement in the amplitude of the evokedmuscle response, as neuromuscular transmission fails in some muscle fibers

due to depletion of available acetylcholine. In single fiberelectromyography, abnormal variation in the relative latency of muscle

fiber contraction can be demonstrated when two fibers innervated by thesame 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.

2. Antibody testing. Serum antibodies that bind to the acetylcholinereceptor 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 autoimmuneconditions. They are highly specific for myasthenia gravis in patientswhose clinical presentation is typical.

3. 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 isachieved, 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 increaseuntil 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

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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 beachieved 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 (generallyseveral 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. BothB- 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. Thymectomyis recommended in all patients with thymoma.

Finally, oral anticholinesterase agents are used for symptomatic relief. Mestinon isthe 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 onthe 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 presynapticdisorder 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 theimmune response to VGCCs on tumor cells. Symptoms of LEMS often develop before the

tumor becomes symptomatic, which may reflect the beneficial effect of the immuneresponse 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 associatedwith autonomic findings such as anhidrosis, dry mouth, and erectile dysfunction.

Antibodies to VGCCs are detectable in the serum in most patients with LEMS. Thediagnosis 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 incrementin the amplitude of the

response. This is not common in myasthenia unless the deficit is very severe. The incrementafter 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 asimmunotherapy. 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-DAPblocks 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 thepathogenic 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 motorneurons 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 includeamyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), spinal muscular atrophy

(SMA), focal motor neuron disease, X-linked spinobulbar muscular atrophy (SBMA, or

Kennedys 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 wellas 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

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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, orextrapyrimidal 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 theextent 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 casesthe 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 carefulsearch 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 exceedinglyrarely. 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 oflymphoma 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 bodymyositis, 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 inthe 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 tocell 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 ismandatory. 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 adultswhich, 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, myopathicfeatures on EMG, and characteristic findings on muscle biopsy. IBM is discussed furtherabove 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 isimportant not to miss the diagnosis.

ALS typically begins focally and spreads to adjacent regions. Thus, if the initialsymptom 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. Bulbar-

onset 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 ofupper motor neuron dysfunction, such as spasticity and hyperreflexia, predominate, while in

others there is more prominent involvement of lower motor neurons, characterized byatrophy 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 anddysphagia. 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. Forunclear 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 progressslowly 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 inthe 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 bythe ALS care team.

Etiology

Although a great many hypotheses have been put forward, the cause of ALS remainsunknown. 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 withinthe axon, and accelerated apoptosis of motor neurons. Despite numerous clinical trials, onlyone 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

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The management of ALS is largely supportive. Occupational and physical therapists

can be very helpful in devising strategies to maintain function despite disability. Patientswith 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 ortizanidine.

Ventilatory dysfunction poses a special problem in ALS. Mild to moderate ventilatory

insufficiency can often be managed successfully with noninvasive positive pressureventilation such as BiPAP (bilevel positive airway pressure). BiPAP is often remarkably

effective even in patients who have severe ventilatory dysfunction and are dependent uponmechanical 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 patientsperceive 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 toventilatory 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 motorsymptoms 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 aneuropathy is generally reduced to a manageable list of possibilities.

How does one determine these things in clinical practice? The time courseis self evident.

The distribution and modalities afffectedcan also be determined largely from history and

examination, and can be buttressed by EMG/NCS. To reliably determine the nature of theprimary pathology, one needs electrodiagnostic studies and, at times nerve biopsy as well,

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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:

1. Symmetric, sensory-predominant, axonal polyneuropathy. This is the pattern seen withmost metabolic, toxic, and nutritional causes of polyneuropathy, and is thus the pattern

most commonly seen by physicians in primary care. These neuropathies are length-dependent; 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 greatestexposure 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 ofnumbness, 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. Examplesof 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 neuropathiesusually develop gradually over a period of months to years.

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axona demyelinati

multifocal

diffuse

vasculitiinfiltrative

metabolitoxicnutritional

CMT II CMT I

CIDP

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2. Very symmetric sensorimotor axonal or demyelinating neuropathy. The presence ofsignificant numbness andweakness 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 neuropathiespresent 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 primarypathology, disability in CMT develops because of progressive loss of axons. Thus, patients

with CMT I demonstrate very slow nerve conduction velocity throughout life but onlydevelop 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 thatnormal 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 notquite 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 assymmetric 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 besupported by CSF examination, which characteristically demonstrates a high protein without

a cellular infiltrate (albuminocytologic dissociation;see Guillain-Barre Syndrome), and byevidence of demyelination on nerve biopsy. CIDP is usually treated with corticosteroids,

intravenous immunoglubulin, plasma exchange, or cyclophosphamide. CIDP generally presentswith 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 toPressure 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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Radiculopathy, plexopathy, and mononeuropathy are usually due to extrinsic compression,

trauma, or infiltration. Specifically, the most common causes of radiculopathy are extrinsiccompression 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 masslesions, 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, occurringmost commonly in diabetics; and postradiation injury.The most common cause of

mononeuropathies is compressive, either repetitive, minor trauma (median entrapment atthe 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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