FRCA Notes

Myasthenia Gravis

The curriculum asks for knowledge of the implications of myasthenia gravis, and the principles of anaesthesia for such patients.

September 2019 featured a CRQ on this topic (55% pass rate); marks were lost on clinical aspects of the question.

Relevant Primary FRCA Sections

  • Physiology: The Neuromuscular Junction
  • Pharmacology: Anticholinesterases

Resources

  • Myasthenia gravis is the most common disorder of the neuromuscular junction
    • Congenital myasthenic syndromes exist, though their management is quintessentially the same as that of myasthenia gravis

  • Incidence 1 - 2/1,000
  • Bimodal distribution, either:
    • Young females (20 - 30yrs; 3x female preponderance)
    • Older males (60 - 70yrs)
  • A B-lymphocyte-mediated, auto-immune condition characterised by IgG antibodies against various post-synaptic proteins at the NMJ:
    • Nicotinic acetylcholine receptor (nAChR; 80%)
    • Muscle-specific kinase (MuSK; 4%)
    • Lipoprotein receptor-related peptide 4 (LRP4; 2%)
    • Agrin
  • It is seronegative in 5% of cases

  • These antibodies reduce the number of functional receptors by:
    • Blocking acetylcholine binding to the receptor
    • Increasing rate of degradation of receptors
    • Triggering complement-induced damage to the NMJ
  • Overall there is reduced AChR density and only ∽30% normally functioning receptor number; the 'margin of safety' at the NMJ is lost
  • There is consequenly a decreased amplitude of post-synaptic potentials and a failure to instigate muscular contraction

    • Thymic association

  • 75% of cases are associated with thymic disorders:
    • Thymus gland hyperplasia (early - onset disease) or atrophy (late - onset disease)
    • Thymoma (10 - 15%)

    Associated auto-immune conditions

  • Auto-immune thyroid disease (15%)
  • SLE (1 - 8%)
  • Rheumatoid arthritis (4%)
  • Type 1 diabetes mellitus
  • Scleroderma
  • Pernicious anaemia
  • Polymyositis/dermatomyositis
  • Addison's disease
  • Vitiligo

  • The cardinal feature is voluntary muscle weakness
  • Said weakness is exacerbated by exercise/muscle use (fatiguability) and relieved with rest

  • 15% of patients will have pure ocular myasthenia; the remaining 85% will have generalised disease
Ocular muscles Facial muscles Bulbar function Limb muscles Respiratory muscles
Diplopia Inability to smile Dysphagia Voluntary muscle weakness Reduces respiratory effort
Ptosis Inability to close mouth Dysarthria / nasal speech Fatiguable weakness Ventilatory failure (crisis)
External ophthalmoplegia Impaired facial expression
Strabismus (squint) Difficulty chewing

Classification of myasthenia gravis

  1. Ocular only
  2. Mild weakness; responding to therapy
  3. Moderate weakness; less responsive to therapy
  4. Acute fulminating presentation ± respiratory dysfunction
  5. Myasthenic crisis requiring mechanical ventilation

  • History and examination
  • 'Ice pack test'; ptosis improves with application of ice pack as lower temperature enhances NMJ transmission
  • EMG; characteristic progressive decline in CMAP amplitude with repetitive stimulation
  • Tensilon test using 10mg IV edrophonium
  • Detection of anti-nAChR autoantibodies
  • CT/MRI of mediastinum to check for thymoma
  • Thyroid function tests

  • Anticholinesterases e.g. pyridostigmine

  • Immunosuppression
    • Typically corticosteroids e.g. prednisolone 20 - 60mg/day
    • ± azathioprine as a steroid-sparing agent

  • Thymectomy if <60yrs old and thymoma present

  • Plasma exchange ± IVIg; for short-term remission, in the management of crisis or to optimise pre-operatively

  • Myasthenic crisis is the presenting feature in 20% of patients with MG, and there is a 15 - 20% lifetime incidence for those with the disease

Precipitating factors

  • Infection (most commonly)
  • Unfortunately, an array of frequent happenings in the perioperative period are known to trigger crises:
    • Surgery itself
    • Pain
    • Stress
    • Drugs, including NMBA
    • Hypothermia (and hyperthermia)
    • Sleep deprivation
  • Pregnancy

Clinical features

  • Inability to support their own head; the chin falls onto the chest
  • Absent cough
  • Absent gag reflex and risk of aspiration
  • Respiratory distress
    • Use of accessory muscles
    • Paradoxical abdominal breathing
    • Vital capacity <20ml/kg (<30 - 40% predicted)
    • Respiratory failure
    • Inadequate post-operative ventilation

Management of crisis

  • 66 - 90% will require invasive ventilation
  • High-dose steroids, either prednisolone or pulsed methylprednisolone
  • Other immunosuppression e.g. azathioprine, mycophenolate, cyclophosphamide, rituximab
  • Plasma exchange
  • IVIg

Perioperative management of the patient with myasthenia gravis

  • The general approach should be to use LA or RA, as the majority of issues arise owing to GA
  • If GA is required, appropriate pre-operative planning should take place

History and examination

  • History of the disease, including:
    • Disease duration and severity
    • Presence of bulbar symptoms
    • Respiratory muscle involvement
    • Associated auto-immune conditions
    • Thorough drug history

  • Careful airway assessment as:
    • Coalescing rheumatoid disease may limit neck ROM
    • Large thymoma may cause tracheal compression

Investigations

  • FBC
  • U&E
  • LFTs
  • TFTs

  • 12-lead ECG

  • Respiratory muscle function i.e. vital capacity

Risk assessment

  • Consent and discuss with the patient the possibility of prolonged post-operative mechanical ventilation
Factors increasing the risk of requiring post-operative ventilation
Chronic lung disease
Pyridostigmine dose >750mg/day
Duration of disease >6yrs [most predictive]
Pre-operative FVC <2.9L
Grade 3 or 4 myasthenia

Optimisation

  • Consider admission up to 48hrs prior to surgery in those undergoing major elective surgery, for:
    • Monitoring of respiratory function
    • Titration of anticholinesterases and steroids
    • Use of plasma exchange/IVIg
    • Chest physiotherapy

  • Ensure patient is first on the list

Monitoring

  • Standard AAGBI monitoring
  • Arterial line for those undergoing median sternotomy for thymectomy
  • Use continuous, quantitative neuromuscular monitoring if NMBA are to be used

Drug management

  • Traditionally, anticholinesterases are held on the morning of surgery
  • Missed doses may manifest as post-operative weakness
  • Pyridostigmine 60mg PO is equivalent to 2mg IV or neostigmine 500μg IV
  • Steroids should be given on the morning of surgery and additional doses given i.e. steroid cover

    • Drugs to avoid in myasthenia gravis
    Antibiotics:
    Aminoglycosides (e.g. gentamicin)
    Fluoroquinolones (e.g. ciprofloxacin)
    Macrolides (e.g. clarithromycin)
    Polymixins (e.g. colistin)
    β-adrenergic antagonists
    D-penicillamine
    Desferrioximine
    Magnesium
    Sodium channel antagonists (e.g. quinidine, procainamide)
    Statins

  • Consider glycopyrrolate if bulbar dysfunction and high secretion burden
  • The parasympatholytic effect may also reduce risk of vagal potentiation, which may be a side-effect of anticholinesterases

Regional technique

  • LA/RA may be used to avoid GA or as adjuncts to spare sedating opioid analgesics
  • In theory ester LA metabolism is impaired by regular anticholinesterase medications so amide LA should be used

  • Care should be taken when using neuraxial techniques; impairment of the accessory muscles by high block may be poorly tolerated
  • There's a relative contraindication to interscalene or supraclavicular BPB techniques owing to ipsilateral phrenic nerve paralysis

General anaesthetic technique

  • Avoid if possible
  • If unavoidable, aim to use short-acting agents to minimise respiratory depression and promote early recovery
  • Remifentanil TCI may be beneficial by negating the need for NMBA for intubation

  • SV ± pressure support may be acceptable for short procedures although excessive respiratory effort should be avoided
  • PPV should be used for longer procedures

NMBA

  • Patients may have an abnormal response to NMBA, even in pure ocular myasthenia
    • There is relative resistance to suxamethonium; the ED95 is 2.5x higher in MG
    • Phase II block may develop

    • There is extreme sensitivity to non-depolarising NMBA
      • 10% dose of pancuronium required
      • 30 - 40% dose of atracurium/vecuronium required
    • Administer 1/10th of normal dose and titrate to quantitative ToF

  • As such, NMBA should be avoided
  • Instead, intubate under deep volatile anaesthesia following propofol induction, or remifentanil infusion
  • If NMBA are required the rocuronium + sugammadex is preferable as anticholinesterase reversal should be avoided
  • Patients should be fully reversed prior to extubation with a ToF ratio of >0.95, which is associated with reduced incidence of post-operative pulmonary complications in MG

  • Majority can be safely extubated without issue, but have a low threshold for monitoring in an HDU environment
  • Those undergoing trans-sternal thymectomy are likely to require HDU post-operatively
  • Anticholinesterases are re-started at lower dose in the post-operative period
  • Suitable multimodal analgesia should be provided