Myasthenia Gravis

Author: Ammar M Salem / Editor: Yasmin Sultan / Reviewer: Kaja Rasheed, Kathryn Blackmore / Code: HAP33, NeuC8, NeuP8, RP5, SLO1Published: 06/09/2021

 

Context

Myasthenia gravis (MG) is a complex disease with many different signs and symptoms, which may be obvious or subtle.

It can cause a life-threatening true neurological emergency characterised by impending respiratory failure. The emergency physician (EP) should be able to promptly recognize, appropriately investigate and initiate treatment when faced with such a crisis

Definition

The name myasthenia gravis, which is Greek in origin, means ‘grave muscle weakness’.

MG is the most common neuromuscular junction (NMJ) disorder. It is an autoimmune disease caused by antibodies to the acetylcholine receptor on the postsynaptic membrane at the NMJ.

MG is characterised by weakness and fatigability of the voluntary muscles.

The annual incidence of MG ranges from approximately 7 to 23 new cases per million.

All ethnic groups and all ages may be affected.

It has a bimodal peak of incidence with the first peak in the third decade and the second peak in the sixth decade (‘young women and old men’).

It is probably under diagnosed in the elderly population.

The NMJ consists of a motor nerve terminal and muscle membrane.

Its function is to amplify a relatively weak nerve impulse and thereby produce a strong electrical impulse in the muscle capable of initiating muscle contraction.

There are three components of the NMJ:

  • Presynaptic membrane
  • Synaptic cleft
  • Postsynaptic membrane

Abnormalities of the NMJ

Abnormalities of the NMJ in MG are postsynaptic in location (in contrast to the presynaptic abnormality in Lambert-Eaton syndrome).

Anti-acetylcholine receptor (anti-AChR) antibodies are found in 80-90% of patients with generalised MG and 50-60% of Ocular MG.

Approximately 10-20% of patients with acquired MG do not have anti-AChR antibodies (seronegative MG). The presence of antibodies against muscle specific protein kinase (MuSK) appears to define a subgroup of patients with MG.

Although MG is predominantly caused by antibodies produced by B-cells, T-cells have also been shown to be important in the pathogenesis.

Thymic abnormalities are found in nearly 75% of patients with MG. Pathological changes are lymphoid follicular hyperplasia (70%) and thymoma (10%). The remaining 20% have other abnormalities.

Learning bite

Statistically, 80% of patients have acetylcholine receptor (AChR) antibodies. Most of those patients who don’t have AChR antibodies have MuSK antibodies instead. Approximately 75% of patients have thymus abnormalities and 10% of these patients have thymoma.

Table 1: Classes of MG
Class Aetiology
Acquired autoimmune Most common
Transient neonatal Maternal anti-acetylcholine receptor antibodies
Drug induced Aminoglycosides, quinine, procainamide
Congenital syndrome Acetylcholine receptor deficiency, slow channel syndrome and fast channel syndrome

There are four classes of MG based on aetiology [2].

Symptoms

Typically, patients present with a history of weakness and fatigue of voluntary (skeletal) muscles. Symptoms worsen on exertion and improve at rest. There is diurnal variation with worsening of symptoms in the later part of the day.

Most commonly affected muscles in order of frequency:

  1. Ptosis
  2. Diplopia
  3. Proximal limb weakness
  4. Facial weakness
  5. Neck flexors/extensors

Ptosis and Other Features

A common presenting feature is ptosis, which is often partial and may be unilateral.

The extraocular muscles are affected initially in about 50% and, eventually, in 90% of cases.

Ptosis improves after a period of sleep (the sleep test) or with the application of ice on the lid (the ice test).

The pupils are typically spared in MG. The face may appear expressionless. The mouth may be open and the patient may have to support the jaw with their hand.

Ocular muscle weakness may be the only feature throughout the course in about 10% of patients.

Deep tendon reflexes are intact or may be brisk.

There is no objective sensory deficit and no deficit in cerebellar function.

There may be dysphonia from laryngeal weakness. There may be dysphagia from weakness of muscles involved in chewing and swallowing.

Learning bite

Ptosis is the commonest physical sign in MG. It is seen in up to 90% of patients. The pupil is unaffected.

Osserman’s Classification

Table 1: Osserman’s classification in MG
  Asymptomatic
1 Ocular signs and symptoms
2 Mild generalised weakness
3 Moderate generalised weakness, bulbar dysfunction, or both
4 Severe generalised weakness, respiratory dysfunction, or both

The severity and progress of the disease is assessed using the Osserman classification [5, 6].

Myasthenic Crisis

 

A myasthenic crisis (MC) is an acute exacerbation of MG leading to:

  • Weakness of the upper airway muscles resulting in obstruction and/or aspiration

and/or

  • Weakness of the respiratory muscles causing reduced tidal volumes

Incidence

About one-fifth of patients with MG experience a crisis, usually within the first two years of diagnosis [7].

Such crises should not be fatal, as long as patients receive timely respiratory support and appropriate immunotherapy to reduce the myasthenic weakness of the upper airway and respiratory muscles [8].

MC is more likely in patients whose history includes previous crisis, oropharyngeal weakness, or thymoma [9].

Learning bite

Approximately 20% of patients will experience a myasthenic crisis, characterised by airway compromise or respiratory failure.

Presentation

In MC, the patient may look anxious with rapid and shallow breathing due to fatigue of respiratory muscles. Paradoxical breathing and recruitment of accessory muscles with inspiration are important clinical signs.

Dysarthric speech and stridor indicate imminent airway obstruction (bulbar myasthenia) [10].

Cardiac arrhythmias, occur in about a fifth of patients with an MC [11].

Common precipitating factors for MC include:

  • Respiratory tract infection
  • Sepsis
  • Stress, surgery, trauma and pregnancy
  • Inadequate treatment
  • Drugs
  • Initial high dose steroid therapy: some patients (approximately 10%) [11] have a paradoxical worsening of MG if steroids are started at high dose. This is referred to as a ‘steroid dip’ [1,10]
  • Idiopathic: approximately 30% [10]

Medications that may trigger MC include:

  • Aminoglycoside and quinolone antibiotics
  • Antiarrhythmics such as quinidine and procainamide
  • Antihypertensives including B-blockers and calcium channel blockers
  • Neuromuscular blocking agents
  • Neuropsychiatric drugs such as phenytoin and lithium
  • Magnesium containing compounds

Bulbar myasthenia

Findings of bulbar myasthenia associated with upper airway compromise include:

  • Flaccid dysarthria with hypernasal, staccato or hoarse speech
  • Dysphagia
  • Tongue weakness
  • Vocal cord abductor paralysis which may produce laryngeal obstruction with stridor [8]

Learning bite

MC is a life-threatening complication of MG. Respiratory failure requires early recognition and prompt management.

Cholinergic Crisis

 

A cholinergic crisis (CC) is an over-stimulation at an NMJ due to an excess of acetylcholine (ACh).

In MG, this occurs as a result of excessive inhibition of the acetylcholinesterase (AChE) enzyme, which normally breaks down acetylcholine. This is a consequence of too high a dose of AChE inhibitors.

In CC, respiratory failure may be present alongside other typical cholinergic symptoms e.g. miosis, diarrhoea, urinary incontinence, bradycardia, emesis, increased lacrimation, or hypersalivation. These features may also be present in organophosphate poisoning.

Excessive ACh stimulation of striated muscles at the NMJ produces flaccid muscle paralysis that can be clinically indistinguishable from weakness due to MC [12].

Main Tests Used

Table 1: Tests used in the diagnosis of MG
Test Where used
Edrophonium* (Tensilon test) Cholinesterase inhibitor. Side effects: bradycardia and/or hypotension
Ice test Not commonly used, applicable only when ptosis present
Acetylcholinreceptor antibody in serum May be the diagnostic “gold standard”, titres do not always correspond with the severity of MG [14]
Repetitive nerve stimulation Sensitive 75%, not specific, uncomfortable to patient
Single fibre electromyography Most sensitive, not specific
Anti-MuSK antibodies For subgroup of seronegative MG
Chest CT/MRI For associated thymic tumours
Brain MRI Where structural brain stem lesion is possible

The main tests used in the diagnosis of MG are shown in the table.

The edrophonium test

The ‘edrophonium test’ is performed to identify MG infrequently; its application is limited to the situation when other investigations do not yield a conclusive diagnosis.

This test requires the intravenous administration of edrophonium chloride (Tensilon, Reversol) or neostigmine (Prostigmin) drugs that block the breakdown of acetylcholine by cholinesterase (cholinesterase inhibitors) and temporarily increases the levels of acetylcholine at the MNJ. In people with MG involving the eye muscles, edrophonium chloride will briefly relieve weakness [10].

In the past, the edrophonium test was routinely performed to confirm the diagnosis and distinguish undertreatment from overtreatment of MG, this practice has been largely abandoned as it is potentially dangerous in impending cholinergic crisis.

Radioimmunoassay test to detect the antibodies that bind to AchR is considered the diagnostic ‘gold standard’ [2]. AchR antibody titers correlate poorly with severity of disease.

Muscle fatigability tests

Muscle fatigability can be tested for in many muscles [8]. Examples include:

  • Looking upward and sideways for 30 seconds to check for ptosis and diplopia
  • Looking at the feet while lying on the back for 60 seconds
  • Keeping the arms stretched forward for 60 seconds
  • The ‘peek sign’: after complete, initial apposition of the lid margins, they quickly (within 30 seconds) start to separate and the sclera starts to show [3]

Learning Bite

The ‘edrophonium test’ is performed to identify MG infrequently; its application is limited where the patient has obvious ptosis. Diagnosis should be confirmed by electrophysiologic and/or immunologic tests.

Additional Screening

Are there any conditions for which MG patients should be screened?

The following are diseases known to be associated with MG:

  • Thyroid disease
  • Diabetes mellitus
  • Rheumatoid disease
  • Perinicious anaemia
  • Systemic lupus erythaematosus (SLE)
  • Sarcoidosis
  • Sjögren’s syndrome
  • Polymyositis

Despite advances in the treatment of MG, there is only a small evidence base. The following treatment modalities are available:

Acetylcholinesterase inhibitors

These drugs increase the availability of the acetylcholine to act on the AChRs.

They are usually the initial drugs used in treating MG; however, they do not modify the course of the disease and provide only symptomatic benefit.

Pyridostigmine is the most frequently used drug.

Corticosteroids

These are needed to treat MG of moderate or greater severity and in mild disease that fails to respond fully to acetylcholinesterase inhibitors.

Oral prednisolone, usually started at a low dose on an alternate-day regimen, and gradually increased, is the recommended first choice short-term immunosuppressant [1,15]

Immunosuppressants

Because of the serious side effects associated with long-term steroid therapy, other immunosuppressant drugs are used as ‘steroid-sparing agents’.

Azathioprine, cyclophosphamide, cyclosporine, methotrexate and mycophenolate mofetil have been used in treating MG.

Azathioprine is the first choice in this class of drugs.

We still lack good randomised controlled trial data on longer-term efficacy, steroid-sparing effect and safety of immunosuppressants in MG [16].

There is no data from randomised controlled trials (RCT) on the impact of any form of treatment on the risk of progression from ocular to generalised MG [20].

Plasmapheresis

Plasmapheresis produces rapid, but temporary, improvement by reducing the amount of AChR antibodies. Indications are:

  • MC
  • Severe MG before thymectomy
  • Early postoperative period
  • Symptom worsening during tapering or initiation of immunosuppressive therapy

No adequate RCTs have been performed to determine whether plasma exchange improves short- or long-term outcome of MG. However, many case series studies report short-term benefit from plasma exchange in MG, especially in MC [21].

Intravenous immunoglobulins (IVIG)

The IVIG mechanism of action remains unknown.

IVIG has the same indications as plasmapheresis. However, in contrast to plasmapheresis, it does not require expensive equipment or a large bore vascular access.

Plasmapheresis usually works quicker than IVIG.

Direct comparison of the two therapies shows them to be equally effective [2,7,10,16-17].

Learning bite

Both plasmapheresis and intravenous immunoglobulin administration have been demonstrated in many case series to provide short-term benefit.

Thymectomy

There are two different indications for thymectomy in MG:

First, thymectomy for thymic tumours associated with around 10% of patients with MG [2,4].

Second, thymectomy for the treatment of MG in the absence of thymoma. It is generally agreed that patients with generalised MG between the ages of adolescence and 60 years should be offered thymectomy as 80%-85% of patients eventually experience improvement in their MG after thymectomy [2]. The precise role of the thymus in MG is still not determined nor is it clear why a minority of patients derive no benefit from the procedure [2,4].

Thymectomy is not effective in anti-MuSK-positive MG.

Introduction

Within the emergency department (ED), assessment of the patient in crisis includes:

  • Step 1: Determine the airway patency and respiratory function
  • Step 2: Confirm the diagnosis of MC
  • Step 3: Search for potentially treatable trigger of the crisis
  • Step 4: Involve the neurology team and intensive care unit (ICU) team

We will consider each of these in turn on the next four pages.

Airway Patency

Key Questions:

  • Does the patient need intubation?
  • Does the patient have a satisfactory swallow?

Because the muscle weakness associated with NMJ dysfunction in MG fluctuates, no single parameter can be used to determine when an MG patient needs respiratory support.

Non-invasive ventilation

Non-invasive ventilation (bilevel positive airway pressure or BiPAP) may prevent the need for intubation in myasthenic patients who have not developed marked hypercapnia [8]. Hypercapnia reflects a more severe degree of neuromuscular respiratory failure than hypoxia alone [19].

The decision to intubate can be straightforward in an MG patient with stridor or history of regurgitation and aspiration. However, other patients have subtle signs of deterioration.
Oxygen saturations can be misleading in patients receiving O2 therapy.

Learning bite

BiPAP should be considered in selected patients with MC who have respiratory compromise (without hypercapnia) and with the ability to synchronise with the machine [22]. A trial of BiPAP before the development of hypercapnia can prevent intubation and prolonged ventilation, reducing pulmonary complications and the lengths of ICU and hospital stay [22].

Endotracheal intubation

Endotracheal intubation may be necessary prior to differentiating between MC and CC [12].

Where there is doubt, the cause of respiratory failure can best be determined after the airway and ventilation have been secured.

Learning bite

The criteria for endotracheal intubation for mechanical ventilation in patients with MC is not well defined and decisions are based on physicians’ preferences and clinical judgement [19].

Direct laryngoscopy/nasoscopy

Direct laryngoscopy/nasoscopy may be useful to demonstrate vocal cord paralysis when bulbar myasthenic findings are not otherwise obvious [8].

Debate exists as to the best method of rapid sequence induction (RSI) in the MG patient. Several strategies can be used. As these patients are weak to start with, the simplest strategy is to use an induction agent and no muscle relaxant [18].

In untreated MG patients, decreased AChR cause succinylcholine (depolarising drug) resistance but increased sensitivity to nondepolarising agents. However, in treated patients these effects can be unpredictable [18]. Therefore, if muscle relaxants are to be used, either the physician must use a larger dose of succinylcholine (1.5-2 mg/kg), or a smaller dose (by factor of 50%) of a rapid onset nondepolarising relaxant, such as rocuronium.

Potential Triggers

Key Point:

Taking a careful history and performing a detailed examination may identify potential triggers for the MC.

Take a careful history and perform a detailed physical examination

Findings, for example fever, upper respiratory tract infection, pneumonia, urinary tract infection, may identify possible triggers for the MC.

Carefully review medication and recent surgery or trauma

Drugs that may worsen MG:

  1. Neuromuscular blockers
  2. Antibiotics: Aminoglycosides, clindamycin, fluroquinolones, ketolides, Vancomycin
  3. Cardiovascular drugs: betablockers, procainamide, quinidine

Others: botulinum toxin, Magnesium, monoclonal antibodies, quinine, chloroquinine, penicillamine

Antibiotics are indicated only if there is strong evidence of infection. Empiric antibiotic use is not recommended as some antibiotics can interfere with neuromuscular transmission. Clostridium difficile infection has been associated with prolonged MC [11].

Baseline investigations include:

  • CXR
  • ECG
  • FBC
  • U&Es
  • C-reactive protein/erythrocyte sedimentation rate
  • Blood culture

Involve Specialist Support

Key Point:

The course of MG is difficult to predict [12].

A MG patient in crisis will need ICU admission for one or more of the following:

  • Respiratory support
  • Fluid and electrolyte management
  • Intravenous immunoglobulins: 2 g/kg given over 2-5 days [8-9]
  • Plasmapheresis: 2-3 L of plasma is removed three times a week until improvement. Most patients require a total of five or six exchanges [8-9]

In a recent study in the US, the trend of IVIG utilisation has increased compared to plasma exchange and thymectomy [7].

Although there are reports of successful treatment of MC with continuous intravenous infusion of pyridostigmine, there is generally no role for cholinesterase inhibitors in the acute setting of MC. There is a risk of life-threatening cardiac arrhythmias due to the muscarinic effects of intravenous cholinesterase inhibitors [8,11].

Learning bite

All MG patients who present to ED with signs of MG exacerbation or a complication associated with MG treatment require admission and expert evaluation.

Learning bite

Continuous infusion of cholinesterase inhibitors is associated with life-threatening cardiac arrhythmias and is unsafe.

What are the factors that would lead to a poor prognosis in MG?

Older age and respiratory failure are predictors of poor prognosis in MG [7]. Median duration of hospitalisation for MG crisis is one month. Patients usually spend half of this time intubated in ICU [9].

What effect on mortality does the duration of intubation have?

The duration of intubation is an important short-term predictor of functional outcome after a crisis.

What is the mortality rate for patients in crisis?

Mortality rate during hospitalisation for crisis is approximately 4-8%. This has decreased from nearly 50% in the 1960s [11,13].

The emergency physician should be aware of the following issues:

  • The differential diagnosis of any patient presenting to the ED with respiratory failure of unknown cause should include neuromuscular respiratory failure
  • Complaints of shortness of breath or dysphagia, especially new onset, should be taken very seriously in MG patients
  • The clinical features of impending crisis can be subtle, especially in the MG patient with vague symptoms
  • The course of MG is difficult to predict
  1. Sathsivam S. Steroids and immunosuppressant drugs in myasthnia gravis. June 2008 vol 4 No 6. DOI: 10.1038/ncpneuro0810.
  2. Thanvi BR, Lo TC. Update on myasthenia gravis. Postgrad Med J. 2004 Dec;80(950):690-700.
  3. Vincent A, Clover L, Buckley, et al. Evidence of underdiagnosis of myasthenia gravis in older people. Journal of Neurology, Neurosurgery & Psychiatry. 2003;74:1105-1108.
  4. Murthy JMK. Thymectomy in myasthenia gravis. Neuorology India Jul-Aug 2009 Vol 57 Issue 4.
  5. Calhoun RF, Ritter JH, Guthrie TJ et al. Results of transcervical thymectomy for myasthenia gravis in 100 consecutive patients. Ann Surg 1999;230:555-61.
  6. Urschel JD, Grewal RP. Thymectomy for myasthenia gravis. Postgraduate Medical Journal. 1998;74:139-144.
  7. Alshekhlee A, Miles JD, Katirji B et al. Incidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals. Neurology 2009;72:1548-1554.
  8. Juel VC. Myasthenia gravis: management of myasthenic crisis and perioperative care. Seminars in neuorology, Volume 24, Number 1, 2004.
  9. Bedlack RS, Sanders DB. How to handle myasthenic crisis. Essential steps in patient care. Postgraduate medicine, Volume 107, Number 4, April 2000.
  10. Bershad EM, Feen ES, Suarez JI. Myasthenia gravis crisis. Southern medical journal, Vol 101, No 1, January 2008; 0038-4348/0-2000/10100-0063.
  11. Gold R, Schneider-Gold C. Current and future standards in treatment of myasthenia gravis. Neurotherapeutics, vol 5, 535-541, October 2008.
  12. Hetherington KA, Losek JD. Myasthenia gravis. Myasthenia vs. cholinergic crisis. Pediatric emergency care, Vol 21, No 8, August 2005; 0749-5161/05/2108-0546.
  13. Lacomis D. Myasthenic crisis. Neurocritical care, Vol 3, 2005;03:189-194.
  14. Armstrong SM, Schumann L. Myasthenia gravis: diagnosis and treatment. Clinical practice, Vol 15, Issue 2, February 2003.
  15. Diaz-Manera J, Rojas-Garcia R, Illa I. Treatment strategies for myasthenia gravis. Expert opinion.Pharmacother. 2009;10(8):1329-1342.
  16. Hart IK, Sharshar T, Sathasivam S. Immunosuppressant grugs for myasthenia gravis. Journal of Neurology, Neurosurgery & Psychiatry 2009 80:5-6; 10.1136/jnnp.2008.144980
  17. Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database of systemic Reviews 2008. Issue 1. Art. No.: CD002277. DOI: 10.1002/14651858.CD002277.pub3.
  18. Smulowitz PB, Zeller J, Sanchez LD, et al. Myasthenia gravis: lessons for the emergency physicians. European journal of emergency medicine. 2005, Vol 12 No 6;12:324-326.
  19. Rabinstein A, Wijdicks EFM. BiPAP in acute respiratory failure due to myasthenic crisis may prevent intubation. Neurology 2002;59:1647-1649.
  20. Benatar M, Kaminski H. Meidcal and surgical treatment for ocular myasthenia. Cochrane Database of Systemic Reviews 2006, Issue 2. Art. No.: CD005081. DOI: 10.1002/14651858.CD005081.pub2.
  21. Gajdos P, Chevret S, Toyka K. Plasma exchange for myasthenia gravis.Cochrane Database of Systemic Reviews 2002, Issue 4. Art. No.: CD002275. DOI: 10.1002/14651858.CD002275.
  22. Seneviratne J, Mandrekar J, Wijdicks EF et al. Noninvasive ventilation in myasthenia gravis. Arch Neural 2008;65(1):54-58.
  23. Carr AS, Cardwell CR, McCarron P; et al. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol. 2010;10:46. Epub 2010 Jun 18.

1 Comments

  1. Dr Eltigani Seedahmed Ibnaouf Ahmed says:

    excellent module about MG.

Leave a Reply