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 that may unmask or worsen myasthenia gravis

• Antibiotics (Aminoglycosides, Clinda, Fluoroquinolones, Vancomyacin)
• Cardiovasular drugs (Beta blockers, procainamide)
• Other (Botox, quinines, Magnesium)

Drugs Usually well-tolerated in myasthenia gravis but occasionally associated with an exacerbation

• Local anesthetics
• Antibiotics (Tetracycline/doxy, Macrolides, Flagyl, nitrofurantoin)
• Anticonvulsants (carbamazepine, ethosuximide, gabapentin, phenobarbital, phenytoin)
• Butyrophenones (haldol)
• Phenothiazines (chlorpromazine/prochlorpromazine)
• Calcium Channel Blockers
• Steroids
• Opthalmic drugs (betaxolol/timolol/proparacaine)
• Other (Iodinated contrast agent)

Clinical Features

• Muscle weakness
  • Proximal extremities
  • Neck extensors
  • Facial/bulbar muscles (dysphagia, dysarthria, dysphonia)
• Ocular weakness
  • Ptosis
  • Diplopia
  • CN III, IV, or VI weakness

Differential Diagnosis

Drug-induced myasthenia

• Antibiotics (aminoglycosides, fluroquinolones, clindamycin, metronidazole, macrolides)
• Steroids
• Anticonvulsants (phenytoin, barbiturates, lithium)
• Psychotropics (haloperidol)
• Beta-blockers / calcium-channel blockers
• Local anesthetics
• Opioids
• Anticholinergics (diphenhydramine)
• NMJ blocking agents (rocuronium, succinylcholine)

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

• Symptoms worsen with repetitive use / as the day progresses
  • 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.

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

Management

Always evaluate:

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

Medications

• Pyridostigmine and neostigmine primarily used for symptomatic relief but does not alter course of crisis
  • Note that in myasthenic crisis, acetylcholinesterase inhibitors are discontinued to avoid excessive bronchial secretions
  • Continued use of these meds also prevents assessment of other treatment modalities and can increase muscle weakness if used in excess
  • Primary medications in crisis are IVIG and plasmapheresis

1. Pyridostigmine
   • If patient's usual dose has been missed the next dose is usually doubled
   • PO route: 60-90mg q4hr
   • IV route: 1/30th of the PO dose (2-3mg) by slow IV infusion
2. Neostigmine
   • 0.5mg IV
3. Intubation
   • 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
4. Plasmapherisis
5. IVIG

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