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Myasthenia Gravis (MG)

Diagnosis and management of Myasthenia Gravis for doctors, medical student exams, finals, MRCP and USMLE

 

Background to Myasthenia Gravis 

  • Myasthenia Gravis (MG) is an autoimmune condition where an immune response is directed towards the receptors within the neuromuscular junction (NMJ)
  • It manifests as weakness, the key characteristic of which is fatigueability
  • The Acetylcholine receptor (AChR) is responsible for generating an action potential by receiving Acetylcholine (Ach) from across the synapse
  • If these receptors are damaged or blocked, the transmission from the post synaptic membrane is blocked making muscular contraction less likely

 

Epidemiology of Myasthenia Gravis 

  • MG affects women more than men as is typical for autoimmune conditions
  • There are usually two groups of patients:
    • Young women (20-35) who present with a generalised, and often acute condition
    • Older men (60-75) who usually present with prominent oculobulbar involvement
  • The antibody responsible is most commonly the AchR Ab (Acetylcholine receptor antibody) which is situated on the post synaptic membrane of the neuromuscular junction
    • These are present in approximately 90% of patients who present with generalised MG
  • Other antibodies associated with the condition include anti-MUSK (anti muscle specific kinase), anti-striated muscle antibodies, and anti-thyroid antibodies

 

Presentation of Myasthenia Gravis 

  • Patients usually present with fatigueable weakness
    • This means that they get progressively weak with muscle use and over the course of the day. The weakness improves with rest
  • Generalised MG can present and/or deteriorate fast and may represent an emergency if respiratory muscles are involved
  • Ocular and bulbar involvement is common therefore patients often present with:
    • Ptosis
    • Swallowing difficulties
    • Speech disturbance
    • In the elderly population, bulbar involvement can lead to recurrent aspiration pneumonias

 

Click here for how to demonstrate muscle fatigueability in a myasthenia examination 

 

Differential Diagnosis of Myasthenia Gravis

  • Acutely (rapidly progressive or sudden weakness)
    • Infection
      • Botulism
      • Lyme disease
    • Inflammatory
      • Guillain-Barré Syndrome (GBS) and variants
    • Vascular
      • Brainstem or spinal cord infarct
  • Ptosis or eye movement disorder
    • Bilateral Horners syndrome or third nerve palsy (check pupil for involvement)
    • Thyroid eye disease
    • Sarcoid
    • Lyme disease
    • Mitochondrial disease
  • Oculo-bulbar weakness
    • Pseudobulbar palsy (c0rticobulbar tract lesion)
    • Osmotic demyelination
    • Space occupying lesion
    • Vascular (stroke)
    • Motor neurone disease (look for fasciculations, especially of the tongue)
    •  Infection
      • Botulism
      • Lyme disease
    •  Parainfectious/Inflammatory
      • Guillain-Barré Syndrome and variants

 

Video on the pathogenesis and treatment of myasthenia gravis

 

Diagnostic tests in Myasthenia Gravis

  • Antibody testing
    • Anti-AChR antibodies are present in approximately 90 percent of patients with classical myasthenia, but can be as low in as 50-70 percent in ocular disease
      • Also note there can be false positive AChR Abs (at low titers) in Lambert-Eaton Myasthenic Syndrome (approximately 5%) and Motor Neuron Disease (3-5% percent)
    • Anti-MUSK antibodies
      • Antibodies to the Muscle Specific Kinase (MuSK) are present in 40-50 percent of those with generalized myasthenia gravis who are AChR-Ab negative
    • Anti-striated muscle antibodies, and anti-thyroid antibodies can also be present but may not be specific
    • Approximately 10% of patients are ‘seronegative’ (negative AChR and MUSK antibodies).
    • As such antibodies in MG are complex and, though a key part of reaching the diagnosis, do not need to be positive for a diagnosis to be made
  • Neurophysiological testing (diagnosis is usually made with this)
    • Single fibre EMG
      • Shows increased jitter
    • EMG repetitive stimulation
      • Shows progressive decrementation in muscle action potential (i.e. fatigueability of action potential amplitude)
  • Tensilon/Edrophonium test (historically)
    •  In the Tensilon/Edrophonium test  a short acting AChE (Acetylcholine-esterase) inhibitor is given, and compared with a placebo (with both patient and administrator being blind to which is which)
    • If this test is positive the patient will have a temporary and sometimes quite marked improvement in symptoms with the edrophonium, not with the placebo
    • The risk of bradycardia induced by edrophonium means this is rarely done in practice
    • If done, it should always be performed with atropine ready and cardiac monitoring during administration of both the edrophonium and placebo (saline)

 

Initial management of Myasthenia Gravis

  • Acutely, patients should have forced vital capacity (FVC) measured
    • If this is low (<1.5l) then make sure ITU are at least aware of the patient, as they can rapidly deteriorate and require intubation and ventilation
    • Measure this at least 4 hourly in patients with acute/relapsed MG at presentation
    • A baseline ABG is useful
  • Be aware that an acute LRTI may lead to significant decompensation
    • Investigate with bloods and chest x-ray
    • ABG
      • Type 2 respiratory failure (in a patient with normal lungs) is a late sign and indicates marker neuromuscular weakness
    • Treat an LRTI as appropriate, continuing to monitor respiratory function with FVC

 

Further investigations of Myasthenia Gravis after initial management

  • As mentioned above, patients should always have the forced vital capacity (FVC) measured. This is an ESSENTIAL BEDSIDE TEST to ensure there is no respiratory muscle involvement or compromise
  • Thymoma
    • At diagnosis, patients should have their chest and mediastinum imaged to look for evidence of associated thymoma (10-15%) or thymic hyperplasia (50-60% particularly young, generalised MG)
    • Removal of thymoma is essential as they have malignant potential
    • Removal of the thymus in individuals with thymic hyperplasia has been found to have a positive affect on the myasthenic symptoms

 

Treating the symptoms

  • Pyridostigmine is an AChE inhibitor
    • It has a duration of action of about 3-5 hours and is used over the day to boost the ACh levels in the synaptic gap to improve transmission
  • It has cholinergic side effects of increased salivation and patients may require help controlling secretions
    • Usually hyoscine butylbromide is given alongside
    • Topical atropine drops can be used on the tongue
  • It can also lead to abdominal cramps and diarrhoea, which are worse at higher doses
  • As such, pyridostigmine needs to be started at a low dose and uptitrated as required

 

Treating the underlying condition

  • Immunosuppression is the main stay of treatment
  • Acutely (and in flares)
    • IVIG and/or plasma exchange
      • If plasma exchange is available, always exchange BEFORE giving IVIG (or you will just exchange all the IVIG out of circulation)
    • Steroids (e.g. methylprednisolone or prednisolone)
      • NB. Steroids may lead to a transient and sometimes significant worsening of MG and should therefore be uptitrated gradually and patients monitored closely.
  • Longer term
    • Steroids (e.g. prednisolone)
      • NB. Steroids may lead to a transient and sometimes significant worsening of MG and should therefore be uptitrated gradually and patients monitored closely
    • Steroid sparing agents are used, usually azathioprine
      • This is often started alongside steroids at diagnosis
      • TPMT levels should be checked as those with low levels are at risk of sensitivity to azathioprine
      • Other immunosuppressive therapies are also sometimes used, e.g. ciclosporin, methotrexate and mycophenolate mofetil in patients not responsive to steroids and azathioprine
      • In treatment resistant cases, increasing success is being seen with rituximab
  • Thymectomy
    • Thymectomy can cause improvement and even remission in up to 80% of MG, especially the young population, and is usually recommended

 

Video with examination (demonstrating ptosis) in myasthenia gravis

 

Complications of Myasthenia Gravis

  • Respiratory failure
    • If require ITU and ventilation often then need tracheostomy at least temporarily
  • Aspiration pneumonia
  • Increased venous thromboembolic risk

 

Prognosis of Myasthenia Gravis

  • On treatment, symptoms can usually be managed and on immunosuppression the underlying disease process can be controlled
  • Mortality attributed to myasthenia is approximatley 4%, with the main risk factors being age older than 40 years, short history of progressive disease, and thymoma
    • Patients with treatment resistant myasthenia and who present acutely may have a significant greater morbidity and mortality

 

Click here for questions on Myasthenia Gravis (MG)

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