Myasthenia GravisSean Green

July 31, 2013

Definition: A chronic disease characterized by rapid fatigue of striated muscle; most commonly caused by autoantibody-mediated neuromuscular blockade at the post-synaptic motor-end plate.

Epidemiology: Ranges from 0.5-2 million cases per 100,000 to 1,000,000 live births in the US. Can occur at any age

o Female incidence peaks in 30s, while male incidence peaks in 60s Females are more likely to be diagnosed with a 3:2, F:M ratio

o Males more likely to develop ocular symptomology with 1.5:1 ratio On average, younger age of onset for those of Asian ancestry

Clinical Manifestations: Three clinical variants In childhood disease:

o Neonatal myasthenia gravis: Infants born to MG mothers can have transient secondary syndrome due to circulating maternal antibodiesresp insufficiency, inability to suck/swallow, general hypotonia/weakness

Duration of days to weeks requiring vent support and gavage feeding Regain normal strength after Auto-Ab disappearance and no increased risk of MG devo

later in lifeo Juvenile myasthenia gravis: occurs in late infancy and childhoodo Congenital myasthenia gravis: Severe, permanent disorder without spontaneous remission

Episodic apnea is common! Resp insufficiency often preceded by viral illness Tranmitted by autosomal recessive defects in post-synaptic molecules (rapsyn in >85%

cases) NO circulating auto-antibodies! >60 ID genetic mutations

RAPID MUSCLE FATIGUE! Upward gaze examining ptosis after 30-90 sec, repetitive fist/hand closings producing fatigue

o Symptomatic most late in day and when tired Diplopia and ptsosis are common; younger children may hold open eyelids is severe ptosis obstructing

vision; pupillary response to light is preserved Dysphagia and facial weakness are common with feeding difficulties often being a cardinal sign (impaired

chewing) Poor head control due to weakness of neck flexor muscles; limb-girdle/distal muscles of hands can be

affected in most cases Left untreated MG is progressive and can lead to respiratory muscle involvement ASPIRATION RISK!

Common Comorbidities: Occasionally associated with Hashimoto’s disease hypothyroidism In children/adults, thymomas result in unique Eaton-Lambert syndrome

Diagnosis: EMG more specific vs. muscle biopsy

o Normal motor nerve conduction velocity with progressive diminishes in muscle potential with repeated stimulation usually limited to clinically affected muscles

Auto-Ach antibodies are inconsistently demonstratedo Anti-AChR Ab and Anti-MuSK Ab (+) in 30% of adolescents and adults, but rare in prepubertal

children Anti-MuSK Ab key to fetal development

o Possible mutated AChE gene in congential cases

Immune/inflammatory markers usually elevated: ANA, CK, ESR, elevated IgG CT abdo (anterior mediatstinum) may show thymic hypertrophy or thymoma Clinical Myasthenia Gravis Test: requires administration in-house due to likelihood of complications

such as arrhythmia or cholinergic crisis!o Children >2 y/o

Required specific fatigable weakness! AChE Challenge: Edrophonium 0.04mg/kg administered IV dose to r/o allergic

rxn/extreme AntiACh SE sensitivity; followed by 0.1-0.2mg/kg (max 10mg) IV infusion Effects should be seen w/i 10 sec and disappear w/i 120 sec (e.g. distance between

upper and lower eyelids or ability to swallow) LA AChE not useful in Dx; Neostigmine test also useful, but not as definitively diagnostic Atropine (0.01mg/kg) should be available to block aute muscarinic effects (abdo

cramps/diarrhea, broncotracheal secretions, arrhythmia)o Children <2 y/o

EKG monitoring required b/c increased susceptibility to cardiac arrhythmia; IV neostigmine is contraindicated!!

Atropine rescue of 0.1/kg should be available Neostigmine IM 0.04mg/kg; repeat dose may be administered 4hr after if equivocal

effect seen Peak effect seen in 2- to 40 min post-dose

Treatment: Cholinesterase-inhibitors: Primary therapeutic agents

o Neostigmine IM 0.04mg/kg Q4H to Q6Ho Most tolerate PO neostigmine 0.4mg/kg Q4H to Q6H

Give 30min prior to meal if dysphagia to improve swallowingo Pyridostigmine is slightly longer acting and may provide an alternativeo OD can lead to cholinergic crisis tx w/ atropine which blocks muscarinic effects w/o blocking

nicotinic effects Long-term steroid treatment and thymectomy can be considered curative in patients with thymus

hypertrophy/tumoro Especially pts with high Anti-AChR plasma auto-Ab w/ sx < 2 yrs

Plamapheresis and IVIG have shown benefit in steroid-resistant patients, especially those with high circulating levels of Anti-AChR plasma auto-Ab

o Pheresis only provides temporary remission Rituximab has shown benefit as therapy in refractory patients

Prognosis: Many experience spontaneous remission after a period of months to years while others have permanent

disease extending into adulthood Immunosupression, thymectomy and hypothyroidism may provide a cure Mortality is now 3-4%, with principal risk factors being age older than 40 years, short history of

progressive disease, and thymoma