Approach to Patients With

Neuromuscular Disorders
Anthony A. Amato, MD
Chief, Neuromuscular Division and Director, Clinical Neurophysiology Laboratory
Brigham and Womens Hospital
Associate Professor of Neurology
Harvard Medical School
Boston, Massachusetts

INTRODUCTION a true sensory level is not evident in GBS but should be present in
transverse myelitis and other structural abnormalities involving the
The approach to patients with neuromuscular disorders is chal- spinal cord.
lenging. As in other neurological diseases the key to arriving at the
correct diagnosis is careful localization of the lesion. Weakness can The presence of motor and sensory symptoms and signs are helpful
be the result of central lesions (brain or spinal cord processese.g., in distinguishing peripheral neuropathies from anterior horn cell
brainstem infarct, central pontine myelinolysis, transverse myelopa- disorders, myopathies, and neuromuscular junction disorders.
thy), anterior horn cell disease (e.g., amyotrophic lateral sclerosis However, some types of peripheral neuropathy are predominantly
[ALS], poliomyelitis), peripheral neuropathy (e.g., Guillain-Barr or purely motor and thus can be difficult to distinguish these other
syndrome [GBS]), neuromuscular junction defects (botulism, disease processes. Most neuropathies are associated with distal
Lambert-Eaton myasthenic syndrome [LEMS], myasthenia gravis greater than proximal weakness. However, significant proximal
[MG]), or myopathic disorders. The most important aspect of as- weakness can be seen in certain peripheral neuropathies (e.g., GBS,
sessing individuals with neuromuscular disorders is taking a thor- chronic inflammatory demyelinating polyneuropathy [CIDP]).
ough history of the patients symptoms, disease progression, and Further, although usually associated with proximal weakness,
past medical and family history as well as performing a detailed certain myopathies and rarely even neuromuscular junction disor-
neurologic examination. This is not to say that the electrodiagnos- ders can manifest with primarily distal weakness.
tic (EDX) examination, laboratory data, and muscle biopsies are
not important, but the physicians clinical acumen based on the Amyotrophic lateral sclerosis is the result of degeneration of upper
historical aspects of the disease and the clinical examination provide and lower motor neurons. The degeneration of lower motor neurons
the guiding force for performing the most appropriate confirma- leads to muscle weakness, atrophy, and fasciculations, which typi-
tory tests to most expeditiously arrive at a correct diagnosis. cally begins focally. Upper motor neuron involvement manifests as
spasticity and pathologically brisk DTRs. While most patients over
It is usually not difficult to distinguish generalized weakness sec- time develop both upper and lower motor neuron deficits, some
ondary to a cerebral or brainstem insult from other causes of muscle patients continue to have pure lower motor neuron abnormalities,
weakness, because in these central disorders weakness is accompa- while others have only upper motor neuron signs. Some of the
nied by impaired consciousness. Myelopathies can be more trouble- hereditary spinal muscular atrophies present with generalized sym-
some to diagnose. Compressive lesions of the involving spinal cord metrical, proximal greater than distal, weakness and can be difficult
and the nerve roots can result in a combination of upper and lower to distinguish from myopathic disorders.
motor neuron abnormalities which can mimic ALS and vice-versa.
Acute transverse myelitis can be associated with rapid quadriparesis The key in distinguishing neuromuscular junction defects from
in which the deep tendon reflexes (DTRs) are initially absent from myopathies is the fluctuation in symptoms and signs in the
a shocked cord. Such cases are not uncommon initially as GBS. former. Patients with MG usually fatigue during repetitive activ-
Although both conditions are usually associated with sensory loss, ity while patients with LEMS can actually improve with contin-
 Approach to Patients With Neuromuscular Disorders AANEM Course

ued physical exertion. Neuromuscular junction disorders have a

predilection to affect the extraocular muscles which are less com- Table 1 Differential diagnosis of the floppy infant
monly affected in myopathies.

The following discussion is a reasonable approach to evaluating Central nervous system disorders (most common etiology)
patients with neuromuscular complaints.
Anterior horn cell
Spinal muscular atrophy type I and II
MEDICAL HISTORY
Peripheral neuropathy
While obtaining the medical history, the clinician should attempt Congenital hypomyelinating/amyelinating neuropathy
to define onset and course of the illness as well as the distribution CMT III (Dejerine-Sottas)
of symptoms. The differential diagnosis of generalized weakness CMT type I and CMT type II (rare)
presenting in infancy (Table 1) is different from that presenting
Giant axonal neuropathy
later in childhood or early adult life (Table 2) and those disorders
manifesting in late adulthood (Table 3). The rate of disease pro- Neuromuscular junction
gression is important to pursue with the patient. Certain disorders Infantile botulism
progress acutely over days or weeks (Table 4), while others evolve
Infantile myasthenia gravis
more slowly over months (Table 5). The course of the disease may
be chronic and progressive, monophasic, or relapsing. The increas- Congenital myasthenia
ing health consciousness of some individuals presents a good op-
Myopathy
portunity to gauge the rate of disease progression with respect to
distance previously run, weight lifted, or games played. A steady Congenital myopathies (all of them can present in infancy)
reduction in these exercise-related parameters may be important Muscular dystrophies
clues for establishing a pattern of gradual and progressive physical Congenital muscular dystrophies
decline.
Dystrophinopathy/sarcoglycanopathy (rare)

The patients presenting symptoms are dependent upon the muscle Congenital myotonic dystrophy
groups that are predominantly affected. Early manifestation of proximal Metabolic myopathies
lower extremities weakness is progressive difficulty climbing stairs and Glycogen storage defects
in arising from a chair, commode, or the floor. The patient may note
Acid maltase deficiency
that the upper extremities may now be required to provide assis-
tance in pulling them up the stairs with a hand rail or in pushing Debrancher deficiency
them up from a seat. Weakness of the anterior compartment of Branching enzyme deficiency
the distal lower extremity results in foot drop. These patients will Myophosphorylase deficiency (rare)
complain of frequent tripping or stubbing of the toes because of
Disorders of lipid metabolism
the inability to dorsiflex the foot when walking. Involvement of the
posterior compartment of the distal legs leads to difficulty standing Carnitine deficiency
on ones toes. Fatty acid-Acyl-CoA dehydrogenase deficiencies
Mitochondrial myopathies
Weakness about the shoulder girdles may impact on the patients
Benign and fatal infantile myopathy
ability to perform activities of daily living, such as brushing hair
and lifting objects. Distal upper extremity weakness usually pres- Leighs syndrome
ents with progressive difficulty with grip. Patients will describe dif- Endocrine myopathies (e.g., hypothyroidism)
ficulty opening jar tops and twisting or turning door knobs.
CMT = Charcot-Marie-Tooth
A patient with neck weakness will often complain of difficulty
lifting their head off a pillow. Further, sudden braking or accelerat-
ing in a car can cause the head to jerk back and forth. Involvement
of cranial muscles may result in ptosis, diplopia, dysarthria, or dif- small intrinsic hand muscles. Alternatively, some muscle groups
ficulty chewing and swallowing. may be noted to be enlarged. Some disorders are associated with
fasciculations, myalgias, cramps, stiffness or myotonia, periodic
The examiner should ask about the presence of extreme fluctuations paralysis, and myoglobinuria. If these symptoms are not offered by
in strength during the day or associated with physical activities. Such the patient, their presence should be inquired by the clinician.
fluctuations in strength are more typical of neuromuscular junc-
tion disorders. Observant patients may also detect a progressive It is important to inquire about sensory symptoms. Patients may
loss of muscle bulk about various aspects of their body, particularly complain of feeling numb, but this word has different meanings
involving the anterior thigh, shoulder, and occasionally face and for different people. If not offered by the patient, the examiner
AANEM Course Numbness, Tingling, Pain, and Weakness 

Table 2 Weakness presenting in childhood or early adulthood

Anterior horn cell Congenital muscular dystrophy (partial merosin deficiency)

Spinal muscular atrophy type III Myotonic dystrophy
Poliomyelitis Other dystrophies (e.g., FSHD, EDMD)
Amyotrophic lateral sclerosis Metabolic myopathies
Glycogen storage defects
Peripheral neuropathy
Acid maltase deficiency
Acute or chronic inflammatory demyelinating polyneuropathy
Debrancher and branching enzyme deficiency
Hereditary neuropathies
Disorders of lipid metabolism
Neuromuscular junction
Carnitine deficiency
Botulism
Fatty acid-Acyl-CoA dehydrogenase deficiencies
Myasthenia gravis
Mitochondrial myopathies
Congenital myasthenia
Periodic paralysis
Lambert-Eaton myasthenic syndrome
Electrolyte imbalance
Myopathy Hyperkalemia
Congenital myopathies Hypokalemia
Central core Hypophosphatemia
Multicore Hypercalcemia
Centronuclear Endocrine myopathies
Nemaline Toxic myopathies
Myofibrillar Inflammatory myopathies
Muscular dystrophies Dermatomyositis
Dystrophinopathy (Duchenne or Becker) Polymyositis (after age 20)
Limb-girdle muscular dystrophies Infectious myositis

EDMD = Emery-Dreifuss muscular dystrophy; FSHD = facioscapulohumeral muscular dystrophy

should specifically ask the patient about the presence or absence of including myopathies, are not associated with severe muscle pain or
sensory loss or tingling, prickly, or burning pain. tenderness. Some patients with various forms of muscular dystrophy
or inflammatory myopathy will describe mild or sometimes moder-
Fatigue is also a non-specific complaint. Most patients referred to a ate myalgias. The pain associated with these disorders myopathies
neuromuscular clinic or the neurophysiology laboratory for evalu- is typically described as a deep, aching discomfort in the muscles
ation of fatigue do not have a primary neuromuscular disorder. and is seldom severe enough to warrant analgesics. Usually the pain
Their symptoms are best characterized as asthenia or the subjective is diffuse rather than localized and is not tender. However, severe
loss of energy. Although such patients often complain of feeling myalgias and tenderness can accompany fasciitis, myositis related
weak all over, examination of muscle strength is typically normal to infections, and rhabdomyolysis/myoglobinuria caused by various
or limited by give-way. This is not to say that patients with neuro- metabolic myopathies, electrolyte disturbances, and toxins.
muscular disorders do not experience fatigue. Certainly, pathologic
fatigue can be demonstrated in patients with certain neuromuscular In many patients referred for evaluation of severe muscle pain,
disorders by electrophysiologic testing (e.g., repetitive stimulation) the symptoms are psychosomatic rather than organic in etiology.
or by provocative exercise testing. However, in organic disorders as Such patients typically describe severe generalized muscle pain and
opposed to psychosomatic illness, fatigue is usually accompanied by tenderness unrelieved by analgesic medications. The symptoms of
objective muscle weakness. severe muscle pain are usually accompanied by complaints of gen-
eralized weakness or fatigue as previously described. In addition,
Likewise, muscle pain (myalgias) is a common symptom in patients the patients frequently describe exquisite tenderness even to light
referred to a neuromuscular clinic. Most neuromuscular disorders, touch. Despite these severe symptoms, there is no objective evi-
 Approach to Patients With Neuromuscular Disorders AANEM Course

Table 3 Weakness presenting in middle to late adulthood

Anterior horn cell Metabolic myopathies

Spinal muscular atrophy type III Glycogen storage defects
Kennedys disease Acid maltase deficiency
Poliomyelitis Debrancher deficiency
Amyotrophic lateral sclerosis Disorders of lipid metabolism (rare)
Mitochondrial myopathies
Peripheral neuropathy
Periodic paralysis
Hereditary neuropathies
Familial hypoKPP manifests within the first 3 decades
Acute or chronic inflammatory demyelinating polyneuropathy
Familial hyperKPP usually manifests in the first decade
Drug-induced or toxic neuropathies
Electrolyte imbalance
Diabetic neuropathy
Hyperkalemia
Amyloid
Hypokalemia
Vasculitis
Hypophosphatemia
Neuromuscular junction
Hypercalcemia
Botulism
Endocrine myopathies
Myasthenia gravis
Toxic myopathies
Lambert-Eaton myasthenic syndrome
Myopathy associated with systemic disease (e.g., cancer), poor
Myopathy nutrition, disuse
Congenital myopathies Amyloid myopathy
Myofibrillar myopathy Inflammatory myopathies
(Others types are uncommon) Inclusion body myositis (most common inflammatory
myopathy after the age of 50)
Muscular dystrophies
Dermatomyositis
Dystrophinopathy (Becker)
Polymyositis (after age 20)
Limb-girdle muscular dystrophies
Infectious myositis
Oculopharyngeal dystrophy
Bent spine/dropped head syndrome

hyperKPP = hyperkalemic periodic paralysis; hypoKPP = hypokalemic periodic paralysis

dence of a neuromuscular disease on clinical examination, labora- attempting to define the possible mode of inheritance or degree of
tory testing, electrophysiological studies (electromyography/nerve genetic penetrance. When a hereditary disorder is suspected, it is
conduction study [EMG/NCS]), or muscle biopsy. valuable to examine affected family members. Some patients may
claim a family history of a particular disorder but upon examining
The past medical history of patients should be addressed because affected family members a different disease may be diagnosed. In
various medical diseases are associated with neuromuscular dis- addition, some family members who are asymptomatic may be
orders. For example, inflammatory myopathies may be seen in found to have mild signs of disease on a thorough examination.
patients with connective tissue disease; concurrent autoimmune Thus, the past medical and family history as well as a pertinent
disorders may be present in patients with MG; LEMS is associated review of symptoms provide insights into the type of disorder po-
with small cell lung cancer; and neuropathies are common in pa- tentially affecting the patient.
tients with diabetes mellitus. The review of symptoms should assess
systemic complaints that may be associated with a specific neuromus- In patients with progressive weakness, a history regarding possible
cular disorder (e.g., arthralgias to assess for underlying connective toxin exposures is important. These exposures may come from the
tissue disease). A careful family history is also vitally important in work or home environment or from medications. Such toxins can result
AANEM Course Numbness, Tingling, Pain, and Weakness 

Table 4 Neuromuscular disorders presenting with acute or Table 5 Differential diagnosis of chronic progressive
subacute proximal weakness proximal weakness

Anterior horn cell Anterior horn cell

Poliomyelitis Amyotrophic lateral sclerosis

Peripheral neuropathy Spinal muscular atrophy type III

Guillain-Barr syndrome Kennedys disease

Porphyria Peripheral neuropathy

Diphtheria Chronic inflammatory demyelinating polyneuropathy
Tick paralysis Multifocal motor neuropathy
Toxic neuropathies Toxic neuropathies
Diabetic amyotrophy Neuropathy associated with systemic disorders
Vasculitis Connective tissue disease (e.g., vasculitis)
Carcinomatous infiltration (e.g., leukemia, lymphoma) Diabetes mellitus
Paraneoplastic neuropathy Amyloidosis

Neuromuscular junction Paraneoplastic

Botulism Carcinomatous infiltration (e.g., leukemia, lymphoma)

Lambert-Eaton myasthenic syndrome Neuromuscular junction

Myasthenia gravis Lambert-Eaton myasthenic syndrome

Myopathy Myasthenia gravis

Periodic paralysis Myopathy

Electrolyte imbalance Periodic paralysis
Endocrinopathies Electrolyte imbalance
Inflammatory myopathies Endocrinopathies
Dermatomyositis Inflammatory myopathies
Polymyositis Dermatomyositis
Infectious myositis Polymyositis
Note: Inclusion body myositis does not present acutely Infectious myositis
Toxic myopathies Note: Inclusion body myositis does not present acutely
Metabolic myopathies Toxic myopathies
Glycogen and lipid disorders in association with Metabolic myopathies
myoglobinuria Glycogen and lipid disorders in association with
myoglobinuria

in damage of the peripheral nerves, neuromuscular junction, or muscle. nesses or just to being a clumsy child. Also, parents may bring a
The severity of the clinical manifestations often depends upon the considerable amount of guilt to the examination and the physician
type of toxin as well as the dose and duration of the exposure. must be aware of this potential problem. The parents fears and
associated guilt should be dealt with and not ignored. If necessary,
When children are concerned, the parents must be questioned with professional counseling should be offered in addition to treating
great care and sensitivity. The heightened concern of the parents the patient. Often, when a child is ill, the entire family is affected,
may cause them to unconsciously omit important details of the which can in turn have profound physical and psychological reper-
patients status as related to various other associated childhood ill- cussions on more than just the patient.
 Approach to Patients With Neuromuscular Disorders AANEM Course

PHYSICAL EXAMINATION
Table 6 Differential diagnosis of distal weakness
Following the above acquired medical history, a complete neu-
rological examination should be performed. The distribution of
symptoms and pattern of weakness is of utmost importance. Most Cervical disease
myopathies preferentially affect the proximal more than distal Multilevel radiculopathy (C7, C8, T1)
muscles, while distal muscles are more severely involved than proxi-
Lower trunk brachial plexopathy
mal muscles in most types of peripheral neuropathy. However, the
distal muscles can be weaker than the proximal muscles in certain Syringomyelia
neuromuscular disorders other than peripheral neuropathy (Table Tumor of the cord
6). Likewise, significant proximal weakness can be seen in disor-
ders other than myopathies (ALS, spinal muscular atrophy [SMA], Lumbosacral disease
GBS, CIDP, MG, LEMS). Certain neuromuscular disorders can Tumor of the conus medularis
predominantly affect or have an early predilection for the ocular Polyradiculopathy (L4, L5, S1, S2)
muscles (Table 7).
Lumbosacral plexopathy

The physical examination actually begins during the taking of Motor neuron disorders
the history. Extraocular, facial, jaw, pharyngeal, tongue, and neck Distal spinal muscular atrophy
weakness may be apparent by just observing the patient during the
Amyotrophic lateral sclerosis
interview. For example, a mitochondrial myopathy or MG should
be considered in patients observed to have ptosis or ophthalmopa- Neuromuscular junction
resis. Patients with myotonic dystrophy often have facial weakness, Myasthenia gravis (rare)
temporalis muscle wasting, and frontal balding. A characteristic
Congental myasthenia gravis (e.g., slow ion channel defect)
rash is typically present in patients with dermatomyositis. Thus,
specific neuromuscular disorders can be diagnosed or at least Peripheral neuropathies
strongly suspected by casually observing the patient while taking
Charcot-Marie-Tooth disease and related hereditary
their medical history. neuropathies
Multifocal demyelinating motor or sensorimotor neuropathies
It is essential that the patient undress except for undergarments and
a gown for an adequate examination. The patients posture while Vasculiltis
sitting, standing, and walking should be assessed. Weakness of the Toxic/metabolic neuropathies
spine extensor may require the patient to lean forward on their arms
or rest against the examining table to maintain an upright posture Intrinsic muscle disorders
particularly for more than a few minutes. Some patients may have Distal myopathies/dystrophies
head drop related to neck extensor weakness. When standing, the Facioscapulohumeral muscular dystrophy
patient should be observed from the side as well as the front and
Scapuloperoneal syndromes
back. On side viewing, the clinician can detect excessive lumbar
lordosis, hyperextension of the knee (genu recurvatum), and ankle Emery-Dreifuss muscular dystrophy
contractures in patients with proximal muscle weakness. An exces- Oculopharyngodistal muscular dystrophy
sive lordosis implies the hip extensors are too weak to maintain the Myotonic dystrophy
center of gravity in its normal position without accessory muscle
Acid maltase deficiency
assistance. The weight line is purposefully brought posterior to the
hip joints so that the patient can rest on the hip ligaments. This is Debrancher enzyme deficiency
all accomplished through the previously noted compensatory exces- Phosphorylase b kinase deficiency
sive lumbar lordosis. With quadriceps weakness, the knee extensors Myofibrillar myopathy
may become unable to resist the normal knee flexion moment
Central core disease
during stance with a potential for falling secondary to buckling at
the knee. The patient attempts to compensate for this problem by Centronuclear myopathy
shifting the weight line anterior to the knee. This hyperextension Nemaline myopathy
of the knee (known as genu recurvatum or back-kneeing) provides Inclusion body myositis
stability to the knee while standing and walking. An exaggerated
Focal myositis
lumbar lordosis and genu recurvatum can result in an unfavorable
dorsiflexion moment at the ankle, which is compensated by plantar
AANEM Course Numbness, Tingling, Pain, and Weakness 

Table 7 Neuromuscular causes of ptosis or rising up the shoulder secondary to poor fixation may be noted,
ophthalmoplegia particularly in patients with facioscapulohumeral muscular dys-
trophy. Proximal arm weakness also may result in drooping of the
shoulders and inward rotation of the arms. In addition, shoulder
Peripheral neuropathy girdle weakness can cause the horizontal or downward rotation of
Guillain-Barr syndrome the clavicles, diagonal or horizontal displacement of the anterior
axillary lines, and the dorsum of the hands to face forwards rather
Miller-Fisher syndrome
than to the side.
Neuromuscular junction
During both quiet standing and ambulation, the muscles should be
Botulism
inspected for any signs of wasting or hypertrophy not only in the
Lambert-Eaton myasthenic syndrome extremities, but also about the head and neck. The clinician should
Myasthenia gravis observe for fasciculations, which are signs of motor neuron or pe-
Congenital myasthenia ripheral nerve disease. Visible muscle cramping and the presence
of continuous muscle activity (e.g., myokymia) should be noted.
Myopathy Muscles should be palpated for tone and tenderness.
Mitochondrial myopathies
Kearn-Sayres syndrome Muscles can be percussed in the upper and lower extremity as well
as the face, including the tongue. Percussion of the muscle directly
Progressive external ophthalmoplegia
may reveal a pronounced contraction of a small portion with a
Oculopharyngeal and oculopharyngodistal muscular dystrophy delayed relaxation (percussion myotonia). Myotonia can predomi-
Myotonic dystrophy (ptosis only) nantly affect proximal or distal muscles depending on the specific
Congenital myopathy myopathy. Myotonia typically can be demonstrated distally and
in the tongue in myotonic dystrophy, while proximal extremity
Myotubular
muscles are affected in proximal myotonic myopathy (PROMM).
Nemaline (ptosis only) Action myotonia can also be assessed by having the patient sustain
Hyperthyroidism/Graves' disease (ophthalmoplegia without a grip for a brief period and then release the grip. One sees a slow
ptosis) relaxation with action myotonia. Myotonia generally improves
with repetition. In contrast, paramyotonia worsens with repetitive
activity. This is best demonstrated in patients with paramyotonia
congenita by having them repeatedly open and close their eyes;
eventually patients have difficulty completely opening their eyes.
flexion and slight heel rise (patient is seen to stand on his/her tip- When myotonia or paramyotonia is elicited, the physician should
toes). inquire about the patients response to activity and cold temperatures
because these conditions worsen the symptoms in specific myotonic
During ambulation the patient with proximal leg weakness may be disorders. Other abnormalities can be noted on percussion. A peculiar
observed to have a wide-based waddling gait with the above noted wave of muscle contraction emanating from the site of percussion is
hyperlordosis, genu recurvatum, and toe walk. The waddling gait seen in so-called rippling muscle disease. Occasionally, a mounding
is essentially a result of hip abductor weakness which is incapable of the muscle as opposed to a contraction indentation can be observed.
of preventing the pelvis from dropping excessively, i.e., a positive This phenomena is referred to as myoedema and can be observed in
Trendelenburg during ambulation. Compensatory abnormal shoul- patients with hypothyroidism.
der motions can also be seen as a result of attempting to control
gravity throughout the gait cycle and prevent falling. With disease Manual muscle testing is extremely important and the author
progression, the patient begins to fall more frequently and display recommends using the Medical Research Council (MRC) scale
associated signs of bruises and superficial skin lesions about the for uniformity and hence understandability from one physician
knees and hands. Patients with weakness of the anterior compart- to another: Grade 0: no visible contraction; Grade 1: trace con-
ment of the distal lower extremity will have foot drop and the traction; Grade 2: full movement across the joint with gravity
so-called steppage gait. Instead of a normal heel-strike, the patient eliminated; Grade 3: full movement across the joint against gravity;
lands flat-footed or strikes the ground with the toes first. To avoid Grade 4: full movement against gravity plus some resistance; Grade
tripping, the patient lifts the knee higher than normal in order for 5: normal strength. A modification of this scale is usually em-
them to clear the ground during the swing phase of ambulation. ployed by adding plus (e.g., 4+) or minus signs (e.g., 3) next to
Distal lower extremity strength should also be assessed by having the numbers for a finer distinction or degrees of muscle weakness
the patient walk on their heels and toes. between those larger grades. The MRC scale has been demonstrated
to have excellent intraobserver and interobserver reliability. Face,
Weakness of the shoulder girdle can result in winging of the neck, and upper and lower extremity muscles should be tested and
scapula. In addition, a trapezius hump caused by the scapula documented in the patients chart so as to provide an ability to
 Approach to Patients With Neuromuscular Disorders AANEM Course

document any changes over time. The author routinely grades the sign), after rubbing the anterior aspect of the shin (Oppenheimers
strength of the orbicularis oculi; jaw; tongue; neck flexion and ex- sign), or after pricking the extensor aspect of the toe (Bings sign).
tension; shoulder abduction, flexion, and extension; elbows flexion Plantar responses are extensor in patients with upper motor neuron
and extension; wrist flexion and extension; finger and thumb lesions, otherwise they are normal. In patients with significant
flexion, extension, and abduction; hip flexion, extension, and weakness of the toes, a plantar response may be unobtainable and
abduction; knee flexion and extension; ankle dorsiflexion; plantar therefore not interpretable.
flexion, inversion, and evasion; and toe flexion and extension. As
the MRC scores reflect movement against gravity, muscle groups Sensation to various modalities (temperature, pain, touch, vi-
must be tested against gravity. Thus, neck flexion should be assessed bration, and proprioception) should be assessed in all patients.
with the patient supine; neck extension, hip extension and knee Temperature and pain are conveyed by small-diameter nerve
flexion with the patient prone; and hip abduction with the patient fibers, while deep touch, vibration, and proprioception are mainly
on their side. Examining the patient in these positions is essential conveyed by large-diameter sensory nerves. Some neuropathies
in accurately assessing their strength and can detect weakness not predominantly affect small-diameter nerve fibers (e.g., amyloid
noted if the patient were examined only in a seated position. neuropathy), while other neuropathies have a predilection for larger
fibers (e.g., CIDP). The sensory examination should be normal in
A functional assessment of motor strength should be assessed. To patients with pure motor neuron disease, myopathy, or MG unless
evaluate patients with possible hip girdle weakness, the clinician the patient has a concurrent neuropathy. Mild sensory symptoms
should observe the patient arise from the floor without grabbing and signs may be seen in LEMS.
onto nearby objects. A rather characteristic sequence of events
is seen to occur with weak patients first assuming a position on Examining children can be a challenge, particularly infants. Infants
the hands and knees and progressing up their legs, i.e., the so- can be positioned prone to observe if they are capable of extend-
called Gowers sign or maneuver. One can also observe the patient ing their head. An inability to do so suggests weakness of the neck
perform a deep knee bend, arise from a squat or a chair, climb extensor muscles. Most infants have considerable subcutaneous fat
stairs, run, or hop on one foot to detect subtle weakness. Recording that makes muscle palpation quite difficult. Palpating neck exten-
the time it takes to perform specific tasks (e.g., climbing 10 steps sor muscles is a good place to attempt this evaluation secondary to
or walking 30 feet) is helpful, especially in monitoring a functional little subcutaneous fat overlying this muscle group. Neck flexion
response to a particular therapy or in following the natural progres- strength can be assessed as the child is pulled by the arms from a
sion of the disorder. In patients with myasthenia gravis, it is useful supine to sitting position. Crying during the examination allows
to measure and record the time it takes for ptosis to appear after the opportunity to assess the childs vocalization (e.g., presence of
sustained upgaze. a weak cry) and fatigability to the physical examination. Muscle
weakness in infants is usually characterized by overall decrease in
Muscle tone is assessed as normal, decreased, or increased. Increased muscle tone and many children with profound weakness are char-
tone or spasticity is caused by upper motor neuron lesions. Muscle acterized as a floppy infant. This terminology does not necessarily
tone in most myopathies, neuromuscular junction disorders, and imply a neuromuscular disorder. In fact, most floppy infants exhibit
neuropathies is usually normal or sometimes decreased. Deep decreased tone secondary to a central nervous system problem. It is
tendon or muscle stretch reflexes are graded as: 0 = absent, 1+ = important to examine the parents of floppy infants for possibility of
decreased (usually requires reinforcement maneuvers to obtain), a neuromuscular disorder. This is particularly important in children
2+ = normal, 3+ = brisk (spread to other muscle groups), 4+ = suspected of having myotonic dystrophy. The author has diagnosed
pathologically brisk (clonus). The DTRs are brisk in patients with a number of infants with congenital myotonic dystrophy by exam-
upper motor neuron lesions and are decreased in patients with ining the mother who was asymptomatic. In addition, weakness
lower motor neuron disease and peripheral neuropathy. Reflexes are can transiently develop in infants born to mothers with MG.
normal in patients with myasthenia gravis but are usually dimin-
ished in patients with LEMS. During the early phases of myopathic After obtaining a detailed medical history and physical examina-
disorders, DTRs are usually present, but as the disease progresses tion, the site of the lesion (upper motor neuron, anterior horn cell,
they may diminish or become unobtainable. Specific myopathies peripheral nerve, neuromuscular junction, or muscle) responsible
are associated with decreased or absent reflexes and may have a for the neuromuscular symptoms and signs is usually apparent.
predilection for certain muscle groups. For example, the knee jerk In patients in whom the site is still unclear, further testing is re-
is reduced early in the course of inclusion body myositis when quired. Electrophysiological testing with EMG and NCS can be of
other reflexes are still relatively normal. On the other hand, certain considerable help in localizing the lesion to the anterior horn cell,
reflexes appear to be spared even late in the course of the disease peripheral nerve, neuromuscular junction, or muscle. Features on
(e.g., ankle jerks are frequently present in patients with Duchenne EMG/NCS can also help identify the specific disorder (e.g., MG,
muscular dystrophy despite severe generalized weakness). Plantar LEMS, and Charcot-Marie-Tooth disease type 1). Specific labora-
responses are usually assessed by striking the sole of the foot and tory tests are ordered depending on the localization of the disease
looking for pathological dorsiflexion or extension of the big toe (a process to confirm the site of the lesion and to identify the specific
positive Babinski sign). The normal response is plantar flexion of neuromuscular disease. Early and correct diagnosis of a neuro-
the toes. The pathologic extension of the big toe can also be dem- muscular disorder is essential, particularly if it is treatable (e.g.,
onstrated after striking the lateral aspect of the foot (Chaddocks inflammatory neuropathies and myopathies, MG, LEMS). Even
AANEM Course Numbness, Tingling, Pain, and Weakness 

in chronic disorders in which progression can not be halted (e.g., with acquired demyelinating neuropathies and M-spikes to look for
muscular dystrophy, ALS), diagnosis is important because there osteosclerotic or lytic lesions. Patients with monoclonal gammopathy
are therapies available to improve quality of life. Further, correct should also be referred to a hematologist for consideration of a bone
diagnosis is essential for genetic counseling. In the remainder of marrow biopsy. In patients with a mononeuropathy multiplex pattern
the discussion, the specific laboratory tests which are ordered when of involvement, the author orders a vascultitic workup to include
evaluating a patient with a neuromuscular complaint are outlined. the above laboratory tests as well as these: cryoglobulins, hepatitis
serology, anticytoplasmic nuclear antibodies, Western blot for Lyme
disease, human immunodeficiency virus (HIV), and occasionally a
LABORATORY TESTING cytomegalovirus (CMV) titer.
Motor Neuron Disease
There are many autoantibody panels (various antiganglioside
antibodies) being marketed for screening routine neuropathy
In patients suspected of having motor neuron disease (anterior patients for a treatable condition. However, as noted in the discus-
horn cell disease), the author orders routine complete blood count sion above, these autoantibodies have no proven clinical utility or
(CBC) and blood chemistries. Hyperthyroidism and hyperparathy- added benefit provided one performs a good clinical examination
roidism may superficially resemble motor neuron disease because and obtains detailed electrophysiological studies (EMG/NCS). The
of the weakness associated with brisk DTRs and fasciculations. author typically does not order heavy metal screen, unless there
However, the weakness in these disorders have a myopathic basis. is a history of possible exposure or features on the examination
A serum protein electrophoresis is obtained because there may be which are suspect (e.g., severe painful sensorimotor and autonomic
an increase in various lymphoproliferative disorders in patients with neuropathy and alopecia: thalium; severe painful sensorimotor
ALS. Unfortunately, the relationship does not appear causative as neuropathy with or without gastrointestinal (GI) disturbance and
treatment of the underlying lymphoproliferative does not change Mees lines: arsenic; wrist/finger extensor weakness and anemia with
the course of the motor neuron disease. In patients with symmetri- basophilic stippling of red blood cells: lead).
cal and proximal greater than distal weakness, DNA analysis for
hereditary SMA may be useful. In patients with suspected GBS or CIDP, a lumbar puncture is im-
portant to look for an elevated cerebrospinal fluid (CSF) protein. In
Much has been made in the literature about the utility of anti- idiopathic cases of GBS and CIDP, there should not be a significant
ganglioside antibodies, in particular anti-GM-1 antibodies, in number of cells in the CSF. If cells are present, one should consider
assessing for a treatable cause of motor neuron disease. However, HIV infection, Lyme disease, sarcoidosis, or lymphomatous or
the author has not found this laboratory test to be clinically useful. leukemic infiltration of nerve roots. Some patients with GBS and
Anti-GM-1 antibodies can be present in a low concentration in a CIDP have increased liver function tests (LFTs). In these cases, it
number of neuropathic conditions. In high titers, the presence of is important to also check for hepatitis B and C, HIV, CMV, and
these antibodies is quite specific for multifocal motor neuropathy Epstein-Barr virus infection. In patients with an axonal GBS (by
(MMN), which is a potentially treatable condition. Unfortunately, EMG/NCS) or those with a suspicious coinciding history (e.g.,
the sensitivity of antibody testing in MMN is low (as many as 50% unexplained abdominal pain, psychiatric illness, significant auto-
of patients with MMN have absent titers). Further, MMN can usually nomic dysfunction), it is reasonable to screen for porphyria.
be distinguished clinically from motor neuron disease. Weakness is in
the distribution of specific nerves in MMN as opposed to a myotomal In patients with a severe sensory ataxia, a sensory ganglionopathy
or nerve roots pattern of weakness in motor neuron disease. In addi- or neuronopathy should be considered. The most common causes
tion, pathologically brisk DTRs and extensor plantar responses are not of sensory ganglionopathies are Sjgrens syndrome and a paraneo-
seen in MMN. The most useful test in assessing whether a patient has plastic neuropathy. Neuropathy can be the initial manifestation of
a potentially treatable motor neuropathy is an EMG/NCS. Patients Sjgrens syndrome. Thus, one should always inquire about dry eyes
with MMN have electrophysiological evidence of conduction block and mouth in patients with sensory signs and symptoms. Further,
or other features of demyelination. some patients can manifest sicca complex without full-blown
Sjgrens syndrome. In patients with sensory ataxia, the author
Neuropathies orders a Sjgrens antibody test SSa and SSb in addition to the
routine ANA. Further, the patients are referred to ophthalmology
In patients with generalized symmetric peripheral neuropathy, the for a Rose Bengal stain and Schirmers test. They are also referred
author orders routine CBC, chemistries, urinalysis, thyroid function to ear-nose-and-throat for biopsy of the lip or parotid gland to
tests, B12, folate, erythrocyte sedimentation rate (ESR), rheumatoid confirm a diagnosis of Sjgrens syndrome. To workup a possible
factor, antinuclear antibody (ANA), and serum protein electropho- paraneoplastic sensory or sensorimotor polyneuropathy, anti-Hu
resis (SPEP). In a patient suspected of a lymphoproliferative disease antibodies are ordered. These antibodies are most commonly seen
or amyloidosis or if the nerve conduction studies are demyelinat- in patients with small cell carcinoma of the lung. Importantly, the
ing, serum and urine immunofixation electrophoresis (IFE) rather paraneoplastic neuropathy can precede the detection of the cancer
than an SPEP (an IFE is more sensitive at identifying a monoclonal and should lead to periodic imaging of the chest with computed
gammopathy) are ordered. Skeletal surveys are ordered in patients tomography (CT) or magnetic resonance imaging.
10 Approach to Patients With Neuromuscular Disorders AANEM Course

Neuromuscular Junction Disorders Table 8 Etiologies of secondary hypokalemic and

In patients in whom a neuromuscular junction defect is a possibil- hyperkalemic paralyses
ity, acetylcholine receptor antibodies (MG) and antibodies directed
against the voltage-gated muscle calcium channel (LEMS) can be
Hypokalemic paralysis
assayed. Although these antibodies are quite specific, they are not
100% sensitive and can be negative in patients with the neuro- Thyrotoxic periodic paralysis
muscular disorder in question. A chest CT should be ordered in Renal tubular acidosis
patients with MG to look for thymic hyperplasia (evident in 40%) Villous adenoma
or thymoma (present in 10%). A chest CT scan should also be
Bartters syndrome
performed on patients with LEMS because of the association with
small cell carcinoma of the lung. Botulism is caused by the exotoxin Hyperaldosteronism
of the bacteria, Clostridium botulinum. Infantile botulism is con- Chronic or excessive use of diuretics, corticosteroids, licorice
tracted by ingestion of bacterial spores (e.g., usually from contami- Amphotericin B toxicity
nated honey) which subsequently colonize the gut and release the
Alcoholism
toxin. Wound botulism can occur following colonization of deep
wounds such as those that occur in compound fractures or subcu- Toluene toxicity
taneous injection sites in drug addicts. Botulism can also arise from Barium poisoning
food poisoning resulting from the direct ingestion of the toxin from
Hyperkalemic paralysis
improperly canned and cooked foods. The toxin can be assayed in
the serum and stool in suspected cases. Polymerase chain reactions Addisons disease
can identify the organism in biological specimens and food. Hypoaldosteronism (hyporeninemic)
Isolated aldosterone deficiency
Myopathies Excessive potassium supplementation
The single most useful blood test in a patient evaluated for weak- Potassium-sparing diuretics (e.g., spironolactone, triamterene)
ness is a serum creatine kinase (CK) level. The upper limit of Chronic renal failure
normal in the ambulatory population for serum CK is dependent Rhabdomyolysis
on the sex and race of an individual and is typically higher than
most established laboratory normative data. For instance, the upper
limit of normal for serum in black males is in the low 500s IU/L;
in black females, white males, and hispanics the CK can be in the liver functions tests of such patients on treatment, it is essential to
300s IU/L range; and in white females the upper limit of normal is check to GGT and CK levels, not just the AST, ALT, or LDH as
in the 200s IU/L. Importantly, mild elevations in serum CK can be these later enzymes may become elevated from an exacerbation of
seen in neurogenic processes such as motor neuron disease or other the underlying myositis rather than from liver damage.
rapidly denervating processes in which large amounts of muscle
tissue acutely degenerate. However, the serum CK is rarely elevated Other blood work which is routinely ordered in patients suspected
above 1000 IU/L in these conditions. In addition, it is important of having a myopathy are routine electrolytes. Hyper- and hypoka-
to note that not all patients with myopathies have elevated serum lemia can be caused by a number of conditions and can result in
CK levels. Further, the serum CK levels do not correlate with the generalized weakness (Table 8). Likewise, hyper- and hypocalce-
degree of muscle weakness in any given patient. mia may lead to generalized weakness. Thyroid function tests are
obtained because both hyper- and hypothyroidism are associated
It is important for clinicians to know that other enzymes which with myopathies. In patients suspected of having an inflammatory
are routine screened for on routine laboratory tests (e.g., asparte myopathy, an ESR and antinuclear antibody are ordered to assess
amino transferase [AST], alanine amino transferase [ALT], and for an underlying connective tissue disease. A serum protein elec-
lactate dehydrogenase [LDH]) can also be elevated in muscle trophoresis or immunofixation looking for a monoclonal gammop-
disorders. Many physicians initially suspect a liver disease upon athy should be ordered to help exclude non-familial amyloidosis.
seeing an elevated AST, ALT, and LDH. However, one must recall With the explosion in our understanding of molecular genetics, there is
that AST, ALT, LDH, and aldolase are expressed in muscle as an ever-expanding list of hereditary myopathies which can be diagnosed
well as the liver. Unfortunately, it is not uncommon for patients by way of deoxyribonucleic acid (DNA) testing. These include various
with primary muscle disorders to have undergone liver biopsies types of muscular dystrophy, mitochondrial myopathy, congenital
before the correct diagnosis of a myopathy was made. In order to myopathy, and hereditary forms of periodic paralysis.
distinguish elevation of these enzymes due to liver disease versus a
myopathic process, a serum CK which is specific for muscle disease
and gamma glutamyl transferase (GGT) which is specific for liver ELECTRODIAGNOSTIC EXAMINATION
disease should be obtained. In this regard, treatment of inflam-
matory myopathies with certain immunosuppressive agents (i.e., The EDX medicine examination is useful in localizing the site of
azathioprine and methotrexate) are hepatotoxic. In following the the neuromuscular lesion, determining the pathogenic basis of the
AANEM Course Numbness, Tingling, Pain, and Weakness 11

disease process, and occasionally identifying the specific disorder. testing were uninformative. Single-fiber EMG measures the jitter
Occasionally, an EDX medicine consultant may detect abnormali- between two single muscle fibers belonging to the same motor unit.
ties not suspected by the referring physician because of the nature of Jitter is increased in MG. However, increased jitter is not specific
the disease only manifesting electrically at the time of the patients for MG as it can be seen in any pathological process involving
presentation, or suggest an entirely different list of disorders. remodeling of the neuromuscular junction (e.g., reinnervation in
motor neuron disease, neuropathies, necrotizing myopathies).
Nerve Conduction Studies

Motor and sensory NCSs are invaluable in assessing patients with HISTOLOGICAL EVALUATION
neuromuscular disorders. Routine NCSs are most useful in the
evaluation of patients for a peripheral neuropathy. The abnormali- An important decision a clinician must make is whom to send for
ties apparent on these NCSs can help assess whether the pathogenic a biopsy and what tissue to biopsy. In general, most patients with
process is targeting the nerve axon or myelin. In axonopathies, the a myopathy will require a muscle biopsy. The clinical examination,
amplitudes of sensory and motor responses are decreased, but the laboratory workup, and electrophysiological studies can indicate a
velocities are relatively normal or only slightly diminished. In de- myopathy is present but usually does not indicate the exact type
myelinating disorders, the conduction velocities are slowed, while of myopathy. There are of course exceptions in which the clinical
the amplitudes of the responses are preserved. Nerve conduction phenotype in combination with the appropriate laboratory and
studies can also assess if the neuropathic process is generalized or electrophysiological studies allows diagnosis without need for a
multifocal, hereditary or acquired, and more importantly whether biopsy (e.g., myotonic dystrophy). In contrast, the value of a nerve
or not the neuropathy is potentially treatable. Sensory conduction biopsy is limited. Nerve biopsies are warranted if one is suspicious
studies are normal in motor neuron disease, myopathies, and neu- for amyloid neuropathy or vasculitis. In most instances, the ab-
romuscular junction diseases. Motor studies can reveal decreased normalities present on biopsies do not help distinguish one form
amplitudes in motor neuron disease, peripheral neuropathies, and of peripheral neuropathy from another (aside from what is already
LEMS. apparent by clinical examination and the NCS). Unfortunately,
nerve biopsies are limited by post-biopsy complications. Following
Repetitive Stimulation a nerve biopsy, there is usually permanent numbness in the respec-
tive cutaneous distribution. Further, there can be significant neuro-
Repetitive stimulation studies are useful in distinguishing neu- pathic pain in the distribution of the nerve for several months and
romuscular junction disorders (i.e., botulism, LEMS, and MG) potential for growth of painful neuroma.
from myopathies, which they can resemble. In patients with MG,
baseline motor responses are of normal amplitude. However, a dec- Muscle Biopsies
rementing response is seen following slow rates (2-3 Hz) of repeti-
tive stimulation. Ten seconds of exercise may correct this decrement Despite the fact that the physiology of muscle tissue is extremely
(post-exercise facilitation), while 1 minute of exercise will result in complex, there is a limited number of ways in which muscle can
an increase of the decrement (post-exercise exhaustion). In botu- react to disease. The manner in which these reactions are critically
lism and LEMS the baseline motor amplitudes are low. Decrement evaluated is through either an open (minor surgical procedure) or
may be seen following low rates of repetitive stimulation. An in- closed (needle/punch) muscle biopsy. Some authorities prefer open
crementing response may be seen following fast rates of repetitive muscle biopsy because several large samples can be obtained and
stimulation (20-50 Hz). This is a painful procedure and is rarely processed for routine and electron microscopy (EM), metabolic
necessary because 10 seconds of exercise can usually reproduce a analysis, and protein analysis (Western blot). Others recommend
significant increase in amplitude from baseline in these disorders. needle muscle biopsies in which the individual samples sizes are
small but many more areas of potentially affected muscle tissue can
Needle Electromyography be assessed via smaller incisions. The author prefers open biopsy
especially in multifocal processes, such as in inflammatory myopa-
The routine needle EMG examination is performed with particular thies and in those myopathic disorders which require electron mi-
attention paid to motor unit action potential duration, morphol- croscopy for confirming a diagnosis. The muscle selected for biopsy
ogy, amplitude, and recruitment. It is also important to assess for should be mildly weak, preferably MRC grade 4. If the muscle
the presence of abnormal insertional and spontaneous activity. A is too weak (i.e., MRC grade 3 or less), the tissue typically has
thorough examination of multiple muscles is necessary, especially in end-stage damage and it is often impossible to distinguish certain
mild or moderately severe disease states. By assessing these various myopathic disorders from severe neurogenic atrophy. In patients
components, the EDX medicine consultant can usually determine with little, if any, weakness on examination, needle EMG can be
whether the lesion is neuropathic or myopathic. Special techniques helpful in selecting the muscle to biopsy. However, it is important
such as quantitative EMG may be required in difficult or borderline to biopsy the contralateral muscle in order to avoid artifact from
cases. Single-fiber EMG is useful in diagnosing patients with MG needle EMG. The best muscle to biopsy is the biceps brachii, if it is
in whom repetitive stimulation, a tensilon test, and autoantibody affected. Alternative muscles are the deltoid or quadriceps muscle.
12 Approach to Patients With Neuromuscular Disorders AANEM Course

The gastrocnemius muscle should be avoided because there can to assess the morphology of the nerve fibers and to distinguish
be neurogenic changes related to an asymptomatic radiculopathy axonopathies from myelinopathies. Teased fiber preparations better
which may make diagnosis of a myopathy difficult. assess the pathological process of individual nerve fibers.

The muscle specimen is routinely analyzed by light and EM. In ad- Skin Biopsies
dition, biochemical assays for various enzyme deficiencies (e.g., gly-
cogen and lipid storage diseases), Western blot for specific protein There has been an increase in literature on the utility of skin
abnormalities (e.g., dystrophin), and DNA analysis for genetic mu- biopsies in patients with peripheral neuropathy. Following a
tations (e.g., mitochondrial myopathies) can be performed on the punch biopsy of the skin in the distal lower extremity, immu-
biopsy specimen. Amyloid deposition can be detected with Congo nological staining can be used to measure the density of small
red or crystal violet staining. Various immune staining techniques unmyelinated fibers. The density of these nerve fibers is reduced in
are employed for the diagnosis of specific muscular dystrophies patients with small fiber neuropathies in which NCSs and routine
(e.g., dystrophin staining for Duchenne and Becker muscular dystro- nerve biopsies are often normal. This technique may allow for an
phy, merosin staining for congenital muscular dystrophy, sarcoglycan objective measurement in patients with mainly subjective symp-
stains for limb-girdle muscular dystrophies, emerin stain for Emery- toms. The ease of the technique and ability to perform a number of
Dreifuss muscular dystrophy). Immune staining is also useful in the repeat skin biopsies allows clinicians the ability to better define the
early diagnosis and in understanding the pathogenesis of the different natural history of various small fiber neuropathies and to monitor
inflammatory myopathies and vasculitis (e.g., stains for complement, response of the neuropathy to various therapies.
membrane attack complex, immunoglobulins, human leukocyte
antigens, and cell markers). Electron microscopy is used for detailed
evaluation of the ultrastructural components of muscle fibers. RECOMMENDED READING

Nerve Biopsies 1. Amato AA, Dumitru D. Approach to neuropathies. In: Dumitru

D, Amato AA, Zwartz MJ, editors. Electrodiagnostic medicine, 2nd
As noted above, nerve biopsies are usually reserved for patients edition. Philadelphia: Hanley & Belfus, Inc.; 2002. p 885-897.
suspected of having amyloidosis or vasculitis. The author only bi- 2. Barohn RJ. Approach to peripheral neuropathy and neuronopathy.
opsies a nerve if it is abnormal on NCS. The sural nerve is biopsied Semin Neurol 1998;18:7-18.
because it is a pure sensory nerve and a biopsy will not result in 3. Brooke MH. Clinical evaluation of patients with neuromuscular
loss of motor function. In patients suspected of having vasculitis, disease. In: Schapira AH, Griggs RC, editors. Muscle diseases.
Boston: Butterworth-Heinemann; 1999. p 1-31.
a combination of biopsying the superficial peroneal nerve (pure
4. Dumitru D, Amato AA, Zwartz MJ. Electrodiagnostic medicine, 2nd
sensory) and the underlying peroneus brevis muscle (the biopsies edition. Philadelphia: Hanley & Belfus; 2002.
can be obtained from a single small incision) increases the diag- 5. Griggs RC, Mendell JR, Miller RG. Evaluation and treatment of
nostic yield. Tissue can be analyzed by frozen section and paraffin myopathies. Philadelphia: FA Davis; 1995.
section to assess the supporting structures for evidence of vasculitis 6. Mendell JR, Kissel JT, Cornblath DR. Diagnosis and management of
or amyloid deposition. Semi-thin plastic sections and EM are used peripheral nerve disorders. Oxford: Oxford University Press; 2001.