Myasthenia Gravis

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Myasthenia Gravis :

Myasthenia Gravis DR ANGELO SMITH M.D WELLING HEALTHCARE PRIVATE LTD

Myasthenia Gravis:

Myasthenia Gravis Disease of the neuromuscular junction characterized by fluctuating weakness of certain skeletal muscle groups.

Background:

Acquired autoimmune disorder Clinically characterized by: Weakness of skeletal muscles Fatigability on exertion. First clinical description in 1672 by Thomas Willis Background

Anatomy :

Neuromuscular Junction (NMJ) Components: Presynaptic membrane Postsynaptic membrane Synaptic cleft Presynaptic membrane contains vesicles with Acetylcholine (ACh) which are released into synaptic cleft in a calcium dependent manner ACh attaches to ACh receptors (AChR) on postsynaptic membrane Anatomy

Anatomy:

Neuromuscular Junction (NMJ) The Acetylcholine receptor (AChR) is a sodium channel that opens when bound by ACh There is a partial depolarization of the postsynaptic membrane and this causes an excitatory postsynaptic potential (EPSP) If enough sodium channels open and a threshold potential is reached, a muscle action potential is generated in the postsynaptic membrane Anatomy

Pathophysiology:

In MG, antibodies are directed toward the acetylcholine receptor at the neuromuscular junction of skeletal muscles Results in: Decreased number of nicotinic acetylcholine receptors at the motor end-plate Reduced postsynaptic membrane folds Widened synaptic cleft Pathophysiology

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Pathophysiology:

Pathophysiology Anti-AChR antibody is found in 80-90% of patients with MG Proven with passive transfer experiments MG may be considered a B cell-mediated disease Antibodies

Pathophysiology:

Pathophysiology T-cell mediated immunity has some influence Thymic hyperplasia and thymomas are recognized in myasthenic patients

Epidemiology :

Frequency Worldwide prevalence 1/10,000 (D) Mortality/morbidity Recent decrease in mortality rate due to advances in treatment 3-4% (as high as 30-40%) Risk factors Age > 40 Short history of disease Thymoma Sex F-M (6:4) Mean age of onset (M-42, F-28) Incidence peaks- M- 6-7 th decade F- 3 rd decade Epidemiology

Clinical Presentation:

Fluctuating weakness increased by exertion Weakness increases during the day and improves with rest Extraocular muscle weakness Ptosis is present initially in 50% of patients and during the course of disease in 90% of patients Head extension and flexion weakness Weakness may be worse in proximal muscles Clinical Presentation

Clinical presentation :

Progression of disease Mild to more severe over weeks to months Usually spreads from ocular to facial to bulbar to truncal and limb muscles Often, symptoms may remain limited to EOM and eyelid muscles for years The disease remains ocular in 16% of patients Remissions Spontaneous remissions rare Most remissions with treatment occur within the first three years Clinical presentation

Clinical presentation:

Basic physical exam findings Muscle strength testing Recognize patients who may develop respiratory failure (i.e. difficult breathing) Sensory examination and DTR’s are normal Clinical presentation

Clinical presentation :

Clinical presentation Muscle strength Facial muscle weakness Bulbar muscle weakness Limb muscle weakness Respiratory weakness Ocular muscle weakness

Clinical presentation :

Clinical presentation Facial muscle weakness is almost always present Ptosis and bilateral facial muscle weakness Sclera below limbus may be exposed due to weak lower lids

Clinical presentation:

Bulbar muscle weakness Palatal muscles “Nasal voice”, nasal regurgitation Chewing may become difficult Severe jaw weakness may cause jaw to hang open Swallowing may be difficult and aspiration may occur with fluids—coughing and choking while drinking Neck muscles Neck flexors affected more than extensors Clinical presentation

Clinical presentation :

Limb muscle weakness Upper limbs more common than lower limbs Clinical presentation Upper Extremities Deltoids Wrist extensors Finger extensors Triceps > Biceps Lower Extremities Hip flexors (most common) Quadriceps Hamstrings Foot dorsiflexors Plantar flexors

Clinical presentation:

Respiratory muscle weakness Weakness of the intercostal muscles and the diaghram may result in CO2 retention due to hypoventilation May cause a neuromuscular emergency Weakness of pharyngeal muscles may collapse the upper airway Monitor negative inspiratory force, vital capacity and tidal volume Do NOT rely on pulse oximetry Arterial blood oxygenation may be normal while CO2 is retained Clinical presentation

Clinical presentation:

Occular muscle weakness Asymmetric Usually affects more than one extraocular muscle and is not limited to muscles innervated by one cranial nerve Weakness of lateral and medial recti may produce a pseudointernuclear opthalmoplegia Limited adduction of one eye with nystagmus of the abducting eye on attempted lateral gaze Ptosis caused by eyelid weakness Diplopia is very common Clinical presentation

Clinical presentation:

Co-existing autoimmune diseases Hyperthyroidism Occurs in 10-15% MG patients Exopthalamos and tachycardia point to hyperthyroidism Weakness may not improve with treatment of MG alone in patients with co-existing hyperthyroidism Rheumatoid arthritis Scleroderma Lupus Clinical presentation

Clinical presentation :

Causes Idiopathic Penicillamine AChR antibodies are found in 90% of patients developing MG secondary to penicillamine exposure Drugs Clinical presentation

Clinical manifestations:

Clinical manifestations Variable course May be precipitated by emotional stress, pregnancy, menses, secondary illness, trauma, temperature extremes, hypokalemia, ingestion of drugs with neuromuscular blocking agents, surgery.

Differentials:

Amyotropic Lateral Sclerosis Basilar Artery Thrombosis Brainstem gliomas Cavernous sinus syndromes Dermatomyositis Lambert-Eaton Myasthenic Syndrome Multiple Sclerosis Sarcoidosis and Neuropathy Thyroid disease Botulism Oculopharyngeal muscular dystrophy Brainstem syndromes Differentials

Work-up:

Lab studies Anti-acetylcholine receptor antibody Positive in 74% 80% in generalized myasthenia 50% of patients with pure ocular myasthenia Anti-striated muscle Present in 84% of patients with thymoma who are younger than 40 years Work-up

Work-up:

Lab studies Interleukin-2 receptors Increased in generalized and bulbar forms of MG Increase seems to correlate to progression of disease Work-up

Work-up:

Imaging studies Chest x-ray Plain anteroposterior and lateral views may identify a thymoma as an anterior mediastinal mass Chest CT scan is mandatory to identify thymoma MRI of the brain and orbits may help to rule out other causes of cranial nerve deficits but should not be used routinely Work-up

Work-up:

Electrodiagnostic studies Repetitive nerve stimulation Single fiber electromyography (SFEMG) SFEMG is more sensitive than RNS in MG Work-up

Treatment:

AChE inhibitors Immunomodulating therapies Plasmapheresis Thymectomy Important in treatment, especially if thymoma is present Treatment

Treatment:

AChE inhibitor Pyridostigmine bromide (Mestinon) Starts working in 30-60 minutes and lasts 3-6 hours Individualize dose Adult dose: 60-960mg/d PO 2mg IV/IM q2-3h Caution Check for cholinergic crisis Others: Neostigmine Bromide Treatment

Treatment:

Immunomodulating therapies Prednisone Most commonly used corticosteroid in US Significant improvement is often seen after a decreased antibody titer which is usually 1-4 months No single dose regimen is accepted Some start low and go high Others start high dose to achieve a quicker response Clearance may be decreased by estrogens or digoxin Patients taking concurrent diuretics should be monitored for hypokalemia Treatment

Treatment Behavioral modifications :

Diet Patients may experience difficulty chewing and swallowing due to oropharyngeal weakness If dysphagia develops, liquids should be thickened Thickened liquids decrease risk for aspiration Activity Patients should be advised to be as active as possible but should rest frequently and avoid sustained activity Educate patients about fluctuating nature of weakness and exercise induced fatigability Treatment Behavioral modifications

Complications of MG :

Respiratory failure Dysphagia Complications secondary to drug treatment Long term steroid use Osteoporosis, cataracts, hyperglycemia, HTN Gastritis, peptic ulcer disease Pneumocystis carinii Complications of MG

Prognosis:

Untreated MG carries a mortality rate of 25-31% Treated MG has a 4% mortalitiy rate 40% have ONLY occular symptoms Only 16% of those with occular symptoms at onset remain exclusively occular at the end of 2 years Prognosis

Rehabilitation:

Strategies emphasize Patient education Timing activity Providing adaptive equipment Providing assistive devices Exercise is not useful Rehabilitation

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