MYASTHENIA GRAVIS

Autoimmune Disorder characterized by a fluctuating degree and variable combination of weakness in ocular, bulbar, limb, and respiratory muscles due to an antibody-mediated, T-cell dependent immunological attack directed against proteins in the POST-synaptic membrane of the NMJ specifically, of auto-antibodies against nicotinic ACh-R or muscle-specific receptor tyrosine kinase (MuSK). Two Types of Myasthenia Gravis (MyG) o Ocular Myasthenia = weakness limited to the eyelids and extraocular muscles. 50% of patients with Ocular MyG are seropositive for anti-AChR Abs or MuSK. o Generalized MyG = weakness affects ocular muscles and a variable combo of bulbar, limb, and respiratory muscles. 90% of patients with Generalized MyG are seropositive for anti-AChR Abs or MuSK. Age of onset: any age possible but tends to have a bimodal distribution: o 10-30YO (female predominance) o 50-70YO (male predominance) Thymus and the Origin of Autoimmunity in MyG o Thymic abnormalities are seen in the majority of patients that are AChR-Ab(+). o Thymic Hyperplasia with germinal follicles occurs in 70%. o Thymoma occurs in 10%. o Thymus has been evaluated as the possible source of antigen to drive the autoimmune process. o T-lymphocytes play important role in MyG by binding to the AChR and stimulating B cell antibody production. General features o Skeletal muscle weakness, often with true fatigue of a specific muscle Not a sensation of tiredness; not generalized muscle fatigue o Ptosis or diplopia are the most common initial findings o Reflexes preserved (vs. LEMS) o Worse at the end of the day. Improves with rest. o Early in disease course (while patient still has adequate AChR), the Sxs may be absent upon awakening. o Muscles that are stimulated repeatedly (e.g. extraocular muscles) are more prone to fatigue. Muscle Group Affected Presenting Symptoms Ptosis (weak eyelids)

(% of pts affected)
Ocular Muscles (50%)

Elicit ptosis on exam by asking pt to sustain an upward gaze or by holding up the opposite eyelid with the examiners finger (curtain sign)
Binocular diplopia (weak extraocular muscles )

Diplopia will disappear if pt closes one eye.

Bulbar Muscles (15%)

Pupils are always spared in MyG (vs. botulism) Fatiguable chewing (weak jaw muscles)

Occurs half-way through meal; Pt often uses their fingers under the jaw to keep their mouth shut.
Dysarthria & Dysphagia for solids and liquids (weak oropharygneal [striated] muscles of the upper esophagus)

Speech has nasal quality or may be of low intensity.

Facial Muscles Neck and Limb Muscles (<5%) Respiratory Muscles

Myasthenic Sneer (mid-lip rises but the outer corners of mouth fail to move) Orbicularis oculi weakness identified on exam when prying eyes open during forced-eye closure Pt has lost her smile or appears expressionless Dropped Head Syndrome Posterior neck muscles ache due to added effort of keeping head up Proximal muscle weakness > distal Arms affected more than legs Myasthenic Crisis: respiratory insufficiency/failure

DIAGNOSTIC TESTS Tensilon (Edrophonium) Test Ice Pack Test Injection of Edrophonium (acetylcholinesterase inhibitor) will preserve ACh in the NMJ, resulting in immediate increase in muscle strength (i.e. ptosis resolves after infusion of the drug). Based on physiologic principle of improved neuromuscular transmission at lower muscle temperatures Used in pts with ptosis, but NOT helpful for those with extraocular muscle weakness (+) in ~90% of pts with generalized MyG, ~99% in pts with a thymoma and MyG, and ~50% of pts with ocular MyG. AChR-Ab titers correlate poorly with disease severity between patients (+) in ~45% of pt with generalized MyG who are AChR-Ab(-) Not present in pt with ocular MyG (usually) Not associated with presence of underlying thymoma AChR-Ab(-)/MuSK(+) MyG pts have female preponderance, less responsive to acetylcholinesterase inhibitors, good response to plasma exchange and immunosuppresion (except azathioprine) (+) in 80% of MyG pts with Thymoma. (perhaps a useful marker) 75% diagnostic sensitivity Low-rate RNS= Decremental response of greater than 10% High-rate RNS = normal (decremental if severe) Low-rate = decremental High-rate = incremental facilitation 95% diagnostic sensitivity Not specific for MyG, but may be abnormal in motor neuron disease, polymyositis, peripheral neuropathy, LEMS, and other NMJ disorders.

BEDSIDE TESTS

Easy to perform Very Sensitive High False (+)

AChR-Ab SEROLOGIC TESTS

Specific/Confirmatory

MuSK-Ab

Anti-striated muscle Ab

ELECTROPHYSIOLOGICAL STUDIES

Repetitive Nerve Stimulation (RNS)

vs. LEMS

Specific/Confirmatory
Single-fiber EMG

DDx of Ocular MyG Thyroid Ophthalmopathy Kearns-Sayre Syndrome Brainstem and motor CN pathology

DDx of Generalized MyG Generalized fatigue (tiredness) Motor Neuron Disease (ALS) LEMS Botulism Penicillamine-induced myasthenia Congenital myasthenic syndromes

Oculo-bulbar signs Reflexes: normal Edrophonium: good response Thymoma in 15% HRS: normal or decrement AChR-Ab in 70-90%

MyG

Proximal muscles, esp leg Absent/ reflexes Poor response SmCLC in 75% Increment VGCC-Ab in 50-90%

LEMS