Myasthenia Gravis

Postsynaptic acetylcholine receptor (motor end plate) autoantibody attack. Historical and exam clues to the diagnosis are fatigue that is worsened with activity and diminished with rest (so-called fatigable weakness). In MG, there is typically proximal muscle weakness (shoulders and hips) rather than distal (forearm and hand) weakness, as demonstrated by her difficulty raising her arms. Proximal leg weakness typically presents with trouble getting up (ilopsoas) and down stairs (quadriceps), and getting out of a low chair (however, wrist drop or foot drop would not be expected in MG). Bulbar features include, commonly, diplopia and ptosis that is worsened with such activities as reading and driving, as well as dysarthria, fatigable chewing, dysphagia, and nasal speech (“mushy” speech). When asked to smile, patients may exhibit a “myasthenic snarl”. Note that some patients have pure ocular findings (eyes and eyelids), so-called ocular myasthenia gravis. Cogan’s twitch sign demonstrates subtle weakness of the superior rectus and inferior oblique muscles. Deep tendon reflexes will not be affected, which helps distinguish MG from neuropathy (decreased reflexes), myopathies (decreased reflexes) and, notably, Lambert-Eaton myasthenic syndrome (decreased reflexes). Respiratory failure (myasthenic crisis) is a critical finding in MG and is life-threatening. Notably, patients may fail to maintain adequate lung volumes before they demonstrate deoxygenation, so assessment of forced vital capacity (FVC) and negative inspiratory force (NIF) is essential. Oxygen saturation is not a good predictor of respiratory capacity in neuromuscular illness. You can ask patient to exhale and count (without inspiring) to get a sense of their respiratory capacity. The first treatment consideration in myasthenic crisis is ventilatory support because the life-threatening nature of the respiratory failure. Treatment with plasmapharesis and IVIG are used to treat the myasthenia gravis antibody load. In myasthenic crisis, pyridostigmine is generally avoided because of its lack of efficacy in severe disease and the risk of increasing salivation in the setting of poor oropharyngeal control (risk of aspiration). Causes of myasthenic crisis include infection, surgery, exacerbating medications (eg, aminoglycosides, fluoroquinolones, macrolides, beta-blockers, magnesium, succinylcholine), pregnancy/childbirth. Note that it is important to ask about any recent reduction in steroids or other treatments, as patients are often being weaned off of steroids or other medications in their management. Icepack test – cooling the eyelids with ice can improve ptosis in MG. Prolonged upgaze to evoke ptosis. Edrophonium (Tensilon) Test – Edrophonium is a reversible acetylcholinesterase inhibitor that will produce fast/temporary resolution of symptoms; it can quickly diagnose MG but requires monitoring: atropine must be available to counteract bradycardia or bronchospasm. Acetylcholine (Ach) antibody testing: binding, blocking, modulating antibodies. Ach antibodies are found in 85% of patients with generalized muscle weakness in 70% of patients with ocular weakness, only. Note that presence of autoantibodies in patients with ocular myasthenia connoted a higher risk of progression to generalized myasthenia. Also, muscle-specific kinase (MuSK) antibody testing (present in a minority of patients). Repetitive nerve conduction studies demonstrate decreased compound muscle action potential (CMAP) response following low frequency (3 Hz) repetitive nerve stimulation and following prolonged exercise. Single fiber EMG can be used to evaluate for increased jitter but this is a technically difficult study to perform, so don’t expect it as an answer on USMLE. Muscle biopsy is not typically used in the diagnosis of myasthenia gravis but if performed will show an abnormal postsynaptic membrane – thinned-out (shallow) and smooth. Chest CT with contrast to assess for thymoma (~15% of patients). More commonly, there will be thymic hyperplasia (~65% of patients). Thyroid function tests to rule out thyrotoxicosis (~5% of patients) Pyridostigmine is a cholinesterase inhibitor, which increases availability of acetylcholine at the postsynaptic membrane, thus this provides symptomatic management but does not impact the underlying severity of the illness. Immune-modulators (steroids, mycophenolate, azathioprine, etc...) reduce the production of acetylcholine antibodies. Intravenous Immunoglobulin (IVIG) and plasmapharesis reduce the load of acetylcholine antibodies. Avoidance of exacerbating medications; there are numerous medications that can worsen MG but pay attention for aminoglycosides (eg, gentamicin), fluroquinolones (eg, ciprofloxacin), macrolides (eg, azithromycin), beta-blockers (eg, metoprolol), magnesium, succinylcholine. Thymectomy for thymoma. The epidemiology of myasthenia gravis produces a bimodal distribution: Early-onset MG is more common in women (20 - 40 yo) Late-onset MG is more common for men (55 - 75 yo). Note that thymoma is more common in older patients. There is a strong association with family history of MG and also other autoimmune disorders (rheumatoid arthritis, autoimmune thyroid disease, systemic lupus erythematosus, etc…). Pathophysiology is presynaptic P/Q voltage-gated calcium channel antibodies (vs postsynaptic junction acetylcholine antibodies in MG). Look for proximal, symmetric lower extremity weakness ( “load in the pants” gait) that improves with muscle facilitation (activation – note that this is the opposite of myasthenia gravis). There is autonomic dysfunction (dry mouth, constipation), not a typical finding in MG. There are decreased reflexes that increase with muscle facilitation wehreas reflexes in MG are normal. Look for a history of small cell lung cancer, as ~ 50% of cases are paraneoplastic from this illness. Repetitive nerve stimulation in Lambert-Eaton demonstrates an INCREASE in the CMAP with fast frequency (50 Hz) stimulation (along with post exercises (muscle facilitation)). In MG, there is DECREMENT with slow frequency (3Hz) stimulation. Treatment includes 3,4-diaminopyridine (3,4-DAP) for symptomatic improvement along with typical myasthenia gravis immune therapies. Pathophysiology is a presynaptic toxin attack of SNARE proteins which prevent docking/fusion of the acetylcholine synaptic vesicle and prevent acetylcholine release. There is descending flaccid paralysis: oculbulbar and facial weakness, specifically there is ptosis (eyelid drooping), facial and extraocular movement weakness (limitation of extraocular mobility, expressionless (flat) facies), and dysarthria/dysphagia (choking and regurgitation). Flaccid paralysis descends from the neck and shoulders, extending distally along the upper extremities, and subsequently develops in the pelvis and thighs before it descends down the lower extremities. Respiratory arrest can occur from diaphragm (and accessory muscle) failure in combination with pharyngeal weakness. Blocking of cholinergic transmission results in: Constipation and mydriasis (pupillary widening) from parasympathetic inhibition and hypohidrosis from inhibition of post-ganglionic cholinergic sympathetic fibers. Causes of botulinum toxicity include: Contaminated foods produce toxin in an anaerobic milieu; Wound botulism; Infant botulism (Intestinal colonization can occur in infants because they lack the normal bowel florae necessary to compete with C. botulinum); Inhalational botulism; Iatrogenic intramuscular botulism injection can result in systemic botulism. References and additional information can be found in the following tutorials: Pathophysiology of Neuromuscular Junction Disorders Myasthenia Gravis & Other Neuromuscular Junction Disorders