Download approach to the patient with suspectedmyasthenia gravis or als

APPROACH TO
THE PATIENT WITH
SUSPECTED MYASTHENIA
GRAVIS OR ALS:
A CLINICIAN’S GUIDE
KEY POINTS
A
Julie Rowin
ABSTRACT
Myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) are neuromuscular
disorders that may share certain symptoms but have vastly different pathophysiologies, treatments, and outcomes. ALS is a fatal neurodegenerative disease that
causes death of motor neurons in the brain, brainstem, and spinal cord, leading to
weakness of voluntary muscles including bulbar, respiratory, facial, trunk, and limb
muscles. MG is an autoimmune disease of the neuromuscular junction that leads
to a similar distribution of weakness with the additional involvement of the
extraocular muscles. The hallmark of MG is fatigable muscle weakness, but
patients with ALS may also have fatigue, particularly early in the disease course.
Despite these similarities, MG and ALS have distinct clinical characteristics that,
when recognized, aid the clinician in making the correct diagnosis.
Continuum Lifelong Learning Neurol 2009;15(1):13–34.
INTRODUCTION
The aim of this chapter is to provide
guidelines to the clinician for evaluating a patient who presents with
suspected myasthenia gravis (MG) or
amyotrophic lateral sclerosis (ALS).
Clinically speaking, MG and ALS have
distinct clinical features, but there
are also occasional commonalities in
their presentations, and these two disorders may, therefore, coexist in the
differential diagnosis of a particular
patient. As the treatments and prognoses are vastly different, it is obviously desirable to secure the diagnosis
as early in the course of the disease
A
Myasthenia
gravis (MG) and
ALS may
have some
commonalities
in their
presentation
and therefore
can coexist in
the differential
diagnosis. As
the treatments
and prognosis
are vastly
different for
these two
disorders, it
is best to
diagnose the
patient as early
in the course of
the disease as
possible.
The diagnosis of
MG and ALS
can generally
be made
clinically and
then supported
by laboratory
tests and
studies.
as possible. This chapter will review
the presenting symptoms and characteristic clinical signs of MG and ALS
and provide distinguishing features
of the two diseases when both are
included in the initial differential diagnosis. Possible pitfalls in the diagnosis of both disorders will be
highlighted. In general, ALS and MG
can be readily diagnosed based on a
thorough clinical evaluation, which is
then supported by appropriate diagnostic laboratory and imaging studies.
The complete differential diagnosis
of ALS and MG will be covered in
subsequent chapters.
Relationship Disclosure: Dr Rowin has nothing to disclose.
Unlabeled Use of Products/Investigational Use Disclosure: Dr Rowin has nothing to disclose.
Copyright # 2009, American Academy of Neurology. All rights reserved.
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
13
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
A
A
A
The clinical
hallmark of MG
is the presence
of fluctuating
fatigable muscle
weakness that
is brought on
by activity
and improves
with rest.
Maneuvers
that fatigue
specific muscle
groups can be
very useful in
eliciting signs
of weakness
in patients
with MG.
Initial symptoms
involve the
ocular muscles
in most patients
with MG.
TABLE 1-1
14
MYASTHENIA GRAVIS
MG produces symptomatic weakness
that predominates in certain muscle
groups and typically fluctuates in response to effort and rest. The diagnosis
of MG is primarily based on the clinical
history and examination findings demonstrating this distinctive pattern of
weakness. Confirmation of the clinical
diagnosis may be obtained using pharmacologic, immunologic, and electrophysiologic tests, which are described
in a subsequent chapter.
Clinical Diagnosis
The clinical hallmark of MG is the
presence of fatigable muscle weakness.
It is useful to distinguish fatigable
muscle weakness from general fatigue
or exhaustion. Patients with fluctuating
fatigable muscle weakness due to MG
will describe weakness in a specific
group of muscles that is brought on
by activity and improves with rest. In
contrast, patients with general fatigue
or exhaustion due to any number of
causes will typically report all-over
weakness, tiredness, or lack of energy. Patients with MG may have
symptoms and signs only after exertion or at the end of the day. This may
result in little detectable objective
weakness at the time of examination, often delaying the diagnosis. Maneuvers that fatigue specific muscle
groups can be very useful in eliciting
signs of weakness in patients with
MG because patients with generalized
fatigue or malaise do not typically display true muscle weakness with these
maneuvers (Table 1-1).
Characteristic clinical symptoms.
Initial symptoms involve the ocular
muscles in up to 85% of patients with
MG (Grob et al, 2008), and these patients will report ptosis, intermittent
diplopia, or both. A majority of these
patients (approximately 80%) will subsequently develop generalized MG. Occasionally, patients will report blurred
vision rather than diplopia, often
prompting them to change their eyeglasses in an attempt to correct the
problem. Ptosis may not be noticed
until it obscures vision. Patients with
Fatiguing Maneuvers in Suspected Myasthenia Gravis
Clinical Fatiguing
Maneuver
Manifestation in Symptomatic
Myasthenia Gravis
Sustained upgaze
(30 to 60 seconds)
Enhances ptosis and elicits medial
rectus weakness
Medial rectus muscle is usually
most severely involved
extraocular muscle
Sustained abduction of
the arms (120 seconds)
Patient can no longer hold arms
up, or weakness becomes apparent
with subsequent manual testing
Dysarthria or shortness of
breath may be enhanced
Sustained elevation of
leg while lying supine
(90 seconds)
Patient can no longer hold leg up,
or weakness becomes apparent
with subsequent manual testing
Dysarthria or shortness of
breath may be enhanced
Repeated arising from
chair without use of
arms (up to 20)
Fatigues after several attempts
Early/mild weakness may cause
exaggerated lean-forward and
‘‘buttocks-first’’ maneuver
Counting aloud (1 to 50)
Enhances dysarthria
Nasal, lingual, or labial
Comments
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ptosis will note that the severity of the
eyelid droop varies during the course
of the day, often worsening after exercise, reading, while driving, and with
exposure to direct sunlight. Nearly all
patients with MG will develop ocular
manifestations at some point during
the course of their illness.
Up to 20% of patients with MG may
have prominent oropharyngeal symptoms early in the disease course, including dysarthria, dysphagia, and
difficulty chewing (Grob, 1953). This
percentage is higher in anti–musclespecific receptor tyrosine kinase (MuSK)
antibody positive MG. (The clinical
phenotype of anti–MuSK-positive MG
is discussed in the subsequent chapter.)
At times, oropharyngeal symptoms may
be present with minimal associated
ocular symptoms, particularly in lateonset and anti–MuSK-positive disease.
Weakness of palatal muscles may result in a nasal quality to the voice.
Speech may become slurred with prolonged talking, eg, talking on the
telephone or giving a speech or presentation. Swallowing concerns may
be limited to mild difficulty with solid
foods, eg, ‘‘feels like the food gets
stuck.’’ More serious symptoms, such
as nasal regurgitation of liquids and
aspiration, are indicators of more advanced disease. Patients with MG who
have difficulty chewing often describe
progressively weaker chewing force
with each successive bite. The difficulty is worse with solid foods, particularly meat. There is no associated
pain, differentiating this complaint
from jaw claudication due to temporal arteritis.
Rarely, patients with MG may present with respiratory muscle weakness
without other prominent MG symptoms (Jani-Ascadi and Lisak, 2007).
However, the vast majority of patients
with respiratory muscle weakness have
ocular and bulbar concerns. Patients
with diaphragmatic weakness will of-
ten have orthopnea as an early symptom. This may lead to respiratory
compromise when the patient is
placed in the supine position. Patients
with MG and respiratory muscle weakness may report an inability to draw a
full breath. They often describe their
breathing as rapid and shallow, which
may be misinterpreted as hyperventilation due to anxiety.
Fatigable extremity weakness in MG
may affect any muscle group and may
be asymmetric. Rarely, weakness may
be very focal, affecting distal limb
muscles (Nations et al, 1999) or neck
extensors (D’Amelio et al, 2007) selectively. Characteristically, muscles are
noted to weaken with repeated use,
and strength improves with rest. Patients may note the development of
a footdrop with prolonged walking,
hip extension weakness with climbing
several flights of stairs, shoulder muscle fatigue with activities that require
holding the arms above the head, and
weakness of finger flexors and extensors with prolonged typing. Symptoms
may worsen with exposure to extreme
heat or emotional stress. Infection,
systemic illness, pregnancy, the menstrual cycle, or drugs that affect neuromuscular transmission may also
exacerbate myasthenia. Patients may
report that they plan activities for early
in the day when their strength is at
its peak. On the other hand, severe
disease may cause prominent muscle
weakness in which fatigability is not
necessarily apparent.
Physical signs. The classic physical signs of MG include ptosis, ophthalmoparesis, bulbar weakness, and
fatigable extremity weakness. Unfortunately, the clinical presentation in
individual patients is often quite variable, and the diagnosis may be difficult. A history of fatigable weakness in
specific muscle groups should prompt
further investigation for a neuromuscular junction (NMJ) defect, regardless
KEY POINTS
A
A
A
A
Nearly all patients
with MG will
develop ocular
manifestations
at some point
during the
course of
their illness.
Approximately
20% of patients
with MG may
present with
prominent bulbar
symptoms.
Rarely, patients
with MG may
present with
respiratory muscle
weakness without
other prominent
MG symptoms.
However, the
majority of
patients with
respiratory muscle
weakness have
ocular and bulbar
concerns.
Symptoms of
MG may worsen
with exposure
to extreme
heat, emotional
stress, infection,
systemic illness,
pregnancy,
the menstrual
cycle, or drugs
that affect
neuromuscular
transmission.
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15
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
A
A
A
A
16
A history of
fatigable
weakness in
specific muscle
groups should
prompt further
investigation for
a neuromuscular
junction defect,
regardless of
whether clinical
signs of
weakness are
observed on
examination.
Myasthenic
patients with
little or no
ptosis at rest
may develop
ptosis after
sustained
upgaze for 60
to 180 seconds.
The pattern of
extraocular
muscle weakness
in MG is typically
asymmetric and
not isolated to
the distribution
of a single
cranial nerve.
Sustained upgaze
for 30 seconds
is usually
sufficient
to produce
weakness of
the medial
rectus muscles
in MG.
of whether clinical signs of weakness
are observed on examination. In a
patient with suspected MG, the following muscle groups should be
specificallytested:facial,ocular,oropharyngeal, respiratory, axial, and limb
muscles. The distribution of weakness
in a large cohort of patients with MG
(Grob et al, 2008) is given in Table 1-2.
All patients had some degree of detectable ocular muscle weakness, but
only 17% had purely ocular involvement. The incidence of purely ocular
and oculobulbar weakness was significantly higher in males compared with
females in this cohort, while ocular
with generalized weakness was more
prevalent in females.
Ocular muscle weakness. The extraocular muscles and the eyelid elevators are involved to different degrees
in individual patients with MG. Pupillary responses are normal. Eyelid ptosis is usually asymmetric and may vary
considerably during the course of the
examination. Ptosis is worsened with
sustained upgaze. Resting the lids by
having the patient close the eyes for
30 seconds may lessen the ptosis for
a time. Patients with little or no ptosis
Distribution of
Weakness in a
Large Cohort of Patients
With Generalized Myasthenia
Gravis (n = 609)
TABLE 1-2
Distribution
of Weakness
Percentage
of Patients
Localized ocular
17%
Ocular and
generalized
Ocular and bulbar
50%
Ocular and limb
20%
13%
Data from Grob D, Brunner N, Namba T, Pagala M.
Lifetime course of myasthenia gravis. Muscle Nerve
2008;37(2):141–149.
at rest may develop ptosis after
sustained upgaze for 60 to 180 seconds. Manual elevation of the more
ptotic lid may worsen ptosis on the
contralateral side, a phenomenon known
as enhanced ptosis (Gorelick et al,
1981). Finally, ptosis may improve
in response to local cooling of the
lid (Larner, 2004). To compensate
for ptosis, the frontalis muscle may
be chronically contracted, and unilateral frontalis ‘‘hypercontraction’’ is a
clue that the lid elevators are weak on
that side.
The pattern of extraocular muscle
weakness in MG is typically asymmetric and not isolated to the distribution
of a single cranial (III, IV, VI) nerve.
The pattern of weakness may fluctuate
and change even during the course of
a single examination. The medial rectus
muscle is most frequently affected,
followed by the superior and lateral
rectus muscles. Rarely, weakness may
be isolated to the lateral recti. Examination of extraocular movements should
include a minimum of 15 to 30 seconds
of lateral and superior gaze holding.
The cover-uncover test may elicit
mild weakness of a specific extraocular
muscle by causing shifting fixation
in the direction of action of the weak
muscle. Sustained lateral gaze will produce fatigable weakness of the medial
or lateral rectus muscles. With attempted lateral gaze, the adducting eye may
not move, and the abducting eye may
demonstrate nystagmus that becomes
coarser as the lateral rectus muscle
fatigues, a phenomenon called pseudointernuclear ophthalmoplegia. Sustained upgaze for 30 seconds is usually
sufficient to produce weakness of the
medial rectus muscles in MG. It is important to be aware that holding the
stimulus for upgaze too close will elicit a
failure of convergence alone that is not
necessarily an abnormal finding. If diplopia or dysconjugate gaze is due to a
failure of convergence alone, moving the
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target farther from the patient will improve the abnormality. Conversely, moving the target farther away will exacerbate the problem in MG and increase
the apparent separation of the images.
Facial muscles. Many patients with
MG have a characteristic facial appearance. Facial weakness may produce
a ‘‘sagging’’ appearance and loss of
facial expression. Often, patients will
elevate an eyebrow by contracting the
frontalis muscle in an attempt to
compensate for ptosis. With blinking
or eyelid closure, the sclera may
not be completely covered because
of weakness of the orbicularis oculi
muscle. Weakness of eyelid closure is
seen in most patients with MG and
should be specifically sought by asking
patients to forcefully close their eyes
while the examiner attempts to manually open the eyelids. Weakness of the
orbicularis oris muscle may produce
the characteristic horizontal or ‘‘snarling’’ appearance with attempts to smile.
Patients may also have difficulty puffing
their cheeks or pursing their lips. With
attempts to purse the lips, a ‘‘horizontal pucker’’ is frequently observed
because of the inability to approximate
the sides of the mouth.
Oropharyngeal muscles. The dysarthria in MG is often characterized by
nasal speech due to posterior pharyngeal weakness and articulation abnormalities with labial and lingual
consonant and vowel distortion caused
by facial and tongue weakness. Laryngeal weakness may cause speech
output to be hypophonic (breathy,
whispered, or hoarse). Again, these
abnormalities are brought on (or worsened) by sustained talking. It is sometimes useful to ask MG patients with
bulbar symptoms to count up to 50, and
listen for the development of nasal
speech and labial and lingual dysarthria.
Patients with dysphagia should be
examined carefully for palatal weakness. The soft palate should be ob-
served as the patient says ‘‘Ah’’ to
make sure it rises normally in the
midline. Weakness of the tongue muscles may also cause dysphagia because
of abnormal movement of the bolus of
food in the oral cavity. Tongue protrusion should be checked by having
the patient protrude the tongue into
the cheek while the examiner applies
resistance on the outside surface of
the cheek. Some experience is required to determine the amount of
resistance to apply and the force of
protrusion that is normal.
Patients with MG who have difficulty chewing usually give a revealing
history as described above. When these
patients are examined, weakness of
jaw closure due to masseter and temporalis muscle weakness may be present. Weakness of jaw opening due to
pterygoid muscle weakness, on the
other hand, is rarely seen in MG even
with relatively severe weakness of
the masseter muscles. This pattern of
weak jaw closure and relatively strong
jaw opening is quite typical of MG.
The masseter and temporalis muscles
are checked by having the patient
clamp the jaws together while the
examiner attempts to separate them
by applying downward pressure on
the chin. It is best to sustain a moderate level of downward pressure for
a period of 30 seconds rather than
applying momentary pressure forcefully. The pterygoid muscles are evaluated by having the patient open the
jaw while the examiner applies upward pressure below the chin.
Respiratory muscles. It is frequently
difficult to reliably distinguish the
status of the respiratory muscles
from the functional status of the lungs
themselves. However, simple observation is often quite revealing. Patients
with respiratory muscle weakness due
to MG often present with tachypnea
and shallow breathing. They may be
anxious because of an inability to draw
KEY POINTS
A
A
A
A
Weakness of
eyelid closure
is seen in
most patients
with MG.
Weakness of the
orbicularis oris
muscle in
patients with
MG may
produce the
characteristic
horizontal or
‘‘snarling’’
appearance
with attempts
to smile.
The dysarthria in
MG is often
characterized
by nasal speech
caused by
posterior
pharyngeal
weakness.
The pattern of
weak jaw
closure and
relatively
preserved jaw
opening is
typical of MG.
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17
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
A
A
A
A
18
A weak sniff and
cough along
with tachypnea
or tachycardia
are signs of
significant
respiratory
muscle
weakness.
Arterial blood
gas measurements
are a relatively
insensitive
measure of
impending
respiratory
decompensation
in MG.
Some patients
with MG
will have
intermittent
symptomatic
dyspnea by
history and
normal
pulmonary
function tests
and bedside
respiratory
muscle strength
measurements.
Patients with MG
with respiratory
muscle
weakness will
often have
coexisting
weakness of
neck flexion/
extension.
a full breath. Asking patients to inspire
forcefully and loudly through the
nose (inspiratory sniff) can give one a
good indication of inspiratory muscle
strength. To assess expiratory muscle
function, patients should be asked to
cough or clear their throat. Outward
protrusion of the abdomen against
the examiner’s hand is an indirect
measure of diaphragmatic strength
since the abdominal contents will be
pushed upward instead of outward if
the diaphragm is weak. A weak sniff
and cough along with significant
tachypnea or tachycardia are signs of
clinically important respiratory muscle
weakness.
Formal measurements of pulmonary
function such as forced vital capacity
may be useful but are also dependent
on a number of factors, including
pulmonary status. Results should be
interpreted carefully in patients with
MG, given the fluctuating nature of the
disease. It is not uncommon for an MG
patient with intermittent symptomatic
dyspnea by history to have normal
pulmonary function tests and bedside
respiratory muscle strength parameters. The normal tests are reassuring
but should not lead to the suggestion
that the complaint is factitious or not
potentially clinically relevant. Repeated
testing of respiratory parameters will
cause a worsening with each subsequent trial in MG patients with ventilatory muscle weakness and may exhaust
the breathing muscles. Arterial blood
gas measurements are a relatively insensitive measure of impending respiratory decompensation in MG since the
initial changes are usually consistent
with hyperventilation and may falsely
be attributed to anxiety. By the time
carbon dioxide retention occurs, the
respiratory muscles have already begun
to decompensate. MG patients with
respiratory muscle weakness will often
have weakness of neck flexion or extension, which may be a useful associ-
ation if there is any doubt that the
respiratory decompensation is due to
myasthenic weakness.
Axial/limb muscles. Patients with
MG may have weakness in many different patterns affecting the limb and
axial muscles. Patients with mild disease may have weakness limited to the
neck flexor muscles. Typically, neck
flexion is weaker than neck extension
in patients with MG, although occasionally patients will present with
the ‘‘dropped head syndrome’’ and
have severe neck extension weakness
(D’Amelio et al, 2007). Initial presentations with severe neck extensor
muscle weakness have also been reported in MuSK-antibody-positive MG
(Casasnovas et al, 2007). Finger and
wrist extensors and shoulder abductor
muscles are most likely to be affected
in the upper limb. In the lower extremity, the foot dorsiflexors and hip
flexors are most frequently involved.
Weakness is usually relatively symmetric, but may be asymmetric and
even focal. At the author’s institution,
we have observed weakness of finger extension involving a single digit
and asymmetric weakness of foot
dorsiflexion resulting in a unilateral
footdrop in patients with MG. Hand
muscles, particularly finger extensors,
appear to be involved more frequently
than distal leg and foot muscles
(Nations et al, 1999).
Fatigable muscle weakness may be
demonstrated by having patients sustain arm abduction for a period of
time or by having them raise a leg
at an angle of 308 to 408 while lying
supine and maintain this position
against gravity. Patients may be tested
in this way until they fatigue, or the
muscles may be manually tested after
a period of 1 to 2 minutes of fatiguing
exercise. Arising from a low chair
without using the arms 10 to 20 times
repeatedly is a good test for hip
extensor muscle fatigue.
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AMYOTROPHIC LATERAL
SCLEROSIS
ALS is a progressive neurodegenerative
disease of upper motor neurons
(UMNs) and lower motor neurons
(LMNs) that has both sporadic and
inherited forms. It is a disease with no
significant treatments that alter the
disease course and a poor prognosis.
It can be a difficult disease to diagnose
since mimics of ALS exist, and clinical
phenotypes are heterogeneous. Patients
most often report progressive asymmetric weakness in the distal limbs.
However, weakness may manifest in
any body segment (bulbar, cervical,
thoracic, or lumbosacral) and affect
eating, swallowing, speaking, fine motor control, walking, and eventually
breathing. Life expectancy on average
is between 3 and 5 years from the date
of diagnosis, with a shorter survival
time for bulbar onset patients.
KEY POINTS
TABLE 1-3
"
Upper Motor
Neuron and Lower
Motor Neuron
Signs of ALS
A
Upper Motor Neuron Signs
Weakness
Spasticity
Hyperreflexia
Babinski sign
Relatively retained muscle
bulk, mild (disuse) atrophy
"
Lower Motor Neuron Signs
Weakness
Flaccidity
A
Hyporeflexia
Fasciculations
Loss of muscle bulk, severe
(neurogenic) atrophy
A
Clinical Diagnosis
The hallmark of the clinical diagnosis
of ALS is the presence of UMN and
LMN signs (Table 1-3) coexisting in
multiple body regions (cranial, cervical, thoracic, or lumbosacral) in the
relative absence of sensory abnormalities. To date, no pathognomonic diagnostic test is available, and the
diagnosis is entirely a clinical one. Patients with findings suggestive of ALS
are typically assigned to differing levels
of diagnostic certainty (suspected, possible, probable, and definite) based
on a set of defined diagnostic criteria
known as the El Escorial criteria. These
criteria were established in 1991 for
research purposes and were recently
revised (Brooks et al, 2000). A definite
diagnosis of ALS requires the presence
of UMN and LMN features in three
or more body regions (cervical, thoracic, lumbosacral, and cranial). Probable ALS is classified as LMN and
UMN signs in two regions, and proba-
ble ALS (laboratory supported) is classified as LMN and UMN signs in one
region plus EMG evidence of acute
denervation in two or more muscles
in two or more limbs (Brooks et al,
2000). These criteria have proved to be
useful for the standardization of diagnostic criteria for clinical research
studies. However, when it comes to
the diagnosis of the patient in the
earlier stages of the disease, these
criteria may be too strict as many
patients will not meet the criteria for
definite or probable ALS at the time
of presentation. A careful neurologic
examination, however, even early in
the course of the disease can aid in
making the correct diagnosis. This
section will give the examiner bedside
tools for the examination of a patient
with suspected ALS. As the diagnosis of
ALS is a clinical one, and no one test can
provide definitive confirmation, recognition of classic and variant presentations is critical. Diagnostic support
A
In MG, neck
flexion is typically
weaker than
neck extension,
and finger and
wrist extensors
and shoulder
abductor muscles
are most likely
to be affected in
the upper limb.
In the lower
extremity, the
foot dorsiflexors
and hip flexors are
most frequently
involved.
In MG, limb
weakness is
usually relatively
symmetric,
but may be
asymmetric, and
is rarely focal.
The hallmark of
the clinical
diagnosis of ALS
is the presence
of upper and
lower motor
neuron signs
coexisting in
multiple body
regions in the
relative absence
of sensory
abnormalities.
The diagnosis of
ALS is a clinical
one as no single
test can absolutely
confirm the
diagnosis. With
support from
electrodiagnostic
studies and MRI
studies, however,
the diagnosis is
usually possible
even in relatively
early disease.
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19
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
A
A
A
A
20
A
Most patients
with ALS will
present with
the chief
concern of
weakness in a
limb. The next
most common
presenting
symptom is
dysarthria or
dysphagia.
Muscle
fasciculations in
the limbs and
torso are
common in ALS
and unless
profuse often
go unnoticed
by the patient.
Muscle
cramping is
a common
symptom
in ALS.
Paroxysmal
laryngospasm,
sialorrhea, and
pseudobulbar
affect are all
relatively
common
symptoms in
ALS patients
with bulbar
disease.
All patients
with suspected
ALS should
be asked
to disrobe
so that the
examiner may
observe for
fasciculations.
from electrodiagnostic and MRI studies
can also aid in arriving at the appropriate diagnosis by confirming multisegmental LMN disease and eliminating
structural brain or spinal cord pathology. The differential diagnosis of ALS
is discussed in detail in the chapter
‘‘Clinical Spectrum of Motor Neuron
Disorders.’’
Characteristic symptoms. Most
patients with ALS will present with the
chief concern of asymmetric weakness
affecting a limb. The next most common initial presentation consists of oropharyngeal or bulbar weakness causing
dysarthria or dysphagia (Traynor et al,
2000). The remaining patients will present less typically with head drop,
shortness of breath, fasciculations, or
rarely, cognitive dysfunction. Typically,
symptoms have been present and progressively worsening for months when
the patient initially presents for evaluation. Patients may have difficulty precisely
dating the onset of symptoms but will
usually recall vague symptoms of fatigue,
clumsiness, loss of hand dexterity, etc,
prior to the onset of frank weakness
and/or atrophy. These initial symptoms
may be discounted and often attributed
to aging. Some patients have a rapidly
progressive course with survival of less
than 1 year from the onset of symptoms, while other patients progress much
more slowly, far outliving the 5-year
life expectancy.
Muscle fasciculations in the limbs
and torso are almost a universal feature of ALS but may also be seen in
other disorders affecting the motor
neurons and may be experienced in
the normal population as well. In ALS,
fasciculations, unless profuse, often go
unnoticed by the patient. In fact, the
patient’s spouse or partner may notice
the fasciculations before the patient
does. Muscle cramping is a common
symptom in ALS and motor neuron
disorders in general. Cramps may be
quite painful and bothersome and
occur after contraction of the involved
muscle or at rest. Muscle cramps may
be particularly bothersome when they
involve a non–limb muscle such as the
jaw or trunk muscles. Often cramping
is precipitated by an ordinary contraction or a change in muscle length. For
example, a yawn can precipitate a
painful jaw cramp, or a simple twisting
movement of the torso can precipitate
muscle cramps involving the trunk.
The cramping tends to be more severe
during the early stages of the disease
when reinnervation is prominent and
tends to subside when muscles become very weak and atrophic. Paroxysmal laryngospasm may be thought
of as a cramp affecting the laryngeal
muscles and tends to be a very anxietyproducing symptom for patients. When
the spasm occurs, the patient cannot
draw a breath and appears to be
choking. The spasm typically subsides
within several seconds, but the involuntary nature and the unpredictability
of the spasm leads to an understandable feeling of panic.
Sialorrhea is caused by progressive
weakness of oral, lingual, and pharyngeal muscles and is a frequent and
embarrassing problem in ALS patients
with bulbar symptoms. Pseudobulbar
emotional lability can coexist with
other UMN signs involving the bulbar muscles. This manifests as excessive uncontrollable or uncharacteristic
laughing or crying.
Physical signs. All patients with
suspected ALS should be observed for
the presence of fasciculations. This absolutely requires that the patient disrobe since fasciculation may be most
prominent in the torso, periscapular
region, and proximal thigh. Unlike benign fasciculations, which typically are
infrequent and tend to involve one
motor unit causing recurrent twitching of the same muscle or group of
muscle fibers, fasciculations in ALS
generally occur in multiple motor
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units simultaneously and continuously. When present in this pattern, they
aid in the diagnosis of ALS as they can
be considered an LMN finding in the
body region where they are observed.
Fasciculations are not invariably present in ALS at all stages of disease,
however, and they may not be visible
in some patients. In other patients,
very close observation is needed to
adequately detect the presence of fasciculations. On the other hand, the
patient who presents with a report of
profuse and constant muscle twitching, but on examination has no
observable fasciculations, almost invariably does not have ALS but likely
has a benign fasciculation syndrome.
A classic sign in ALS is tongue fasciculations, and the differential diagnosis of tongue fasciculations is given
in Table 1-4. It is not unusual for the
normal tongue to exhibit tremulous
movements upon protrusion or with
maintaining the tongue in a certain
position. These movements should
not be confused with tongue fascicu-
TABLE 1-4
Differential
Diagnosis of
Tongue Atrophy
and Fasciculations
"
Lower motor neuron disease
(ALS, Kennedy disease,
spinal muscular atrophy,
poliomyelitis)
"
Muscle-specific receptor
tyrosine kinase myasthenia
(atrophy only)
"
"
"
Brainstem lesion
"
Idiopathic hypoglossal
neuropathy (unilateral)
"
Organophosphates
Base of the skull tumor
Radiation in the area of the
hypoglossal nerve
lations. When tongue fasciculations
are present, they are generally quite
obvious and have a characteristic
multifocal distribution involving the
entire tongue and the appearance of
small wriggling or dimpling under the
tongue surface. Observation of the
tongue for the presence of fasciculations may be aided either by having
the patient open the mouth as widely
as possible while allowing the tongue
to rest on the floor of the mouth or by
having the patient protrude the
tongue outside the mouth and then
gently bite down on it, allowing the
examiner to inspect the outer aspects
of the tongue. Tongue fasciculations
are typically present in ALS when
there is LMN degeneration involving
the tongue muscle, and they are
usually associated with varying degrees of tongue weakness and atrophy. Weakness of the tongue may be
present without fasciculations if bulbar weakness is due to UMN degeneration.
Weakness of the tongue is an extremely useful sign in ALS, as useful
as tongue fasciculations, and probably
more reliable. Weakness of the tongue
in ALS can best be assessed by having
the patient protrude the tongue into
the cheek and hold it there while the
examiner applies resistance from outside the cheek. The tongue weakness
in ALS tends to be symmetric. Some
ALS patients with advanced bulbar disease cannot move their tongue voluntarily at all. However, it is possible
to have moderately advanced disease
without significant tongue involvement if the patient has mostly spinal
disease. In bulbar disease with a prominent UMN component, tongue bulk
and the strength of tongue protrusion
may appear to be normal. These
patients will exhibit difficulty quickly
moving the tongue side to side or
into and out of the mouth because
of UMN dysfunction.
KEY POINT
A
Extremely useful
diagnostic
signs in ALS
are tongue
fasciculations
and tongue
weakness.
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21
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
A
A
A
A
22
A
The presence
of pathologic
reflexes such as
hyperactive
muscle stretch
reflexes,
Hoffmann sign,
Babinski sign,
and crossed
adductor
reflexes can aid
in the diagnosis
of ALS.
The limb
weakness in
ALS more
commonly
presents
distally and
asymmetrically.
Weakness in ALS
is segmental,
meaning that it
may start focally
involving one or
two myotomes.
A hyperactive
gag reflex, an
increased jaw
jerk, or a positive
snout reflex
can help to
localize UMN
dysfunction
above the
cervical
spinal cord.
Respiratory muscle
compromise may
be present before
the patient
becomes overtly
symptomatic.
Although facial weakness is not
classically considered to be a characteristic sign in ALS, it may be present,
particularly in more advanced disease.
The finding of facial weakness in ALS
is potentially helpful because one of
the important differential diagnoses
of ALS is cervical spinal stenosis, and
clinical findings above the neck, such
as facial weakness, tongue weakness,
or dysarthria, can rule out this possibility. As in MG, the facial weakness
in ALS tends to be symmetric, but
unlike MG, in most cases, it is not
present until later in the disease
course. One way to test lower facial
muscle strength is to have the patient
puff out the cheeks. Normally, one
should be able to hold some resistance to this maneuver. For upper
facial weakness, squeezing the eyes
tightly shut while the examiner
attempts to open the lids is another
helpful bedside test. More severe facial
weakness and characteristic facial fasciculations in a patient with a more
chronic disease course suggest the
diagnosis of X-linked bulbospinal neuronopathy (see the chapter ‘‘Clinical
Spectrum of Motor Neuron Disorders’’).
The presence of pathologic reflexes
such as hyperactive muscle stretch reflexes, Hoffmann sign, Babinski sign,
and crossed adductor reflexes can
aid in the diagnosis of ALS, especially
when LMN signs such as atrophy or
fasciculations are located in the same
body region. Relative preservation of
reflexes (nonpathologic) in the distribution of severe muscle weakness and
atrophy is also a sign of UMN dysfunction. A hyperactive gag reflex, an increased jaw jerk, or a positive snout
reflex can help to localize UMN dysfunction above the cervical spinal cord.
Limb weakness. Unlike in MG
where limb weakness usually affects
proximal muscles relatively symmetrically, the limb weakness in ALS can
present in any muscle group, but
more commonly presents distally and
asymmetrically in a limb, eg, with a
weak and atrophic hand or footdrop.
Weakness in ALS is segmental, meaning that muscles belonging to the same
myotome and innervated by the same
pool of motor neurons are affected
similarly. The disease may initially start
focally in one or two myotomes, a
pattern that may mimic a radiculopathy clinically and electrodiagnostically, except for the relative absence
of pain and sensory symptoms. A
further discussion of the characteristics of limb weakness in ALS appears
later in this chapter.
Respiratory muscle weakness. ALS
affects the diaphragm and intercostal
muscles, and weakness in these muscles is obviously of critical importance.
Orthopnea or dyspnea with exertion
is typically the initial symptom of
respiratory muscle weakness in ALS.
However, respiratory muscle compromise is often present before the patient becomes overtly symptomatic,
presenting with nocturnal oxygen desaturations, daytime fatigue, or sleep
disturbances. Some patients never feel
short of breath despite significant ventilatory compromise, especially if the
ventilatory impairment has been more
slowly progressive.
Examination of respiratory muscle
function at the bedside consists of
having the patient perform an inspiratory sniff and cough as a test of
inspiratory and expiratory muscle function respectively. Protrusion of the
abdomen against resistance may also
be helpful as a rough bedside indication of diaphragmatic strength as
described in the previous sections for
MG. Bedside measurement of forced
vital capacity is commonly used in
most multidisciplinary ALS clinics as an
indicator of diaphragmatic function.
This test is more reliable than it is in
MG since in ALS, diaphragmatic weakness is not likely to fluctuate, and ALS
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patients are less likely to have significant facial weakness, at least in the
earlier stages. Occasionally, patients
with ALS are diagnosed only after they
are unable to be weaned from a ventilator. This unfortunate situation may
occur for the patient who presents
with more focal diaphragmatic weakness or occasionally in the elderly
patient whose weakness or walking
difficulties are dismissed as features of
old age. Right heart failure can develop from untreated respiratory failure
and is generally a late finding. Lower
extremity edema, however, may occur
as a result of venous stasis (dependent
edema in a weak limb) or from right
heart failure.
Bulbar (oropharyngeal) weakness.
Involvement of bulbar muscles in ALS
produces dysarthria, dysphagia, and
sialorrhea. When UMN involvement is
present, the patient has slow speech
and spastic dysarthria, increased jaw
jerk, normal-appearing but weak or
slow tongue, pseudobulbar laughing or
crying, and pathologic reflexes such
as an increased jaw jerk, hyperactive
gag reflex, or a snout reflex. With LMN
involvement, the patient may have
flaccid dysarthria, as well as weakness, atrophy, and fasciculations of
the tongue. Typically both UMNs and
LMNs are involved, producing a mixed
spastic and flaccid dysarthria. A discussion contrasting the features of dysarthria and dysphagia due to ALS and
MG can be found later in this chapter.
Cognitive impairment and behavioral changes. Although the degenerative process in ALS predominantly
affects the motor system, cognitive
and behavioral symptoms have been
described in patients with ALS for
some time. Some degree of cognitive
impairment may occur in as many
as 22% to 35% of patients with ALS.
Frontotemporal dementia is associated with ALS in approximately 3% to
5% of cases (Lomen-Hoerth et al,
2004). In most patients, the cognitive
impairment manifests as mild frontal
lobe dysfunction that may lead to
poor judgment, difficulty with problem solving, and inattention, while
memory and praxis remain relatively
intact (Murphy et al, 2007). Patients
may display disinhibited behavior,
obsessive-compulsive behavior, or may
become withdrawn and disinterested.
Often, in milder cases of cognitive
changes, the patient and family are
unaware of any impairment. Speech
dysfunction often coexists with the
cognitive impairment, thus making the
recognition of the cognitive change
more difficult.
Truncal weakness. Weakness in ALS
may affect the thoracic body region or
core muscles. The signs and symptoms
of this may include difficulty keeping
the body erect, difficulty sitting up in
bed, incoordination, and even pelvic
floor weakness. Occasionally loss of
core muscle strength can lead to an
apparent gait imbalance because of an
inability to stabilize the core muscles
while walking. This may mislead the
unwary clinician to suspect coexistent
primary cerebellar dysfunction, but in
ALS there are no additional signs of
cerebellar dysfunction such as limb
ataxia or nystagmus. Additional signs
of truncal involvement may include
absent superficial abdominal reflexes
and fasciculations on the abdomen
and back.
History of weight loss. Weight loss
is a very common symptom in ALS.
Weight loss may occur on the basis of
malnutrition caused by severe swallowing difficulties and loss of dexterity
in the upper limbs. Loss of appetite
leading to cachexia can occur when
respiratory dysfunction is present. Loss
of muscle mass due to denervation
atrophy may also contribute to the
weight loss in some patients. Finally, a
state of hypermetabolism has been
described in patients with ALS. The
KEY POINTS
A
A
A
A
When bulbar
muscles are
involved in ALS,
a characteristic
mixed spastic and
flaccid dysarthria
is typical.
Frontotemporal
dementia is
associated with
ALS in about 3%
to 5% of cases.
Mild cognitive
impairment
occurs in up to
22% to 35% of
patients with ALS.
Occasionally loss
of core muscle
strength in
patients with
ALS can lead to
gait imbalance,
misleading the
clinician to
suspect primary
cerebellar
dysfunction.
Weight loss
is a common
symptom in ALS
and may have
multiple causes,
including
malnutrition,
loss of muscle
mass, and a
hypermetabolic
state.
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23
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
A
A
A
A
24
A hallmark of ALS
is the relative
absence of
sensory
symptoms
and findings.
However, about
one-third of
patients with ALS
report some
mild sensory
symptoms.
When double
vision and
ptosis are not
clearly present
and the patient
is antibody
negative,
making the
correct
diagnosis of
MG may be
a challenge.
ALS and MG may
both present
with dysarthria,
dysphagia,
fatigability, and
limb or axial
weakness.
Ptosis and
extraocular
muscle
weakness clearly
distinguish MG
from ALS as
the ocular
muscles are
spared in ALS.
origin of this hypermetabolic state is
uncertain, but it may occur in as many
as 50% of patients with ALS (Desport
et al, 2005).
Mild sensory symptoms. A hallmark
of ALS is the relative absence of
sensory symptoms and findings. A
recent report, however, indicates that
about one-third of patients with ALS
report some mild sensory symptoms
(Hammad et al, 2007). This is generally
in the form of mild distal sensory loss.
Often the symptom will be present,
but the sensory examination will be
entirely normal. Sural sensory conduction studies may be abnormal in
approximately the same proportion
(one-third) of patients, and in the
study of Hammad and colleagues (2007)
a pathologic loss of large myelinated
fibers was observed in over 90% of
patients who had sural nerve biopsies.
It is unclear whether these findings
are the result of normal aging processes or whether there is a true association with the underlying degenerative
process.
DISTINGUISHING FEATURES OF
ALS AND MYASTHENIA GRAVIS
ON CLINICAL PRESENTATION
The most common presenting symptoms in MG are double vision (or
blurred vision) and ptosis. Ocular findings such as these clearly distinguish
MG from ALS, as the ocular muscles are
spared in ALS. However, when double
vision and ptosis are not clearly present, making the correct diagnosis may
be a bit more challenging as illustrated
by Cases 1-1 and 1-2. Additionally,
10% to 15% of patients with MG will
be anti-acetylcholine receptor (AChR)
negative, and up to 60% of these
patients will also be MuSK-antibody
negative (see the chapter ‘‘Myasthenia
Gravis: Immunopathogenesis, Diagnosis, and Management’’), often leaving the diagnosis in question. Both ALS
and MG may present with dysarthria
and/or dysphagia, fatigability, and limb
or axial weakness. Clinical clues that
can help to accurately determine the
cause of these symptoms and signs as
caused by ALS, MG, or some other
disorder are presented later in this
chapter.
Prominent Dysarthria/Dysphagia
Patients presenting with reports of dysarthria and/or dysphagia may have
central or peripheral nervous system disease. The neurologic differential diagnosis for this complaint is long
(Table 1-5). In particular, patients who
present with isolated slowly progressive dysarthria with or without dysphagia can be diagnostically challenging,
and both ALS and MG are diagnostic
possibilities in these patients. After
structural CNS causes are ruled out by
TABLE 1-5
"
Neurologic
Differential
Diagnosis of
Dysarthria and
Dysphagia
CNS Disease
Brainstem lesion
Cerebrovascular disease
(pseudobulbar palsy)
Syringomyelia
"
Neuromuscular Disease
Bulbar presentation of ALS
Kennedy disease
Bulbar polio
Myasthenia gravis
Botulism
Myopathy
Neuropathy such as
Guillain-Barré syndrome
or chronic inflammatory
demyelinating polyneuropathy
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KEY POINTS
A
Case 1-1
A 57-year-old woman presented reporting an inability to lift her head
off her chest and shortness of breath with exertion for the past 4 to
5 months. She had no significant medical history. She denied double vision
or blurred vision, droopy eyelids, speech or swallowing difficulties, or limb
weakness. She was diagnosed with MG at an outside institution after
an edrophonium (Tensilon) test and was reportedly responding to
pyridostigmine treatment (60 mg every 6 hours) with a subjective
improvement in neck strength and breathing. Recently, however, the
pyridostigmine was noted to be less effective. Anti–AChR-binding
antibodies were reportedly negative. Repetitive nerve stimulation
(RNS) performed in a hand muscle and on the trapezius muscle was normal,
but single fiber EMG (SFEMG) performed on the extensor digitorum
communis muscle showed an increased mean jitter. MRI of the cervical
spine showed mild disc bulges and osteophytes at several levels but no
evidence of cord or nerve root compression.
Physical examination revealed a respiratory rate of 12 breaths per
minute, a normal mental status, and normal cranial nerve function with
the exception of a head drop with neck extensor strength graded at
3/5 and neck flexor strength graded at 4-/5. She had mild symmetric
weakness (4+) in arm abduction, but otherwise her limbs were strong.
Her reflexes were 2+ and symmetric throughout, and her sensory and
gait examinations were normal. Repeat EMG was performed to clarify
the diagnosis. Nerve conduction studies (NCS) were normal, but
conventional needle EMG showed fibrillation and fasciculation potentials
in multiple proximal and distal upper extremity muscles, in the
sternocleidomastoid muscle, and in the thoracic paraspinal muscles. Motor
unit action potentials in the upper extremity muscles were variable;
some showed a normal appearance and others had long duration,
increased amplitude, and polyphasia, consistent with reinnervation. The
results were interpreted as showing evidence of a multisegmental motor
neuronopathy and were felt to support the clinical diagnosis of ALS.
Comment. This patient presented with a head drop and exertional
dyspnea, which are symptoms that could be associated with various
neuromuscular disorders (Table 1-8). She was mistakenly thought to have
MG on the basis of a ‘‘positive’’ edrophonium test and abnormal SFEMG.
Repeat studies, however, showed abnormalities on conventional needle
EMG that were consistent with motor neuron disease. A response to
edrophonium or even pyridostigmine may be misleading in cases of ALS,
particularly early in the disease course. This patient appeared to respond
initially, at least subjectively, to treatment with cholinesterase inhibitors
despite having ALS. Similarly, an abnormal SFEMG can also be misleading
in cases where conventional EMG is not performed, with a failure to diagnose
primary nerve or muscle disease causing secondary NMJ dysfunction.
brain imaging, neuromuscular disease
is the next consideration.
Although unusual, MG may present
with isolated dysarthria or dysphagia
(Llabres et al, 2005). The presentation
will typically have a fatigable component while the dysarthria and dyspha-
A
It is more typical
for a patient with
ALS as opposed
to MG to present
with isolated
bulbar findings
because of the
segmental nature
of the disease
(progressive
bulbar palsy).
In ALS, there is
usually a spastic
quality to the
speech. Therefore,
the speech is
slow, effortful,
and has a harsh
or ‘‘strangled’’
vocal quality.
gia in ALS are typically nonfluctuating
and progressive. Early in the course
of ALS, however, the patient may
describe a fluctuating history with the
dysarthria being more pronounced at
the end of the day or after prolonged
talking. As time goes by, the speech
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25
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINT
A
26
In MG, the
dysarthria is
typically flaccid
and hypernasal
with lingual and
labial dysfunction.
Case 1-2
A 74-year-old man with a diagnosis of MG was transferred from an outside
facility for further management. He was in his usual state of health until
2 months previously. At that time, he developed dysphagia and shortness
of breath. He was admitted to an outside hospital where he required
intubation and ventilation. AChR antibodies were reported as positive
by the outside hospital. RNS studies reportedly showed an abnormal
decrement to 3-Hz stimulation in a hand muscle and a superimposed
cervical radiculopathy. Prior to his transfer, he had been treated with
pyridostigmine 30 mg twice daily and had received five plasmapheresis
treatments. He was successfully extubated shortly after completion of
plasmapheresis. He was subsequently treated with a course of IV
immunoglobulin treatments, prednisone 60 mg daily, and mycophenolate
mofetil 750 mg twice daily. Despite these treatments, his respiratory
status declined, and he had recently undergone tracheostomy and
percutaneous endoscopic gastrostomy tube placement.
On physical examination, the patient was awake and alert and
ventilated through a tracheostomy. His cranial nerve examination showed
normal extraocular muscle strength and normal facial strength. There
was no ptosis. He had mild tongue weakness and clearly visible tongue
fasciculations. He was not able to lift his head off the pillow. He had
asymmetric shoulder girdle weakness, more severe on the right compared
with the left. Distal upper extremity strength, including finger extension,
was normal. His hip flexion was mildly weak bilaterally. He had right foot
dorsiflexion weakness (4-/5). Fasciculations were observed in the anterior
chest, right upper arm, and right thigh. Reflexes were asymmetric: 2+
on the right and 3+ on the left. Needle EMG and NCS were performed
showing normal motor and sensory NCS as well as normal RNS studies in
the sternocleidomastoid muscle. Needle EMG showed positive waves,
fibrillations, and fasciculation potentials in multiple proximal and distal
muscles of the right arm and leg and in the rectus abdominus muscle.
Multiple muscles showed motor unit potentials, which were large in
amplitude and duration with polyphasia.
Upon further investigation, the patient’s ‘‘seropositivity’’ had been
based on elevated AChR-blocking antibody titers, which when repeated
were found to be in the normal range. Anti–AChR-binding antibody titers
were not elevated. He was diagnosed with ALS.
Comment. This patient was mistakenly diagnosed with MG based on
‘‘positive antibodies.’’ Since the AChR-blocking and AChR-modulating
antibody tests are not as widely used for the diagnosis of MG, their
specificity is uncertain. AChR-blocking antibodies most frequently are
found in patients with anti–AChR-binding antibodies and are present in
isolation only 1% of the time. This finding should have been repeated or
another means of diagnostic confirmation should have been sought. A
thorough clinical and electrodiagnostic evaluation, not even requiring RNS
or SFEMG, would have established the diagnosis in this case.
difficulty will become more prominent
and consistently present with less of a
fluctuating nature. The dysarthria in
MG typically maintains its fatigable and
fluctuating character throughout the
course of the disease. It is more typical
for a patient with ALS than a patient
with MG to present with isolated
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bulbar findings because of the segmental nature of the disease. For ALS,
the term progressive bulbar palsy is
often used to describe patients who
present in this way.
In MG, generally other clinical clues,
such as ptosis, diplopia, or fatigable
weakness in the setting of normal reflexes and normal muscle bulk, can
often lead to the diagnosis. An important clue to distinguish dysarthria
associated with MG from that of ALS
is the character of the dysarthria itself
(Table 1-6). For example, patients
with ALS, generally speaking, have a
distinctive dysarthria with a combination of spastic and flaccid qualities.
TABLE 1-6
"
Clinical
Characteristics of
Dysarthria in
Myasthenia
Gravis and ALS
Myasthenia Gravis
Fatigable
Fluctuating
Flaccid qualities: hypernasal,
breathy, hoarse
Normal cadence of speech
Associated tongue and
palate weakness
Less often an isolated finding
"
ALS
Progressive
Combination of spastic
and flaccid
Spastic qualities: slow
effortful speech and
tongue movements, harsh
or ‘‘strangled’’ quality
Flaccid qualities: tongue
fasciculations, atrophy,
and weakness
Can be an isolated finding
Bilateral damage of the UMNs of the
pyramidal tracts imparts a spastic
quality to the speech. Therefore, the
speech is slow and effortful and has a
harsh or ‘‘strangled’’ vocal quality. The
patient with ALS may also display slow
arduous movements of the tongue in
addition to tongue weakness. Tongue
atrophy and fasciculations may or may
not be present in the ALS patient with
tongue weakness, depending on the
degree of UMN versus LMN involvement. In contrast, in MG the dysarthria
is flaccid, and myasthenic speech often
has a nasal quality resulting from the
presence of palatal weakness. There is
no spastic quality to the speech as the
UMN is not involved in MG. The
speech is slurred in MG, but generally
the cadence is normal, and patients
with MG do not show tongue atrophy
or fasciculations. Patients with MG
may have tongue protrusion weakness
but do not show the slow arduous
tongue movements seen in ALS.
Dysphagia may be a presenting
symptom in MG and ALS, and distinguishing features of the dysphagia
seen in these two disorders are given
in Table 1-7. An early symptom of
dysphagia due to pharyngeal weakness in ALS is the inability to effectively
clear the throat of mucus. Often
patients will describe a nagging feeling
that phlegm is stuck in the throat and
they cannot clear it. Some patients
may refer to this as a ‘‘tickle’’ in
the throat. In contrast, this is not a
common symptom in MG. More commonly, patients with MG will have a
tendency to regurgitate through the
nose because of palatal weakness or
into the oral cavity from upper esophageal weakness (Colton-Hudson et al,
2002).
KEY POINTS
A
A
A
A
The speech can
be slurred in MG,
but generally the
cadence is normal
in contrast to
ALS, where
speech is typically
slow due to
upper motor
neuron
involvement.
Patients with MG
may have tongue
weakness but
do not show
the slow
arduous tongue
movements seen
in many patients
with ALS.
An early symptom
of dysphagia or
pharyngeal
weakness in ALS
is the inability to
effectively clear
the throat of
mucus.
Patients with
MG tend to
regurgitate
through the nose
due to palatal
weakness or into
the oral cavity
from upper
esophageal
weakness.
Head Drop
Table 1-8 shows the differential diagnosis for a patient presenting with
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27
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
A
A
Head drop in
ALS is often
associated with
diaphragmatic
weakness
because of
the fact that
both the
phrenic nerve
and nerves that
innervate the
neck extensor
muscles
originate
from the
upper cervical
segments.
When a patient
with ALS
presents with
limb weakness,
the dysfunction
is generally very
apparent on
the examination
and is often
more severe
and widespread
than reported.
TABLE 1-7
"
Clinical
Characteristics
of Dysphagia
Myasthenia Gravis
Nasal or oral regurgitation
more common
Chewing and swallowing
worse toward the end
of the meal
Difficulty initiating swallowing
(‘‘Won’t go down’’)
Multiple swallows required
(‘‘Food gets stuck’’)
Significant weight loss
uncommon
Rarely an isolated symptom
"
ALS
Difficulty clearing throat
of secretions
Limb Weakness
The clinical features of limb weakness
in patients with MG versus patients
with ALS are summarized in Table 1-9.
When a patient with ALS presents
with limb weakness, the dysfunction
is generally very apparent on the
examination and often associated with
prominent muscle atrophy, fasciculations, and/or hyperreflexia. Elicitation
of a reflex, even a ‘‘normal’’ reflex
in a weak and atrophic muscle is an
abnormal finding and indicates UMN
Nagging phlegm in throat
Progressively increasing
meal duration
TABLE 1-8
Drooling
Differential
Diagnosis of
Head Drop
Choking
Associated weight loss
May be presenting symptom
28
cervical myotomes. Since both the
phrenic nerve and nerves that innervate the neck extensor muscles
originate from the upper cervical
segments, associated diaphragmatic
weakness will often be present. For
this reason, head drop can be an
ominous sign in ALS.
head drop. Head drop can be the
presenting symptom in ALS or MG. It
can also be the presenting symptom in
isolated neck extensor myopathy. It is
far less common for head drop to be
the presenting or sole manifestation
of the other diseases listed in the
differential diagnosis in Table 1-8.
Generally speaking, when head drop
is seen in MG, other signs or symptoms, such as ptosis, extraocular muscle weakness, facial weakness, or
fatigable limb weakness, usually lead
one to the correct diagnosis. Since ALS
affects the anterior horn cells in a
segmental fashion, head drop would
indicate involvement of the upper
"
"
"
Myasthenia gravis
"
Inflammatory myopathy
(polymyositis, inclusion-body
myositis)
"
Chronic inflammatory
demyelinating polyneuropathy
"
Isolated neck extensor
myopathy
"
Congenital muscular
dystrophy (mutations in
LMNA or SEPN1 genes)
"
Congenital myopathy
(nemaline myopathy)
"
"
"
Hypothyroidism
ALS
Parkinson disease and
parkinsonism
Syringomyelia
Post–mantle irradiation
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TABLE 1-9
"
Characteristics
of Limb Weakness
in ALS and
Myasthenia Gravis
Myasthenia Gravis
Examination findings less
than expected from history
Demonstrable with fatiguing
maneuvers
Preferential involvement of
proximal muscles and finger
extensor muscles
Bilateral/symmetric or mildly
asymmetric
Absence of atrophy,
fasciculations
Normal muscle stretch reflexes
"
ALS
Examination findings more
than expected from history
Tends to be distal on
presentation (hand intrinsic
muscles, footdrop)
Bilateral/asymmetric
(or unilateral)
Associated atrophy and
fasciculations
Atrophic muscle with
intact reflex
involvement. For example, a biceps
muscle that is graded as a 2 or 3 on the
Medical Research Council scale and is
atrophic with fasciculations should
have a reduced muscle stretch reflex
presuming it is weak because of a
purely LMN lesion. If this muscle has a
relatively normal or hyperactive muscle stretch reflex, this is evidence of a
combination of UMN and LMN disease
as the cause for the weakness. Once
ALS presents in a particular spinal
segment, it generally progresses to
involve the same spinal segment on
the contralateral side, thus produc-
ing segmental weakness bilaterally
but asymmetrically. Also, if a patient
with ALS complains of weakness, the
patient almost invariably will have
an abnormal manual muscle strength
examination. In addition, it is not uncommon to find weakness on examination that the patient did not
realize was present. The contrary is
often true in MG, as patients may
complain of severe weakness and
fatigue that cannot be clearly demonstrated on physical examination. Fatiguing maneuvers must often be utilized
in the clinic in order to elicit this
weakness on the physical examination.
Limb weakness in ALS can occur
in any muscle group, but the most
common presentation of limb weakness in ALS is asymmetric distal
limb weakness. For example, weakness and wasting of intrinsic hand
muscles (both median-innervated and
ulnar-innervated muscles) in a unilateral
or asymmetric fashion is a typical
presentation. Alternatively, footdrop is
also a common presentation. Footdrop in ALS can be distinguished from
peroneal mononeuropathy or lumbar
radiculopathy by the lack of associated
pain or sensory symptoms. There is also
usually weakness outside of the peroneal or L4-5 distribution, UMN reflex
changes, or more widespread changes
on EMG than would be suspected with
a mononeuropathy or isolated lumbar
radiculopathy.
Bowel and Bladder Function
In most instances, bowel and bladder
function are spared in ALS and MG.
However, despite the fact that the
classic teaching is that bowel and
bladder function are spared in ALS,
urinary urgency and dribbling are not
uncommon in patients with ALS who
have a spastic paraparesis as well as
in patients with pelvic floor weakness. Frank incontinence, however,
is generally not present until late in
KEY POINTS
A
A
A
The patient
with MG may
complain of
severe weakness
and fatigue that
cannot be clearly
demonstrated
on physical
examination.
Fatiguing
maneuvers must
often be utilized
in the clinic in
order to elicit this
weakness.
The most common
presentation of
limb weakness
in ALS is
asymmetric distal
limb weakness,
eg, weakness
and wasting of
intrinsic hand
muscles (both
medianinnervated and
ulnar-innervated
muscles) in a
unilateral or
asymmetric
fashion, or
unilateral or
asymmetric
footdrop.
Symptoms of
bladder
dysfunction,
such as urinary
urgency and
dribbling, may
occur in ALS,
but frank urinary
incontinence is
not present.
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29
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINT
A
Constipation
is a common
symptom in ALS
and has multiple
potential causes.
TABLE 1-10
30
the disease course. Constipation tends
to be a common problem in patients
with ALS and is likely multifactorial. It is
often difficult for a patient with ALS to
travel to the restroom; therefore, in
order to avoid frequent restroom visits,
the patient will tend to drink less fluids,
leading to a dehydrated state. Other
factors leading to constipation include
decreased mobility, malnutrition, and
voluntary muscle weakness, leading
to a weak Valsalva maneuver during
evacuation.
Rarely, bladder dysfunction will be a
symptom of MG, probably as a result
of pelvic floor weakness. Bowel evacuation may be similarly affected.
The signs and symptoms of ALS and
MG are compared and contrasted in
Table 1-10.
Summary of Signs and Symptoms in ALS and Myasthenia Gravis
Symptom or Sign
ALS
Myasthenia Gravis
Weakness
+++
+++
Atrophy
+++
–
Fasciculations
+++
–
Hyperreflexia or areflexia
+++
–
Ptosis
–
+++
Extraocular muscle weakness
–
+++
Reduced saccades
++
–
Dysarthria
Spastic and flaccid
Flaccid/nasal speech
Dysphagia
++
++
Bladder urgency
++
+
Constipation
++
–
Shortness of breath
++ Associated with
low FVC
++ May be present with
normal or low FVC
Head drop
+++
++
Difficulty clearing phlegm from throat
+++
+
Regurgitation of food or drink
through nose
–
++
Limb weakness without atrophy
or fasciculations
–
+++
Fatigable limb weakness
+
+++
Finger extensor weakness relative
to intrinsic hand muscle weakness
–
++
Footdrop
+++
+
+++ Common symptom
++ Symptom present
+ Symptom rarely present
– Symptom generally not present
FVC = forced vital capacity.
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Fatigue
Motor fatigue is a common complaint
in patients with ALS, but it is usually
not included in the clinical assessment
of these patients. The etiology of
fatigue in these patients is most often
attributed to unstable neuromuscular
transmission in reinnervating NMJs,
but other causes may be relevant.
Higher firing rates of surviving motor
axons attempting to compensate for
the loss of motor neurons may be
a likely explanation for the activitydependent dysfunction in ALS (Vucic
et al, 2007). It is also likely that central
factors contribute to the complaints of
fatigue in ALS.
Compared with the fatigability
reported by patients with MG, patients
with ALS more often report general
fatigue that has both physical and
psychological components. Patients with
ALS also frequently report excessive
daytime somnolence, which may be
an indicator of nocturnal hypoventilation. Earlier in the disease course, when
dysfunction is limited to a particular
body region or myotome, patients
with ALS may have true fatigable muscle weakness with symptoms that
worsen with use of the affected muscle and improve with rest. This pattern
may occasionally be seen in patients
with initially isolated bulbar palsy, making the clinical distinction from MG
difficult.
PITFALLS IN THE DIAGNOSTIC
TESTING OF MYASTHENIA
GRAVIS AND ALS
Electrodiagnostic Testing in
Myasthenia Gravis
RNS studies and SFEMG are the
electrodiagnostic tests used to confirm
the presence of a defect in neuromuscular transmission in MG. However,
emphasis should be placed on the
importance of performing conventional needle EMG and sensory and
motor NCS in patients suspected of
MG before proceeding to more specialized tests. This is because RNS and
SFEMG abnormalities are relatively
nonspecific. Other primary disorders
affecting the nerve or motor neuron
and even muscle may show abnormalities on RNS and/or SFEMG that may
be mistaken for MG. For example,
abnormal decremental responses on
RNS and increased jitter on SFEMG
may both be present in patients with
motor neuron disease (Case 1-1). As
noted, this is explained by the fact that
in motor neuron disease, reinnervating NMJs have impaired neuromuscular transmission because of the
immaturity of the reinnervating nerve
terminal. In a more rapidly evolving
motor neuron disease such as ALS, a
higher number of NMJs probably are
either actively reinnervating or recently denervated, increasing the likelihood of finding a secondary defect of
neuromuscular transmission. In MG,
however, the conventional NCS and
EMG studies are normal, while in
primary neurogenic or myopathic conditions, the conventional NCS and
EMG reveal the primary abnormality.
In addition, increased jitter on SFEMG
testing will be accompanied by the
finding of increased fiber density in
ALS, while fiber density will be normal
in MG.
KEY POINTS
A
A
Abnormal
findings on
repetitive nerve
stimulation and
single fiber EMG
are relatively
nonspecific and
may be seen in
neurogenic
conditions
associated
with ongoing
reinnervation,
such as ALS.
In MG, the
conventional
nerve conduction
studies and EMG
are typically
normal, while in
primary nerve or
muscle disease,
the conventional
nerve conduction
studies and
EMG usually
reveal the primary
abnormality.
Electrodiagnostic Testing
in ALS
As stated previously, ALS is a clinical
diagnosis, and no specific laboratory
or imaging test can absolutely confirm
or refute the diagnosis. The utility of
electrodiagnostic testing, including
EMG, in providing supportive evidence in favor of the diagnosis has
been affirmed (de Carvalho et al,
2008), but the results of this testing
must always be interpreted in the
context of the clinical presentation.
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31
" SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
A
A
A
32
In early spinal
ALS, EMG
abnormalities
may mimic a
radiculopathy.
Multisegmental
denervation
may not
become
apparent until
later in the
disease course.
In the case of
bulbar-restricted
ALS, the EMG
may be normal
or near normal.
This is especially
true if the
patient’s bulbar
symptoms are
predominantly
caused by upper
motor neuron
degeneration.
EMG is helpful
in the diagnosis
of ALS when
asymptomatic
body regions,
or body regions
showing only
upper motor
neuron signs
clinically, reveal
evidence of
denervation. It
is recommended,
therefore, that
cranial, cervical,
thoracic, and
lumbosacral
body regions
be examined
thoroughly in
all patients with
suspected ALS.
See Table 1-11. In the context of ALS,
electrodiagnostic testing can favor the
diagnosis of ALS by showing multisegmental active denervation (denervation in cranial, cervical, thoracic,
and/or lumbosacral body regions) that
localizes proximal to the dorsal root
ganglia, ie, sparing sensory nerve conduction potentials. Recent recommendations advocate attributing equivalent
significance to fasciculation potentials as fibrillation potentials in recognizing denervation (de Carvalho et al,
2008). These findings are not specific
for ALS as polyradiculopathy may
have the same electrodiagnostic appearance. In early spinal ALS, EMG
abnormalities may mimic those of a
focal radiculopathy, and multisegmental denervation may not be apparent
until later in the disease course. Also,
in the case of bulbar-restricted ALS,
the EMG may be normal or near
normal. This is especially true if the
patient’s bulbar symptoms are predominantly caused by UMN degeneration. In this case, even EMG of the
tongue may not show clear abnormalities. EMG of the sternocleidomastoid
muscle has a similar sensitivity compared to the tongue in patients with
bulbar symptoms and should be examined if the tongue is normal. It is
important to keep in mind, however,
that an abnormal EMG in a cranialinnervated muscle may also be caused
by a structural or infiltrating lesion of
the lower brainstem, which should be
investigated with the appropriate neuroimaging studies.
EMG is most helpful in the diagnosis of ALS when asymptomatic body
regions show abnormalities that add
to the distribution of LMN dysfunction
demonstrated clinically. It is recommended, therefore, that cranial, cervical, thoracic, and lumbosacral body
regions be thoroughly investigated
(generally unilateral is sufficient) in
all patients with suspected ALS.
TABLE 1-11
"
Pattern of
Electrodiagnostic
Findings in ALS
and Myasthenia
Gravis
ALS
EMG confirmation depends
on multisegmental neurogenic
involvement (cranial, cervical,
thoracic, and/or lumbosacral
body regions) in the absence
of another cause to explain
such findings
Early spinal ALS can mimic
radiculopathy
Can be normal or near normal
in bulbar-restricted ALS
May show a decrement on
repetitive nerve stimulation
studies
Typically shows normal sensory
conductions but can be
abnormal in up to one-third
of patients.
Motor conduction studies
can be low amplitude, and
F waves can be borderline
prolonged
"
Myasthenia Gravis
Decrement on repetitive
nerve stimulation may or
may not be present and is
more likely present in weak
muscle; proximal muscles are
more sensitive
Abnormal jitter on single
fiber EMG is seen in 95%
of patients, if two or more
muscles are tested
Single fiber EMG is abnormal
in weak muscle
Conventional EMG is normal
Conventional nerve
conduction studies are normal
Acetylcholinesterase Inhibitors
A clinical response to edrophonium
or to treatment with pyridostigmine
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(Mestinon) is supportive evidence in
favor of the diagnosis of MG (see the
chapter ‘‘Myasthenia Gravis: Immunopathogenesis, Diagnosis, and Management’’). However, a clinical response
to cholinesterase inhibitors can occur
in a variety of conditions and therefore
is not entirely specific for MG. Any
condition causing impaired neuromuscular transmission has the potential to
respond positively to cholinesterase
inhibitors. This includes patients with
ALS particularly in the early phases of
disease when reinnervation is actively
compensating for ongoing denervation and new NMJs are continually
formed by collateral sprouting. As
illustrated in Case 1-1, the response
to cholinesterase inhibition in neurogenic disease is relatively short-lived
and typically wears off as the disease
progresses.
Anti-acetylcholine Receptor
Antibodies
A high titer of anti–AChR-binding antibodies essentially confirms the diagnosis of MG in a patient with a clinical
presentation suggestive of the disease.
False-positive results are believed to
be very rare. Other AChR antibody
tests that measure the blocking of
the acetylcholine binding site on the
AChR (AChR-blocking antibodies) and
determine the effect of antibodies on
the turnover and expression of AChR
on muscle cells (AChR-modulating antibodies) are also commercially avail-
able. As detailed in the chapter ‘‘Myasthenia Gravis: Immunopathogenesis,
Diagnosis, and Management,’’ AChRmodulating antibodies occur in about
3% to 4% of patients with MG who
are anti–AChR-binding antibody negative, while AChR-blocking antibodies
occur in about 1% of patients who are
anti–AChR-binding antibody negative.
False-positives may occur with these
tests, so they should be interpreted
with caution. Ideally, positive AChRblocking or AChR-modulating antibody
test results should be confirmed with
repeat testing or other confirmatory
diagnostic evidence, such as electrodiagnostic confirmation of a primary
defect in neuromuscular transmission.
CONCLUSIONS
The details of the clinical presentations
form the basis of an accurate diagnosis
of autoimmune MG and sporadic ALS.
While a number of diagnostic tests may
provide supportive data in favor of the
diagnosis, these tests are generally
nonspecific, with one notable exception
(anti–AChR-binding antibodies) and absolutely must be interpreted in the
context of the clinical picture. Certain
clinical presentations (ie, dysarthria, dysphagia, dropped head syndrome) may
suggest either the diagnosis of MG or
ALS, but the correct diagnosis can usually be determined by a careful assessment of the clinical history, neurologic
examination, and the judicious use of
supportive diagnostic testing.
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A
A
A clinical response
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of testing
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SUGGESTED ADDITIONAL READING
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Lancet Neurol 2007;6(11):994–1103.
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