Myasthenia Gravis (MG) and Myasthenic Crisis (NEUROLOGIC EMERGENCY)
Carson T. Lawall, MD
Associated topics
1. Respiratory Failure in Neurologic Disease
2. Acute Inflammatory Demyelinating Polyneuropathy
3. Lambert Eaton Myasthenic Syndrome
4. Neurologic Disorders in Pregnancy
Epidemiology
5-15 cases per 100,000 people. 15-20% of patients with Myasthenia Gravis have a Myasthenic Crisis in
their lifetime. If one considers thymoma a neoplasm, it could be considered the most common
Paraneoplastic disease.
There is a bimodal distribution of disease with onset at age 20’s-30’s affecting mostly women, as well as
a second group with onset age 60-70 mostly affecting men. In total 80-90% of patients will be
acetylcholine receptor antibody positive, however patients who present later (in the second age group)
are less likely to be antibody positive. Patients with ocular myasthenia are acetylcholine receptor
antibody positive 50% of the time. There may be an association with HLA antigens B8, DRw3, and
DQw2.
Clinical Presentation
Myasthenia Gravis (MG) Presents as fluctuating weakness of voluntary muscles, sometimes preceded
by, or concomitant with, medical illness, URI, or UTI. Patients often have diplopia, ptosis, limitation of
facial movement, and bulbar findings (nasal speech, difficulty swallowing) at presentation with
progression to involve additional voluntary muscles of the body, although this pattern is not always seen
and voluntary muscle weakness may be the first presenting sign. Dysarthria and dysphagia may also be
present, especially with prolonged chewing or talking. Bulbar weakness may interfere with airway or
clearing secretions. Weakness tends to worsen with repetitive use and while it may be symmetric it is
often asymmetric.
Myasthenic Crisis can be precipitated by infection, change in medications, and surgery.
Key History: Consider Asking about, diplopia, difficulty chewing, shortness of breath, exercise tolerance,
rate of deterioration, recent illness, sick exposures, surgery, travel, change in medications, herbal
medications, history of fluctuating weakness/previous spells, history of intubation, difficulty
walking/rising from bed/raising head, previous treatment for Myasthenia, change in diet, drug use
(especially black tar heroin given risk for botulism).
Myasthenic Crisis
Acute respiratory failure due to worsening Myasthenia Gravis requiring admission to the intensive care
unit. Presents often with generalized weakness, with or without subjective shortness of breath.
Respiratory Compromise
MIF >-30 is worrisome for need to intubate (MIF should be less than -30 [-40 being less than -30])
FVC <15 mL/kg or less than 1L total (some papers suggest 20mL/kg) is worrisome for need of intubation
A drop of MIF or FVC 50% or greater than the first recorded value is also concerning for the need to
intubate. Patients can deteriorate rapidly.
Normal MIF is <-60, Normal FVC is > 60 mL/kg
Respiratory failure is a frequent cause of death and may present insidiously. If a patient has bulbar
weakness that precludes them from protecting their airway they may require intubation.
Ocular Myasthenia
Myasthenia limited to the extra-ocular movments of the eye as well as the eyelid (ptosis). Often
improves with the “ice pack test” and often (50%) are Ach-R Ab negative. May not need immune
suprresion in some cases (although there is limited evidence that steroid treatment may decrease the
risk of developing generalized myasthenia), and can be treated with Acetylcholinesterase inhibitors.
Exam
ABC’s, Vitals, Mean Inspiratory Flow (MIF [or NIF in some institutions]), Forced Vital Capacity (FVC)
General Medical Exam – for evidence of infection, aspiration, rash, abdominal pain/UTI.
Neurologic Exam – Special attention to Cranial Nerves, papillary response (should be normal), eye
movements, ptosis, weakness with sustained muscle action (fatigue with upgaze over 90 seconds,
fatigue of a proximal muscle group [deltoid] and distal muscle group [finger extensors, wrist extensors),
proximal muscle weakness, neck flexion/extension. Reflexes should be normal. Sensation should be
preserved. Coordination deficits should be proportional to patient’s weakness.
Differential Diagnosis
1. Myasthenia Gravis
2. Lambert Eaton Myasthenic Syndrome
3. Acute Inflammatory Demyelinating Polyneuropathy (AIDP/GBS)
4. Botulism
5. Amyotrophic Lateral Sclerosis (ALS)
6. Myopathy
7. Muscular Dystrophy
8. Multiple Sclerosis
9. Periodic Paralysis
10. Hypercalcemia
11. Hyponatremia
12. Hypo/Hyperkalemia
13. Hypothyroidsim (can also exacerbate MG)
14. Tick Paralysis
Differential Diagnosis for Myasthenic Crisis
1. Myasthenic Crisis
2. Acetylconlinesterase overdose (AKA: Cholinergic Crisis) – Very Rare
3. Botulism
4. AIDP/GBS
5. Organic Phosphate Poisoning (pesticide poisoning)
Causes/Pathophysiology
Antibodies to Acetylcholine Receptors on skeletal muscle (cardiac and smooth muscle are not affected),
lead to increased turnover of the Acetylcholine receptor, blockade of Acetylcholine binding of the
receptor, decreased available receptor for binding, change in the neuromuscular junction leading to
decreased surface area for presentation of acetylcholine receptor. Other Autoantibodies that may
cause myasthenia include the Anti-MuSK (Muscle Specific Receptor Tyrosine Kinase) antibody and the
Anti-Titin (a striated muscle protein) antibody, but are less common.
Diagnostic testing
Imaging
1. MIF and FVC – should be obtained in the emergency department as soon as possible.
2. CT or MRI chest- to evaluate for thymoma, or underlying medical illness
3. CXR – evaluate for infection or thymoma.
4. EMG/NCS – Decremental response to stimulation. Single Nerve Fiber EMG may show “jitter”
which is 90% sensitive, but not specific.
5. MRI brain and orbits with and without contrast – to evaluate patients with ocular myasthenia
and rule out other causes of cranial nerve or eye movement dysfunction.
Laboratory
Basic: CBC, ESR/CRP, CK, Serum Chemistry, iCa, Ca/Mg/Phos, U/A, Ach-R Ab (present in 80-95% of
generalized MG but only 50% of Ocular Myasthenia), TSH, fT4
PPD – should be tested before immune suppression started.
Antibody titers do NOT correlate to the severity of the disease.
Advanced: Anti-MuSK Ab, Anti-Titin Ab, ABG*. ANA, RF, DS-DNA, cANCA/pANCA, SSA/SSB (anti Ro/La),
ESR, CRP, Anti-Thyroglobulin Ab, Anti-Thyroperoxidase Ab.
In some instances: Blood Cultures, Urine Cultures
*Of note: ABG will be normal right until respiratory compromise so it is not a helpful marker of function,
however, it may show if a patient is retaining CO2, or if they are in more dire circumstances than
previously thought.
Other: Tensilon test**, Ice Pack Test – can improve Ptosis if present in ~8/10 patients with MG.
**Tensilon test will improve function in several neurologic diseases and is non-specific to MG. It also
has some risk of fatal arrhythmia and should be done with caution.
Lumbar Puncture – No role for lumbar puncture unless concerned for other causes of weakness such as
AIDP.
Tensilon (Edrophonium) Test
1. Place Peripheral IV, place patient on Cardiac Monitoring, have Crash Cart available.
2. Prepare Atropine 2mg in a syringe.
3. Prepare Edrophonium 10mg (1mL) in a 1mL tuberculin Syringe
4. Inject Edrophonium 2mg (0.2mL) slowly over 15 secondsand observe for side effects and clinical
improvement.
Improvement should occur in 30 seconds and last 5 minutes.
5. If no side effects or improvement, Inject remaining 8mg (0.8mL) of Edrophonium and monitor
for symptomatic improvement.
If symptomatic bradycardia, dyspnea, or syncope occurs, inject 1mg IV atropine.
*There are varied regimens for the tensilon test.
Treatment
1. Close monitoring and supportive Care: follow MIF/FVC every 4-6hrs until stable, mechanical
ventilation if needed. Consider admission to step down unit or ICU. Avoid Incentive Spirometry
as it may cause respiratory fatigue. Pay close attention to bulbar weakness and have a low
threshold to make patients NPO if at risk for aspiration, or prepare to intubate if they cannot
protect their airway. *Some Authors advocate that patients with severe disease or rapidly
progressing disease should be treated as though they are in crisis and should be started on a
rapidly acting immune therapy such as IVIG or plasmapheresis.
2. Treatment of underlying Infections/Cause – Patients with Myasthenia are often chronically
immune suppressed and may be at risk for opportunistic infections, or aspiration pneumonia
from poor airway protection as well as diseases in the general population.
3. Cholinesterase inhibitors*: Pyridostigmine (mestinon) – Symptomatic treatment which
improves strength, however does not change the underlying disease. Dose starting at 30mg PO
TID, titrate to effect 30-120mg Q3-8H, max of 1500mg/day. IV dose is 1/30th of the PO dose
and can be used in patients who are an aspiration risk given bulbar weakness. Alternatively, a
feeding tube can be placed for PO meds.
In some cases one could consider stopping the cholinesterase inhibitor if it is not clear as the to
cause of the patient’s weakness.
Patients with pure Ocular Myasthenia may only require treatment with acetylcholinesterase
inhibitors and not necessarily immune modulation.
*overtreatment with cholinesterase inhibitors can cause weakness and possibly cholinergic
crisis-however, this is very uncommon. In patients on ventilator support and/or having
difficulty weaning from the vent, one may consider stopping the Cholinesterase inhibitor for a
short time to see if the patient improves as patients in the ICU may have decreased clearance
and overtreatment is a possibility.
4. Steroids: Steroids are the first line therapy, however they can worsen symptoms acutely
through a variety of mechanisms (increased production of Acetylcholinerase, structural
similarity to neuromuscular blocking agents) and must be used with caution. There are several
different approaches to treatment. High dose steroids should only be initiated in the hospital as
they can cause an acute decline, and one generally starts them in the setting of IVIG treatment
or plasmapheresis (or must be prepared to start IVIG or plasmapheresis if the patient declines
after steroids). If it occurs, steroids generally will lead to weakness 3-5 days after treatment and
weakness generally lasts 3-10 days. This can occur in 50% of patients with 10% requiring
mechanical ventilation. In some cases, one may prefer to start IVIG or Plasmapheresis without
steroids. Steroids generally start to have an effect in approximately 2 weeks after initiation of
treatment and maximal effect at 6mo to 1 year.
Inpatient Regimen (High Dose) – start at Prednisone 60mg PO QDAY, then wean to lowest
tolerated dose over several months to a year.
Outpatient Regimen (Low Starting dose) – Start at Prednisone 25mg PO QDAY titrate to 60mg
PO QDAY by increasing 5mg PO QDAY every 3-4 days and closely following clinical response then
wean to lowest tolerated dose over several months to a year.
It may take several trials to discover the lowest tolerated dose. One must be careful to follow
the clinical course during treatment to avoid worsening which may be caused by steroids. If the
patient reports worsening strength, one should consider slowing their taper or titration. Some
authors suggest an alternating day regimen to reduce sided effects of steroids.
Steroids are the preferred treatment in young women of childbearing age.
5. Steroid Sparing or Steroid Adjunctive therapies: (often used with steroids to achieve a lower
maintenance dose, or wean off) Generally, one of the following agents is chosen:
Azathioprine - Start with test dose of Azathioprine 50mg PO QDAY for 1-2 weeks and monitor
for side effects, if tolerated increase with slow titration to target dose of 2-3mg/kg day. Clinical
benefit is not seen for 6 months after initiation of treatment. Contraindicated in liver failure or
patients with bone marrow suppression.
Mycophenylate Mofetil – Start at 500mg po bid, if tolerated for 1-4 weeks, increase to 1000mg
PO BID. Onset of action slightly faster than Azathioprine, 4-40 weeks (11 average).
Contraindicated in patients with bone marrow suppression. Associated with a risk of leukemia.
Cyclosporine – Start with Cyclosporine 2.5mg/kg PO BID (total 5mg/kg/day). One should titrate
to trough level, side effects and clinical response. Generally works more quickly than
Azathioprine or Mycophenylate Mofetil, as effect is seen in 1-2 months. Contraindicated in
renal failure, often avoided in older patients.
Other Steriod Sparing treatments: Cyclophosphamide, Tacrolimus, Rituximab. Consider review
of more recent evidence if considering these therapies.
6. Surgery – Thymectomy is controversial. While no RCT has shown benefit, anecdotal evidence
suggests that it is effective. Patients under age 65 (50 in some institutions) may be eligible for
thymectomy. All patients with a thymoma should be considered for surgery as while it is rarely
malignant it can be locally invasive. Benefit of surgery does not occur for several months or
even years after the procedure.
Surgery may precipitate Myasthenic Crisis, so patients should be in the best condition possible
before surgery, with lowest dose possible corticosteroids to prevent problems with wound
healing. Frequently patients will undergo IVIG treatment or plasmapheresis (2-5 cycles) 1 week
prior to surgery to prevent worsening of disease with surgery.
7. IVIG – IVIG 1-2g/kg IV Infusion is sometimes used monthly as a bridging therapy in patients who
are unable to take steroids, until another agent becomes effective such as Mycophenylate
Mofetil or Azathioprine.
8. Plasmapheresis – May also be used as a bridging therapy.
Myasthenic Crisis Treatment
9. Supportive Care as above
10. Steroids – Steroids do not have a clear effect in the acute management of myasthenic crisis, and
may worsen symptoms. One could consider starting steroids (and some authors suggest this),
however given the lack of evidence for a rapid effect and potential to exacerbate symptoms
even to the point of requrining intubation, (see ref. 1) there is no clear indication for steroids. If
started the beneficial effect is seen at 2-6 weeks.
11. IVIG – (many brands) – Dosed at 2g/kg total over 5 days (0.4mg/kg/day usually infused over ~6
hours but varies based on the brand and dosing instructions for the particular type of IVIG).
Alternatively, 1g/kg IVIG dosed over one day was shown to be equivalent to 2g/kg IV, although
there was a trend to superiority of the 2g/kg dose in a small randomized controlled trial.
12. Plasmapheresis/Plasma exchange – Dosed as one plasma volume exchange for 3-5 treatments
on alternating days. There is limited RCT data, but non-randomized trials suggest significant
(sometimes dramatic) improvement. In patients with respiratory failure, Plasma exchange has
been shown to work faster than IVIG with more patients extubated at 2 weeks than the IVIG
group (26 IVIG patients 27 Plasma exchange), but overall outcome appears to be equivalent
based on this trial and Cochrane review.
Adjunctive Treatments
Patients on chronic steroids and immune suppression may require PCP pneumonia prophylaxis with
TMP/SMZ. Chronic steroid treatment may lead to osteoporosis, gastric ulcers, infections, and diabetes
mellitus and may require prophylaxis. (Calcium Supplement, Vit D, proton pump inhibitors, Glycemic
Control) Patients with side effects from pyridostigmine may benefit from glycopyrrolate 1mg TID for
secretions and Lomotil or Immodium for diarrhea.
Prognosis
Most patients will have a normal life span, however despite modern treatment, mortality for
Myasthenia Gravis remains 3-8%. Formerly, Mortality for Myasthenia Gravis was over 30 percent.
Medications To avoid in Myasthenia Gravis*
Antibiotics
Aminoglycosides – (gentamycin, tobramycin, neomycin, paromomycin, amikacin,
kanamycin, streptomycin), Tetracyclines, Fluoroquinolones, Ampicillin,
Azithromycin, Erythromycin, Sulfonamides,
--Cephalosporins are OK.
Anticonvulsants carbamazepine, gabapentin, phenytoin
Cardiovascular
beta-blockers (including timolol eye drops), calcium channel blockers,
procainamide, quinidine, lidocaine, procaine
Hormones
ACTH, corticosteroids, oral contraceptives, thyroxine
Neuromuscular
Succinocholine, Curare Derivatives (vecuronium, rocuronium etc.)
Blockers
Psychiatric
Phenothiazines (chlorpromazine/thorazine)
Other
These medications are associated with some case reports of Myasthenic
Exacerbations but would not be expected to cause an exacerbation: cimetidine,
citrate, chorloquine, cocaine, diazepam, lithium, quinine, trihexylphenidyl,
radiocontrast, gemfibrizil, HMG-CoA inhibitors (statins)
MEDICATIONS NEVER TO USE IN MYASTHENIA
D-Penicillamine, Botulinum Toxin, interferon alpha
*Bold Medications especially should be avoided
Characteristics/Differentiation between Botulism, Cholinergic and Myasthenic Crisis
Exam/History
Myasthenic Crisis
Cholinergic Crisis
Pupils
Normal/Reactive
Miosis (small pupils)
Possible Large pupils due to
increased sympathetic drive
Vision
Frequent Diplopia
Possible diplopia
Heart Rate
Bowel Symptoms
Normal
None
Normal to Bradycardic
Diarrhea, Vomiting, Increased
Salivation
Muscle Symptoms
Weakness
Cramping/Weakness
Sweating
Urinary Symptoms
Pulmonary Symptoms
Normal
Normal
May have shortness of breath.
Diaphoresis
Urinary Incontinence
May Have Wheezing, Mucous
Plugging, Shortness of breath
Reflexes
Usually Normal
Usually Normal
Botulism
Impaired Pupillary response.
Dry eyes.
Blurry vision Due to loss of
accommodation, and Double
vision, often secondary to 6th
nerve palsy.
-Diarrhea, Nausea, vomiting,
then constipation, ileus, due to
smooth muscle paresis. Dry
Mouth.
Weakness, “Descending
Paralysis”
Normal to Anhydrosis
Urinary Retention
May have Shortness of breath.
Normal early, then depressed
or absent.
Normal
Mental Status
Normal
Possibly Confused
*Not all of the above symptoms need to be present for cholinergic crisis or botulism.
**Historically the Tensilon test (Edrophonium) was used to differentiate Cholinergic Crisis from Myasthenic crisis as Myasthenic
Crisis should improve, and Cholinergic Crisis should worsen with edrophonium, however clinically it is unreliable, there is little
utility if the patient requires ventilatory support as one would provide support until the patient improves in either scenario, and
is associated with cardiac arrhythmia risk, especially in older patients.
References/Recommended Reading
1. Jani-Acsadi A, Liask R. Myasthenic Crisis: Guidelines for prevention and treatment. Journal of
the Neurological Sciences. 2007;261:127-133
2. Discussions with Dr. Stephen Hauser and Dr. Andrew Josephson, Professors Rounds 4/2/2008
3. Mehta S. Neuromuscular Disease Causing Acute Respiratory Failure. Respiratory Care. 2006; 51
(9): 1016-1023
4. Drachman DB. Myasthenia Gravis. New England Journal of Medicine. 1994; 330:1797-1810
5. Berman B, Ambrose J, Douglas V, Ho E, Ganguly K, Kamel H, Kerchner G, Lee A, Maccotta L.
UCSF Department of Neurology Resident Curriculum. 5th edition. University of Califonia San
Francisco. San Francisco. 2007-2008.
6. Pascuzzi RM. Medications and Myasthenia Gravis (A Reference for Health Care Professionals)
www.myasthenia.org. 2000. Updated 2007.
7. Bird SJ. Treatment of Myasthenia Gravis. UpToDate.com.
https://vpn.ucsf.edu/online/content/,DanaInfo=www.utdol.com+topic.do?topicKey=muscle/45
57&selectedTitle=3~150&source=search_result. 4/15/2007.
8. Bird SJ. Chronic Immunomodulating Therapies for Myasthenia Gravis. UpToDate.com.
https://vpn.ucsf.edu/online/content/,DanaInfo=www.utdol.com+topic.do?topicKey=muscle/94
65&selectedTitle=9~150&source=search_result. 1/13/2006
9. Newton E. Myasthenia Gravis. eMedicine.com.
http://www.emedicine.com/emerg/TOPIC325.HTM. 3/14/2007
10. Scherer K, Bedlack RS, Simel DL. Does This Patient Have Myasthenia Gravis? JAMA.
2005;293:1906-1914
11. Schneider-Gold C, Gajdos P, Toyka KV, Hohlfeld RR. Corticosteroids for myasthenia gravis.
Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD002828. DOI:
10.1002/14651858.CD002828.pub2.
12. Gajdos P, Chevret S, Toyka K. Plasma exchange for myasthenia gravis. Cochrane Database of
Systematic Reviews 2002, Issue 4. Art. No.:CD002275. DOI: 10.1002/14651858.CD002275.
13. Qureshi AI, Choudhry MA, Akbar MS, et al. Plasma exchange versus intravenous
immunoglobulin treatment in myasthenic crisis. Neurology. 1999;52(3):629-32
14. Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane
Database of Systematic Reviews 2008, Issue 1. Art. No.: CD002277. DOI:
10.1002/14651858.CD002277.pub3.
15. Geyer JD, Keating JM, Potts DC, Carney PR. Neurology for the Boards. 3rd Ed. Lippincott
Williams and Wilkins. Philadelphia. 2006