Review: Myasthenic Crisis
Review: Myasthenic Crisis
Review: Myasthenic Crisis
Review
Myasthenic crisis
A. CHAUDHURI1 and P.O. BEHAN2
1
From the Essex Centre for Neurological Sciences and 2Division of Clinical Neurosciences, University
of Glasgow, Scotland, UK
Summary
Myasthenic crisis is a life-threatening medical neuromuscular paralysis which in most cases,
emergency requiring early diagnosis and res- can be achieved clinically. High dose corticoster-
piratory assistance. It can affect between one-fifth oids in combination with plasma exchange or
and one-third of all patients with generalized immunoglobulin are the cornerstone of treatment
autoimmune myasthenia gravis. Myasthenic crisis for this fully reversible cause of neuromuscular
is to be distinguished from other causes of acute paralysis.
Introduction
Myasthenic crisis is a reversible cause of neuromus- Medline for articles on ‘myasthenic crisis’,
cular paralysis, which needs to be diagnosed and ‘myasthenia gravis’ and ‘respiratory failure’ between
treated promptly. It is typically associated with 1966 and 2007. Only articles in English or with
autoimmune myasthenia gravis, which has an English translation were reviewed. In addition, we
estimated population prevalence of 200–400 per searched appropriate reference texts to support the
million.1 The commonest form of myasthenia gravis discussion. The articles were selected on the basis of
is characterized by acquired antibodies against post- their relevance and originality.
synaptic acetylcholine receptors (AChR) in the
motor end plate of skeletal muscles. Injury from
immune complex deposition and complement Classification of myasthenia
activation reduce the contact area of the post-
synaptic surface, which, together with the loss of Failure of transmission across neuromuscular junc-
functional AChR molecules, reduce the safety of tion may occur due to a variety of reasons, and the
neuromuscular transmission leading to impulse defining feature of any myasthenic syndrome is
blockade at the motor end plate (Table 1). Here, painless, fatigable weakness of voluntary muscles
we review the diagnosis and management of (Table 2). Congenital myasthenic syndromes repre-
myasthenic crisis, a life-threatening medical emer- sent a heterogeneous group of disorders caused by
gency which may potentially challenge emergency genetic defects in neuromuscular transmission.
physicians and neurologists. Congenital myasthenic syndromes do not weaken
respiratory muscles and consequently are not
implicated in myasthenic crisis. D-penicillamine-
Search criteria induced myasthenia gravis is caused by an auto-
The present review was based on our reading of the immune mechanism similar to anti-AChR antibody
standard medical texts and a search of PubMed and positive myasthenia gravis but the symptoms usually
Address correspondence to Dr A. Chaudhuri, Consultant Neurologist & Clinical Lead in Neurology, Queen’s
Hospital, Rom Valley Way, Romford, Essex RM7 0AG. email: chaudhuria@gmail.com
! The Author 2008. Published by Oxford University Press on behalf of the Association of Physicians.
All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Complement binding and activation at the post-synaptic junction of motor end plate;
Destruction of synaptic membrane which becomes unfolded (simplified) with reduction of surface area of contact;
Cross-linking of AChR molecules on the post-synaptic membrane leading to endocytosis and degradation
of the linked receptor protein resulting in fewer receptors in the neuromuscular junction;
Functional block of AChR resulting in fewer competing receptors available for binding of acetylcholine
released during neuromuscular transmission.
Table 2 Classification of acquired myasthenic who present with predominant facial, bulbar and
syndromes respiratory weakness, lingual atrophy and relatively
mild limb weakness.2 Up to 50% of anti-AChR
Autoimmune antibody negative patients may segregate into the
Pre-synaptic: LEMS category of MuSK-MG.3 Patients who do not have
Post-synaptic: AChR-MG and MuSK-MG anti-AChR or MuSK-antibodies (antibody-negative
Neonatal (passive transfer of maternal
MG), such as those with ocular myasthenia, have a
antibodies in AChR-MG)
Drug induced: D-penicillamine
clinical phenotype very similar to AChR-MG. The
Toxic HLA-haplotypes of AChR-MG and MuSK-MG are
Botulism also different and the immunopathogenesis of
Neuroparalytic envenomation (e.g. tick and myasthenia in MuSK-MG is probably independent
snake bites) of thymus, which plays a pivotal role in the
Organophosphate and carbamate poisoning mechanism of disease in AChR-MG. A comparison
Overdose of anti-cholinesterases of AChR-MG and MuSK-MG is shown in Table 3.
There are only rare examples of acquired myasthe-
nia gravis who have shared clinical features and
antibodies against both AChR and MuSK.4 Presence
disappear after drug withdrawal. Acute toxic paraly- of non-AChR and MuSK antibodies, such as anti-titin
sis of neuromuscular junction transmission leading and ryanodine receptor antibodies, are reported in
to severe muscle weakness and respiratory failure patients with severe disease regardless of the clinical
may also be caused by curare, snake venom, tick subgroup.5
bite and botulism. Antibodies directed against By definition, all patients with myasthenic crisis
voltage-gated calcium channels in the pre-synaptic are in respiratory failure due to muscle weakness
side of motor end plate are responsible for Lambert and require ventilatory assistance. These cases fall in
Eaton myasthenic syndrome (LEMS). A few cases of the categories 3 and 4 in the Osserman classification
LEMS have been associated with autoimmune of myasthenia gravis,6 and class V of the disease
myasthenia gravis and although some patients with severity staging proposed by the Myasthenia Gravis
LEMS may experience transient or mild involvement Foundation of America.7 These classifications are
of bulbar muscles, respiratory failure due to LEMS shown in Table 4. Myasthenic patients in whom
alone is extremely rare. post-operative extubation has been delayed beyond
The term myasthenic crisis refers to respiratory 24 h because of respiratory weakness are also
weakness in patients with acquired, autoimmune considered to be in crisis. In the pre-immunotherapy
form of myasthenia gravis. Neonatal myasthenia era, myasthenic crisis had significant mortality (up to
gravis results from passive transfer of maternal 75%), but it has fallen below 5% due to rapid access
antibodies and is self-limiting. Autoimmune to respiratory support and immunotherapy in the
myasthenia gravis is currently divided into two recent years.8
groups, which are clinically and immunopathologi-
cally distinct. The commonest form of myasthenia
gravis is associated with anti-AChR antibodies
(AChR-MG) and the past literature of myasthenic
Mechanism
crisis is largely based on this group. Since 2000, a Myasthenic crisis is caused by severe weakness of
second group of patients with myasthenia gravis has respiratory muscles, upper airway muscles (bulbar
been identified who have autoantibodies directed myasthenia) or both. It is typically precipitated by
against muscle specific tyrosine kinase (MuSK). poor control of generalized disease, medical treat-
Patients with MuSK-antibody associated myasthenia ment for bulbar myasthenia (steroids and antic-
gravis (MuSK-MG) are usually younger women holinesterases); concomitant use of certain
Osserman’s classification
(1) Localized, non-progressive disease (ocular myasthenia)
(2) Gradual onset generalized disease (involving more than one group of striated muscles, both skeletal and bulbar)
(3) Acute fulminant generalized disease with severe bulbar involvement
(4) Late severe disease (usually developing 2 years or more after symptoms in category 1 or 2)
(5) Muscle atrophy (not due to disuse) in late generalized disease, restricted to skeletal muscles and usually
related to the duration of the disease and clinical severity (myasthenic myopathy)
Myasthenia Gravis Foundation of America classification
Class I: ocular myasthenia, also may have weakness of eye closure
Class II: mild weakness of non-ocular muscles
Class III: moderate weakness of non-ocular muscles
Class IV: severe weakness of non-ocular muscles
Class V: requiring intubation, with or without mechanical ventilation
Class II–IV are each divided into subgroups (a) (predominant limb and trunk muscle weakness) and
(b) (predominant bulbar weakness); severity of ocular muscle weakness does not affect the staging.
antibiotics, muscle relaxants, benzodiazepines, myasthenic crisis in pregnancy carries high perinatal
b-blockers and iodinated radiocontrast agents mortality.15
(Table 5); systemic infections often involving the
respiratory tract, aspiration and surgery. Other
recognized triggers for crisis in refractory myasthe- Differential diagnosis
nia are emotional stress, hot environment, sudden
elevation of body temperature9 and hyperthyroid- Acute respiratory paralysis due to neuromuscular
ism, with autoimmune thyroid disease being a weakness may be a presenting feature of a number
common association of myasthenia gravis. of disorders affecting motor neurons, peripheral
The life-time prevalence of myasthenic crisis in nerve, neuromuscular junction and muscles
patients with myasthenia gravis is roughly between (Table 8). Respiratory paralysis is a recognized
20% and 30%8,10,11 and it usually occurs during feature of drug overdose and envenomation and
the course of first symptomatic presentation in the may complicate central nervous system disorders
young and later in the course of the disease in the due to brainstem (medullary) or high cervical spinal
elderly (Table 6).12,13 White patients with general- cord pathology. Weakness of eye muscles (ptosis
ized myasthenia gravis are more likely to respond and external ophthalmoplegia) is common in AChR-
poorly to treatment than black patients.14 Pregnancy MG and patients may have any combination of
is associated with an aggravation of myasthenia weak eye movements, even simulating internuclear
gravis in approximately a third of all women and ophthalmoplegia. Myasthenia gravis is probably the
Table 6 Demographic features of early and late onset myasthenic crisis in adultsa
a
Compiled from the literature.
most frequent cause of bulbar palsy presenting as Marked autonomic symptoms, poorly reactive,
dysphonia, dysarthria and dysphagia in conjunction dilated pupils with loss of accommodation and
with ptosis and ocular palsy. Atrophy of tongue is a diminished tendon reflexes are suggestive of botu-
typical feature of MuSK-MG,16 but presence of both lism. Paralytic poliomyelitis and acute diphtheritic
wasting and fasciculations of tongue muscle clearly paralysis, both extremely rare in the Western world,
point away from myasthenic crisis and are more may also present with bulbar weakness and
likely to be the result of motor neuron disease respiratory failure.
(progressive bulbar palsy), bulbospinal muscular Weakness of facial muscles is a feature which is
atrophy (Kennedy’s disease, Fazio-Londe and common to myasthenia gravis, Guillain Barre
Brown-Vialetto syndromes), syringobulbia or skull syndrome and acute polymyositis. AChR-MG
base pathology. Bulbar palsy and respiratory muscle patients have weakness of both neck flexors and
weakness is also a feature of acute inflammatory extensors, occasionally selectively affecting the
demyelinating polyneuropathy (Guillain Barre syn- extensor muscles (the hanging or dropped head
drome), which may occasionally be associated with sign). Patients with MuSK-MG and acute polymyo-
bilateral ptosis. Although tendon reflexes may be sitis have marked weakness of neck flexors. Weak
retained early in the course of evolving Guillain neck flexors are also a feature of Guillain Barre
Barre syndrome, presence of normal tendon reflexes syndrome and often correlate with respiratory
in an established case with severe muscle weakness muscle weakness. Disproportionate weakness of
and respiratory failure would be most unusual. anterior neck muscles is a feature shared by
progressive muscular dystrophies (such as type 1 patients with a known diagnosis of myasthenia
myotonic dystrophy), motor neuron disease, spino- gravis taking high doses of oral anticholinesterases
muscular atrophy and syringomyelia. Limb weak- as the mainstay of therapy. Cholinergic crisis in
ness is usually most obvious in proximal muscles in myasthenic patients is uncommon in today’s prac-
myasthenia gravis and acute polymyositis, and both tice as most symptomatic patients with generalized
proximal and distal in Guillain Barre syndrome. disease receive immunotherapy as preferred treat-
Primary disorders of muscle and neuromuscular ment and anticholinesterases are largely restricted to
junction do not generally weaken arm muscles short-term symptom control. More commonly, cases
disproportionately and respiratory muscle weakness of respiratory paralysis due to cholinergic crisis are
in conjunction with paralysis of arms and shoulders associated with toxic exposure to organophosphate
would be more typical of anterior horn cell disease insecticides. In occasional patients with myasthenia
(motor neuron disease or poliomyelitis) and periph- gravis on higher doses of oral anticholinesterases
eral neuropathy. Guillain Barre syndrome and spinal (pyridostigmine or neostigmine), the clinical features
cord pathology are the two likely causes of are sufficiently distinct from myasthenic crisis (no
respiratory failure associated with severe leg weak- ptosis, small pupils, muscle fasciculations, hypersa-
ness. Adult-onset acid maltase deficiency may livation, bradycardia, diarrhoea, bowel and bladder
present with respiratory muscle weakness and incontinence).
these patients often have contracture of calf Neuromuscular weakness in critically ill patients
muscles. Features of marked and symptomatic is commoner than anticipated, with reports estimat-
autonomic disturbance are typical of botulism, less ing 33–82% of patients being affected after receiving
commonly observed in Guillain Barre syndrome and ventilation for >4 days.17 Diaphragmatic weakness
rarely reported in myasthenic crisis. is common and there may be superimposed
Previously, it was customary to differentiate neuromuscular junction transmission defect (‘critical
between cholinergic crisis and myasthenic crisis in illness neuromuscular junction abnormality’).
Eye
External +++ +a ++
Ophthalmoplegia
Pupils Normal and Small and Normal, Normal Dilated Normal May
reactive reactive but may and and sluggish and reactive be small
not reacta reactive but reactiveb
Face
Ptosis +++ b
Facial weakness ++ +++ ++ +
Limb muscles
Weakness ++ ++ +++ +++ +++ +++ +++
Fasciculations +++ +++
Tendon reflexes ++ ++ + +++ and/ +++ or
Plantar reflex Flexor Flexor Flexor/ Flexor Flexor/ Extensor Extensor
absent absent
Sensations Normal Normal Symptoms/ Normal Symptoms Normal Sensory level
signs
Sphincter control Normal Normal Sometimes Normal Lost Normal Lost
lost
Autonomic symptoms +++ + +++ +
a
In Miller Fisher syndrome (a variant of Guillain Barre syndrome).
b
Only if Horner’s syndrome is associated.
is necessary.19 Other clinical rules for predicting trial found no significant superiority of 2 g/kg dose
impending ventilator failure and need for airways over 1 g/kg dose in patients with exacerbation of
protection are inability to raise the head due to neck myasthenia gravis.25 A randomized trial of daily
muscle weakness and paradoxical breathing. As in versus alternate day plasma exchange in severe
any other condition with neuromuscular paralysis, myasthenia gravis found no superiority of one over
an experienced clinician should anticipate the need the other in terms of outcome.26 The clearance of
for respiratory assistance in myasthenic crisis rather MuSK-antibody during serial sessions of plasma-
than deal with emergency intubation (‘when in pheresis for MuSK-MG27 was comparable to the
doubt, intubate’). Non-invasive ventilation (NIV) has experience in AChR-MG. IgA-deficient myasthenic
been used as an alternative to intubation and patients should not receive IVIg; plasmapheresis is
mechanical ventilation for patients in myasthenic not recommended in patients with cardiac failure,
crisis,20 but the experience of NIV in acute sepsis, hypotension and pregnancy; it is also not
neuromuscular paralysis is still relatively limited. considered to be a suitable procedure in paediatric
NIV has the potential, however, to reduce the patients. The wider availability and ease of admin-
incidence of prolonged intubation and tracheost- istration of IVIg makes it an automatic choice as the
omy in neuromuscular paralysis. first-line therapy for myasthenic crisis since access
There have been few randomized controlled to plasmapheresis, particularly during out-of-hours,
treatment trials in myasthenic crisis and both is restricted to selected centres and major teaching
plasma exchange and human intravenous immuno- hospitals only.
globulin (IVIg) are comparable in terms of efficacy The use of continuous anticholinesterase (intra-
on the basis of clinical evidence,21–23 only one of venous pyridostigmine) as a therapy for myasthenic
which21 was a prospective study. However, crisis22 remains controversial, especially because of
response to plasma exchange may be more pre- the risk of cardiac complications (arrhythmia and
dictable and we take the view that plasma exchange myocardial infarction). Coronary vasospasm form
is probably more effective than IVIg in myasthenic excessive anticholinergic treatment is known to be
crisis. In one retrospective multi-centre review of 54 an iatrogenic cause of myocardial infarction in
episodes of myasthenic crisis,24 plasma exchange myasthenia gravis.28 Besides the risk of cardiac
had a superior outcome for ventilatory status at 2 complication, large doses of anticholinesterases
weeks (P = 0.02) and functional outcome at 1 month promote excessive salivary and gastric secretions,
(P = 0.04). The recommended therapeutic dose of which may increase the risk of aspiration pneumo-
IVIg is 2 g/kg but a randomized double-blind clinical nia. Immunoadsorption therapy was used to treat
Baseline
Blood:
‘The 3 Cs’: cell count, culture and CRP
Urea, creatinine and electrolytes (Na, K)
Creatine kinase (CK)
TSH
Liver enzymes (ALT, GGT)
Calcium profile
ECG
Chest X-ray
Specific (as appropriate for the individual case)
Serum antibody (AChR, MuSK, voltage-gated calcium channels)
Toxic screen (suspected poisoning/overdose)
Metabolic screen (porphyria)
Neurophysiology (EMG, single fibre EMG for orbicularis oculi, nerve conduction and repetitive motor nerve
stimulation of limb and facial muscles)
Cerebrospinal fluid analysis by lumbar puncture (Guillain Barre syndrome, poliomyelitis)
Muscle biopsy (polymyositis, acid maltase deficiency)
MR imaging (spinal cord/brain)
Gene mutation analysis (muscular dystrophy and spinal muscular atrophy)
Table 11 Key points about myasthenic crisis myasthenia gravis, but there is insufficient evidence
at present to make a recommendation38 and the
Myasthenic crisis is a rare but potentially life- potential risk of progressive multifocal leucoence-
threatening medical emergency and the diagnosis phalopathy from immunosuppression makes ritux-
should be clinically suspected. imab an unlikely choice. A recent Cochrane review
Patients in myasthenic crisis require ventilatory concluded that use of ciclosporin and cyclophos-
assistance and usually respond to a combination of
phamide, with or without steroids, was associated
high-dose corticosteroids and plasma exchange or
human intravenous immunoglobulin.
with improved outcome after 6 months of treatment
There is some evidence to suggest that pre-emptive and treatment benefit remained unproven for
thymectomy in anti-AChR-MG may prevent pro- azathioprine, tacrolimus or mycophenolate.39
longed or severe myasthenic crisis. Ciclosporin may be the preferred immunosuppres-
Pharmacological management of myasthenic crisis is sive agent in myasthenia gravis in the shorter term as
largely based on observational studies as there have azathioprine effect does takes longer than 6 months,
been very few randomized controlled trials of and sometimes up to 18 months during which
treatment, a situation which is unlikely to change in period alternative immunotherapy (corticosteroids,
the near future. intermittent plasma exchange or IVIg) would be
required.
A neglected issue in the care of myasthenic
prednisolone is highly effective in symptom control. patients is the need for psychological support. It has
Patients already receiving high-dose steroids during been long recognized that sudden emotional stress,
recovery from myasthenic crisis require to be treated feelings of anxiety, aggression and envy may
for several weeks (usually 18–24 weeks). We start increase myasthenic weakness and chronic weak-
biphosphonate therapy for bone protection against ness may influence the personality of the sufferer.6
steroid-induced osteoporosis at the same time when Some of these symptoms may relate to the medica-
steroids are instituted. It is our practice to introduce tions (steroids and anticholinesterases), but psycho-
azathioprine when the patient is ready to go home. logical support of a patient recovering from
The reason for initiating azathioprine nearer the time myasthenic crisis is no less important than drug
of discharge is primarily to ensure that an appro- therapy. Home-based inspiratory muscle training
priate steroid dose has been established to stabilize and breathing exercises are helpful for patients with
myasthenic symptoms. The onset of therapeutic generalized myasthenia gravis and may improve
effect of azathioprine is usually delayed for at least 6 respiratory muscle strength and endurance.40
months by which time steroids are tapered off to an
alternate daily maintenance dose. Our practice is to
continue treatment with oral prednisolone at a dose Conclusion
of 1 mg/kg for first 8–10 weeks before tapering it by
Diagnosis of myasthenic crisis should be suspected
5 mg every week, which minimizes the risk of
clinically and patients with impending crisis must be
steroid-induced myopathy. Azathioprine is consid-
admitted to an intensive care unit for respiratory
ered to be relatively safe as an immunosuppressant
support. The key issues regarding the management
during pregnancy, but treatment should not be
of myasthenia gravis are summarized in Table 11.
initiated during pregnancy. It is metabolized to
The condition is fully reversible and carries no long-
mercaptopurine by the enzyme thiopurine methyl-
term disability if treated quickly and appropriately.
transferase (TPMT). It is a good practice point to
Thymectomy soon after first symptomatic presenta-
measure TPMT enzyme activity in the blood before
tion of generalized AChR-MG may prevent pro-
commencing azathioprine treatment in order to
longed myasthenic crisis. Patients with MuSK-MG
identify individuals who are homozygous for low
have a higher risk of myasthenic crisis because of
TPMT activity and consequently carry a higher risk
bulbar weakness and may require prolonged
of myelosuppression. There is also a small increase therapy.
in the life-time risk of cancer on long-term use.
Ciclosporin, methotrexate or mycophenolate is an Conflict of interest: None declared.
alternative when patients are intolerant or unre-
sponsive to azathioprine and tacrolimus is only
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