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Myasthenia Gravis
Aka: Myasthenia Gravis
- Pathophysiology
- Neuromuscular Autoimmune Disease
- Antibodies form to nicotinic acetylcholine receptors
- Affects post-synaptic mambrane of the neuromuscular junction
- Results in fluctuating and variable, progressive weakness and true fatigability
- Associated with thymoma in up to 25% of cases
- Epidemiology
- Annual Incidence: 10-20 new cases per million
- Prevalence: 150-200 cases per million
- Age of onset (multimodal)
- Neonatal Myasthenia Gravis (transient related to maternal antibodies)
- Ages 20-30 (predominantly female)
- Ages 50-80 (predominantly male)
- Types
- Ocular Myasthenia Gravis
- Eyelid weakness (Ptosis)
- Extraocular Muscle Weakness (Diplopia)
- Seronegative in 50% of cases
- Progresses to generalized Myasthenia Gravis within 2 years in 50% of cases
- Generalized Myasthenia Gravis
- Includes ocular Muscle Weakness as above AND
- Bulbar weakness (Dysarthria, Dysphagia, fatigable chewing)
- Extremity weakness
- Respiratory Muscle Weakness
- Seronegative in 10% of cases
- Other forms
- Thymoma-associated Myasthenia Gravis
- Associated Conditions
- Neuromyelitis optica
- Autoimmune Thyroid disease
- Systemic Lupus Erythematosus
- Rheumatoid Arthritis
- Presentations
- Early course
- Typically transient with symptom free intervals lasting days to weeks
- Ocular Myasthenia Gravis (50%)
- Ptosis
- Diplopia (vertical or horizontal)
- Bulbar symptoms (15%)
- Dysarthria
- Dysphagia
- Fatigable chewing
- Isolated motor weakness (<5%)
- Proximal limb weakness
- Other sites of isolated Muscle Weakness are less common presentations (neck weakness, distal limb weakness, respiratory Muscle Weakness)
- Symptoms
- Muscle Weakness provoked by exertion
- May be precipitated by infection, fever, stress and other acute factors
- Ocular weakness
- Eyelid Muscle Weakness resulting in Ptosis (unilateral or bilateral)
- May increase with sustained upward gaze
- Extraocular Muscle Weakness resulting in binocular Diplopia (vertical or horizontal)
- Resolves with covering one eye
- Pupil reaction is always spared in ocular myasthenia
- Bulbar weakness
- Fatigable chewing (often mid-way through a meal)
- Patient may need to use their fingers to lift the jaw, and close the mouth
- Dysarthria
- Nasal quality or low intensity voice
- Dysphagia
- Difficulty Swallowing liquids and solids
- Aspiration may occur with myasthenia crisis
- Nasal regurgitation
- Occurs if Palate weak
- Facial Muscle Weakness
- Loss of expression (especially loss of smile, or sneer appearance)
- Neck Muscle Weakness
- Neck flexor Muscle Weakness
- Neck extensor Muscle Weakness
- May give "dropped head" appearance with head flexed over chest later in the day
- Extremity Muscle Weakness (asymmetric)
- Arms affected more than legs
- Proximal Muscle Weakness are typically more affected than distal muscles
- Distal wrist extensors and foot dorsiflexors are most often involved
- Respiratory Muscle Weakness
- Respiratory insufficiency may progress to Respiratory Failure (myasthenia crisis)
- Signs
- See symptoms above
- Muscle Weakness as above
- Deep Tendon Reflexes normal
- Specific Tests
- Ice Pack Test
- Cold pack applied to eye with Ptosis for 2 minutes
- Myasthenia Gravis related Ptosis improves with cold applied
- Tensilon Test (Edrophonium Test)
- Cholinesterase Inhibitor given and Motor Strength improves in Myasthenia Gravis
- Labs: Specific Antibody
- Seronegative Myasthenia Gravis occurs in 6-12% of cases (most frequently ocular Myasthenia Gravis)
- Acetylcholine Receptor Antibody (AChR-Ab)
- Binding AChR-Ab is typically used as it has best efficacy
- Blocking AChR-Ab may be indicated in some cases due to its high Specificity
- Modulating AChR-Ab may slightly increase Test Sensitivity but at the risk of False Positives
- Present in 50% of Ocular Myasthenia Gravis
- Present in 80-90% of generalized Myasthenia Gravis
- Muscle-Specific Receptor Tyrosine KinaseAntibody (MuSK-Ab)
- Absent in most cases of ocular Myasthenia Gravis
- Present in 38-50% of generalized Myasthenia Gravis patients who are AChR-Ab negative
- Labs: Other testing
- Electromyogram (EMG)
- Decremental response to repetitive nerve stimulation
- CT neck or MRI neck
- Thymoma evaluation
- Thyroid Function Test
- Hyperthyroidism (3-8%)
- Rheumatoid Factor (RF)
- Antinuclear Antibody (ANA)
- Differential Diagnosis
- Ocular Myasthenia Gravis mimics
- Hyperthyroidism (including Thyroid ophthalmopathy)
- Kearns-Sayre Syndrome
- Brainstem lesions
- Generalized Myasthenia Gravis mimics
- Amyotrophic Lateral Sclerosis (ALS)
- Lambert-Eaton Syndrome
- Associated with cancer, and typically affects proximal extremity Muscle Weakness
- Botulism
- Neurasthenia
- Intracranial Mass lesion with extraocular affect
- Drug-induced Myasthenia
- Penicillamine
- Polymyxin
- Tetracycline
- Aminoglycosides
- Procainamide
- Propranolol
- Phenothiazine
- Lithium
- Complications
- Aspiration Pneumonia
- Myasthenia Crisis
- Respiratory compromise
- Cholinergic crisis (excessive Acetylcholinesterase Inhibitor)
- See Cholinergic Toxicity
- Management: Medication
- Anticholinesterase (Cholinergic)
- Provides symptomatic relief
- Most effective on extremity weakness and bulbar symptoms
- Less effective on Ptosis
- Least effective on Diplopia
- Pyridostigmine Bromide (Mestinon)
- Child: 0.5 - 1 mg/kg every 4-6 hours up to 7 mg/kg/day
- Adult: 30 mg three times daily (may be increased to maximum of 120 mg every 4 hours while awake)
- Onset: 15-30 minutes
- Peaks: 2 hours
- Duration: 3-4 hours
- Neostigmine
- Less commonly used
- Immunosuppressive therapy
- Prednisone
- Start at 20 mg qd
- Increase gradually by 5 mg every 3 days to 60mg
- Continue for 3 months OR
- Until clinical improvement stops or declines
- Taper gradually to every other day
- Azathioprine (Imuran)
- Dosing
- 2 mg/kg/day
- Efficacy
- Effective when given with Prednisone
- Effect not seen for 6 months or more
- Monitoring
- Complete Blood Count (CBC)
- Liver Function Tests (LFT)
- Plasmapheresis (Plasma Exchange) and IVIg
- Indicated for emergent worsening/crisis
- Response rate: 70%
- Management: Thymectomy
- Indications
- Age <60 years
- Inadequately controlled on Pyridostigmine
- Thymoma discovered
- Effect
- Clinical improvement after thymectomy in 80%
- Benefits may not be seen for 6 months
- Transcervical thymectomy may be preferred
- References
- Calhoun (1999) Ann Surg 230:555-61 [PubMed]
- Precautions
- Avoid antibiotics that significantly exacerbate neuromuscular weakness
- Aminoglycosides
- Fluoroquinolones
- Telithromycin (Ketek)
- Macrolides (Erythromycin, Azithromycin) - less effect than other agents above
- Avoid miscellaneous agents that exacerbate neuromuscular weakness
- Magnesium
- Class Ia Antiarrhythmics (e.g. Quinidine, Procainamide, Amiodarone)
- High-dose Corticosteroids
- Iodinated Contrast Dye (seen primarily with older contrast dyes)
- References
- Hayes in Herbert (2015) 15(9):14
- References
- Bird (2013) Myasthenia Gravis, in Shefner and Targoff, UpToDate, Wolters Kluwer
- Keesey (2004) Muscle Nerve 29:484 [PubMed]