INVITEDREVIEVV ABSTRACT: Myastheniagravis(MG)isasyndromeoffluctuatingskeletal

muscleweaknessthatworsenswithuseandimproveswithrest.Eye.facial.
oropharyngeal, axial, andlimb muscles may beinvolved in varying combi-
nations and degrees of severity. Its etiology is heterogeneous. divided
initially between those rare congenital myasthenic syndromes. which are
genetic, and the bulk of MG. which is acquired and autoimmune. The
autoimmune conditions are divided in turn between those that possess
measurableserum acetylcholine receptor(AChR) antibodiesandasmalier
groupthatdoesnot.ThelattergroupincludesthoseMG patientswhohave
serum antibodies to muscle-specifIC tyrosine kinase (MuSK). Therapeutic
considerationsdifferforearly-onsetMG,late-onsetMG,andMGassociated
with the presence ofa thymoma. Most MG patients can betreated effec-
tively. butthereisstilla needformorespecifiC immunologicalapproaches.
Muscle NeNe 29:484-505.2004
CLINICAL EVALUATION AND MANAGEMENT OF
MYASTHENIA GRAVIS
JOHNC. KEESEY, MD
Department of Neurology, UCLA School of Medicine, Los Angeles. California, USA
Accepted 8January 2004
"Myasthenia gravis pseudoparalytica (general-
isata)" was the name recommended by Friedrich
Jolly at the meeting of the Berlin Society for Psychi-
atry and Nerve Disease on November 13, 1899, to
describe a peculiar condition of fluctuating weak-
ness described earlier byWIlhelm Erb of Heidelberg
in 1879, Hermann Oppenheim in Berlin in 1887, .
and Samuel Goldflam in Warsaw in 1893, all of
Whom emphasized the bulbar aspects of this condi-
tion.
B1
Jolly objected to his colleagues' terms that
emphasized the bulbar aspects, because, he argued,
more of the nervous system than the bulb or brain-
stem might be involved. Perhaps because he was the
Professor of Nervous Diseases at the University of
Berlin, his views prevailed that day in Berlin, and his
term (without "pseudoparalytica" or "generalisata")
was eventually adopted by the rest of the world, as
well. The condition finally came to be known as
myasthenia gravis (MG), a strange combination of a
Abbreviations:AChR. acetylcholinereceptor:eMS.congenitalmyasthenic
syndromes;HlA,humanleukocyteantigen; Mg,intravenous immunoglobu-
lins; MG.myastheniagravis;MRI.magneticresonanceimaging;MuSK,mus-
cle-specific receptor tyrosine kinase; RNS, repetitive nerve stimulation;
SFEMG. single-fiberelectromyography
Keywords:clinical; diagnosis;myastheniagravis;treatment
Correspondenceto: J. Keesey,1144IliffStreet.PacificPalisades.caJjfomla
90272;e-mail: jkeesey@ucla.edu
C 2004 WileyPeriodicals,Inc.
PubHshed online 16 March 2004 in Wiley InterScIence (www.interscience.
wiley.com).DOI10.1002!mus.20030
.",...-....,,\
Greek-derived word for "muscle weakness" and a
Latin word for "heavy" or "severe."
The neuromuscular junction became the focus
of the disease in 1935, when MaryWalker discovered
that physostigmine and later neostigmine (Prostig-
min), both inhibitors of the enzyme acetylcholines-
terase, provided effective temporary relief of the
symptoms of MG.66 Debates about whether the ab-
normalities at the neuromuscular junction were on
the nerve side or the muscle side of the neuromus-
cular junction continued until 1973, when Daniel
Drachman and colleagues demonstrated by radioac-
tive snake toxin binding that the number of muscle
acetylcholine receptors (AChRs) in human myas-
thenic muscles was reduced to 11-30% of that in
normal control muscles.lI6 Three years later, in
1976, Jon Lindstrom and associates showed that
85% of MG patients had measurable serum anti-
bodies to human muscle AChRs.80 Also in 1976,
the removal of immunoglobulin antibodies from
three MG patients by a series of daily plasma ex-
changes resulted in dramatic temporary improve-
ment in strength.
ll9
In 1977 passive transfer of
immunoglobulin antibodies from MG patients to
mice was shown to reproduce the disease in
mice,I55 evidence that MG is an antibody-mediated
autoimmune disease. In light of recent develop-
ments,however, it should be noted that the latter
two studies did not identify the specific antibodies
that cause the weakness.
69
484 MyastheniaGravis MUSCLE&NERVE April 2004
late-onsetdisease, andthepresenceorabsenceofa
thymoma, serumAChRantibodies, andserumanti-
bodiesotherthan those bindingtheAChR.
Acquired versus Congenital Myasthenia. An ac-
quired transient weakness tenned "neonatal myas-
thenia," attributed to antibodies crossing the pla-
centafrommothertofetus, occursinabout12% of
infantsborntomotherswithautoimmuneMG.7.110A
myasthenicchildborn to a motherwithoutautoim-
muneMGmayhaveoneofa rapidlygrowinglistof
rarecongenitalmyasthenicsyndromesthathavenow
beenseparatedinto genetic defects ofpresynaptic,
synaptic, or postsynaptic neuromuscular transmis-
sion (Table1).Someoftheconditionshavecharac-
teristic clinical presentations.
98
,106 Although occa-
sionally patients with congenital myasthenia reach
near-adulthoodbefore the congenital natureofthe
myasthenia is recognized, the onset ofcongenital
myasthenicsyndromesusuallyoccursbefore2years
ofage.
72
However, acquired autoimmune myasthe-
niahas beenidentifiedas early as 1year ofage.I!l7
Thus, thedistinctionbetweenacquiredandcongen-
ital myasthenia is a particularproblemin the pedi-
atric age group. Familial autoimmune MG, with
AChR antibodies in a majority ofrelated patients,
hasalsobeenreported.l,!l4
SexandAge. Myastheniagraviscanoccuratanyage
from birth to the tenth decade. The peakages of
onset ofacquired MG in females are between the
teens and the thirties, whereas in males they are
between 50 and 70 years ofage.
ll5
However, the
curves ofonset age are both bimodal,145 with an
early-onset group and a late-onset group for both
sexes (Fig. 2).Theearly-onsetautoimmuneMG (be-
Table1.Congenitalmyasthenicsyndromes.
Anatomicalsite Defect
Presynaptic Defectiveacetylcholinesynthesisorpackaging
(episodiCapnea, ''familialinfantilemyasthenia,"
abnormalcholineacetyltransferase)
Reduced quantalreleasewith/withoutsynaptic
vesicles
DefICientacetylcholinereleasebynerveimpulses
Lambert-Eaton-likesyndrome
Synaptic Endplateacetylcholinesterasedeficiency
Postsynaptic Decreasedresponsetoacetylcholine:
acetylcholinereceptorsubunitmutations;
rapsynmutatfons(recaptorclustering);
fast-channelsyndromes
Increasedresponsetoacetyicholine:
slow-channelsyndromes
Plectindeficiencywithepidermolysisbullosa
MUSCLE&NERVE April 2004 485
100
.. ~ andIIIldoIradIe8IIn1uba11an
90
80
I
70
,
60
~
50
40
:i
30
If!.
20
10
0
1900 10 20 30 40 50 80 70 80 90
Year
FIGURE1.Thecurveplottingpercentmortalityfrommyasthenia
gravis (open circles) from 1905 to 1985is labeled with various
therapeuticadvancesintheyearsthattheywereinstituted.Also
plottedisthecurveofknown prevalenceofMG (closedcircles),
which increased as diagnOSis improved. Percentmortality from
MG decreased with diagnosis and inclusion of less severely
affectedpatientswhosurvivedanddecreasedfurtherwithuseof
endotrachialintubation,assistedventilation,antibiotics, and ste-
roids. (Reproduced from Grob.
43
From Myasthenia Gravis and
Myasthenic Disorders, edited byAndrewEngel, copyright1999
byOxford University Press, Inc. Used bypermission ofOxford
UniversityPress, Inc.)
By theendofthe 1970s,mostpatientssuffering
from fluctuatingweakness andfatigue ofeye, limb,
orbulbarmusclescouldbeidentifiedasvictimsofan
acquiredautoimmune reaction attheneuromuscu-
larjunctions.Bycontrast,amuchsmallergroupwas
then realized to have one ofseveral inherited non-
immune neuromuscular junction disorders. This
knowledge, as wellas respiratorysupportandinfec-
tioncontrol(Fig. 1),providedseveraleffective treat-
mentsfor bothgroups, so thattheoutlookfor my-
astheniapatients todayisusuallynotas "gravis" as it
wasinJolly'sday,whentheircounterpartsfrequently
died from respiratory muscle weakness. Indeed,
someexpertshavesuggested thattheacquiredcon-
ditionshouldnowbecalled"autoimmunemyasthe-
nia"insteadof myastheniagravis, contrastingitwith
the various rare genetic disorders that are tenned
"congenitalmyasthenicsyndromes."
MYASTHENIA GRAVIS AS A HETEROGENEOUS
SYNDROME
The difference between autoimmune andcongeni-
talmyastheniaisonlyoneofseveraldistinctions that
can be made among patients with MG. Others in-
cludeageofonsetinthetwosexes,early-onsetversus
MyastheniaGravis
100 -
90 I
c:
80 ,g
70 ~
....
60
It
C!J
50
::!
Q
-
40
~
SO
II)
20 ~
Q.
10
c
g

0
~
120
-Males
100
.,
80
4)
20
0
..
.
,
.
,
,
,
.
,
,
'.,
l
,
.
,
.
.
,
.
,
-
<10 10.18 2t 3Nt .... ..1D-79 >110
Age Onset
FIGURE 2. The age ofonset. within decades, of symptoms of 906
patients with acquired myasthenia gravis andno thymoma. The
bimodal curves for males (open squares and solid line) and
women (closed diamonds and dottedline) suggest the presence
of early onset MG and late-onset MG for both sexes. (Repro-
duced from Sanders et al.
l29
With permission of Uppincott Wil
Iiams & Wilkins.)
lowtheageof40years
22
or50years
l45
) isassociated
withhumanleukocyteantigen (HLA)-B8andDRw3
among Caucasian MG patients, whereas latcx>nset
MG (over 50 years
I
) is associated with a variety of
otherHLA markers. A separate, thirdgroup, com-
prising10-15%ofallMGpatients,consistsofthose
MGpatientswhoalsohaveathymoma,anepithelial
tumor ofthe thymus gland; the agcx>f-onset inci-
dencecurveforthepatientspeaksinthelateryears,
andthereis noHLAassociation.!Althoughthepre-
senting symptoms of old and young patients are
similar,patientsoverage50yearstendtoprogressto
moreseveredisease.
29
ThenumberofMGpatientsworldwidehasbeen
steadily increasing over time,us probably because
both thegeneralpopulation andMG patientshave
longer life spans (Fig. 1). Although the weighted
mean prevalence ofMG for the 1980-1989decade
was 60 per million,ll8 several recent studies from
various European countries and the United States
reponpointprevalenceratesofMG intherangeof
100 to 150 permillion population,lls and current
estimates place theprevalencein theUnitedStates
at about 200 per million.
llS
The number ofnew
patientsperyear-theannualincidencerate-alsois
rising. although perhaps not as fast as prevalence
rates.
llB
ArecentstudyfromSpainreponedanover-
all annual incidence rate of21 new MG cases per
millioninhabitants,witharemarkableincreasewith
age; anannualincidence ratefor MG patientsover
65yearsoldwas calculatedas 63permillionandwas
explainedby the general agingofthe population.l!
486 Myasthenia Gravis
Theoldestageof onsetforMGsofarreponedis98
years. 117
Ethnlcitr. TherearealsodifferencesbetweenAsian
andCaucasianpopulationsintheclinicalandimmu-
nological manifestations ofMG, theformer having
moreMG casesconfinedtotheextraocularmuscles
andupto30%of patientspresentingbeforetheage
of10 years.IS Thisjuvenilcx>nsetocularmyasthenia
inAsians is stronglyassociatedwith HLA-Bw46 and
DR9.46 Ingeneral, differentHLAassociations occur
inJapanese,94Indian,86.and Chinese
46
MG patients,
whodonotexpressthelatcx>nsetpeak.17
Seropositive and Seronegative Myasthenia: Discovery
of Anti-MuSK Antibodies. As mentionedearlier, 75-
90%ofpatientswithMGhavemeasurableantibodies
in their sera that bind to human muscle nicotinic
AChR.Il!9Thepresenceoftheseantibodies, together
with themeasuredloss ofAChRs in MG muscles,36
was convincing evidence that MG is an antibody-
mediatedautoimmunedisease.Attention turnedto
the10-25%ofseronegativeMG patientswhosesera
contained no measurable AChR antibodies. The
clinicalfeaturesofthetwogroupsweredescribedas
very similar,148 although the seronegative patients
weremorelikelytohavepurelyocularmyastheniaor
milderdisease.!29 Recentlylocalizedinvolvementof
muscleweakness,especiallyoftheface, tongue,and
pharynx, with associated muscle atrophy, has been
emphasizedinseronegative MG.159 Someseronega-
tive MG patients improvedwhen theywere treated
withplasmaexchange,9l!andimmunoglobulinsfrom
someseronegativeMGpatientswereabletopassively
transfer a distinct disease to mice. Neuromuscular
transmissionwassignificantlyimpaired,butantibody
was notboundtoAChRs, andAChRloss was mini-
mal.
9S
Theresultssuggestedthatsomecasesof sero-
negativeMGwerealsoantibody-mediatedbutbyan
antibody different from those directed toward the
acetylcholine receptor.
In 2001, 70% of24 serum samples from previ-
ouslyseronegativegeneralized patientswere re-
portedtocontainaserumantibodyagainstaprotein
on the muscle side ofthe neuromuscularjunction
otherthantheAChR, namelymuscle-specific recep-
tor tyrosine kinase (MuSK), which mediates agrin-
inducedclusteringofAChRs duringsynapseforma-
tion.
50
Thiswas confirmedin2002byareportfrom
Italy thatfound 13 of21 seronegative MGpatients
(62%) hadanti-PlIOantibodies, subsequentlyiden-
tifiedas anti-MuSKantibodies,1S4andagainin2003
fromtheUnitedStates,where 12 of32seronegative
patients (37%) had MuSK serumantibodies,131It is
MUSCLE & NERVE April 2004
FIGURE 3. The fluctuating nature of myasthenic weakness throughout the day, as measured every 2 h while awake over a 35-day period
by an MG patient. Each horizontal line represents a day, arranged in 5 weeks. Short vertical lines on the hOrizontal lines indicate the times
each day at which anticholinesterase medication was taken. The times of two plasmapheresis treatments (exchange #20 and exchange
#21) are also shown. The upper trace each day plots arm extension duration (in seconds), and the two lower traces plot grip strength of
each hand (in kilograms). (Reproduced from Keesey et al.
63
by permission of the New York Academy of Sciences.)
presumed that the MuSK antibody may be the cause
of MG in these patients, although the function of
MuSK in mature neuromuscular synapses is not
clear.
Initially, MuSK antibody-positive patients were
described as having "typical fatigable muscle weak-
ness,"5O but the Italians noted a distinct clinical pic-
ture of prominent ocular and bulbar involvement
with frequent respiratory problems,35.1s4 whereas the
third group in the United States did not find such a
clinical presentation but rather found prominent
neck, shoulder, or respiratory muscle weakness with
little or delayed ocular muscle involvement.
I30
At
present the clinical description of this small group
(9-10%) ofMG patients remains incomplete.
The new categories, however, all share the clini-
cal hallmark of fluctuating weakness of specific mus-
cles, made worse by use of those muscles and im-
proved at least partially by resting them. We
continue to call this clinical condition myasthenia
gravis, or MG. Unless the clinician thinks of the
possibility of MG, the whole train of confirming
diagnostic tests and effective treatments will not be
initiated.
RECOGNIZING CLINICAL PRESENTATIONS OF
MYASTHENIA GRAVIS
The distinctive fluctuating skeletal muscle weakness
of MG may vary from day to day or even from hour
to hour, usually increasing as the day progresses
(Fig. 3).63 In some patients, the weakness can also
fluctuate from muscle to muscle. Finding that mus-
cle weakness and its distribution vary from one ex-
amination to the next is helpful in making the clin-
ical diagnosis of MG. Usually muscle bulk is normal
in MG, but muscle atrophy can occur in isolated
muscles.72 Involuntary smooth muscles of the gut,
blood vessels, uterus, and the heart muscle are not
involved in MG. Deep tendon reflexes are typically
normal, and skin sensation is intact.
Different muscles may be predominandy affected
in different patients, so that a variety of clinical
presentations may occur. It is convenient to organize
Myasthenia Gravis MUSCLE & NERVE Apri12004 487
these signs and symptoms as they relate to eye, facial,
oropharyngeal, axial, and limb muscles.
Eye Muscles. Diplopia. Most MG patients have oc-
ular symptoms at the onset of their illness.l
44
The
patients notice fluctuating blurred vision or frank
diplopia, usually not present (if only for a few sec-
onds) immediately upon awakening. Diplopia occurs
initially during gaze laterally or upward, and it typi-
cally worsens while driving, watching television, or in
the evening. It goes away if one eye is closed. The
symptom may be caused by weakness of only one
extraocular muscle or of any combination of eye
muscles.
By comparison, patients with inherited neuro-
muscular diseases with which MG might be con-
fused-such as oculopharyngeal muscular dystro-
phy, myotonic dystrophy, or chronic progressive
external ophthalmoplegia-usually do not complain
of diplopia despite profound ophthalmoplegia,
probably because the eye muscle weakness is sym-
metrical and has progressed so slowly that the brain
has accommodated for the decreased ocular move-
ments.
Gaze ParesG. The possibility ofMG may be over-
looked if bilateral ophthalmoplegia comes on
acutely over less than 1 week.
5O
The eye muscle
weakness of MG may also mimic the internuclear
ophthalmoplegia and dissociated nystagmus charac-
teristic of a midline brainstem lesion, most com-
monly attributed to multiple sclerosis.I
46
Dysthyroid
ophthalmopathy may coexist with MG or be con-
fused with it.
H7
Thyroid eye disease is characterized
by static nonfluctuating diplopia and gaze paresis
(without ptosis), caused by swelling and weakness of
one or several eye muscles. detected by orbital mag-
netic resonance imaging (MRI) or ultrasound. Re-
stricted motion on forced ductions also can be help-
ful in differentiating dysthyroid myopathy from
extraocular muscle weakness.
Photophobia. A majority of MG patients. if
asked. will admit that bright light bothers them and
makes their eye muscles weak. Even untreated pa-
tients complain about bright light. so this symptom
cannot be completely explained by the prolonged
constriction-dilatation cycles found in MG treated
with anticholinesterases or prednisone.
77
Pupillary
responses are grossly normal in MG.
Ptosis. The patient may not notice painless pto-
sis unless it is severe. This is usually asymmetrical in
MG, affecting one eye more that the other. Not
infrequently, MG will present as ptosis of one eye
that resolves after a few weeks, only to occur later in
the other eye. This curious clinical presentation sug-
gests that factors other than circulating antibodies
must be involved, including perhaps variable ex-
traocular muscle blood flOW,I65 differential muscle
temperatures,53 or different muscle innervation
59
to
these muscles.
A very important clue to the diagnosis of MG is
asymmetrical ptosis that can be seen to fluctuate
during the physician's interview. Although ptosis in
facioscapulohumeral dystrophy may also be asym-
metrical, in most inherited neuromuscular diseases
(noted above) any ptosis is symmetrical and static. In
all these causes of ptosis, including MG, the patient
will try to compensate for levator palpebrae muscle
weakness by frontalis muscle furrowing. When MG
ptosis has been present for many years, it tends to
lose its fluctuating character. and only then should
ptosis surgery be considered.
Facial Muscles. Facial weakness can occur in MG
without ocular involvement,16 but usually the two
occur together. If facial sensation is impaired, a le-
sion affecting cranial nerves such as a nasopharyn-
geal carcinoma should be suspected. In the presence
of normal facial sensation. however, the occurrence
of both eye muscle weakness and facial weakness
strongly suggests MG. The findings may be quite
subtle (Fig. 4).m
Orbicularis Oculi Weakness. A very common sign
of MG is the inability of the patient to maintain
upper eyelid closure against the examiner's manual
efforts to open it. A good effort on the part of the
patient despite eyelid weakness will disclose the pres-
ence of Bell's phenomenon, the rotation of the eye-
balls upward during attempted eyelid closure. Be-
cause patients with blepharospasm of the orbicularis
oculi muscles may complain of difficulty keeping the
eyes open, the condition is sometimes confused with
myasthenic weakness.
1f1
There is usually no diplopia
or photophobia with blepharospasm, and eye clo-
sure is spasmodic and forced with simultaneous ele-
vation of the lower lid.
Orbicularis Oris Weakness. The inability of the
patient to prevent the escape of air through the
pursed lips when the examiner compresses the ex-
panded cheeks is a good sign of lower facial weak-
ness. Laughing reveals the so-called "myasthenic
sneer," so often termed a "snarl," but no sound
accompanies the myasthenic sneer. Such a patient is
unable to whistle, suck through a straw, or blow up a
balloon.
Oropharyngeal Muscles. Tongue Weakness. Slurred
speech and trouble swallowing can be caused by
tongue weakness, most easily assessed by the strength
488 Myasthenia Gravis MUSCLE & NERVE April 2004
FIGURE 4. Comparison of the facial appearance of two patients with MG who are trying to smile. (A) Facial weakness is obvious,
in that the comers of the mouth do not rise, the eyebrows are raised. and .the forehead is wrinkled in an effort to compensate for
partial right-sided ptosis and almost complete left-sided ptosis. (B) The patient (who had a thymoma) looks almost normal except
for a slight droop of the left eyelid and failure of the corners of the mouth to rise when she smiles. Although MG is usually illustrated
by an example such as the severely affected patient in (A), many more MG patients have subtle weaknesses such as those
illustrated by the subject in (9). (Reproduced from Patten.
113
This material is used by permission of Wiley-Liss, Inc., a subsidiary
of John Wiley & Sons, Inc.)
of the tongue pushing against each inner cheek. In
milder cases of MG, slurred speech may be detect-
able only during prolonged talking, such as toward
the end of an interview with a physician.
Hoarseness or articulate whispering is not typical
of MG. The tongue muscle is susceptible to atrophy
in MG,72 and the triple furrowed tongue is a mani-
festation of this atrophy.
Weakness in Chewing. Some patients with MG
may have difficulty in chewing because of weakness
of jaw closure (mainly the masseter muscles),
whereas thejaw openers remain strong. When weak-
ness is severe, thejaw may remain open and have to
be manipulated by hand during chewing.
Dysphagia. One of the most serious symptoms
of myasthenia is dysphagia from weakness of the
tongue and posterior pharyngeal muscles. (The
esophagus, a smooth muscle, is not involved in
human myasthenia, although esophageal d i l t ~
tion is characteristic of certain dogs with myasthe-
nia.l!I9) If pharyngeal muscle weakness is present,
liquids are more difficult to swallow than solids,
and hot food is more difficult than cold food.
Patients sometimes resort to using ice cubes to
obtain needed fluids. Nasal regurgitation of liq-
uids may be a problem if there is palatal muscle
weakness, which also causes nasal speech. Inability
to swallow saliva is the most severe consequence of
pharyngeal weakness and requires oral suctioning.
Once dysphagia has reached this severity, a feed-
ing tube is required not only for administration of
oral medications but also for nutritional supple-
mentation, because by this point inadequate food
intake has probably resulted in malnutrition, com-
pounding the weakness.
Axial Muscles. Neck Muscle Weakness. Muscle pain
is not a common symptom of MG, but painful mus-
cle spasms can occur in MG when weak neck muscles
are called upon to hold the head up. Neck flexors
are more commonly involved in MG than are neck
extensors. Severely affected supine patients have dif-
ficulty in lifting the head off the pillow.
Vocal Cord PcmiIysis. The airway may become
obstructed by closure of the glottis, caused by weak-
ness of the skeletal muscles holding apart the vocal
cords. The latter situation can be detected by stridor,
Myasthenia Gravis MUSCLE & NERVE April 2004 489
or "crowing," during attempted deep inspirations
and may forebode a rapidly developing medical
emergency requiring endotracheal intubation.
Respiratory Muscle Weakness. The most serious
symptom of MG is difficulty in breathing. A myas.'
thenic patient with respiratory insufficiency or the
inability to maintain a patent airway is said to be in
crisis.
67
Vocal cord paralysis can obstruct the airway,
but more commonly the airway is obstructed by se-
cretions that the patient is unable to remove because
coughing is too weak. Coughing requires forcible
use of muscles ofexpiration, and repetitive coughing
especially may rapidly become ineffective in MG.
Even if the airway is patent, muscles used for
inspiration, such as the intercostals and the dia-
phragm, may be too weak to create an adequate
negative inspiratory force -50 cm H
2
0) or vital
capacity (>20 ml/kg body weight). Such a patient
needs to be intubated and the respiration mechani-
cally assisted. Because of concomitant lack of facial
expression, the MG patient in crisis may not look.
distressed but will be restless with rapid shallow
breathing. Typically, such a patient sits bent forward
to maximize the effect of gravity on the diaphragm.
The incidence of crisis among patients with MG
has remained at about 15-20% over the years,IOS but
the reported mortality rate from crisis has declined
from 80% during the 19505 to 6% in the 19708
21
and
to 4% by 1994.
152
The decline in mortality can be
attributed to advances in the management of acute
respiratory failure and the gradually improving rec-
ognition of MG over the years (Fig. 1).
Even patients who are unaware of respiratory
problems may have respiratory muscle weakness that
interferes with their sleep and thereby causes them
to be tired and less attentive during the day.58 Some-
times a sleep study is useful in identifying such prob-
lems.
Pelvic Floor Muscle Weakness. This is an often
overlooked aspect of muscle weakness in MG. How-
ever, some female MG patients with urinary stress
incontinence claim that it is alleviated byanticholin-
esterase medication. Likewise, routine transurethral
resection of prostate tissue in myasthenic men often
leads to urinary incontinence.
42
If, as is usually done,
the proximal sphincter is removed during the sur-
gery, a weak external sphincter may not be able to
perform reflex contractions during cough or
strain.
IS2
Limb Muscles. Perhaps because warmer muscles
have less reserve for neuromuscular transmission,
proximal muscles tend to be involved more than
490 Myasthenia Gravis
distal muscles in MG,5!1 although the severity of in-
volvement is usually asymmetrical.
Proximal Upper-Extremity Weakness. Difficulty in
raising the arms to wash or brush the hair, dress,
apply cosmetics, or shave suggests shoulder and arm
weakness. Upper extremity muscle fatigue can be
tested semiquantitatively by timing the patient's abil-
ity to hold the arms forward in extension. Atrophy of
scapular and forearm muscles is characteristic of a
congenital slow-channel myasthenic syndrome.
32
Prm:imal Lower-Exi:remiIIy Weakness. Difficulty in
walking up stairs or for long distances is also com-
mon in MG. An occasional patient thought to have
limb-girdle dystrophy, with no weakness of muscles
innervated by the cranial nerves, will be discovered
instead to have MG.I05 Lower-extremity muscle fa-
tigue can be tested by asking the patient to cross one
leg over the other up to 50 times; immediate assess-
ment of the strength of the hip flexors will reveal
increased weakness of the active muscles in MG,
compared with the inactive side.
DiSto1 Limb Muscles. Finger extensor weakness,
although rarely symptomatic, is one of the most
common areas of weakness in MG.lol Distal lower-
extremity weakness (foot drop) also may occur.
General Fatigue. Fatigue is formally defined as a
reduced capacity for work following a period of men-
tal or physical activity.133 Even though fatigue and
weakness of specific muscles are characteristic of
MG, only a minority of MG patients complain of a
nonspecific generalized feeling of fatigue. Most MG
patients are motivated to do things, but their mus-
cles will not let them. During occasional good days,
they tend to overexert themselves and later have
increased or prolonged weakness.
In contrast, a feeling of always being tired is
common among the general population, second
only to pain as the most common symptom present-
ing to family practitioners.1
04
Although any chronic
medical disease may result in fatigue, only about 8%
of patients who complain of fatigue are found to
have medical causes of their symptoms; two thirds of
patients complaining of fatigue are said to suffer
from clinical depression.
slI
Many of the symptoms
accompanying affective disorders, such as drooping
eyelids or difficulty in breathing or swallowing, may
mimic those of MG. However, MG patients under-
standably also may become depressed about their
condition.
58
Therefore, it seems clinically important
to differentiate the fatigue of depression or mental
fatigue from physical fatigue. Mental fatigue is sup-
posed to be characterized by problems of alertrIess,
concentration, motivation, and integration,l60 symp-
MUSCLE & NERVE April 2004
tomstypicalofthecontroversialchronicfatiguesyn-
drome,inwhichobjectivemuscleweaknessissaidto
be absent.as Patientswith MGdo notusually mani-
fest such symptoms unless they are depressed or
theirsleep is disturbed by cryptic respiratoryprob-
lems.68
CUNICAL CLASSIFICATIONS OF MYASTHENIA
GRAVIS SEVERITY
Different combinations of muscle groups are af-
fectedinclifferentpatients,andtheseverityofweak-
ness ofparticularmuscles canvary in differentpa-
tients from barely discernible weakness to life-
threatening prostration. In addition, individual
patients differ in the rapidity with which the full
extent of muscle involvement becomes apparent.
Theextent,severity,andprogressionofMGallseem
importantparametersrelated to prognosisandthe
choiceoftreatments.
65
The traditional clinical classification of MGde-
vised by Osserman108 almost 50 years ago tried to
take all these aspectsinto account. First, Osserman
separatedpediatric myastheniaintoneonatal myas-
thenia (ininfantsofmyasthenicmothers) andjuve-
nilemyasthenia (ininfantsofnonmyasthenicmoth-
ers), andthenheseparatedadult-onsetmyasthenia
~
into myasthenia confined to eye muscles (group I,
ocular myasthenia) and generalized myasthenia.
Generalized myasthenia was divided into mild
(group llA), moderate (grouplIB), andsevere in-
volvement, and severe generalized myasthenia was
dividedintoacutesevere MGwithbulbarsymptoms
(groupIII) andlatesevereMGthatdevelopsatleast
2 years after onset (group IV). Group Vwas com-
posedofthosepatientswhoshowedmuscleatrophy.
The main problem with this classification, and
even with the recent one recommended by a Task
ForceoftheMyastheniaGravisFoundationofAmer-
ica,56 is the sul::gective and indefinite nature of
"mild,""moderate,"and"severe."Whatonepatient
regardsas mildincapacitationmightberegardedby
another as severe, and physicians are no more in
agreementaboutthese terms than theirpatients.
Furthermore, there is a sense among experi-
encedclinicians thatmainlyoropharyngealinvolve-
ment is a different and more dangerous kind of
myastheniathan isgeneralizedlimbweakness;itmay
notbepartof a continuumofMGseverity,if sucha
continuum really exists. Some also note that crisis
(respiratory insufficiency necessitating intubation
andassistedventilation) is oftenjustthebadluckof
a superimposedupperrespiratoryinfectionorover"
.........--....,
zealoustreatment,whereasotherSregardcrisisasthe
ultimatein MG severity.
TheTaskForce'sproposedsemiquantitative MG
score for disease severity offers some hope for a
moreobjectivedeterminationofmild,moderate,or
severeinvolvement,especiallyforresearchpurposes,
butitrequiresvalidation andperhapsweighting.s
CLINICAL COURSE OF MYASTHENIA GRAVIS
ThehighlyvariablecourseofMGmakesprediction
ofoutcome in an individual case of recent onset
extremelydifficult,if notimpossible.However,there
doesappearto be anoverall pattern to thenatural
historyofthe disease, even thoughnowadaysMGis
rarelyallowedtorunits naturalcourse.Itshouldbe
keptinmind,however, thatspontaneousremissions
lasting longer than 1 year occurred in between
12%108 and 21%107 of MG patients in early large
series.
Patients who initially have only eye muscle in-
volvement (ocularmyasthenia) areanxioustoknow
whetherthediseasewillgeneralize.Thisisactuallya
rather complex issue, because mild asymptomatic
generalizedweakness may alreadybe presentwhen
the diagnosis ofocular myasthenia is made. Most
recentstudiessuggestthat40-50%ofcasesof ocular
myastheniawillbecomegeneralized,usuallywithin2
years, so thatgeneralization is unlikely butnotim-
possible in patients with ocular myasthenia whose
symptoms have been present for more than 2
years.
25

144
Patients with onlyocularsymptoms have
occasionallybeendiscovered tohave centralcauses
such as meningiomas or aneurysms for their symp-
toms, eitherinsteadofMGorin addition to MG.93
For patients with purely ocular symptoms, MRI of
thebrainshouldbeconsideredif thereis anydiag-
nosticuncertainty,especiallyif theyarenegativefor
AChRbindingantibody.
Earlyinvestigators,whohadlessofa therapeutic
armamentarium than do current investigators,
claimed thatthefull extentofmuscle involvement
wasusuallyapparentwithin3
43
to7
107
yearsofonset
ofthe disease, although some patients hadexacer-
bations even 10 to 25 years afteronset,l7 Simpson
andThomaides
l42
dividedtheclinicalcourseof gen-
eralMGintothreestates: anactivefirststageof5 to
7 years characterized by exacerbations, remissions,
and considerable lability; aninactive stable second
stagelastingabout10years; anda burned-outthird
stageinwhichslowimprovementoccurs.
Amorerecentretrospectivemulticenterstudyof
1152patientsinItalyconfirmedmostofthe gener-
alizations,82 although87% ofthese patientsalready
Myasthenia Gravis MUSCLE & NERVE April 2004 491
had generalized MG when first seen, so that only
19% ofpatients with ocular myasthenia atfirst ob-
servation progressed to generalized findings (con-
firming the remarks about the prognosis ofocular
myastheniamade earlier). Remission without treat-
ment occurred in 11% of patients, and maximal
worsening was observed within 3 years ofonset in
77% ofpatients. Even with treatment, the propor-
tion ofremissions was lower in patients with more
severe disease at the first observation. The authors
interpreted this as suggesting that early diagnosis
andinterventionmayimproveprognosis. Only58%
werecorrectlydiagnosedasMGduringthefirstyear
oftheir illness, but 80% were correctly diagnosed
within 2years.
CONFIRMING THE CUNICAL DIAGNOSIS
Weaknessandfatiguearecommoncomplaintswitha
variety of causes, so it is not surprising that the
diagnosisofMGis often missed inpeopleinwhom
the weakness is mild or restricted to only a few
muscles. Once suspected, the clinical diagnosis
needs to be confirmed. There are various bedside
tests of fatigueby repetitiveorsustainedmovements
oftheeyes,anns,orlegsthathavebeensuggestedto
aid in the diagnosis, butnone are specific for MG.
~
Improvementofptosis on cooling the lid (the so-
called"icepack test") hasbeenparticularlymislead-
ing in my experience, occurring in mitochondrial
muscledisease andevenwitha posteriorcommuni-
catinganeurysm.Thereare threegenerallyaccepted
approaches-immunological, electrophysiological,
andpharmacological-toconfirmingthediagnosis.
Immunological Confirmation. Several serological
testsareavailableformeasuringAChRantibodiesin
the blood, includingblockingantibodies, modulat-
ingantibodies, andbindingantibodies.
76
Themost
reliable is the assay for serum AChR binding anti-
bodies,whichareelevatedin85%ofallMGpatients;
positiveresultsarelesslikelyinpatientswithmildor
purelyocularforms.8\)
None of the congenital myasthenic syndromes
hasanelevatedtiterof AChRantibodies.Acetylcho-
line receptorbindingantibodieswithoutclearman-
ifestations ofMG have been reported in a small
percentageofpatientswithautoimmunethyroiddis-
ease or with autoimmune Lambert-Eaton myas-
thenic syndrome, for the latter ofwhich calcium
channel-binding antibodies are more specmc.
76
However, a positive AChR binding antibody test
combined with an appropriate clinical picture
should provide near certainty ofthe diagnosis of
autoimmune MG. The chance ofreceiving a false-
positive AChR binding antibody test result from a.
reputable laboratory is very small; borderline tests:
shouldbe repeated. Patients negativeforAChRan-
tibodiesshouldbetestedfor MuSKantibodies,OO.lllO
andsomephysicians advocate detection ofimmune
complexes atbiopsied motorendplates as a useful
diagnostic test for antibody-negative autoimmune
myasthenia.
157
Others suggest that a favorable re-
sponse ofseronegative MG to plasmapheresis (see
below) is a useful diagnostic test for autoimmune
myasthenia. 102
Electrophyslologieal Confirmation. Whenseruman-
tibody tests are positive for MG, it is usually not
necessaryto resort to oneofthe otherless specific
methodsofconfirmation. However, standardnerve
conduction studies may reveal the low-amplitude
muscle evoked responses ofLambert-Eaton myas-
thenicsyndromeortherepetitive responsesofslow-
channelorcholinesterase-deficiencycongenitalmy-
asthenicsyndromes.
Surface recording over an appropriate limb or
facial muscle during repetitive nerve stimulation
(RNS) ofthe nerve to that muscle may be under-
taken. Decremental responses on RNS may be ob-
tainedfromweakmyasthenicmuscles as neuromus-
cular transmission becomes blocked. Only 40% of
MGpatientsshowdecrementalresponsesto 2-3Hz
stimulation ofhandmuscles, but the yield can be
increased up to 90% if two or more nerves and
muscles, especially warm proximal muscles, are
tested anddecrementis soughtforseveralminutes
following exercise.
54
Single-fiberelectromyography (SFEMG) is more
sensitivethanRNS fordetectingneuromusculardys-
functioninlimbandfacial muscles, becauseitmea-
.surestheinstabilitythatprecedestheneuromuscular
blockthatRNS can record.l
28
Unlessweakmuscles
aretested,however,SFEMGmaynotprovideconfir-
mation of the presence ofMG. Although neither
RNS norSFEMG results are specific for MG, serial
SFEMG has been shown in experienced hands to
predictorcorroboratechangesinMGdiseasesever-
ity.l3l
Pharmacological Confirmation. Drugsthatworsenor
improve the weakness have longbeenused to con-
firm the diagnosis ofMG. At one time, curare or
quinine was used in very small doses to test for
worseningofMG, butbecause theapproachcanbe
dangerous,itis nowseldomused.
Themostrapid (andsometimesdramatic) phar-
macologicaltestinvolvestheintravenousinjectionof
492 Myasthenia Gravis MUSCLE & NERVE April 2004
2 to 5 mg of edrophonium chloride or Tensilon, a
short-acting anticholinesterase (which also stimu-
lates muscle directly). A positive test requires a mea-
surable change in some sign such as ptosis, gaze
paresis, grip strength, or respiratory function a few
minutes after injection.
1ll
This result is compared
with that obtained from a previous placebo injection
of saline or atropine, the latter to block the musca-
rinic effects of this anticholinesterase. However,
false-positive Tensilon tests have been reported in a
variety of conditions, including brainstem tumors.
28
Because of the possible occurrence of potentially
. lethal vagal bradycardia following Tensilon injec-
tion,41 particularly in elderly persons, some hospitals
now require that the Tensilon test be done in an
emergency room with electrocardiographic monitor-
ing. When this is not appropriate, a safer and more
convenient diagnostic test may be for the untreated
patient to take the longer-acting oral anticholines-
terase medication, pyridostigmine bromide, or Mes-
tinon (discussed below). The medication must be
taken with bland food or after a meal, to minimize
muscarinic stimulation of the gut. The response can
be assessed 1-2 h later by the physician or over a
period of several days at home by the patient.
Differential Diagnosis. Sometimes all the tests are
negative or equivocal in someone whose story and
examination seem to point to a diagnosis of MG.
Positive clinical findings should probably take prece-
denceover negative confinnatory tests. It is appro-
priate for some patients simply to be followed by
their physicians, with a tentative diagnosis ofpossible
or probable MG until the situation clarifies itself
over time.
However, other conditions with fluctuating weak-
ness of eye muscles or bulbar muscles or in a gener-
alized distribution should be considered in the dif-
ferential diagnosis. Conditions that I have mistaken
initially for MG include Lambert-Eaton myasthenic
syndrome, botulism, chronic progressive external
ophthalmoplegia, oculopharyngeal muscular dystro-
phy, mitochondrial myopathy, polymyositis, progres-
sive muscular atrophy, benign essential blepharo-
spasm, and even sleep apnea.
Most patients suspected of having MG undergo
routine electrodiagnostic testing-needle electro-
myography and nerve conduction studies-to ex-
clude many of these possibilities. However, some or'
the rare congenital myasthenic syndromes respond
positively to anticholinesterases and have myasthenic
responses on electrophysiological testing; they usu-
ally require examination of muscle biopsies by spe-
cialized morphological, electrophysiological, and
Myasthenia Gravis
molecular genetic studies to make the specific diag-
nosis.
1
0
6
ASSOCIATED CONDITIONS, ESPECIALLY THYMOMA
Serum autoantibodies other than those against
AChR, especially those against thyroid peroxidase,
thyroglobulin, and gastric parietal cells, are found
several times more often in autoimmune MG than in
other neurological diseases.
76
Similarly, autoim-
mune thyroid disease, rheumatoid arthritis, and lu-
pus erythematosus have been found more often not
only in patients who also had MG but also in their
close relatives.48.141 The presence of concomitant
autoimmune phenomena has suggested that ac-
quired MG may occur in the context of an abnonnal
immune system and be a disorder of immune regu-
lation and control. Several patients undergoing allo-
geneic bone marrow transplantation have developed
MG as immunosuppressive therapy was tapered.
6
The role of T cells in the pathogenesis of MG is
suggested by cellular and humoral responses mea-
sured as MG developed and then improved during
the course of human immunodeficiency virus infec-
tion.
100
Thymoma. The presence of a thymoma, an epithe-
lial tumor of the thymus gland, is the most prevalent
association with MG, and vice versa.
127
Usually be-
nign, thymomas occur in about 15% of adult pa-
tients with MG.125 All MG patients with a thymoma
have elevated serum AChR antibodies. Almost all
have skeletal muscle antibodies in their sera that
cause increased cross-striational immunofluorescent
staining, but so do up to one third of MG patients
without a thymoma.
73
However, most of the latter
group of patients are over the age of 50 years, so the
presence of striational antibodies is highly predictive
of a thymoma in patients under the age of 45-50
years.
20
Among MG patients with thymoma, 80% also
have serum antibodies to titin, a giant filamentous
muscle protein spanning half a sarcomere that is the
predominant protein involved in the immunofluo-
rescent staining, as do 11 %of late-onset MG patients
without thymoma!66 (The main serological differ-
ence between early- and late-onset MG is the pres-
ence of antibodies to muscle titin.!) Patients with
MG who have thymomas also have serum antibodies
to ryanodine receptors (sarcoplasmic reticulum
calcium-release channels), and these correlate signif-
icantly with clinical MG severity.124
The absence of an elevated serum titer of anti-
striated muscle antibodies argues against the pres-
ence of a thymoma,62 but in practice, imaging of the
MUSCLE & NERVE April 2004 493
.
, '.
anterior mediastinum is always required, either by
computed tomography or MRI.62 The sensitivity of
the techniques is about equal, although computed
tomography provides better thymic definition in a
much shorter scanning time, whereas MRI may be
better for assessing possible invasion of vascular
structures if an invasive thymoma is suspected.
s
Chest radiographs, even with oblique views, miss
many thymomas.
8
,62
If a thymoma is detected by imaging and the
patient is asuitable surgical candidate, the thymoma
should be removed along with any remaining thy-
mus, on the theory that these tissues contribute to
the pathogenesis of the disease. Myasthenia gravis
with thymoma is generally regarded as more severe
than MG without thymoma,72 but the long-term clin-
ical outcome in many MG patients who undergo
thymectomy for thymoma may be as favorable as that
for MG patients without thymoma.
12
,124 Myasthenia
gravis can occur for the first time even many years
after the removal of a thymoma,99 circumstantial
evidence that the tumor may have adversely altered
the peripheral T-cell repertoire prior to its remov-
al.54
Although usually benign and encapsulated, thy-
momas can be invasive, as determined by the sur-
geon at the time ofoperation. Invasion of the fibrous
capsule surrounding the tumor is found in 29-37%
of the neoplasms in patients with MG.40 Thymomas
also may invade pleura, pericardium, or other medi-
astinal structures, including nerves and mcyor blood
vessels, and may metastasize throughout the thoracic
cavity or, rarely, to extrathoracic If the
thymoma is found to be invasive, the patient should
be considered for radiation therapy, cyclophospha-
mide,40 or radiopharmaceutical therapy.74
GENERAL TREATMENT MEASURES
Several common-sense approaches should be insti-
tuted before considering because they
can be very effective in coping with MG. Patients
need to be educated to pace their activities so that
they avoid unnecessary fatigue. Plenty of rest, per-
haps by lying down briefly several times during the
day. or by resting the eyes by closing them for a few
minutes each hour, can be helpful. Each patient is
different and, by experiment and experience, can
adopt a daily schedule that optimizes the good times
and minimizes the weak times. Support groups of
MG patients offer many practical ideas for coping
and living with the condition.
Patients should eat a well-balanced diet contain-
ing foods high in potassium. Low potassium levels
are associated with weakness in general, and total
body potassium is reversibly low in MG patients dur-
ing exacerbations.
27
In addition, diuretics, diarrhea,
or frequent vomiting can significantly lower body
potassium. Patients should be assessed for other
treatable autoimmune diseases by obtaining blood
levels of thyroid-stimulating hormone and cobal-
amin (vitamin B
12
). Correction of either hypothy-
roidism or hyperthyroidism can alleviate myasthenic
symptoms.
Avoiding Exacerbations, Many things may tempo-
rarily exacerbate MG weakness. Extremes of temper-
ature, either excessive heat (fever) or cold, should
be avoided. Pain, lack of sleep, overexertion, and
emotional stress should be kept to a minimum. In-
fections can produce increased weakness that may
persist for a while after the infection has resolved.
Although a patient's MG might theoretically worsen
after receiving annual influenza immunization, it
will almost certainly worsen if the patient develops
influenza, especially if bulbar symptoms are present.
The stress of surgery or radiation therapy (for rea-
sons other than MG) also can temporarily worsen
MG.
Often women notice increasing severity of their
MGjust before their menstrual period, during a time
when progesterone is being withdrawn,75 This may
become so severe that it is necessary to block men-
strual periods by long-acting progesterone,l61 to
eliminate recurrent myasthenic crises during men-
strual periods.
Pregnancy and MG. It is not uncommon for ac-
quired MG to manifest itself for the first time during
a pregnancy, but pregnancy does not worsen the
long-term outcome of MG.
7
Of 54 pregnancies in
one study, 20% got better at some time during preg-
nancy, 20% got worse, and 60% remained un-
changed.
7
The course of MG during previous preg-
nancies did not predict the course of subsequent
pregnancies. Mter delivery, MG symptoms worsened
in 28%. Standard drugs used to treat MG, such as
anticholinesterase medications or prednisone, are
not associated with significant risk for congenital
defects and are compatible with breastfeeding. Plas-
mapheresis and intravenous immunoglobulin treat-
ments have been safely carried out during pregnan-
cy.7.
78
Obstetrical problems with myasthenics are
uncommon because the uterus, a smooth muscle, is
unaffected in MG. Only during the second stage of
labor, when voluntary striated abdominal muscles
are used to push, does myasthenic weakness some-
, times become problematic .
494 Myasthenia Gravis
MUSCLE & NERVE April 2004
Table 2. Drugsthatadverselyaffectmyastheniagravis.
Typeof adverseeffect Nameofdrugortoxin
UnmaskorexacerbateMG AdrenocorticosteroidsandACTH
Thyroidpreparations
NeuromuscularblockingagentsOncludingBotulinumtoxin)
Anestheticagents(includingalcohol)
Magnesiumsalts, Epsomsalts
Antiarrhythmics: quinidine,procainamide, phenytoin, gabapentin,verapamil,
intravenouslidocaineorprocaine
Antibiotics
Aminoglycosides: systemicgentamicin,tobramycin,neomycin, paromomycin,
amikacin,kanamycin,streptomycin
Polypeptides:polymyxinB,colistin,colistemethate
Tetracyclines: chlortetracycline,oxytetracycline,tetracycline, demacfocycline,
methacycline.doxycycline. minocycline
Miscellaneous:clindamycin. lincomycin,ciprofloxadn,high-doseampicillin,
intravenouserythromycin
MayinduceMGbyprecipitatinganautoimmune trimethadione, chloroquine, alpha-interferon,interleukin-2,wasp
reaction stings, coralsnakebite
ImplicatedinisolatedinstancesofMG Cimetidine,citrate,chloroquine.cocaine, diazepam. lithiumcarbonate, quinine, beta-
exacerbation' blockersincludingtimololmaleateeyedrops. trihexyphenidylhydrochloride,
radiocontrastmedia(IOthalamicacid,meglumidediatrizoate). gemfibrozil(Lopid),
hydroxymethylglataryl-conenzymeAreductaseinhibitors("statins'j
'Not evaty MG patient is expected to react adversely to thase medications.
Drugs that Exacemate MG. A wide variety of drugs
have been reported anecdotally to affect MG ad-
versely (Table 2). The most Common offenders are
the same medications used to treat acquired MG
(too much anticholinesterase, steroids, or thyroid
medication), but anesthetic agents, muscle relax-
ants, magnesium salts, anticonvulsants, and other
membrane stabilizers for irregular heart rate, as well
as aminoglycoside antibiotics, are generally accepted
to unmask or worsen MG.52,58,l6S Discontinuation of
a drug known to exacerbate MG may therefore help
to relieve symptoms. (Interestingly, the membrane
stabilizer quinidine sulfate improved muscle
strength in slow-channel congenital myasthenic syn-
drome,45) Not all patients react adversely to all the
drugs listed in Table 2. Caution should be employed
inusing the drugs for patients with MG, however,
especially after surgery. Medications play a second-
ary role to good respiratory care in the treatment of
the MG patient immediately postoperatively. The
presence of restlessness or anxiety usually indicates
respiratory insufficiency, and sedatives or tranquiliz-
ers should be avoided until respiration is under con-
trol. For treatment of pain, demerol in two thirds the
usual dose is used instead of morphine, the latter
being avoided because of its depressant effect on
respiration.
Common sense dictates that the need for one of
the medications in Table 2 sometimes takes prece-
dence over the MG.57 A medical alert bracelet is very
helpful to warn medical personnel in case of an
accident or crisis when a patient is unable to com
municate clearly that he or she has MG.
SHORT-TERM TEMPORARY TREATMENTS
Antlchollnesterases. Every MG patient deserves a
trial of oral anticholinesterase medication for
symptomatic relief, because it is the safest and
most rapidly acting medication available. The
drugs block the enzyme acetylcholinesterase at the
neuromuscularjunction, allowing acetylcholine to
linger longer with more chance of stimulating the
remaining functional AChRs and thus provide a
short-term boost to help patients function better.
Some muscles may improve for a few hours,
whereas others may be unresponsive or even
weaken on these medications. Anticholinesterase
medication usually does not completely relieve
symptoms.
There are several drugs in this category, includ-
ing the most commonly used pyridostigmine bro-
mide (Mestinon), available as a scored 6O-mg tablet,
and neostigmine chloride (Prostigmin), available as
a 15-mg tablet Another drug in this category, am-
benonium chloride (Mytelase), available as a 10-mg
tablet, is used less frequently. Because muscle in-
volvement and severity vary so much among patients
MyastheniaGravis MUSCLE&NERVE April 2004 495
with MG, there is no fixed dose or time schedule for
anticholinesterases. For infants and children the
dose is based on body weight, starting at 1 mg per kg
for pyridostigmine and 0.3 mg per kg for neostig-
mine. A typical initial dose for adults is pyridostig-
mine 30 mg or neostigmine 7.5 mg taken three times
daily to ascertain sensitivity to the drug. Anticho-
linesterases can cause abdominal cramps and gut
hyperactivity, so the medication is usually taken after
meals, although a patient with dysphagia may need
to take a dose about an hour before each meal with
a small amount of a bland food, such as crackers or
milk, to minimize cramps and diarrhea.
Some people cannot tolerate even a small dose of
pyridostigmine. Fortunately, certain time-tested
drugs block undesired muscarinic effects of acetyl-
choline without affecting the desired nicotinic ac-
tions at the neuromuscular junction. Oral atropine-
like drugs-such as probanthine, 15 mg, or
hyoscyamine sulfate, 0.125 mg, three times daily--
can be used if necessary to counteract muscarinic
side effects, but they may thicken secretions and
mask warning signs of overmedication.
If a small trial dose is well tolerated, the eventual
adult dose may be somewhere between one half and
two of the 60-mg tablets of pyridostigmine or a sim-
ilar amount of the 15-mg tablets of neostigmine
taken initially no closer than every 4 h, always with
bland food. Different amounts may be needed at
different times of the day, depending on the individ-
ual. Because symptoms of MG are so variable, the
patient should be advised to make only one change
at a time and to do so gradually. The maximum safe
individual dose, in my opinion, is two tablets each
time, but if possible, this should be kept in reserve
for potential myasthenic exacerbations. If anticho-
linesterase medication is of no real benefit after a
week's trial of up to two tablets every 4-6 h, it should
be discontinued, because it treats only the symptoms
of the disease.
In most patients, the effects of both pyridostig-
mine and neostigmine usually peak between 1 and
2 h after ingestion, and the medication wears off
in 3 h or longer. Once the optimal 4-h dose is
determined, then the dose can be administered as
often as every 3 h. Pyridostigmine also comes as a
sustained-release Mestinon Timespan, which re-
leases 60 mg immediately and the remaining 120
mg somewhat variably over the next 6-8 h. It is
useful for patients who require mediation
throughout the night, but the uneven release pro-
vides less predictable results than does ordinary
pyridostigmine. There is also a liquid pyridostig-
mine syrup, 60 mg/5 ml, for children and adults
who have difficulty in swallowing pills. I have little
experience with parenteral anticholinesterases,
which in my hands have produced unstable results,
but pyridostigmine comes as a parenteral solution
of 2 mg/ml and neostigmine, as 0.5 mg/ml, a
milliliter injectable approximately equivalent to
the dose of a single oral tablet. When patients
cannot swallow. I prefer to use pyridostigmine
syrup via nasogastric feeding tube.
The daily dose of anticholinesterase medication
should be as low as pOSSible, to minimize cholinergic
toxicity. The presence of excessive perspiration, sal-
ivation, muscle twitching. or muscle cramps may be
an indication of overmedication, in which case the
anticholinesterase should be taken at longer inter-
vals or in a lower "dose.
Ephedrine. Historically, the drug ephedrine sulfate,
the active ingredient of the Chinese herb ma huang,
was discovered to improve myasthenic weakness a
decade before the similar discovery for anticholines-
terases.
ll1
(The amount of ephedrine in ma huang
varies greatly, however, making it a dangerous alter-
native.) Ephedrine may be useful as an ancilliary
medication, added to anticholinesterases, for those
MG patients who need a little extra strength and are
not bothered by its possible side effects of nervous-
ness, heart palpitations, or insomnia. For adult MG it
is taken as a 25-mg capsules two to three times a day.
Ephedrine also has been found useful in some con-
genital myasthenic syndromes.
Ephedrine is one of the medicines used to treat
asthma. Interestingly, other asthma medications
have a mild positive effect on MG, such as theoph-
ylline
1ll
and terbutaline.
57
I once met a patient with
undiagnosed MG who functioned only by frequent
use of an asthma inhaler. This should be kept in
mind when pulmonary function tests report, on the
basis ofimprovement after a bronchodilator, that an
MG patient has asthma.
Plasmapheresis. Short-term treatment for MG by
plasmapheresis or plasma exchange is sometimes
helpful. The plasma, which contains antibodies, is
removed by the procedure. The procedure is per-
formed once daily for 5 days or every other day for
10 days and costs about $15,000 for such a course. It
often requires placement of a central venous cathe-
ter for circulatory access and can be associated with
infection, blood clotting, bleeding, hypotension, car-
diac arrhythmias, muscle cramps, and toxic reactions
to dtrate.
122
Plasmapheresis is useful when short-
term benefit is critical, such as in an impending
swallowing or respiratory crisis, or prior to proce-
496 Myasthenia Gravis MUSCLE & NERVE April 2004
dures known to make MG worse, such as irradiation
or surgery.I5I It is also used to shorten the time that
a patient in crisis requires to hecome free of assisted
respiration. Patients usually begin to get stronger
within several days, but benefit lasts only 3-6 weeks.
Therefore, although extremely useful for emergen-
cies, repeated plasmapheresis is not recommended
as a long-term treatment.
103
Intravenous Immunoglobulins PYlg). Instead of
drawing off antibodies, as in plasmapheresis, IVIg
delivers pooled antibodies or immunoglobulins
from thousands of donors, a procedure that is
postulated to downregulate, or have a nonspecific
suppressive effect on, the immune system. Once
given in small amounts intramuscularly to MG
patients with reported benefit,39 immunoglobulins
can now be given in larger amounts intravenously
as a 5-6% aqueous solution freshly prepared from
a dry powder that has been purified and stabilized
under special conditions, viruses being inactivated
during its preparation. The usual course of treat-
ment is 400 mg/kg body weight for 5 days,3 al-
though the same total amount as 1 g/kg per day
can be administered over 2 daYS.!l7 The first Mg
treatment is performed in a hospital or doctor's
office in case of an allergic reaction. Thereafter,
Mg usually can be given in the patient's home by
a home-health nurse. It is administered at room
temperature at a slow rate of infusion, beginning
at 25 ml per hour and gradually increasing the rate
to 40-100 ml per hour (maximum rate, 150 ml per
hour).
Because of its relative ease of administration
compared with plasmapheresis, Mg is also pre-
scribed as one to three treatments a month to help
patients maintain strength while tapering pred-
nisone, but otherwise the indications for Mg are the
same as those for plasmapheresis: to improve the
patient's condition quickly but temporarily in crisis
or for impending crisis or upcoming procedures
such as surgery. Improvement begins about 3 to 10
days after beginning treatment, and the beneficial
effects last for about as long as plasmapheresis, an
average of 45 days, with a range of 30 to 120 days,
before myasthenic symptoms begin to recur.
24
Al-
though plasmapheresis has been reported to be ef-
fective on occasions when previous Mg was not,149 if
both procedures are contemplated to end a crisis, it
seems sensible first to remove antibodies with plasma-
pheresis before replacing antibodies with Mg. Neither
procedure is always effective, however, and the degree
of improvement among individual patients varies.
In my OpInIOn the benefits to MG of plasma-
pheresis and Mg are equivalent, and proponents of
one or the other treatment have had difficulty in
showing much difference between them. Efficacy
was similar in a randomized trial of 87 patients com-
paring only three unblinded plasma exchanges with
either 3 or 5 days of Mg,38 and a retrospective study
of 54 episodes of crisis found a superior ventilatory
status and functional outcome at 2 weeks and 1
month, respectively, with plasmapheresis.
I2o
Both
studies concluded that IVIg had fewer complications
than plasmapheresis.
However, IVIg has its share of adverse effects
and potential complications. II If it is administered
too quickly, generalized reactions can occur, such
as headache, backache, muscle pains, flushing,
nausea, chest tightness, tachycardia, low blood
pressure, chills, and fever. Plenty of fluids should
accompany the treatments, to minimize the severe
headache that can otherwise occur, Rarely these
reactions are quite severe, the result of hypersen-
sitivity to gamma globulin; this occurs most often
in patients with antibodies to gamma globulin as a
result of specific immunoglobulin A deficiency.79
Another allergic reaction that can occur with IVIg
is aseptic meningitis, characterized by severe head-
ache and stiff neck. Migraine, seizures, and retinal
vasculitis have been occasionally reported after
MG, as have skin rashes or loss of hair. The Mg
solution is highly viscous, and congestive heart
failure, acute renal failure, and strokes have also
been reported after MG administration. Labora-
tory abnormalities after Mg include low neutro-
phil counts and elevated erythrocyte sedimenta-
tion rate.71 Early case reports of Mg treatment of
MG claimed that the myasthenic symptoms could
worsen initially, as when prednisone is begun in an
MG patient, but this has not been a feature of
recent larger studies. The potential for adverse
effects is another reason besides its expense to use
Mg only in anticipated or actual rapidly deterio-
rating situations.
LONG-TERM IMMUNOLOGICAL TREATMENTS
Therapy should be tailored to the severity of the
disease. For those patients with only mild or ocular
symptoms, conservative MG treatments with a favor-
able risk/benefit ratio are preferable. Patients with
mild involvement are often content to treat their
symptoms with pyridostigmine, even if it does not
completely relieve them, and do not consider it
worthwhile to embark upon more risky or expensive
Myasthenia Gravis MUSCLE & NERVE April2004 497
treatments such as thymectomy, corticosteroids, or
immunosuppression.
However, what one patient thinks is mild, an-
other patient may find incapacitating. Furthermore,
many worry about the very real possibility of worsen-
ing of MG with time. Eventually, the patient with
more than minimal disease will want to discuss how
to obtain a long-term remission. This is especially
true for patients with severe bulbar disturbances, for
whom long-term treatments may protect against
rapid deterioration of swallowing or ventilation.
Without natural spontaneous remission, the patient
seeking more lasting improvement or prevention of
generalized MG is faced with two choices: major
thoracic surgery (thymectomy), or potentially dan-
gerous immunosuppressive drugs. Each approach
has advantages and disadvantages.
Thymectomy for Nonthymomatou5 MG. The thymus
gland is not enlarged in patients with MGI25 but
often shows lymphofollicular hyperplasia, especially
if myasthenia has been present for several years. The
histological appearance of the removed thymus in
seronegative patients is more often but not always
normal or atrophic.
158
The past and present evidence in favor of
thymectomy is complicated by the naturally fluctuat-
ing course of MG, the wide spectrum of severity
among patients, and the variety of surgical proce-
dures used to remove the thymus. Most surgeons
split the sternum in an extended transsternal
thymectomy that visualizes the main part of the thy-
mus in the chest
B5
,96 Other surgical groups cham-
pion a less traumatic approach through the neck,
called an extended transcervical thymectomy, claim-
ing comparable results,140 Superior results are
claimed for a maximal thymectomy, combining both
transsternal and transcervical approaches on the
same MG patient.
54
Recently, video-assisted thoraco-
scopic extended thymectomy was reported to pro-
duce complete stable remissions of nonthymoma-
tous MG in 50% of patients at 6-year follow-up,
similar to that of extended transsternal
thymectomy.8lAlthough recommended as an option
to increase the probability of MG remission or im-
provement, the Quality Standards Subcommittee of
the American Academy of Neurology concluded that
the benefit of thymectomy in nonthymomatous au-
toimmune MG has not been established conclusive-
ly.44 A controlled prospective, double-blind clinical
trial on defined populations sufficiently large for
statistical analysis will be required to satisfy this con-
cern.55
Until the results of such a study are available,
patients and their doctors must continue to make
individual therapeutic decisions on the basis of any
evidence available. The chance to benefit from
thymectomy seems to be better in early-onset
MG.9,123 Because the thymus naturally involutes with
time and the risks of surgery increase with age, at
some age the risks may outweigh the potential ben-
efits. Although thymectomy even after 60 years of
age can be a safe and effective treatment,156 late-
onset MG (>50 years ofage) is less likely to benefit
from thymectomy.I,150 The best outcomes after
thymectomy were in MG patients who had both
AChR antibodies and thymic hyperplasia,97 but lack
of serum antibodies apparently does not preclude a
favorable response to thymectomy,143 although this
is still controversial. However, none of the patients
with MuSK antibody has yet improved after thymec-
tomy.130 Early thymectomy appears to enhance the
opportunity for MG remission in children, although
ethnicity appears to be a consideration.
135
. Improvement, if it occurs, usually does not hap-
pen immediately after surgery but may take up to
several months or years to reach its peak effect.
Improvement from thymectomy is claimed to con-
tinue for from 5 to even 20 years after surgery.85 It is
still impossible to predict beforehand who in partic-
ular will benefit most from thymectomy, and even
after benefit occurs there is still a small possibility of
subsequent relapse. However, thymectomy itself
rarely worsens the long-term course of MG.
Thymectomy is generally reserved for patients
with moderate generalized MG whose myasthenic
symptoms interfere with their lives enough for them
to consider undergoing major thoracic surgery. On
occasion, however, it is considered for young healthy
patients with only ocular symptoms, to prevent
or minimize potential generalization. 132 Repeat
thymectomy has produced successful results in
chronic refractory myasthenia gravis,126 even when
no residual thymus was observed by imaging.
91
Even invasive thymomas are not always detected
with imaging tests and have been discovered unex-
pectedly during thymectomy surgery.70 Such experi-
ences would argue in favor of eventual thymectomy
over immunosuppressive drug therapy in otherwise
healthy young or middle-aged MG patients, once the
patient is up to the surgery. Although it is invasive
and expensive (about $20,000), thymectomy offers
the possibility of an eventually complete symptom-
free and drug-free remission, compared with a re-
mission dependent upon continued treatment with
immunosuppressive drugs.
498 Myasthenia Gravis MUSCLE & NERVE Aprll 2004
Immunosuppressive Drug Therapy. Certain immuno-
suppressive agents have been used to treat MG.
These include prednisone, azathioprine (Imuran),
mycophenolate mofetil (Cellcept), cyclosporine
(Sandimmune and Neoral), and cyclophosphamide
(Cytoxan). Except for prednisone, none is endorsed
by its manufacturer specifically for treatment of MG.
Prednisone. Of the drugs mentioned above,
prednisone is in a class by itself because it is both
immunosuppressive and anti-inflammatory. It even
has a direct and initially adverse effect on the neu-
romuscular junction, so when it is introduced, high-
dose prednisone (50-60 mg daily) may exacerbate
MG to the point of requiring assisted respiration.
112
Prednisone tablets are inexpensive, estimated at less
than $50 a year for typical therapy, but costs can
increase if side effects require treatment.
Many physicians try to avoid the initial worsening
by starting with a low dose of 5-25 mg taken on
alternate days135 and gradually increasing the dose
by 5-12.5 mg every 5-10 days until symptoms im-
prove or a maximum' of 100 mg every other day is
reached. Onset of improvement in muscle strength
is slower by this method, compared with daily high-
dose prednisone; improvement by the latter method
usually begins within 2 weeks but may take as long as
2 months,112 which is still relatively rapid improve-
ment compared with that after thymectomy. About
30% of MG patients on daily high-dose prednisone
therapy eventually experience a drug-dependent
symptom-free remission, and another 50% obtain
marked improvement on prednisone.
112
Favorable
outcomes from prednisone therapy correlated with
increasing age.
23

112
Besides slowness of improve-
ment onset, alternate-day prednisone may result in
less final overall benefit than with daily high dos-
es,138 but also in greatly reduced incidence of unde-
sirable side effects.
A different prednisone regimen is used for hos-
pitalized patients on a respirator because of myas-
thenic crisis. In this context, high-dose prednisone at
1-1.5 mg/kg body weight (60-100 mg) daily is safe,
because the patient's ventilation can be supported
mechanically during any initial worsening that oc-
curs. In 85% of patients on this regimen alone,
improvement occurs within 21 days and 100% re-
spond within 2 months.1l2 When it is safe, the daily
dose of prednisone is slowly decreased by 10 mg each
week to 50 mg daily before converting gradually to
alternate-day maintenance until the patient is on 100
mg every other day. I have had no experience with
pulse therapy of 2 g methylprednisolone over 12 h
every 5 days for MG exacerbations. followed by 30
mg oral prednisone daily, but this regimen is
claimed to produce less initial worsening and more
rapid improvement during such MG crises.
4
High doses of synthetic steroids cause adrenal sup-
pression. The natural production of adrenocortical ste-
roids begins to decrease ifprednisone is taken in doses
higher than 20 mg daily (40 mg every other day) for
longer than a week. Accordingly, during anticipated
stresses such as surgery, supplementary steroids must
then be provided in the form of 100 mg hydrocorti-
sone per liter of intravenouS fluid every 8 h. Once
adrenal suppression has occurred, prednisone must be
tapered slowly over several months. The choice of
prednisone therapy is thus a long-term commitment.
Prednisone has many undesirable effects, usually
related to dose and duration of drug use.!l!l Vitamin
D and bisphosphonates to prevent osteoporosis, and
yearly evaluation for cataracts and glaucoma, have
been recommended.
58
Use of steroids prior to
thymectomy is discouraged by some surgeons be-
cause steroids cause involution of the thymus
47
as
well as inhibition of wound healing,87 but some pa-
tients require the relatively rapid improvement that
careful prednisone treatment offers before they un-
dergo thymectomy. A chronic proximal myopathy of
the lower extremities may occur after prednisone
has been taken for a considerable time and may be
confused with a worsening of MG; reducing the
prednisone dose will improve such weakness,
whereas raising the dose may worsen it.
In my experience the myasthenic symptoms of
many patients can be eliminated with prednisone
alone. Once this occurs, usually after a couple of
months, a very slow tapering of prednisone every 4
weeks by less than 20% of the previous daily dose can
be attempted.
89
Eventually the patient may experi-
ence temporary worsening for a week or so after
decreasing a dose, and this may be a warning that the
tapering should be slowed or even halted for a while.
Once symptoms recur during a taper, relatively large
prednisone increases of 10-20 mg may be required
to restore the previous condition. An equivalent of 5
mg prednisone daily (10 mg every other day) is
regarded as the usual maintenance dose, but pa-
tients can be successfully withdrawn from pred-
nisone if very slow tapering is carefully followed,
requiring a reduction in the dose by 1mg per month
toward the end of the taper.
Azathioprine. Azathioprine is often considered
for those patients who cannot tolerate or do not
respond to prednisone or need help in tapering
prednisone without recurrence of MG symptoms. It
may take 3 months or longer for benefit to become
evident. Once a therapeutically effective dose of 2-3
mg per kg per day has been reached, maximum
Myasthenia Gravis MUSCLE & NERVE April 2004 499
response takes 12 to 36 months to occur.
8S
In a
randomized controlled trial of 34 MG patients com-
paring prednisolone (the active metabolite of pred-
nisone) to initial combined therapy of prednisolone
plus azathioprine, it took approximately 18 months
after its initiation for azathioprine to exert a steroid-
sparing effect.loo
Because of azathioprine's potential to cause
fetal skeletal teratogenicity, it seems wise not to
recommend it for young women who wish to have
children, even though a recent study of pregnancy
in MG claims it is safe.
7
I also avoid it in patients
with a history of previous cancer. Baseline blood
values for complete blood count, liver functions
tests, and amylase or lipase are obtained before
starting azathioprine at one 50-mg tablet daily,
taken at bedtime to minimize nausea. Most of the
undesirable effects of azathioprine manifest them-
selves early, and some are serious. As many as 20%
of patients develop a hypersensitivity reaction that
occurs in the first few weeks of therapy, consisting
of fever, myalgias, nausea, vomiting or flulike
symptoms, loss of appetite, or abdominal pain.
The drug must then be discontinued. Otherwise,
blood is monitored every week while beginning or
increasing the dose of azathioprine because of the
drug's adverse effects of dose-related bone marrow
....
depression, liver dysfunction, or pancreatitis. If
blood tests are stable and the patient tolerates the
medication, it is increased by 25-50 mg weekly,
taken at bedtime to minimize nausea, until a ther-
apeutic daily dose of 2-3 mg/kg is reached. The
dose is decreased if amylase or liver function tests
increase to greater than twice the normal value or
if the white blood count declines below 2800/mJl';
lymphopenia is less worrisome than neutropenia.
Azathioprine causes a macrocytosis of red blood
cells with increased mean corpuscular volume,
which has been suggested as a way of monitoring
dosage and compliance.l
M
Unless some other in-
tervention such as thymectomy produces an effec-
tive remission, patients can rarely discontinue aza-
thioprine without experiencing a relapse of their
MG.90 The annual cost of a therapeutic dose of
azathioprine plus monthly blood tests is estimated
to be about $2500.
58
Mycophentikde MofetiL Only in the last few
years has this biological agent been advocated for
treatment of MG as an immunosuppressive alter-
native to azathioprine. Two open-label series were
reported in 2001, one claiming that 24 of 32 MG
patients either improved their functional status or
were able to reduce their prednisone dosage after
an average of 12 months on mycophenolate,14 the
other reporting similar improvement in 8 of 12
patients after 6 months.1
8
Improvementbegan af-
ter 2 weeks to 2 months in the latter study,18
whereas in the former the mean time to improve-
ment was 5 months.
14
Side effects were few (mainly
nausea, diarrhea, and a low white blood count) in
these preliminary studies. However, lymphomas
and lymphoproliferative disorders occurred more
often (but less than 2%) in mycophenolate-treated
groups of transplant recipients than in similar
groups receiving placebo or azathioprine.
51
The
dose for MG is 1 g twice daily, and the cost of a
therapeutic dose of mycophenolate plus monthly
blood tests is the most expensive of the immuno-
suppressive drugs, estimated to be about $8000
annually.5s
Cyclosporine. The response of MG to cydospor-
ine has been tested in clinical trials at one third the
dose commonly used for immunosuppression dur-
ing organ transplantation. A preliminary random-
ized controlled trial of cydosporine alone at a dose
of 6 mg/kg per day in two divided doses for 10
elderly patients with recent-onset MG showed signif-
icant improvement in six, but four patients discon-
tinued the trial because of nephrotoxicity or persis-
tent nausea. 154 Cydosporine is more often
advocated, like azathioprine, to help MG patients
lower their dosage of prednisone (a "steroid-spar-
ing" effect) .153 A retrospective study of 57 MG pa-
tients who took cyclosporine for an average of 3.5
years claimed that 96% had clinical improvement
that began within weeks of beginning the therapy,
with a maximal response by 7 months on average.
19
Improvement occurred in this study in patients who
had failed to improve with azathioprine; among the
38 MG patients also taking prednisone, that medica-
tion could be decreased or discontinued in 95%.19
The drug is suitable only for compliant patients,
because serum creatinine must be followed regularly
to assess renal toxicity. Hypertension, nausea,
tremor, increased body hair, gingival hyperplasia,
and the possibility of developing a malignancy are
among the adverse effects of cydosporine that cause
many patients to discontinue the drug. A lower dose
of 3-4 mg/kg was recommended as likely to be
better tolerated.
102
The annual cost of a therapeutic
dose of 250 mg per day of generic cyclosporine plus
monthly tests and quanerly drug levels is estimated
to be $5000.
58
Cyclophosphamide. Usually cyclophosphamide is
saved for those few cases of MG refractory to all
other therapeutic modalities. In the initial report, it
was administered as 3-5 mg/kg daily in divided
doses and produced stable remissions ofMG but also
500 Myasthenia Gravis MUSCLE & NERVE April 2004
caused serious adverse effects, including anorexia,
nausea, vomiting, hairloss, lowwhite bloodcount,
andbladderirritation.1l4Nowcyclophosphamideis
usuallyadministeredwiththecooperationof a rheu-
matologistasaweeklyintravenousdoseof 200mgto
decrease the incidence ofadverse side effects and
stillproduceoccasionaldramaticresponsesof refrac-
tory MG. However, a recent randomized double-
blind trial in Argentina of monthly intravenous
"pulses"ofcyclophosphamide (500mgperm
2
body
surface) forayearreportedlyallowedrefractoryMG
patientstoreducesteroiddosesbecauseofimproved
muscle strength.26
An imaginative but risky therapy was recently
reportedtoproducestable remissions in threepre-
viously refractory thymectomized MG patients in
JohnsHopkinsHospital, a centerexperiencedwith
bonemarrowtransplantation: 4days ofintravenous
cyclophosphamide (50 mg/kg daily), followed by
granulocyte colony-stimulatingfactor, producedan
immunoablativetreatmentresemblingbonemarrow
transplantationbutwith preservationof hematopoi-
eticstemcells.
30
Interestingly, de novogeneratedT
cells thatwould be needed to reconstitute the im-
mune system aftersuch a treatmentwere foundin
MG patients even 25 to 54 years after transstemal
thymectomy,l48 either because such thymectomies
areincompleteorbecause theT cellswere released
intothecirculationbeforethymectomyandsurvived
fordecades.
CONCLUSIONS
AlthoughtherapeuticchoicesforindividualMGpa-
tientsarebecomingmoreselectiveas evidenceaccu-
mulatesaboutthedifferentresponsesofcongenital.
ocular.early-onset,late-onset,seronegative,andthy-
momatous MG, currentsurgical andpharmacologi-
cal approaches tononspecific immune suppression
ofMG leave much to be desiredin terms ofeffec-
tiveness andabsence ofadverse effects. Itis hoped
that future treatment strategies will employ more
specific regulation ofimmunityfocusedonselected
antibodiesorimmune cells. approaches thatare at
presentexperimental. The choice oftreatmentfor
an individual MG patient still requires judgment,
experience,andtime.
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