Myasthenia gravis

Background

• Autoantibody degradation, dysfunction, and blockade of acetylcholine receptor at the NMJ
• Thymus is abnormal in 75% of patients
  • Thymectomy resolves or improves symptoms in most patients, especially those with a thymoma
• No sensory, reflex, pupillary, or cerebellar deficits

Drugs Associated with Exacerbations

May Unmask or Worsen

• Antimicrobials (Aminoglycosides, clindamycin, erythromycin, tetracycline, doxycycline, azithromycin, fluoroquinolones, vancomycin, chloroquine, hydroxychloroquine, )
• Cardiovascular drugs (beta blockers, procainamide, quinidine)
• Neuro/psych meds (chlorpromazine, lithium, prochlorperazine, phenytoin, risperidone,
• Other (Botox, quinines, magnesium)

Usually Well-tolerated, but Occasionally Associated

• Local anesthetics
• Antibiotics (Tetracycline/doxycycline, macrolides, metronidazole, nitrofurantoin)
• Anticonvulsants (carbamazepine, ethosuximide, gabapentin, phenobarbital, phenytoin)
• Butyrophenones (haloperidol)
• Phenothiazines (chlorpromazine/prochlorperazine)
• Calcium channel blockers
• Steroids
• Ophthalmic drugs (betaxolol/timolol/proparacaine)
• Other (Iodinated contrast agent)

Clinical Features

Cranial nerve palsy and ptosis in a patient with myasthenia gravis

• Muscle weakness
  • Proximal extremities
  • Neck extensors
  • Facial/bulbar muscles (dysphagia, dysarthria, dysphonia)
• Ocular weakness
  • Ptosis
  • Diplopia
  • CN III, IV, or VI weakness
• Symptoms worsen with repetitive use / as the day progresses

Differential Diagnosis

Weakness

• Neuromuscular weakness
  • Upper motor neuron:
    • CVA
    • Hemorrhagic stroke
    • Multiple sclerosis
    • Amyotrophic Lateral Sclerosis (ALS) (upper and lower motor neuron)
  • Lower motor neuron:
    • Spinal and bulbar muscular atrophy (Kennedy's syndrome)
  • Spinal cord disease:
    • Infection (Epidural abscess)
    • Infarction/ischemia
    • Trauma (Spinal Cord Syndromes)
    • Inflammation (Transverse Myelitis)
      • Acute flaccid myelitis
    • Degenerative (Spinal muscular atrophy)
    • Tumor
  • Peripheral nerve disease:
    • Guillain-Barre syndrome
    • Toxins (Ciguatera)
    • Tick paralysis
    • Diabetic peripheral neuropathy
  • Neuromuscular junction disease:
    • Myasthenia gravis crisis
    • Botulism
    • Organophosphate toxicity
    • Lambert-Eaton myasthenic syndrome
  • Muscle disease:
    • Rhabdomyolysis
    • Dermatomyositis
    • Polymyositis
    • Alcoholic myopathy
• Non-neuromuscular weakness
  • Can't miss diagnoses:
    • ACS
    • Arrhythmia/Syncope
    • Severe infection/Sepsis
    • Hypoglycemia
    • Periodic paralysis (electrolyte disturbance, K, Mg, Ca)
      • Hypokalemic periodic paralysis
      • Thyrotoxic periodic paralysis
    • Respiratory failure
  • Emergent Diagnoses:
    • Symptomatic Anemia
    • Severe dehydration
    • Hypothyroidism
    • Polypharmacy
    • Malignancy
    • Aortic disease - occlusion, stenosis, dissection
  • Other causes of weakness and paralysis
    • Acute intermittent porphyria (ascending weakness)

Evaluation

Right partial ptosis (left picture) with left lid showing compensatory pseudo lid retraction because of equal innervation of the levator palpabrae superioris (Hering's law of equal innervation): Right picture: after an edrophonium test, note the improvement in ptosis.

A chest CT-scan showing a thymoma (red circle).

Workup

ED Workup

Always evaluate:

• Tidal volume
• Forced Vital capacity (normal is >25cc/kg in MG)
• FEV
• Negative inspiratory force (NIF) (normal is -80 to -100; respiratory support is indicated for -20 to 0)
• Ability to handle secretions

Neuro Workup

The following may be considered for neurologic workup, but are not typically indicated in the ED:

• ACh-R antibody testing: first-line investigation. Indication for thymectomy if < 45 years.
  • MuSK antibody testing: for patients negative for ACh-R antibodies
• Thyroid function
• Neurophysiology: Repetitive nerve stimulation is the initial test; if negative, consider single-fibre electromyography.
• MR scan of brain: Patients with negative serology and neurophysiology, and symptoms compatible with ocular myasthenia may have structural brain disease.
• Thymus scanning: All patients with suspected myasthenia, irrespective of distribution (ocular/generalised) or serology (seropositive/negative), should undergo thymus imaging. The modality (CT or MRI) should be decided locally.
• Edrophonium/Tensilon test

Myasthenic versus cholinergic crisis

Flaccid paralysis resulting from cholinergic crisis can be distinguished from myasthenia gravis by the use of the drug edrophonium, which worsens the paralysis caused by cholinergic crisis, but strengthens the muscle in the case of myasthenia gravis. (Edrophonium is an cholinesterase inhibitor hence increases the concentration of acetylcholine present).

• Myasthenic Crisis
  • Respiratory failure is feared complication
  • Much more common
  • Due to medication non-adherence, infection, surgery, tapering of immunosuppressants, meds
• Cholinergic Crisis
  • Excessive anticholinesterase medication may cause weakness and cholinergic symptoms
  • Rarely if ever seen with dose limitation of pyridostigmine to less than 120mg q3hr
  • If on usual dose of meds assume exacerbation due to MG even with cholinergic side effects
• Edrophonium (Tensilon) test to distinguish the two is controversial
  • Give 1-2mg IV slow push. If any fasciculations, respiratory depression, or cholinergic symptoms within a few minutes, problem is likely cholinergic crisis (no more edrophonium). If no evidence of cholinergic excess, give total of 10mg and observe improvement in case of myasthenic crisis.
  • Side effects of Edrophonium: Arrhythmias, Hypotension, Bronchospasm
  • Thus, need to be on a monitor, with atropine on hand
  • Treatment: Atropine

Diagnosis

• Prolonged upward gaze test
  • Have the patient gaze upward at examiner's finger for 30 seconds
  • Diplopia or ptosis that develops is suggestive of MG
• Ice Pack Test - should improve symptoms temporarily (usually ptosis; high specificity)
  • Place ice-pack on eyes for 2 mins, if ptosis decreases by ≥2mm the test is positive
• Acetylcholine receptor antibodies (AcHR-Ab). Positive in 80-90% of generalized MG and 40-55% in Ocular MG.

Management

Avoid medications that can cause/worsen exacerbations (see Background), including magnesium (which can cause respiratory failure)

Myasthenic Crisis

• Acetylcholinesterase inhibitors are discontinued to avoid excessive bronchial secretions
• Intubation (if needed)
  • If possible avoid depolarizing AND non-depolarizing agents
  • If patient requires paralysis use non-depolarizing agent at smaller dose
  • If must use depolarizing agents, will need higher doses
• IVIG
  • 0.4 g/kg/day for 5 days
  • Effect lasts 30-45 days
• Plasmapheresis
  • Effect lasts 15-20 days

Other Medications

Pyridostigmine and neostigmine primarily used for symptomatic relief but does not alter course of crisis. Consider avoiding in ICU ventilated patients, as these may increase secretions. Continued use of these meds also prevents assessment of other treatment modalities and can increase muscle weakness if used in excess

• Pyridostigmine: Titrate up to find the lowest effective dose
  • Initially 30 mg four times daily for 2–4 days
  • Then 60 mg (1 tablet) four times daily for 5 days and experiment with timing
  • Then increase to 90 mg four times daily over 1 week if required.
  • If patient's usual dose has been missed the next dose is usually doubled
  • IV route: 1/30th of the PO dose (2-3mg) by slow IV infusion
• Neostigmine
  • 0.5mg IV
• Prednisolone: If symptomatic despite Pyridostigmine. Monitor diabetes mellitus.
  • Ocular myasthenia gravis
    • Start 5 mg on alternate days for three doses and increase by 5 mg every three doses until symptoms improve.
    • The maximum dose is 50 mg on alternate days or 0.75 mg/kg/alternate day
  • Generalized myasthenia gravis
    • Start 10 mg on alternate days for three doses and increase by 10 mg every three doses until symptoms improve.
    • Maximum dose is 100 mg alternate days or 1.5 mg/kg

Disposition

• Typically MICU or neuro ICU, consideration for thymectomy if not done already
• Consideration for corticosteroids or other immunosuppressants (i.e. corticosteroids, azathioprine, mycophenolate mofetil, cyclosporine)

See Also

• Weakness