KEY POINTS

APPROACH TO A Myasthenia
gravis (MG) and

THE PATIENT WITH ALS may

have some

SUSPECTED MYASTHENIA commonalities

in their
presentation

GRAVIS OR ALS: and therefore

can coexist in

A CLINICIANS GUIDE the differential

diagnosis. As
the treatments
Julie Rowin and prognosis
are vastly
different for
these two
ABSTRACT disorders, it
Myasthenia gravis (MG) and amyotrophic lateral sclerosis (ALS) are neuromuscular is best to
disorders that may share certain symptoms but have vastly different pathophysi- diagnose the
ologies, treatments, and outcomes. ALS is a fatal neurodegenerative disease that patient as early
causes death of motor neurons in the brain, brainstem, and spinal cord, leading to in the course of
weakness of voluntary muscles including bulbar, respiratory, facial, trunk, and limb the disease as
muscles. MG is an autoimmune disease of the neuromuscular junction that leads possible.
to a similar distribution of weakness with the additional involvement of the A The diagnosis of
extraocular muscles. The hallmark of MG is fatigable muscle weakness, but MG and ALS
patients with ALS may also have fatigue, particularly early in the disease course. can generally
Despite these similarities, MG and ALS have distinct clinical characteristics that, be made
when recognized, aid the clinician in making the correct diagnosis. clinically and
Continuum Lifelong Learning Neurol 2009;15(1):1334. then supported
by laboratory
tests and
studies.
INTRODUCTION as possible. This chapter will review
The aim of this chapter is to provide the presenting symptoms and charac-
guidelines to the clinician for evalu- teristic clinical signs of MG and ALS
ating a patient who presents with and provide distinguishing features
suspected myasthenia gravis (MG) or of the two diseases when both are 13
amyotrophic lateral sclerosis (ALS). included in the initial differential di-
Clinically speaking, MG and ALS have agnosis. Possible pitfalls in the di-
distinct clinical features, but there agnosis of both disorders will be
are also occasional commonalities in highlighted. In general, ALS and MG
their presentations, and these two dis- can be readily diagnosed based on a
orders may, therefore, coexist in the thorough clinical evaluation, which is
differential diagnosis of a particular then supported by appropriate diag-
patient. As the treatments and prog- nostic laboratory and imaging studies.
noses are vastly different, it is obvi- The complete differential diagnosis
ously desirable to secure the diagnosis of ALS and MG will be covered in
as early in the course of the disease 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.

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 " SUSPECTED MYASTHENIA GRAVIS OR ALS

KEY POINTS
MYASTHENIA GRAVIS weakness, tiredness, or lack of en-
A The clinical
MG produces symptomatic weakness ergy. Patients with MG may have
hallmark of MG
is the presence that predominates in certain muscle symptoms and signs only after exer-
of fluctuating groups and typically fluctuates in re- tion or at the end of the day. This may
fatigable muscle sponse to effort and rest. The diagnosis result in little detectable objective
weakness that of MG is primarily based on the clinical weakness at the time of examina-
is brought on history and examination findings dem- tion, often delaying the diagnosis. Ma-
by activity onstrating this distinctive pattern of neuvers that fatigue specific muscle
and improves weakness. Confirmation of the clinical groups can be very useful in eliciting
with rest. signs of weakness in patients with
diagnosis may be obtained using phar-
A Maneuvers macologic, immunologic, and electro- MG because patients with generalized
that fatigue physiologic tests, which are described fatigue or malaise do not typically dis-
specific muscle in a subsequent chapter. play true muscle weakness with these
groups can be maneuvers (Table 1-1).
very useful in Characteristic clinical symptoms.
eliciting signs Clinical Diagnosis Initial symptoms involve the ocular
of weakness The clinical hallmark of MG is the muscles in up to 85% of patients with
in patients
presence of fatigable muscle weakness. MG (Grob et al, 2008), and these pa-
with MG.
It is useful to distinguish fatigable tients will report ptosis, intermittent
A Initial symptoms muscle weakness from general fatigue diplopia, or both. A majority of these
involve the or exhaustion. Patients with fluctuating patients (approximately 80%) will sub-
ocular muscles fatigable muscle weakness due to MG sequently develop generalized MG. Oc-
in most patients will describe weakness in a specific casionally, patients will report blurred
with MG.
group of muscles that is brought on vision rather than diplopia, often
by activity and improves with rest. In prompting them to change their eye-
contrast, patients with general fatigue glasses in an attempt to correct the
or exhaustion due to any number of problem. Ptosis may not be noticed
causes will typically report all-over until it obscures vision. Patients with

TABLE 1-1 Fatiguing Maneuvers in Suspected Myasthenia Gravis

Clinical Fatiguing Manifestation in Symptomatic

Maneuver
14
Sustained upgaze
(30 to 60 seconds)
Sustained abduction of
the arms (120 seconds)
Sustained elevation of
leg while lying supine
(90 seconds)
Repeated arising from
chair without use of
arms (up to 20)
Counting aloud (1 to 50)
Myasthenia Gravis
Enhances ptosis and elicits medial
rectus weakness
Patient can no longer hold arms
up, or weakness becomes apparent
with subsequent manual testing
Patient can no longer hold leg up,
or weakness becomes apparent
with subsequent manual testing
Fatigues after several attempts
Enhances dysarthria
Comments
Medial rectus muscle is usually
most severely involved
extraocular muscle
Dysarthria or shortness of
breath may be enhanced
Dysarthria or shortness of
breath may be enhanced
Early/mild weakness may cause
exaggerated lean-forward and
buttocks-first maneuver
Nasal, lingual, or labial

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ptosis will note that the severity of the
eyelid droop varies during the course
of the day, often worsening after exer-
cise, 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 symp-
toms early in the disease course, in-
cluding dysarthria, dysphagia, and
difficulty chewing (Grob, 1953). This
percentage is higher in antimuscle-
specific receptor tyrosine kinase (MuSK)
antibody positive MG. (The clinical
phenotype of antiMuSK-positive MG
is discussed in the subsequent chapter.)
At times, oropharyngeal symptoms may
be present with minimal associated
ocular symptoms, particularly in late-
onset and antiMuSK-positive disease.
Weakness of palatal muscles may re-
sult in a nasal quality to the voice.
Speech may become slurred with pro-
longed talking, eg, talking on the
telephone or giving a speech or pre-
sentation. 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 ad-
vanced disease. Patients with MG who
have difficulty chewing often describe
progressively weaker chewing force
with each successive bite. The diffi-
culty is worse with solid foods, par-
ticularly meat. There is no associated
pain, differentiating this complaint
from jaw claudication due to tempo-
ral arteritis.
Rarely, patients with MG may pres-
ent with respiratory muscle weakness
without other prominent MG symp-
toms (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-
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KEY POINTS
ten have orthopnea as an early symp-
A Nearly all patients
tom. This may lead to respiratory
with MG will
compromise when the patient is develop ocular
placed in the supine position. Patients manifestations
with MG and respiratory muscle weak- at some point
ness may report an inability to draw a during the
full breath. They often describe their course of
breathing as rapid and shallow, which their illness.
may be misinterpreted as hyperventi- A Approximately
lation due to anxiety. 20% of patients
Fatigable extremity weakness in MG with MG may
may affect any muscle group and may present with
be asymmetric. Rarely, weakness may prominent bulbar
be very focal, affecting distal limb symptoms.
muscles (Nations et al, 1999) or neck A Rarely, patients
extensors (DAmelio et al, 2007) selec- with MG may
tively. Characteristically, muscles are present with
noted to weaken with repeated use, respiratory muscle
and strength improves with rest. Pa- weakness without
tients may note the development of other prominent
a footdrop with prolonged walking, MG symptoms.
hip extension weakness with climbing However, the
several flights of stairs, shoulder mus- majority of
patients with
cle fatigue with activities that require
respiratory muscle
holding the arms above the head, and
weakness have
weakness of finger flexors and exten- ocular and bulbar
sors with prolonged typing. Symptoms concerns.
may worsen with exposure to extreme
heat or emotional stress. Infection, A Symptoms of
MG may worsen
systemic illness, pregnancy, the men-
with exposure
strual cycle, or drugs that affect neu-
to extreme
romuscular transmission may also heat, emotional
exacerbate myasthenia. Patients may stress, infection,
report that they plan activities for early systemic illness,
in the day when their strength is at
its peak. On the other hand, severe
pregnancy,
the menstrual
15
disease may cause prominent muscle cycle, or drugs
weakness in which fatigability is not that affect
necessarily apparent. neuromuscular
Physical signs. The classic physi- transmission.
cal signs of MG include ptosis, oph-
thalmoparesis, bulbar weakness, and
fatigable extremity weakness. Unfor-
tunately, the clinical presentation in
individual patients is often quite vari-
able, and the diagnosis may be diffi-
cult. A history of fatigable weakness in
specific muscle groups should prompt
further investigation for a neuromus-
cular junction (NMJ) defect, regardless
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 " SUSPECTED MYASTHENIA GRAVIS OR ALS

KEY POINTS
of whether clinical signs of weakness at rest may develop ptosis after
A A history of
are observed on examination. In a sustained upgaze for 60 to 180 sec-
fatigable
weakness in patient with suspected MG, the fol- onds. Manual elevation of the more
specific muscle lowing muscle groups should be ptotic lid may worsen ptosis on the
groups should specificallytested:facial,ocular,oropha- contralateral side, a phenomenon known
prompt further ryngeal, respiratory, axial, and limb as enhanced ptosis (Gorelick et al,
investigation for muscles. The distribution of weakness 1981). Finally, ptosis may improve
a neuromuscular in a large cohort of patients with MG in response to local cooling of the
junction defect, (Grob et al, 2008) is given in Table 1-2. lid (Larner, 2004). To compensate
regardless of All patients had some degree of de- for ptosis, the frontalis muscle may
whether clinical tectable ocular muscle weakness, but be chronically contracted, and unilat-
signs of
only 17% had purely ocular involve- eral frontalis hypercontraction is a
weakness are
ment. The incidence of purely ocular clue that the lid elevators are weak on
observed on
examination.
and oculobulbar weakness was signifi- that side.
cantly higher in males compared with The pattern of extraocular muscle
A Myasthenic females in this cohort, while ocular weakness in MG is typically asymmet-
patients with with generalized weakness was more ric and not isolated to the distribution
little or no
prevalent in females. of a single cranial (III, IV, VI) nerve.
ptosis at rest
Ocular muscle weakness. The ex- The pattern of weakness may fluctuate
may develop
traocular muscles and the eyelid ele- and change even during the course of
ptosis after
sustained vators are involved to different degrees a single examination. The medial rectus
upgaze for 60 in individual patients with MG. Pupil- muscle is most frequently affected,
to 180 seconds. lary responses are normal. Eyelid pto- followed by the superior and lateral
sis is usually asymmetric and may vary rectus muscles. Rarely, weakness may
A The pattern of
considerably during the course of the be isolated to the lateral recti. Examina-
extraocular
examination. Ptosis is worsened with tion of extraocular movements should
muscle weakness
in MG is typically sustained upgaze. Resting the lids by include a minimum of 15 to 30 seconds
asymmetric and having the patient close the eyes for of lateral and superior gaze holding.
not isolated to 30 seconds may lessen the ptosis for The cover-uncover test may elicit
the distribution a time. Patients with little or no ptosis mild weakness of a specific extraocular
of a single muscle by causing shifting fixation
cranial nerve. in the direction of action of the weak
A Sustained upgaze muscle. Sustained lateral gaze will pro-
for 30 seconds TABLE 1-2 Distribution of duce fatigable weakness of the medial
Weakness in a or lateral rectus muscles. With attemp-
16 is usually
sufficient
Large Cohort of Patients ted lateral gaze, the adducting eye may
With Generalized Myasthenia
to produce
Gravis (n = 609)
not move, and the abducting eye may
weakness of demonstrate nystagmus that becomes
the medial coarser as the lateral rectus muscle
Distribution Percentage
rectus muscles fatigues, a phenomenon called pseu-
of Weakness of Patients
in MG. dointernuclear ophthalmoplegia. Sus-
Localized ocular 17% tained upgaze for 30 seconds is usually
Ocular and 50% sufficient to produce weakness of the
generalized medial rectus muscles in MG. It is im-
Ocular and bulbar 13% portant to be aware that holding the
Ocular and limb 20% stimulus for upgaze too close will elicit a
Data from Grob D, Brunner N, Namba T, Pagala M.
failure of convergence alone that is not
Lifetime course of myasthenia gravis. Muscle Nerve necessarily an abnormal finding. If dip-
2008;37(2):141149.
lopia or dysconjugate gaze is due to a
failure of convergence alone, moving the

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target farther from the patient will im-
prove the abnormality. Conversely, mov-
ing the target farther away will exacer-
bate the problem in MG and increase
the apparent separation of the images.
Facial muscles. Many patients with
MG have a characteristic facial appear-
ance. 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 manu-
ally open the eyelids. Weakness of the
orbicularis oris muscle may produce
the characteristic horizontal or snarl-
ing appearance with attempts to smile.
Patients may also have difficulty puffing
their cheeks or pursing their lips. With
attempts to purse the lips, a horizon-
tal pucker is frequently observed
because of the inability to approximate
the sides of the mouth.
Oropharyngeal muscles. The dysar-
thria in MG is often characterized by
nasal speech due to posterior pharyn-
geal weakness and articulation ab-
normalities with labial and lingual
consonant and vowel distortion caused
by facial and tongue weakness. La-
ryngeal weakness may cause speech
output to be hypophonic (breathy,
whispered, or hoarse). Again, these
abnormalities are brought on (or wors-
ened) by sustained talking. It is some-
times 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 weak-
ness. The soft palate should be ob-
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KEY POINTS
served as the patient says Ah to
A Weakness of
make sure it rises normally in the
eyelid closure
midline. Weakness of the tongue mus- is seen in
cles may also cause dysphagia because most patients
of abnormal movement of the bolus of with MG.
food in the oral cavity. Tongue pro-
trusion should be checked by having
A Weakness of the
orbicularis oris
the patient protrude the tongue into
muscle in
the cheek while the examiner applies patients with
resistance on the outside surface of MG may
the cheek. Some experience is re- produce the
quired to determine the amount of characteristic
resistance to apply and the force of horizontal or
protrusion that is normal. snarling
Patients with MG who have diffi- appearance
culty chewing usually give a revealing with attempts
history as described above. When these to smile.
patients are examined, weakness of A The dysarthria in
jaw closure due to masseter and tem- MG is often
poralis muscle weakness may be pres- characterized
ent. Weakness of jaw opening due to by nasal speech
pterygoid muscle weakness, on the caused by
other hand, is rarely seen in MG even posterior
pharyngeal
with relatively severe weakness of
weakness.
the masseter muscles. This pattern of
weak jaw closure and relatively strong A The pattern of
jaw opening is quite typical of MG. weak jaw
The masseter and temporalis muscles closure and
are checked by having the patient relatively
preserved jaw
clamp the jaws together while the
opening is
examiner attempts to separate them
typical of MG.
by applying downward pressure on
the chin. It is best to sustain a mod-
erate level of downward pressure for
a period of 30 seconds rather than
applying momentary pressure force- 17
fully. The pterygoid muscles are eval-
uated by having the patient open the
jaw while the examiner applies up-
ward 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 observa-
tion 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
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 " SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
a full breath. Asking patients to inspire
A A weak sniff and
forcefully and loudly through the
cough along
with tachypnea nose (inspiratory sniff) can give one a
or tachycardia good indication of inspiratory muscle
are signs of strength. To assess expiratory muscle
significant function, patients should be asked to
respiratory cough or clear their throat. Outward
muscle protrusion of the abdomen against
weakness. the examiners hand is an indirect
A Arterial blood measure of diaphragmatic strength
gas measurements since the abdominal contents will be
are a relatively pushed upward instead of outward if
insensitive the diaphragm is weak. A weak sniff
measure of and cough along with significant
impending tachypnea or tachycardia are signs of
respiratory clinically important respiratory muscle
decompensation weakness.
in MG.
Formal measurements of pulmonary
A Some patients function such as forced vital capacity
with MG may be useful but are also dependent
will have on a number of factors, including
intermittent pulmonary status. Results should be
symptomatic interpreted carefully in patients with
dyspnea by
MG, given the fluctuating nature of the
history and
disease. It is not uncommon for an MG
normal
patient with intermittent symptomatic
pulmonary
function tests dyspnea by history to have normal
and bedside pulmonary function tests and bedside
respiratory respiratory muscle strength parame-
muscle strength ters. The normal tests are reassuring
measurements. but should not lead to the suggestion
A Patients with MG
that the complaint is factitious or not
with respiratory potentially clinically relevant. Repeated
muscle testing of respiratory parameters will
cause a worsening with each subse-
18 weakness will
often have quent trial in MG patients with ventila-
coexisting tory muscle weakness and may exhaust
weakness of the breathing muscles. Arterial blood
neck flexion/ gas measurements are a relatively in-
extension. sensitive measure of impending respi-
ratory 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 ex-
tension, which may be a useful associ-
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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 dif-
ferent patterns affecting the limb and
axial muscles. Patients with mild dis-
ease may have weakness limited to the
neck flexor muscles. Typically, neck
flexion is weaker than neck extension
in patients with MG, although oc-
casionally patients will present with
the dropped head syndrome and
have severe neck extension weakness
(DAmelio et al, 2007). Initial pre-
sentations with severe neck extensor
muscle weakness have also been re-
ported 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 ex-
tremity, the foot dorsiflexors and hip
flexors are most frequently involved.
Weakness is usually relatively sym-
metric, but may be asymmetric and
even focal. At the authors institution,
we have observed weakness of fin-
ger 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 sus-
tain 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.
 KEY POINTS
AMYOTROPHIC LATERAL
TABLE 1-3 Upper Motor A In MG, neck
SCLEROSIS Neuron and Lower flexion is typically
ALS is a progressive neurodegenerative Motor Neuron weaker than
disease of upper motor neurons Signs of ALS neck extension,
(UMNs) and lower motor neurons and finger and
(LMNs) that has both sporadic and " Upper Motor Neuron Signs wrist extensors
inherited forms. It is a disease with no Weakness and shoulder
significant treatments that alter the abductor muscles
Spasticity are most likely
disease course and a poor prognosis.
Hyperreflexia to be affected in
It can be a difficult disease to diagnose
the upper limb.
since mimics of ALS exist, and clinical Babinski sign
In the lower
phenotypes are heterogeneous. Patients Relatively retained muscle extremity, the
most often report progressive asym- bulk, mild (disuse) atrophy foot dorsiflexors
metric weakness in the distal limbs. " Lower Motor Neuron Signs and hip flexors are
However, weakness may manifest in most frequently
any body segment (bulbar, cervical, Weakness involved.
thoracic, or lumbosacral) and affect Flaccidity
A In MG, limb
eating, swallowing, speaking, fine mo- Hyporeflexia weakness is
tor control, walking, and eventually usually relatively
Fasciculations
breathing. Life expectancy on average symmetric,
is between 3 and 5 years from the date Loss of muscle bulk, severe but may be
of diagnosis, with a shorter survival (neurogenic) atrophy asymmetric, and
time for bulbar onset patients. is rarely focal.
A The hallmark of
Clinical Diagnosis the clinical
ble ALS (laboratory supported) is clas- diagnosis of ALS
The hallmark of the clinical diagnosis sified as LMN and UMN signs in one is the presence
of ALS is the presence of UMN and region plus EMG evidence of acute of upper and
LMN signs (Table 1-3) coexisting in denervation in two or more muscles lower motor
multiple body regions (cranial, cervi- in two or more limbs (Brooks et al, neuron signs
cal, thoracic, or lumbosacral) in the 2000). These criteria have proved to be coexisting in
relative absence of sensory abnormal- useful for the standardization of diag- multiple body
ities. To date, no pathognomonic di- nostic criteria for clinical research regions in the
agnostic test is available, and the studies. However, when it comes to relative absence
diagnosis is entirely a clinical one. Pa- the diagnosis of the patient in the of sensory
tients with findings suggestive of ALS earlier stages of the disease, these abnormalities. 19
are typically assigned to differing levels criteria may be too strict as many A The diagnosis of
of diagnostic certainty (suspected, pos- patients will not meet the criteria for ALS is a clinical
sible, probable, and definite) based definite or probable ALS at the time one as no single
on a set of defined diagnostic criteria of presentation. A careful neurologic test can absolutely
known as the El Escorial criteria. These examination, however, even early in confirm the
diagnosis. With
criteria were established in 1991 for the course of the disease can aid in
support from
research purposes and were recently making the correct diagnosis. This
electrodiagnostic
revised (Brooks et al, 2000). A definite section will give the examiner bedside studies and MRI
diagnosis of ALS requires the presence tools for the examination of a patient studies, however,
of UMN and LMN features in three with suspected ALS. As the diagnosis of the diagnosis is
or more body regions (cervical, tho- ALS is a clinical one, and no one test can usually possible
racic, lumbosacral, and cranial). Proba- provide definitive confirmation, recog- even in relatively
ble ALS is classified as LMN and nition of classic and variant presenta- early disease.
UMN signs in two regions, and proba- tions is critical. Diagnostic support

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 " SUSPECTED MYASTHENIA GRAVIS OR ALS

KEY POINTS
from electrodiagnostic and MRI studies occur after contraction of the involved
A Most patients
can also aid in arriving at the appropri- muscle or at rest. Muscle cramps may
with ALS will
present with ate diagnosis by confirming multiseg- be particularly bothersome when they
the chief mental LMN disease and eliminating involve a nonlimb muscle such as the
concern of structural brain or spinal cord pathol- jaw or trunk muscles. Often cramping
weakness in a ogy. The differential diagnosis of ALS is precipitated by an ordinary contrac-
limb. The next is discussed in detail in the chapter tion or a change in muscle length. For
most common Clinical Spectrum of Motor Neuron example, a yawn can precipitate a
presenting Disorders. painful jaw cramp, or a simple twisting
symptom is Characteristic symptoms. Most movement of the torso can precipitate
dysarthria or patients with ALS will present with the muscle cramps involving the trunk.
dysphagia.
chief concern of asymmetric weakness The cramping tends to be more severe
A Muscle affecting a limb. The next most com- during the early stages of the disease
fasciculations in mon initial presentation consists of oro- when reinnervation is prominent and
the limbs and pharyngeal or bulbar weakness causing tends to subside when muscles be-
torso are dysarthria or dysphagia (Traynor et al, come very weak and atrophic. Parox-
common in ALS 2000). The remaining patients will pres- ysmal laryngospasm may be thought
and unless
ent less typically with head drop, of as a cramp affecting the laryngeal
profuse often
shortness of breath, fasciculations, or muscles and tends to be a very anxiety-
go unnoticed
rarely, cognitive dysfunction. Typically, producing symptom for patients. When
by the patient.
symptoms have been present and pro- the spasm occurs, the patient cannot
A Muscle gressively worsening for months when draw a breath and appears to be
cramping is the patient initially presents for evalua- choking. The spasm typically subsides
a common
tion. Patients may have difficulty precisely within several seconds, but the invol-
symptom
dating the onset of symptoms but will untary nature and the unpredictability
in ALS.
usually recall vague symptoms of fatigue, of the spasm leads to an understand-
A Paroxysmal clumsiness, loss of hand dexterity, etc, able feeling of panic.
laryngospasm, prior to the onset of frank weakness Sialorrhea is caused by progressive
sialorrhea, and and/or atrophy. These initial symptoms weakness of oral, lingual, and pharyn-
pseudobulbar
may be discounted and often attributed geal muscles and is a frequent and
affect are all
to aging. Some patients have a rapidly embarrassing problem in ALS patients
relatively
common
progressive course with survival of less with bulbar symptoms. Pseudobulbar
symptoms in than 1 year from the onset of symp- emotional lability can coexist with
ALS patients toms, while other patients progress much other UMN signs involving the bul-
more slowly, far outliving the 5-year bar muscles. This manifests as exces-
20 with bulbar
disease. life expectancy. sive uncontrollable or uncharacteristic
Muscle fasciculations in the limbs laughing or crying.
A All patients
with suspected
and torso are almost a universal fea- Physical signs. All patients with
ALS should ture of ALS but may also be seen in suspected ALS should be observed for
be asked other disorders affecting the motor the presence of fasciculations. This ab-
to disrobe neurons and may be experienced in solutely requires that the patient dis-
so that the the normal population as well. In ALS, robe since fasciculation may be most
examiner may fasciculations, unless profuse, often go prominent in the torso, periscapular
observe for unnoticed by the patient. In fact, the region, and proximal thigh. Unlike be-
fasciculations. patients spouse or partner may notice nign fasciculations, which typically are
the fasciculations before the patient infrequent and tend to involve one
does. Muscle cramping is a common motor unit causing recurrent twitch-
symptom in ALS and motor neuron ing of the same muscle or group of
disorders in general. Cramps may be muscle fibers, fasciculations in ALS
quite painful and bothersome and generally occur in multiple motor

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units simultaneously and continuous-
ly. 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 pres-
ent 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 fas-
ciculations. On the other hand, the
patient who presents with a report of
profuse and constant muscle twitch-
ing, but on examination has no
observable fasciculations, almost in-
variably does not have ALS but likely
has a benign fasciculation syndrome.
A classic sign in ALS is tongue fas-
ciculations, and the differential diag-
nosis 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-
Differential
TABLE 1-4
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
" Base of the skull tumor
" Radiation in the area of the
hypoglossal nerve
" Idiopathic hypoglossal
neuropathy (unilateral)
" Organophosphates
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
lations. When tongue fasciculations
A Extremely useful
are present, they are generally quite
diagnostic
obvious and have a characteristic signs in ALS
multifocal distribution involving the are tongue
entire tongue and the appearance of fasciculations
small wriggling or dimpling under the and tongue
tongue surface. Observation of the weakness.
tongue for the presence of fascicula-
tions 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 de-
grees of tongue weakness and atro-
phy. Weakness of the tongue may be
present without fasciculations if bul-
bar weakness is due to UMN degen-
eration.
Weakness of the tongue is an ex-
tremely 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 out-
side the cheek. The tongue weakness
in ALS tends to be symmetric. Some 21
ALS patients with advanced bulbar dis-
ease cannot move their tongue volun-
tarily at all. However, it is possible
to have moderately advanced disease
without significant tongue involve-
ment if the patient has mostly spinal
disease. In bulbar disease with a prom-
inent 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.
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 " SUSPECTED MYASTHENIA GRAVIS OR ALS
KEY POINTS
Although facial weakness is not
A The presence
classically considered to be a charac-
of pathologic
teristic sign in ALS, it may be present,
reflexes such as
hyperactive particularly in more advanced disease.
muscle stretch The finding of facial weakness in ALS
reflexes, is potentially helpful because one of
Hoffmann sign, the important differential diagnoses
Babinski sign, of ALS is cervical spinal stenosis, and
and crossed clinical findings above the neck, such
adductor as facial weakness, tongue weakness,
reflexes can aid or dysarthria, can rule out this possi-
in the diagnosis bility. As in MG, the facial weakness
of ALS.
in ALS tends to be symmetric, but
A The limb unlike MG, in most cases, it is not
weakness in present until later in the disease
ALS more course. One way to test lower facial
commonly muscle strength is to have the patient
presents puff out the cheeks. Normally, one
distally and
should be able to hold some resis-
asymmetrically.
tance to this maneuver. For upper
A Weakness in ALS facial weakness, squeezing the eyes
is segmental, tightly shut while the examiner
meaning that it attempts to open the lids is another
may start focally helpful bedside test. More severe facial
involving one or
weakness and characteristic facial fas-
two myotomes.
ciculations in a patient with a more
A A hyperactive chronic disease course suggest the
gag reflex, an diagnosis of X-linked bulbospinal neu-
increased jaw ronopathy (see the chapter Clinical
jerk, or a positive Spectrum of Motor Neuron Disorders).
snout reflex
The presence of pathologic reflexes
can help to
such as hyperactive muscle stretch re-
localize UMN
dysfunction
flexes, Hoffmann sign, Babinski sign,
above the and crossed adductor reflexes can
aid in the diagnosis of ALS, especially
22 cervical
spinal cord. when LMN signs such as atrophy or
fasciculations are located in the same
A Respiratory muscle
body region. Relative preservation of
compromise may
reflexes (nonpathologic) in the distri-
be present before
the patient bution of severe muscle weakness and
becomes overtly atrophy is also a sign of UMN dysfunc-
symptomatic. tion. A hyperactive gag reflex, an in-
creased jaw jerk, or a positive snout
reflex can help to localize UMN dys-
function above the cervical spinal cord.
Limb weakness. Unlike in MG
where limb weakness usually affects
proximal muscles relatively symmetri-
cally, the limb weakness in ALS can
present in any muscle group, but
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more commonly presents distally and
asymmetrically in a limb, eg, with a
weak and atrophic hand or footdrop.
Weakness in ALS is segmental, mean-
ing 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 radiculop-
athy clinically and electrodiagnosti-
cally, except for the relative absence
of pain and sensory symptoms. A
further discussion of the character-
istics of limb weakness in ALS appears
later in this chapter.
Respiratory muscle weakness. ALS
affects the diaphragm and intercostal
muscles, and weakness in these mus-
cles is obviously of critical importance.
Orthopnea or dyspnea with exertion
is typically the initial symptom of
respiratory muscle weakness in ALS.
However, respiratory muscle compro-
mise is often present before the pa-
tient becomes overtly symptomatic,
presenting with nocturnal oxygen de-
saturations, daytime fatigue, or sleep
disturbances. Some patients never feel
short of breath despite significant ven-
tilatory 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 inspira-
tory sniff and cough as a test of
inspiratory and expiratory muscle func-
tion respectively. Protrusion of the
abdomen against resistance may also
be helpful as a rough bedside indica-
tion 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 weak-
ness is not likely to fluctuate, and ALS

patients are less likely to have signif-
icant facial weakness, at least in the
earlier stages. Occasionally, patients
with ALS are diagnosed only after they
are unable to be weaned from a ven-
tilator. This unfortunate situation may
occur for the patient who presents
with more focal diaphragmatic weak-
ness or occasionally in the elderly
patient whose weakness or walking
difficulties are dismissed as features of
old age. Right heart failure can devel-
op 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 weak-
ness, atrophy, and fasciculations of
the tongue. Typically both UMNs and
LMNs are involved, producing a mixed
spastic and flaccid dysarthria. A discus-
sion contrasting the features of dysar-
thria and dysphagia due to ALS and
MG can be found later in this chapter.
Cognitive impairment and behav-
ioral changes. Although the degener-
ative 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 associ-
ated with ALS in approximately 3% to
5% of cases (Lomen-Hoerth et al,
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KEY POINTS
2004). In most patients, the cognitive
A When bulbar
impairment manifests as mild frontal
muscles are
lobe dysfunction that may lead to involved in ALS,
poor judgment, difficulty with prob- a characteristic
lem solving, and inattention, while mixed spastic and
memory and praxis remain relatively flaccid dysarthria
intact (Murphy et al, 2007). Patients is typical.
may display disinhibited behavior,
A Frontotemporal
obsessive-compulsive behavior, or may dementia is
become withdrawn and disinterested. associated with
Often, in milder cases of cognitive ALS in about 3%
changes, the patient and family are to 5% of cases.
unaware of any impairment. Speech Mild cognitive
dysfunction often coexists with the impairment
cognitive impairment, thus making the occurs in up to
recognition of the cognitive change 22% to 35% of
more difficult. patients with ALS.
Truncal weakness. Weakness in ALS A Occasionally loss
may affect the thoracic body region or of core muscle
core muscles. The signs and symptoms strength in
of this may include difficulty keeping patients with
the body erect, difficulty sitting up in ALS can lead to
bed, incoordination, and even pelvic gait imbalance,
misleading the
floor weakness. Occasionally loss of
clinician to
core muscle strength can lead to an
suspect primary
apparent gait imbalance because of an cerebellar
inability to stabilize the core muscles dysfunction.
while walking. This may mislead the
unwary clinician to suspect coexistent A Weight loss
is a common
primary cerebellar dysfunction, but in
symptom in ALS
ALS there are no additional signs of
and may have
cerebellar dysfunction such as limb multiple causes,
ataxia or nystagmus. Additional signs including
of truncal involvement may include malnutrition,
absent superficial abdominal reflexes
and fasciculations on the abdomen
loss of muscle
mass, and a
23
and back. hypermetabolic
History of weight loss. Weight loss state.
is a very common symptom in ALS.
Weight loss may occur on the basis of
malnutrition caused by severe swal-
lowing 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
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 " SUSPECTED MYASTHENIA GRAVIS OR ALS

KEY POINTS
origin of this hypermetabolic state is and MG may present with dysarthria
A A hallmark of ALS
uncertain, but it may occur in as many and/or dysphagia, fatigability, and limb
is the relative
absence of as 50% of patients with ALS (Desport or axial weakness. Clinical clues that
sensory et al, 2005). can help to accurately determine the
symptoms Mild sensory symptoms. A hallmark cause of these symptoms and signs as
and findings. of ALS is the relative absence of caused by ALS, MG, or some other
However, about sensory symptoms and findings. A disorder are presented later in this
one-third of recent report, however, indicates that chapter.
patients with ALS about one-third of patients with ALS
report some report some mild sensory symptoms Prominent Dysarthria/Dysphagia
mild sensory (Hammad et al, 2007). This is generally Patients presenting with reports of dys-
symptoms.
in the form of mild distal sensory loss. arthria and/or dysphagia may have
A When double Often the symptom will be present, central or peripheral nervous sys-
vision and but the sensory examination will be tem disease. The neurologic differen-
ptosis are not entirely normal. Sural sensory con- tial diagnosis for this complaint is long
clearly present duction studies may be abnormal in (Table 1-5). In particular, patients who
and the patient approximately the same proportion present with isolated slowly progres-
is antibody
(one-third) of patients, and in the sive dysarthria with or without dyspha-
negative,
study of Hammad and colleagues (2007) gia can be diagnostically challenging,
making the
a pathologic loss of large myelinated and both ALS and MG are diagnostic
correct
diagnosis of fibers was observed in over 90% of possibilities in these patients. After
MG may be patients who had sural nerve biopsies. structural CNS causes are ruled out by
a challenge. It is unclear whether these findings
are the result of normal aging process-
A ALS and MG may
es or whether there is a true associa-
both present TABLE 1-5 Neurologic
tion with the underlying degenerative Differential
with dysarthria,
dysphagia, process. Diagnosis of
fatigability, and Dysarthria and
Dysphagia
limb or axial
weakness. DISTINGUISHING FEATURES OF
ALS AND MYASTHENIA GRAVIS " CNS Disease
A Ptosis and ON CLINICAL PRESENTATION Brainstem lesion
extraocular
muscle The most common presenting symp- Cerebrovascular disease
weakness clearly toms in MG are double vision (or (pseudobulbar palsy)
blurred vision) and ptosis. Ocular find-
24 distinguish MG
from ALS as ings such as these clearly distinguish
Syringomyelia

the ocular MG from ALS, as the ocular muscles are " Neuromuscular Disease
muscles are spared in ALS. However, when double Bulbar presentation of ALS
spared in ALS. vision and ptosis are not clearly pres- Kennedy disease
ent, making the correct diagnosis may
be a bit more challenging as illustrated Bulbar polio
by Cases 1-1 and 1-2. Additionally, Myasthenia gravis
10% to 15% of patients with MG will Botulism
be anti-acetylcholine receptor (AChR)
Myopathy
negative, and up to 60% of these
patients will also be MuSK-antibody Neuropathy such as
negative (see the chapter Myasthenia Guillain-Barre syndrome
or chronic inflammatory
Gravis: Immunopathogenesis, Diag-
demyelinating polyneuropathy
nosis, and Management), often leav-
ing the diagnosis in question. Both ALS

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 KEY POINTS

Case 1-1 A It is more typical

A 57-year-old woman presented reporting an inability to lift her head for a patient with
off her chest and shortness of breath with exertion for the past 4 to ALS as opposed
5 months. She had no significant medical history. She denied double vision to MG to present
or blurred vision, droopy eyelids, speech or swallowing difficulties, or limb with isolated
weakness. She was diagnosed with MG at an outside institution after bulbar findings
an edrophonium (Tensilon) test and was reportedly responding to because of the
pyridostigmine treatment (60 mg every 6 hours) with a subjective segmental nature
improvement in neck strength and breathing. Recently, however, the of the disease
pyridostigmine was noted to be less effective. AntiAChR-binding (progressive
antibodies were reportedly negative. Repetitive nerve stimulation bulbar palsy).
(RNS) performed in a hand muscle and on the trapezius muscle was normal, A In ALS, there is
but single fiber EMG (SFEMG) performed on the extensor digitorum usually a spastic
communis muscle showed an increased mean jitter. MRI of the cervical quality to the
spine showed mild disc bulges and osteophytes at several levels but no speech. Therefore,
evidence of cord or nerve root compression. the speech is
Physical examination revealed a respiratory rate of 12 breaths per slow, effortful,
minute, a normal mental status, and normal cranial nerve function with and has a harsh
the exception of a head drop with neck extensor strength graded at or strangled
3/5 and neck flexor strength graded at 4-/5. She had mild symmetric vocal quality.
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
25
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 gia in ALS are typically nonfluctuating

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 compo-
nent while the dysarthria and dyspha-
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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 " SUSPECTED MYASTHENIA GRAVIS OR ALS

KEY POINT
A In MG, the Case 1-2
dysarthria is A 74-year-old man with a diagnosis of MG was transferred from an outside
typically flaccid facility for further management. He was in his usual state of health until
and hypernasal 2 months previously. At that time, he developed dysphagia and shortness
with lingual and of breath. He was admitted to an outside hospital where he required
labial dysfunction. 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 patients seropositivity had been
based on elevated AChR-blocking antibody titers, which when repeated
were found to be in the normal range. AntiAChR-binding antibody titers
were not elevated. He was diagnosed with ALS.
26 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 antiAChR-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 fluctuating character throughout the

and consistently present with less of a course of the disease. It is more typical
fluctuating nature. The dysarthria in for a patient with ALS than a patient
MG typically maintains its fatigable and with MG to present with isolated

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bulbar findings because of the seg-
mental 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 re-
flexes and normal muscle bulk, can
often lead to the diagnosis. An impor-
tant 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 combina-
tion 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
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KEY POINTS
Bilateral damage of the UMNs of the
A The speech can
pyramidal tracts imparts a spastic
be slurred in MG,
quality to the speech. Therefore, the but generally the
speech is slow and effortful and has a cadence is normal
harsh or strangled vocal quality. The in contrast to
patient with ALS may also display slow ALS, where
arduous movements of the tongue in speech is typically
addition to tongue weakness. Tongue slow due to
atrophy and fasciculations may or may upper motor
not be present in the ALS patient with neuron
tongue weakness, depending on the involvement.
degree of UMN versus LMN involve- A Patients with MG
ment. In contrast, in MG the dysarthria may have tongue
is flaccid, and myasthenic speech often weakness but
has a nasal quality resulting from the do not show
presence of palatal weakness. There is the slow
no spastic quality to the speech as the arduous tongue
movements seen
UMN is not involved in MG. The
in many patients
speech is slurred in MG, but generally
with ALS.
the cadence is normal, and patients
with MG do not show tongue atrophy A An early symptom
of dysphagia or
or fasciculations. Patients with MG
may have tongue protrusion weakness pharyngeal
weakness in ALS
but do not show the slow arduous
is the inability to
tongue movements seen in ALS.
effectively clear
Dysphagia may be a presenting
the throat of
symptom in MG and ALS, and distin- mucus.
guishing features of the dysphagia
seen in these two disorders are given A Patients with
MG tend to
in Table 1-7. An early symptom of
regurgitate
dysphagia due to pharyngeal weak-
through the nose
ness in ALS is the inability to effectively due to palatal
clear the throat of mucus. Often weakness or into
patients will describe a nagging feeling the oral cavity
that phlegm is stuck in the throat and
they cannot clear it. Some patients
from upper
esophageal
27
may refer to this as a tickle in weakness.
the throat. In contrast, this is not a
common symptom in MG. More com-
monly, patients with MG will have a
tendency to regurgitate through the
nose because of palatal weakness or
into the oral cavity from upper esoph-
ageal weakness (Colton-Hudson et al,
2002).
Head Drop
Table 1-8 shows the differential diag-
nosis for a patient presenting with
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 " SUSPECTED MYASTHENIA GRAVIS OR ALS

KEY POINTS
cervical myotomes. Since both the
A Head drop in TABLE 1-7 Clinical
Characteristics phrenic nerve and nerves that in-
ALS is often
associated with of Dysphagia nervate the neck extensor muscles
diaphragmatic originate from the upper cervical
weakness " Myasthenia Gravis segments, associated diaphragmatic
because of Nasal or oral regurgitation
weakness will often be present. For
the fact that more common this reason, head drop can be an
both the ominous sign in ALS.
phrenic nerve Chewing and swallowing
worse toward the end
and nerves that Limb Weakness
of the meal
innervate the The clinical features of limb weakness
neck extensor Difficulty initiating swallowing
(Wont go down)
in patients with MG versus patients
muscles
with ALS are summarized in Table 1-9.
originate Multiple swallows required
from the
When a patient with ALS presents
(Food gets stuck)
upper cervical with limb weakness, the dysfunction
Significant weight loss is generally very apparent on the
segments.
uncommon examination and often associated with
A When a patient
Rarely an isolated symptom prominent muscle atrophy, fascicula-
with ALS
" ALS tions, and/or hyperreflexia. Elicitation
presents with
of a reflex, even a normal reflex
limb weakness, Difficulty clearing throat
the dysfunction in a weak and atrophic muscle is an
of secretions
is generally very abnormal finding and indicates UMN
Nagging phlegm in throat
apparent on
the examination Progressively increasing
and is often meal duration TABLE 1-8 Differential
more severe Drooling
Diagnosis of
and widespread Head Drop
than reported. Choking
Associated weight loss " Myasthenia gravis

May be presenting symptom " ALS

" Parkinson disease and
parkinsonism
" Inflammatory myopathy
head drop. Head drop can be the (polymyositis, inclusion-body
presenting symptom in ALS or MG. It myositis)
28 can also be the presenting symptom in " Chronic inflammatory
isolated neck extensor myopathy. It is demyelinating polyneuropathy
far less common for head drop to be
" Isolated neck extensor
the presenting or sole manifestation myopathy
of the other diseases listed in the
differential diagnosis in Table 1-8. " Congenital muscular
dystrophy (mutations in
Generally speaking, when head drop LMNA or SEPN1 genes)
is seen in MG, other signs or symp-
toms, such as ptosis, extraocular mus- " Congenital myopathy
(nemaline myopathy)
cle weakness, facial weakness, or
fatigable limb weakness, usually lead " Hypothyroidism
one to the correct diagnosis. Since ALS " Syringomyelia
affects the anterior horn cells in a
" Postmantle irradiation
segmental fashion, head drop would
indicate involvement of the upper

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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 mus-
cle 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-
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
ing segmental weakness bilaterally
A The patient
but asymmetrically. Also, if a patient
with MG may
with ALS complains of weakness, the complain of
patient almost invariably will have severe weakness
an abnormal manual muscle strength and fatigue that
examination. In addition, it is not un- cannot be clearly
common to find weakness on ex- demonstrated
amination that the patient did not on physical
realize was present. The contrary is examination.
often true in MG, as patients may Fatiguing
complain of severe weakness and maneuvers must
often be utilized
fatigue that cannot be clearly demon-
in the clinic in
strated on physical examination. Fatigu-
order to elicit this
ing maneuvers must often be utilized weakness.
in the clinic in order to elicit this
weakness on the physical examination. A The most common
Limb weakness in ALS can occur presentation of
limb weakness
in any muscle group, but the most
in ALS is
common presentation of limb weak-
asymmetric distal
ness in ALS is asymmetric distal
limb weakness,
limb weakness. For example, weak- eg, weakness
ness and wasting of intrinsic hand and wasting of
muscles (both median-innervated and intrinsic hand
ulnar-innervated muscles) in a unilateral muscles (both
or asymmetric fashion is a typical median-
presentation. Alternatively, footdrop is innervated and
ulnar-innervated
also a common presentation. Foot-
muscles) in a
drop in ALS can be distinguished from
peroneal mononeuropathy or lumbar unilateral or
asymmetric
radiculopathy by the lack of associated
fashion, or
pain or sensory symptoms. There is also
unilateral or
usually weakness outside of the pero- asymmetric
neal or L4-5 distribution, UMN reflex footdrop.
changes, or more widespread changes
on EMG than would be suspected with A Symptoms of
a mononeuropathy or isolated lumbar bladder 29
dysfunction,
radiculopathy.
such as urinary
urgency and
Bowel and Bladder Function
dribbling, may
In most instances, bowel and bladder occur in ALS,
function are spared in ALS and MG. but frank urinary
However, despite the fact that the incontinence is
classic teaching is that bowel and not present.
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 weak-
ness. Frank incontinence, however,
is generally not present until late in
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 " SUSPECTED MYASTHENIA GRAVIS OR ALS

KEY POINT
the disease course. Constipation tends
A Constipation
to be a common problem in patients
is a common
symptom in ALS with ALS and is likely multifactorial. It is
and has multiple often difficult for a patient with ALS to
potential causes. 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 evac-
uation may be similarly affected.
The signs and symptoms of ALS and
MG are compared and contrasted in
Table 1-10.

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 ++ May be present with
low FVC normal or low FVC
Head drop +++ ++

30 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 activity-
dependent 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 hypoventila-
tion. Earlier in the disease course, when
dysfunction is limited to a particular
body region or myotome, patients
with ALS may have true fatigable mus-
cle weakness with symptoms that
worsen with use of the affected mus-
cle and improve with rest. This pattern
may occasionally be seen in patients
with initially isolated bulbar palsy, mak-
ing 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 neuromus-
cular transmission in MG. However,
emphasis should be placed on the
importance of performing conven-
tional needle EMG and sensory and
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
motor NCS in patients suspected of
A Abnormal
MG before proceeding to more spe-
findings on
cialized tests. This is because RNS and repetitive nerve
SFEMG abnormalities are relatively stimulation and
nonspecific. Other primary disorders single fiber EMG
affecting the nerve or motor neuron are relatively
and even muscle may show abnormal- nonspecific and
ities on RNS and/or SFEMG that may may be seen in
be mistaken for MG. For example, neurogenic
abnormal decremental responses on conditions
RNS and increased jitter on SFEMG associated
with ongoing
may both be present in patients with
reinnervation,
motor neuron disease (Case 1-1). As
such as ALS.
noted, this is explained by the fact that
in motor neuron disease, reinnervat- A In MG, the
ing NMJs have impaired neuromus- conventional
cular transmission because of the nerve conduction
studies and EMG
immaturity of the reinnervating nerve
are typically
terminal. In a more rapidly evolving
normal, while in
motor neuron disease such as ALS, a primary nerve or
higher number of NMJs probably are muscle disease,
either actively reinnervating or recent- the conventional
ly denervated, increasing the likeli- nerve conduction
hood of finding a secondary defect of studies and
neuromuscular transmission. In MG, EMG usually
however, the conventional NCS and reveal the primary
EMG studies are normal, while in abnormality.
primary neurogenic or myopathic con-
ditions, 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.
31
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 evi-
dence 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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 " SUSPECTED MYASTHENIA GRAVIS OR ALS

KEY POINTS
See Table 1-11. In the context of ALS,
A In early spinal TABLE 1-11 Pattern of
electrodiagnostic testing can favor the Electrodiagnostic
ALS, EMG
abnormalities diagnosis of ALS by showing multi- Findings in ALS
may mimic a segmental active denervation (dener- and Myasthenia
radiculopathy. vation in cranial, cervical, thoracic, Gravis
Multisegmental and/or lumbosacral body regions) that
denervation localizes proximal to the dorsal root " ALS
may not ganglia, ie, sparing sensory nerve con- EMG confirmation depends
become duction potentials. Recent recommen- on multisegmental neurogenic
apparent until dations advocate attributing equivalent involvement (cranial, cervical,
later in the thoracic, and/or lumbosacral
significance to fasciculation poten-
disease course. body regions) in the absence
tials as fibrillation potentials in recog- of another cause to explain
A In the case of nizing denervation (de Carvalho et al, such findings
bulbar-restricted 2008). These findings are not specific
Early spinal ALS can mimic
ALS, the EMG for ALS as polyradiculopathy may radiculopathy
may be normal have the same electrodiagnostic ap-
or near normal. Can be normal or near normal
pearance. In early spinal ALS, EMG
This is especially in bulbar-restricted ALS
abnormalities may mimic those of a
true if the May show a decrement on
focal radiculopathy, and multisegmen-
patients bulbar repetitive nerve stimulation
tal denervation may not be apparent
symptoms are studies
predominantly until later in the disease course. Also,
in the case of bulbar-restricted ALS, Typically shows normal sensory
caused by upper conductions but can be
motor neuron the EMG may be normal or near
abnormal in up to one-third
degeneration. normal. This is especially true if the of patients.
patients bulbar symptoms are pre-
A EMG is helpful Motor conduction studies
dominantly caused by UMN degenera-
in the diagnosis can be low amplitude, and
of ALS when tion. In this case, even EMG of the F waves can be borderline
asymptomatic tongue may not show clear abnormal- prolonged
body regions, ities. EMG of the sternocleidomastoid
" Myasthenia Gravis
or body regions muscle has a similar sensitivity com-
showing only pared to the tongue in patients with Decrement on repetitive
nerve stimulation may or
upper motor bulbar symptoms and should be exam-
may not be present and is
neuron signs ined if the tongue is normal. It is more likely present in weak
clinically, reveal important to keep in mind, however, muscle; proximal muscles are
evidence of that an abnormal EMG in a cranial- more sensitive
32 denervation. It
innervated muscle may also be caused
is recommended, Abnormal jitter on single
by a structural or infiltrating lesion of fiber EMG is seen in 95%
therefore, that
cranial, cervical,
the lower brainstem, which should be of patients, if two or more
investigated with the appropriate neu- muscles are tested
thoracic, and
lumbosacral roimaging studies. Single fiber EMG is abnormal
body regions EMG is most helpful in the diagno- in weak muscle
be examined sis of ALS when asymptomatic body Conventional EMG is normal
thoroughly in regions show abnormalities that add
Conventional nerve
all patients with to the distribution of LMN dysfunction
conduction studies are normal
suspected ALS. demonstrated clinically. It is recom-
mended, therefore, that cranial, cervi-
cal, thoracic, and lumbosacral body
regions be thoroughly investigated Acetylcholinesterase Inhibitors
(generally unilateral is sufficient) in A clinical response to edrophonium
all patients with suspected ALS. or to treatment with pyridostigmine

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 KEY POINTS
(Mestinon) is supportive evidence in able. As detailed in the chapter Myas-
A A clinical response
favor of the diagnosis of MG (see the thenia Gravis: Immunopathogenesis,
to edrophonium
chapter Myasthenia Gravis: Immuno- Diagnosis, and Management, AChR- or to
pathogenesis, Diagnosis, and Manage- modulating antibodies occur in about treatment with
ment). However, a clinical response 3% to 4% of patients with MG who pyridostigmine
to cholinesterase inhibitors can occur are antiAChR-binding antibody nega- (Mestinon) is
in a variety of conditions and therefore tive, while AChR-blocking antibodies supportive of a
is not entirely specific for MG. Any occur in about 1% of patients who are diagnosis of MG.
condition causing impaired neuromus- antiAChR-binding antibody negative. However, a
cular transmission has the potential to False-positives may occur with these clinical response
respond positively to cholinesterase tests, so they should be interpreted to cholinesterase
inhibitors can
inhibitors. This includes patients with with caution. Ideally, positive AChR-
occur in a
ALS particularly in the early phases of blocking or AChR-modulating antibody
variety of other
disease when reinnervation is actively test results should be confirmed with conditions
compensating for ongoing denerva- repeat testing or other confirmatory (including ALS)
tion and new NMJs are continually diagnostic evidence, such as electro- and therefore
formed by collateral sprouting. As diagnostic confirmation of a primary is not entirely
illustrated in Case 1-1, the response defect in neuromuscular transmission. specific for MG.
to cholinesterase inhibition in neuro-
CONCLUSIONS A A high titer of
genic disease is relatively short-lived
acetylcholine
and typically wears off as the disease The details of the clinical presentations receptor
progresses. form the basis of an accurate diagnosis (AChR)-binding
of autoimmune MG and sporadic ALS. antibodies is
Anti-acetylcholine Receptor While a number of diagnostic tests may highly specific for
Antibodies provide supportive data in favor of the MG in a patient
A high titer of antiAChR-binding anti- diagnosis, these tests are generally with signs and
bodies essentially confirms the diagno- nonspecific, with one notable exception symptoms
sis of MG in a patient with a clinical (antiAChR-binding antibodies) and ab- suggestive of
presentation suggestive of the disease. solutely must be interpreted in the the disease.
However, the
False-positive results are believed to context of the clinical picture. Certain
specificity of
be very rare. Other AChR antibody clinical presentations (ie, dysarthria, dys-
AChR-blocking
tests that measure the blocking of phagia, dropped head syndrome) may and AChR-
the acetylcholine binding site on the suggest either the diagnosis of MG or modulating
AChR (AChR-blocking antibodies) and ALS, but the correct diagnosis can usu- antibodies has
determine the effect of antibodies on ally be determined by a careful assess-
the turnover and expression of AChR ment of the clinical history, neurologic
not been
established, and
33
on muscle cells (AChR-modulating an- examination, and the judicious use of these tests should
tibodies) are also commercially avail- supportive diagnostic testing. be repeated
when positive
or the diagnosis
should be
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SUGGESTED ADDITIONAL READING

Phuken J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lateral sclerosis.

Lancet Neurol 2007;6(11):9941103.

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