Myasthenic crisis

Myasthenia gravis has appeared in the exam mainly as a foil for Guillain-Barre syndrome, but has more recently graduated to become an SAQ topic all of its own. Historical appearances have included:

• Question 5 from the second paper of 2022: all about myasthenic crisis specifically
• Question 20 from the first paper of 2016: compare GBS with myasthenia gravis. 
• Question 11 from the second paper of 2009, where myasthenia was a valid differential
• Question 20 from the first paper of 2006, where it was a distant differential
• Question 5 from the second paper of 2005, where it was one of three things being compared

So, it would seem it deserves its own summary note. Thus...

The UpToDate entry by Bird is probably a definitive peer-reviewed source for the time-poor candidate who is either a paying customer or endowed with institutional access. The best free alternative would have to be Wendell & Levine (2011) or Schroeter et al (2018).  For some excellent FOAM resources the reader is redirected to the IBCC and LITFL entries, as they are both rich in detail and free of pointless rambling. 

Briefly, on myasthenia gravis

The pathophysiology of things in general is really somewhat deemphasised in the CICM exams, and so only the shortest summary is offered here, as well as a link to redirect the interested reader to a great article by Baets & Stassen (2002).  At the most basic level this thing is an autoimmune disease caused by IgG antibodies against the nicotinic acetylcholine receptor, and finding these antibodies is the most important step in the diagnostic process. These antibodies bind to a  highly immunogenic epitope at the α-subunit of the receptor, and the result is the destruction of the receptor protein which is internalised into the myocyte and degraded. Obviously the binding of antibodies also has a significant immune effect, and produces the complement-mediated destruction of the postsynaptic membrane (though thankfully not the whole myocyte). The membrane grows back, but it has fewer folds and therefore a smaller surface area. 

Clinical features of myasthenia gravis

From Sanders & Massey (2008):

Eye signs:

• Diplopia
• Ptosis
  • May develop within 60 seconds of sustained upard gaze
  • Variably unilateral or bilateral, migrating from eye to eye, and different at different times of the day
  • Improves with ice pack application (neuromuscular transmission improves at lower muscle temperatures, apparently because of increased neurotransmitter release)

Other cranial nerve dysfunction

• Facial muscles (affecting facial expression, eg. corners of the mouth do not lift during a smile, giving a characteristic "sneer" expression)
• Muscles involved in swallowing and mastication
• Tongue weakness, leading to slurred speech

Weakness:

• Proximal more than distal
• Arms more than legs
• Fatiguable: repeated stimulation leads to progressively weaker contraction

Diagnosis of myasthenia gravis

Clinical tests

• "ice pack test" where the ptosis resolves after applying an ice pack to the eye
• Edrophonim challenge, where a short-acting acetylcholinesterase inhibitor is used to quickly and transiently improve muscle power

Biochemical tests

• LRP4 antibodies
• Acetylcholine receptor antibodies: (AChr-Ab)
• Muscle specific tyrosine kinase antibodies (MuSK-Ab)
  • These Anti-MuSK people are often sicker, tend to have more airway reflex problems and respiratory failure, and the onset is often faster. 

Electrophysiology

• Repetitive nerve stimulation: the characteristic finding is a progressive decline in the CMAP amplitude.
• Electromyography: the characteristic finding is "abnormal jitter".
• Fade and post-tetanic facilitation is present on nerve stimulator testing

What else could it be?

• Eaton-Lambert syndrome (antibodies against voltage-gated calcium channels): like myasthenia, except more leg involvement than arm involvement, rarely affecting respiratory or bulbar muscles, and typically related to a neoplasm. And of course also the antibodies are the wrong ones.
• Botulism: also weakness and dysphagia, but the antibodies would be negative, and there are usually prominent autonomic features.
• Guillain-Barre: also prominent autonomic problems, and also the weakness is ascending and ocular muscle involvement is more rare. Again, wrong antibodies. 

Natural history of myasthenia gravis

Hehir & Sylvestri (2018) present a really helpful description of the natural history of this disease. Borrowing from their paper:

• Most people present with eye signs
• Most then go on to develop "genaralised" myasthenia gravis within the next 2-3 years
• Effective and widely available treatment means that most people actually see a decrease in the severity of this disease over the subsequent five years
• Still, most of these people will experience at least one exacerbation during their life
• Of these exacerbations, the vast majority do not meet the definition of "crisis".
• "Crisis" exacerbations affect maybe 15-20% of patients and tend to happen within the first 3 years of the disease, usually following some sort of infectious illness.

So, what is this "crisis" we speak of?

You call that a crisis

Though it might seem to a bit overdramatic to call something a "crisis" or "storm" (because why not "myasthenic conniption" instead), Bedlack & Sanders (2002) defend the term by pointing to the need to have definitions for standardise research and interventional guidelines. A myasthenic crisis is conventionally defined as any myasthenic exacerbation which results in intubation or non-invasive mechanical ventilation, or which prevents extubation following an elective procedure. It therefore depends on the decision to intubate or extubate, and therefore completely contingent on the subjective views of the intensivist and anaesthetist, of whom some might be cowards and others might be cowboys. And it might sound like life-threatening respiratory muscle failure is a good way to define severe disease, but one must be reminded that some of these patients might end up being intubated because of airway reflex problems.  Still, the scientific community seems to have settled on this definition, and that is how it appears in UpToDate.

Management of myasthenic crisis in the ICU

This section is a blend of the 2020 international myasthenia gravis consensus statement and the myasthenia crisis chapter from the Textbook of Neuroanesthesia and Neurocritical Care (2019).

• Remove autoantibodies:
  • Plasma exchange - usually five exchanges, every second day.
  • IV immunoglobulin, 2g/kg over two days - and nobody seems to know the underlying mechanism of action. A single dose of 1g/kg is probably equally effective (Gajdos, 2005)
  • There does not seem to be any difference in outcomes between these strategies
• Prevent synthesis of further antibodies:
  • Corticosteroids are first line. They may cause a transient worsening of the symptoms, though this is not a well-defined complication and may spare some patients according to Lotan et al, 2020. It appears nobody actually understand the mechanism of this. In any case, it does not matter - the patient is having a myasthenic crisis, so is mechanically ventilated by definition, so how much worse could their weakness get? Anyway, the dose is usually about 1.0-1.5mg/kg/day of prednisolone.
  • If steroids are contraindicated for some reason, mycophenolate or azathioprine are alternatives. You can also use them as steroid-sparing agents, to decrease the steroid dose.
  • Rituximab, cyclophosphamide, pulsed streroids if first line therapy does not work
  • Thymectomy is viewed as definitive, but should wait until the patient is stable
• Prevent damage to the neuromuscular junction by complement
  • Eculizumab is an option if the myasthenic crisis is severe and refractory
  • This is an antibody to the terminal C5 complement molecule, and it should prevent the formation of the membrane attack complex which is what damages the neuromuscular junction
• Restore neuromuscular transmission:
  • Acetylcholinesterase inhibitors such as pyridostigmine could be started fairly early, but will probably have little effect in the initial stages of the crisis. They will become more important as the time comes to wean the patient from the ventilator. Pyridostigmine is usually given as 240-480mg/day in several divided doses. 

Drugs that exacerbate myasthenia gravis

Again from the 2020 international myasthenia gravis consensus statement:

• Antibiotics:
  • Aminoglycosides
  • Macrolides
  • Fluoroquinolones
• Beta-blockers
• Hydroxychloroquine
• D-Penicillamine
• Desferrioxamine
• Immune checkpoint inhibitors (ipilimumab, pembrolizumab, atezolizumab, and nivolumab)
• Iodinated contrast media
• Live attenuated vaccines
• Procainamide
• Statins

Extubation for the myasthenia gravis patient

So, with the worst of the myasthenia crisis now largely behind you, the time has come to think about weaning and extubation for your very borderline marginal patient who is probably still as weak as a kitten. It is weird that this aspect was apportioned only 30% of the total mark in Question 5 from the second paper of 2022, as this is probably the area that requires the most skill from the intensivist, whereas merely listing the interventions and classes of myasthenia-exacerbating drugs would be as easily accomplished by ChatGPT. Still, at least it was in there. Specifically, the question of extubation is asked in terms of "methods to address the challenges". It felt like it would be easier to manage this if it were a table:

Challenge	Methods to address the challenge
Residual weakness	Pyridostigmine
Increased secretions (a side-effect of pyridostigmine)	"Propantheline is an antimuscarinic agent that counteracts many of the cholinergic side effects of pyridostigmine without reducing its action at the NMJ" - Farrugia et al, 2020
Slow fluctuating progress	Extubation to NIV is an option, particularly if bulbar function permits. Theoretically weaning could be facilitated by NAVA, but the evidence for that is fairly poor. There is some evidence that elective use of NIV immediately following extubation is better than waiting until the patient develops respiratory failure.
Difficult detection of readiness for extubation	Extubation success can be predicted by improving vital capacity on the ventilator, spontaneous mode, lack of fatuguabuility with sustained "sprints" of lower ventilator support
Concomitant respiratory compromise	It does not need to be said that these borderline patients should  be as free as possible of any other reasons for extubation failure, such as pulmonary oedema or pneumonia.
Steroid and critical illness myopathy	Dietary protein supplementation, physiotherapy, early mobility, use of steroid-sparing agents such as mycophenolate
Poor bulbar function, weak cough	Tracheostomy as a bridge to future normal bulbar function following a course of therapy is a legitimate option

An excellent paper on weaning the patient with neuromuscular disease was published by Torres-Castro et al in 2021, and likely served as the origin for this SAQ. Even though they did not find any papers that fit their inclusion criteria, they discuss the options in some detail, and the ideas in that paper were amalgamated into the table above.