Journal of the Neurological Sciences 261 (2007) 127 133

www.elsevier.com/locate/jns

Myasthenic crisis: Guidelines for prevention and treatment

Agnes Jani-Acsadi, Robert P. Lisak
Department of Neurology, Wayne State University, Detroit, MI 4201 St. Antoine 48201, United States
Available online 4 June 2007

Abstract
Management of myasthenic crisis (MC) requires admission of the patient into a neurological intensive care unit and timely institution of
an efficient and safe treatment. Despite the growing clinical experience with disease modifying immunotherapy there is no clinical consensus
regarding the use of plasma exchange or high dose immunoglobulin treatment in an ICU setting. The choice of treatment modalities seem to
rely mostly on institutional preferences primarily due to a lack of well-designed clinical trials comparing currently available therapeutic
options. In our experience and based on a review of recent literature we advocate the use of plasma exchange (PE) as a primary modality in
the acute care setting, supported by other immunomodulatory medications such as corticosteroids. Pharmacological management cannot
substitute for adequate intensive care management of the respiratory and bulbar insufficiency associated with MC. Every effort should be
done to prevent myasthenic exacerbation/crisis and to develop a maintenance management that leads to effective prevention.
2007 Elsevier B.V. All rights reserved.
Keywords: Myasthenic crisis; Plasma exchange; Corticosteroids

1. Introduction
Acquired myasthenia gravis is an autoimmune disorder of
neuromuscular junction transmission clinically manifesting as
variable and fluctuating weakness of certain muscles.
Symptoms are due to reduced binding of acetylcholine at the
neuromuscular junction (NMJ) due to either the presence of
acetylcholine receptor (AChR) antibodies reducing the
available postsynaptic acetylcholine receptors found on the
end plate of skeletal muscle or by the presence of autoantibodies directed towards other postsynaptic skeletal muscle
components, such as Muscle Specific Kinase (MuSK). Among
others systemic illness, surgery, fever, pregnancy, emotional
upset and certain drugs may exacerbate myasthenic symptoms.
This severe, at times fatal condition may lead to an acute
inability to breath and swallow. This status is defined as
myasthenic crisis [13]. Prevention and treatment of myasthenic crisis (MC) often requires admission to an intensive care
unit, preferably a neuroscience ICU, close observation and
when necessary, intubation of the patient for acute ventilatory
and feeding support. Delay in appropriate medical care may
Corresponding author.
E-mail address: rlisak@med.wayne.edu (R.P. Lisak).
0022-510X/$ - see front matter 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jns.2007.04.045

lead to respiratory arrest and ultimately death. Identifying the

pathogenic mechanisms as autoimmune has lead to better
treatment of these patients that may prevent progression of
their condition to a severe worsening such as seen in
myasthenic crisis. When crisis occurs, acute care, in addition
to supportive therapy, focuses on reducing circulating antibody
titers with plasmapheresis (PE) and/or institution or adjustment
of immunologic disease modifying therapy with high dose
intravenous immunoglobulin and corticosteroids. Despite the
growing interest and newer treatment modalities there is a lack
of well-designed therapeutic clinical trials comparing currently
available treatment modalities including PE and high dose
immunoglobulin treatment (IVIg) in the setting of impending
or manifest MC.
2. Etiology
Acquired MG is a rather heterogeneous group of
autoimmune disorders affecting neuromuscular junction
transmission. It usually presents with fluctuating weakness
of characteristic voluntary muscles. Most commonly they are
related to either isolated ocular dysfunction such as diplopia,
ptosis of the upper eye lids or bulbar symptoms such as
dysarthria, dysphagia, due to limitation of facial and/or

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A. Jani-Acsadi, R.P. Lisak / Journal of the Neurological Sciences 261 (2007) 127133

muscles of mastication, or in addition, to neck and proximal

muscle weakness. If muscles of respiration become markedly
affected, or bulbar function deteriorates to a degree that the
airway and pulmonary toilet is precarious, crisis emerges that
may lead to an acute inability to maintain adequate air entry
and/or aspiration. The patient develops acute respiratory
insufficiency and potentially fatal respiratory arrest.
MG is a relatively rare disease with a variable prevalence
of 5 to 15/100,000 [46]. About 15 to 20% of patients with
MG experience however a myasthenic crisis at some point in
the course of their disease [5,6]. Current statistics still report
an about 3 to 8% mortality rate despite newer treatment and
intense medical care. Due to an increase in life expectancy
and better recognition of the disease the prevalence of MG
has increased representing the well described bimodal
clustering of the incidence of MG across the different age
and gender groups [5,7,8]. Mortality may approach 4% [5,9]
with no documented improvement in fatality rates over the
last several decades.
Many myasthenic patients are chronically immunocompromised and others cannot adequately protect their upper and
lower airways. Hence, most cases of crisis are provoked by
concurrent infections and fever. Infections, including lower and
upper respiratory infections are responsible for at least 70% of
the MC cases [9,10]. Surgical interventions and administration
of different medications are the other important risk factors.
There is a wealth of medications, such as certain antibiotics
(aminoglycosids), some cardiac drugs such as lidocaine, procainamid, and quinidine, phenothiazides and magnesium that
may provoke the first symptoms or worsen MG [2,11,12].
Differentiating autoimmune acquired MG from other nonimmune myasthenic syndromes such as congenital/inherited
myasthenic syndromes or drug/toxin induced disease is important since they do not respond to immunotherapy and require a
different therapeutic approach [1315].
3. Symptoms and signs
Myasthenic crisis is traditionally defined as an acute
respiratory failure due to worsening MG requiring admission
to an intensive care unit (ICU) [16,17]. MC may develop quite
suddenly without any warning due to the specific clinical
features of the myasthenic state camouflaging the severe
respiratory distress: facial weakness, airway collapse and
diaphragmatic and accessory muscle failure leading to inability to protect the airways with preserved oxygen saturation.
In others worsening of primary symptoms related directly to
weakness and the presence or worsening secondary features
(hypercarbia, hypoxia, symptoms of respiratory or other
infections, and weight loss due to dysphagia) of MG may
help identify the patient with impending MC [3].
4. Laboratory and other supportive diagnostic tests
MC is characterized by a drop of forced vital capacity
below 1 L, a negative inspiratory force of 20 cm H2O or less

and the need for mechanical respiratory support. Hence close

monitoring of respiratory status requires regular bedside
pulmonary function testing every 4 to 6 h. Arterial blood gas
analysis commonly shows hypercarbia before hypoxia.
There should be a low threshold for endotracheal intubation
due to the rapid deterioration of the involved bulbar and
respiratory muscles.
If MC is the first presentation of the disease EMG/NCS is
recommended additionally to look for evidence of decrement
with slow frequency repetitive nerve stimulation, preferably
in the weakest muscles. Increased jitter may be detected by
single fiber electromyography in a laboratory experienced to
perform these tests and may provide additional support to the
diagnosis.
If needed serum for anti-acetylcholine receptor or antiMUSK antibodies should be sent for analysis before the
institution of any immunotherapy. Anti-AChR antibodies are
elevated in 85 to 90% of patients with generalized MG.
Thymoma associated MG may present with crisis or as respiratory failure with a mediastinal mass with no known history
of MG. Chest computerized tomography may help in identifying the cause of respiratory failure and lead to initiating
appropriate therapy early in such cases. In some instances
thymectomy for thymoma without known MG can result in
initial presentation of MG in the postoperative period.
MUSK related autoimmune acquired MG presents with
slightly different phenotype than that typical of AChR
antibody mediated general MG. The predilection of the
disease to involve primarily facial, bulbar, respiratory and neck
muscles with relative sparing of the limb muscles [18,19]
makes close assessment of bulbar function (e.g., swallow, gag)
and proper care of excretions (regular suctioning) indispensable. Attention should be given to the same functions in all
other forms of autoimmune MG. We are still learning about
other anti-MUSK antibody clinical phenotypes.
Historically edrophonium was used to distinguish MC
from cholinergic crisis or to support the diagnosis in previously unknown myasthenic patients. Its use in managing
MG was of limited efficiency [20]. It is used less due to the
known cardiac side effects particularly in older individuals,
the subjectivity of testing and the wide spread availability of
immunologic and clinical neurophysiological testing. If the
patient requires ventilatory support there is no need to
distinguish the two crisis entities [3,21].
5. Treatment
Treatment of MG may be aimed either at improving the
availability of Ach in the NMJ to improve neuromuscular
transmission and and/or to modify the basic immunological
cause of acquired MG. Recent articles have repeatedly
highlighted the need for evidence-based data on the different treatment modalities in both MG and MC [22,23].
The lack of appropriate data is also of concern due to the
rising health care costs associated with prolonged ICU care.
To date treatment is based on clinical consensus [1,10,13,

A. Jani-Acsadi, R.P. Lisak / Journal of the Neurological Sciences 261 (2007) 127133

14,17,2427]. Experts agree that early identification, if

possible prevention of the impending crisis, elimination of
potential triggers such as treatment of infections, maintaining appropriate electrolyte balance, appropriate feeding and
long-term ventilatory support with tracheostomy if needed,
assessing and providing the level of intensity of care
necessary to stabilize the patient are mandatory and should
be tailored to fit individual patient needs. These goals
parallel an increase in our knowledge of the pathogenic
mechanism of MG and the ability to recognize and avoid
potential precipitating factors of the crisis. It is also
supported by an increase in the availability of neurological
ICUs and improved management of metabolic and respiratory insufficiencies. Controversy continues to exist however
regarding the benefits of symptomatic therapy (pyridostigmine) or use of corticosteroids in an acute care setting.
There are only few studies available that compare PE and
IVIG in MC and most of them do not address important
issues satisfactorily such as the speed or onset of the effect
or do not include enough patients with crisis [2830].
6. Cholinesterase inhibitors
Symptomatic pharmacologic therapy should always
follow stabilization of the patient via standard ICU processes
(airway, breathing, cardiovascular support). Cholinesterase
inhibitors such as pyridostigmine bromide prolong the
presence and activity of ACh in the endplate synaptic cleft
and are a mainstay of the management of mild to moderate
MG [13]. In the last three to four decades their use has been
less in moderate to severe and /or progressive myasthenia or
MC, certainly not as a solitary treatment. This is based on the
fact that cholinesterase inhibitors may have a variable halflife in severely ill patients and reduced absorption of oral
formulations. Over dosage may lead to increased weakness
and interference with extubation [31,32]. In the era prior to
widespread of ICUs, much was written on the need to
distinguish MC from so-called cholinergic crisis. Hence
most experts are cautious regarding the use of ChEI in an
acute care setting [3,31,32].
In the series of Berroushot [33] (Class IIb evidence) out of
235 MG patents, there were 63 with MC treated in an acute
care setting with pyridostigmine (n = 24), pyridostigmine and
prednisolone ((n = 18) and PE alone (n = 21). They did not
find any significant differences in short-term efficacy,
comparable long-term outcome and side effect profile
between the different regimens. Based on these results they
advocated an approach tailored to the individual patient
considering the precrisis condition of the patient and the
precipitating factors of MC (Class III evidence). In a smaller
retrospective review of patients undergoing quite variable
treatment regimens, O'Riordan et al. continued pyridostigmine therapy in the acute stage in 33 out of 35 cases and
found no obvious effect of the drug on any patient group
[34]. Kawaguchi et al. made no comment regarding AChEI
treatment in the 5 MC patients out of the total 470 patients

129

surveyed [35]. In their current review, Ahmed et al. [21]

emphasizes caution with AChEI use especially in a setting of
planned thymectomy or extubation based on their experience
(Class III). In their retrospective analysis, Panda et al. [36]
reported giving a drug holiday from the AChEI throughout
the period of ventilation for all of their patients. Another
limitation of the AChEI in the setting of MC is the potential
for over treatment and the possibility of cholinergic crisis.
For this reason some advocated stopping pyridostigmine for
a few days until the nature of crisis is clear.
In conclusion there are still no randomized, controlled
trials looking at the efficacy and/or time course of cholinesterase inhibitors in MC. Agents that are frequently used
to enhance ACh quanta release presynaptically such as
guanidine and 3,4-diaminopyrimidine are not used in the
treatment of MC.
7. Immunotherapy of MC
Immunotherapy of MG by definition tackles the basis of
the disease by suppressing or modifying the autoimmune
pathogenic mechanisms of myasthenia gravis. The immunosuppressive/modulatory treatments are however associated with a higher degree of potential complications including
worsening of myasthenia such as seen with initiation of
corticosteroids and numerous well-described side effects
[3,13,37]. Their use has been primarily advocated in patients
with moderate generalized MG who remain symptomatic
after the initiation of AChEI therapy [14,39].
8. Corticosteroid treatment
Use of glucocorticoids (generally prednisone or prednisolone) in MC has not been evaluated systematically. The
principles of use in patients with myasthenia gravis are
similar to their application in other immune-mediated systemic and neuromuscular diseases such as systemic lupus
erythematosus, chronic inflammatory demyelinating polyneuropathy (CIDP) and acquired inflammatory muscle
diseases among others [40]. Historically patients with MG
were among the first to be treated with corticosteroid therapy
[4143]. However there is still a lack of controlled
prospective and randomized trials [39,40].
Corticosteroid formulations may be divided by duration
of their action on ACTH suppression as short- (prednisone,
prednisolone at an effect of less than 24 to 36 h),
intermediate (triamcinolone) and long-acting (dexamethasone) and also by their relative potency (cortisole has a value
of 1, prednisone and prednisolone 4, methylprednisone 5 and
dexamethasone 30) [40,44]. Their ease of application with
oral forms, although not every detail of their metabolism is
quite fully understood, makes them a valuable tool in treating
these diseases, although historically only the shorter acting
forms were used in MG.
The major issue in MC is the acute worsening of weakness
with the initiation of the therapy [3,40,45]. Different regimens

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have been proposed to avoid the other well-described

corticosteroid side effects [38] and to keep a transient
worsening of myasthenia at bay [13,37,40,45]. These regimens suggest that in patients in MC who by definition have
severe deficits and are already in a controlled setting in an
ICU and in need of rapid improvement, a high dose initiation
therapy is recommended. Either PE or IVIG therapy to avoid
severe exacerbation related to therapy should support this. A
starting dose of 60 to 80 mg of prednisone once daily has
been recommended with follow up alternating day or high
doselower dose regimens and taper to reach the minimum
effective dose [13,14]. Different regimens have been published
for maintenance of MG and should be used by adjusting it
to individual patient needs [13,37,40]. These expert opinions
are reflected among others in the published 27 patient case
series of O'Riordan [34] and are followed by most critical
care neurologists [24].
It also has to be emphasized that an acute steroid induced
myopathy may occur in patients who have received nondepolarizing neuromuscular blockade previously and has
also been associated with high dose initiation therapy alone
as first described by Panegyres et al. in 1993 [46].
The Cochrane Review concluded regarding the use of
corticosteroids in MG that there is limited evidence for short
- term benefits (at 2 weeks) in generalized MG when
compared to placebo and only limited data were available for
the 6 months time point. The fluctuating natural course of
MG makes the analysis of long-term data difficult but
clinical experience is suggestive of long-term benefits.
Conversely azathioprine and IVIg showed comparable
long-term results in efficacy with corticosteroids [39].
Azathioprine and the other immunosuppressants such as
cyclosporine, mycophenolate mofetil and cyclophosphamide
or thymectomy are not considered a part of the acute care
protocol since their therapeutic action is delayed.
9. Plasma exchange
The basis of the action of plasmapheresis (PE) in MC is
that it rapidly eliminates the pathological autoantibodies via
mechanical separation or more recently, by immunoadsorption or double filtration techniques [4750]. Traditional
plasma exchange entails removal of the pathogenic antibodies (antinicotinic ACh receptor, anti-MUSK antibodies
and antibodies to as yet to be characterized antigens) and
other plasma components such as soluble adhesion molecules and cytokines [51], separation from other blood
components and then supplementation with 5% human
albumin and crystalloids or rarely fresh frozen plasma to
maintain homeostasis. The procedure may be carried out by
plasma filtration techniques, plasma separation and more
recently by antigen-specific immunoadsorption techniques
[52,53] that enable the return of non-pathogenic blood
components to the patient. A standard course in myasthenia
exacerbation entails 5 to 6 exchanges on alternating days
utilizing 2 to 4 L per exchange [49,50]. Among the newer

apheretic techniques, double filtration PE and immunoadsorption [47] showed similar clinical effects for patients with
generalized myasthenia with only minor differences noted in
post PE serum immunoglobulin levels.
Dau [55] emphasized the importance of patient tailored
treatment regimens based on the clinical severity of the
exacerbation in MC. A series of early, non-randomized
studies [5458] quickly established the beneficial, primarily
short-term effect of PE and since then it has gained wide
application in acute care setting [33,35,59,60]. The 1986
NIH consensus statement supported the use of PE, and no
placebo controlled clinical trials have been conducted [61].
PE has shown benefit in MC, management of exacerbations
and has become a part in presurgical/prethymectomy preparation [62] as well.
One of the limitations of PE is the relatively short-lived
(2 to 3 weeks) improvement in strength that makes the coadministration of other longer acting immunosuppressive
or immunomodulatory agents generally necessary. In
addition, significant limitation of PE is its relatively high
cost, invasive features (need for venous access and cardiac
and hemodynamic instability) and the rare toxic reaction to
the anticoagulants such as citrates [13,17,63]. The report of
the largest PE database, the French plasma exchange registry
reports a decrease in the immediate complications since 1985
due to improved quality of the applied techniques and
plasma substitutes [64].
The only randomized early controlled trial by Gajdos
was limited by co-administration of prednisone and lack
of blinding [65]. Based on their data the Cochrane
Review's evidence based evaluation concludes that further
trials may need to address long-term effects of PE in MC.
The more recent clinical retrospective case series by
Mahalati et al. of 36 patients (32 in MC) over a 10 year
period reported predictable clinical improvement with
successful extubation. They reported no fatalities in the
acute phase by using an average of 7.8 exchanges [66]. The
retrospective case series of Berroushot did not find
however any significant difference between their patients
in MC treated with PE, pyridostigmine or pyridostigmine
and prednisone regarding effect on ventilation, clinical
outcome and fatality rate [33].
10. Intravenous immunoglobulin
The use of high dose intravenous immunoglobulin (IVIg)
has gained wide application in the treatment of autoimmune
and immunopathologically mediated neuromuscular diseases. This was noticeable in the growing number of
publications dealing with its application both in acquired
adult and juvenile MG and other antibody-mediated
neuromuscular diseases such as GuillainBarre syndrome
(GBS), CIDP, Multifocal Motor Neuropathy (MMN) and
dermatomyositis [17,21,29,30,33,6771,74]. The increased
interest can be explained by a number of different factors
such as the relative ease of administration compared to PE,

A. Jani-Acsadi, R.P. Lisak / Journal of the Neurological Sciences 261 (2007) 127133

and a relatively benign long-term side effect profile. There is

however a need to perform more adequately designed clinical
trials to establish short- and long-term efficiency as compared
to the other therapeutic modalities in some of these diseases,
including MG and particularly in MC. Nevertheless it has
become first line therapy in many immune mediated
neuromuscular diseases.
Immunoglobulins are part of the body's immune defense
system. Their mechanism of action in autoimmune diseases
is quite complex and not fully understood [67,72,73]. IVIg
seems to affect immune homeostasis by interfering at multiple levels [74]. The mode of action most directly related to
MG is likely the modulation of the pathogenic autoantibody response. Other actions include the inhibition of complement activation and interference with the membrane
attack complex (MAC) formation, modulation of Fc receptors, down regulation of the pathogenic cytokine responses,
suppression of T cell function and finally interference with
antigen recognition [73].
The procedure usually entails the administration of 0.4 g/
kg body weight human pooled IgG over 3 to 5 days, although
alternative regimens have been proposed earlier for different
autoimmune disorders with what appears to be comparable
results [67,74,75]. The side effect profile is considered
benign in patients with no significant comorbidities such as
renal disease, diabetes, hypercoagulabilty, hypertension,
immobility and advanced age. Adverse reactions include
mostly minor reactions, such as headache, chills, myalgias,
transient hypertension and are mostly associated with early
or rapid therapy initiation [7476]. More severe side effects
include allergic reactions, renal failure, thrombotic events
and serum sickness [13,68]. A temporary suppression of
levels of formed elements of blood may also be seen [77].
Current preparations should not have the earlier problems of
Hepatitis C contamination [13]. Another limitation is the
quite significant cost associated with high doses of IVIg that
has to be taken into account in addition to the shortage of
relevant, evidence based clinical information in an acute care
setting. There have also been periodic regional shortages of
IVIg.
Clinical consensus and data of non-randomized clinical
trials and case series (class III) seem to point to a benefit in
maintenance therapy of MG [7880]. Jongen [81] in a
retrospective, unblinded and uncontrolled analysis of a small
number of patients found in 56% (9 out of 16) patients
improvement with the peak effect at 7 days. This was less
than the 61 % of patient improvement noted by Gajdos [28].
All of the studies had different patient selection criteria and
differed in their outcome measures, so it is quite problematical to draw a clear causal correlation to IVIg.
11. Comparison of plasma exchange and intravenous
immunoglobulin treatment in myasthenic crisis
Lewis et al. [82] advocated the use of PE over IVIg
based on early clinical results with PE and a good clinical

131

response to PE in myasthenic patients refractory to IVIg

[83,84]. Since then other studies have compared PE with
IVIg in MC. The retrospective study series of 54 patients by
Qureshi [29] found better short-term (one month) outcome
with PE, despite higher morbidities. Gajdos in an earlier
smaller and the first comparative randomized clinical study
involving 87 patients did not show a clear difference
between the 2 modalities and the alternative treatment
regimens of 3 or 5 days (Class III) [27]. They stressed
however that IVIg exhibited a very limited risk and a better
tolerance profile than PE. Dalakas in a recent review
advocated the use of IVIg as a suitable alternative to PE for
acute and maintenance therapy of MG [74]. Two of the
randomized clinical trials included in The Cochrane Review
used IVIg for treatment of myasthenic exacerbation but
only the Gajdos study compared PE and IVIg. The study
was not blinded. Moreover the mean total volume
exchanged seemed to be less than what was used by
several other groups in MG/MC. Therefore it was
concluded that there is no evidence to support preferentially
either PE or IVIg treatment for myasthenic exacerbations
[30].
12. Conclusion
The introduction of neurological intensive care units has
put its stamp on the management of myasthenic crisis. Early
recognition, better identification of etiological and precipitating factors and appropriate management of the respiratory and bulbar failure make this severe condition more
accessible to newer treatment modalities. These are aimed at
correction or modulation of the underlying immune
pathologic mechanisms. In our experience the treatment of
MC with plasma exchange has proven to lead to fast and
predictable recovery. This is supported by a 20 year history
of safe and reliable clinical efficiency. Side effects and
availability will be less of a factor in a neurological ICU
ready to deal with the pertinent issues and with a plasma
exchange team, including those responsible for obtaining
venous access, when that is an issue. Although widely
accepted as a first line therapy in many of the autoimmune
neuromuscular diseases, including the treatment of moderately severe myasthenia, there is so far no evidence based
clinical data to support the use of IVIg as a primary
treatment modality for MC. The short-term management of
myasthenic crisis should virtually always be followed with
appropriate long-term immunosuppressive therapy. New
randomized controlled clinical studies will be needed to
further clarify the risks and benefits associated with high
dose IVIg treatment and the newer techniques in plasma
exchange.
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