Myasthenia Gravis

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Myasthenia Gravis :

Myasthenia Gravis

Background:

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

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Myastheniagravis (from Greek " muscle", " weakness", and Latin : gravis "serious“;) It is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability . It is an autoimmune disorder, in which weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine.

Anatomy :

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

Postsynaptic surface:

Postsynaptic surface Ach + AChR Opening AChR ion channel End-plate potential generation Opening VGSC at the bottom of synaptic fold Muscle action potential and contraction

Epidemiology :

Epidemiology Frequency Annual incidence in US- 2/1,000,000 (E) 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

CAUSES:

CAUSES Idiopathic Acquired autoimmune Penicillamine AChR antibodies are found in 90% of patients developing MG secondary to penicillamine exposure Drugs Transient neonatal (passive transfer of maternal anti-AChR antibodies) Congenital myasthenic syndrome

CAUSES:

CAUSES Drugs Antibiotics (Aminoglycosides, ciprofloxacin, ampicillin, erythromycin) B-blocker (propranolol) Lithium Magnesium Procainamide Verapamil Quinidine Chloroquine Prednisone Timolol Anticholinergics

Differentials:

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

Pathophysiology:

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:

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*

Clinical Presentation:

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 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:

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

Bulbar :

Bulbar Dysarthria Dysphagia Dysphonia Masticatory weakness – jaw closure > jaw open

Clinical presentation :

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

Clinical presentation:

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

Work-up:

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

Electrodiagnostic studies: Repetitive Nerve Stimulation:

Electrodiagnostic studies: Repetitive Nerve Stimulation Low frequency RNS (1-5Hz) Locally available Ach becomes depleted at all NMJs and less available for immediate release Results in smaller EPSP’s

Electrodiagnostic studies: Repetitive Nerve Stimulation:

Electrodiagnostic studies: Repetitive Nerve Stimulation Patients w/ MG AchR’s are reduced and during RNS EPSP’s may not reach threshold and no action potential is generated Results in a decremental decrease in the compound muscle action potential Any decrement over 10% is considered abnormal Should not test clincally normal muscle Proximal muscles are better tested than unaffected distal muscles

Repetitive nerve stimulation :

Repetitive nerve stimulation Most common employed stimulation rate is 3Hz Several factors can afect RNS results Lower temperature increases the amplitude of the compound muscle action potential Many patients report clinically significant improvement in cold temperatures AChE inhibitors prior to testing may mask the abnormalities and should be avoided for atleast 1 day prior to testing

Electrodiagnostic studies: Single-fiber electromyography :

Electrodiagnostic studies: Single-fiber electromyography Concentric or monopolar needle electrodes that record single motor unit potentials Findings suggestive of NMF transmission defect Increased jitter and normal fiber density SFEMG can determine jitter Variability of the interpotential interval between two or more single muscle fibers of the same motor unit

Electrodiagnostic studies: Single-fiber electromyography :

Electrodiagnostic studies: Single-fiber electromyography Generalized MG Abnormal extensor digiti minimi found in 87% Examination of a second abnormal muscle will increase sensitivity to 99% Occular MG Frontalis muscle is abnormal in almost 100% More sensitive than EDC (60%)

Workup Pharmacological testing:

Workup Pharmacological testing Edrophonium (Tensilon test) Patients with MG have low numbers of AChR at the NMJ Ach released from the motor nerve terminal is metabolized by Acetylcholine esterase Edrophonium is a short acting Acetylcholine Esterase Inhibitor that improves muscle weakness Evaluate weakness (i.e. ptosis and opthalmoplegia) before and after administration

Workup Pharmacological testing:

Workup Pharmacological testing Before After

Workup Pharmacological testing:

Workup Pharmacological testing Edrophonium (Tensilon test) Steps 0.1ml of a 10 mg/ml edrophonium solution is administered as a test If no unwanted effects are noted (i.e. sinus bradychardia), the remainder of the drug is injected Consider that Edrophonium can improve weakness in diseases other than MG such as ALS, poliomyelitis, and some peripheral neuropathies

Treatment:

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

Corticosteroids :

Corticosteroids Oral prednisolone : first choice Onset of action 1-3 mo. If patient is critically ill one should start on a high dose every day and use additional short-time treatments to overcome the temporary worsening When remission occurs, the dose should be slowly reduced to minimum effective dose given on alternate days

Immunosuppressants :

Immunosuppressants “steroid sparing agents” Azathioprine Cyclophosphamide Cyclosporin Methotrexate Mycophenolate mofetil

Treatment Behavioral modifications :

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

Complications of MG :

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

Prognosis:

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

Rehabilitation:

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

References:

References 1. Delisa, S. A., Goans, B., Rehabilitatoin Medicine Principles and Practice, 1998, Lippencott-Raven 2. Kimura, J., Electrodiagnosis in Diseases of Nerve and Muscle, F.A.Davis Company, Philadelphia 3. Rosenberg, R. N., Comprehensive Neurology , 1991, Raven Press Ltd 4. O’sullivan, Schmidtz, Physical Medicine and Rehabilitation Assessment and Treatment, pg. 151-152 5. Grabois, Garrison, Hart, Lehmke, Neuromuscular Diseases, pgs. 1653-1655 6. Shah, A. K., www.emedicine.com, Myasthenia Gravis , 2002, Wayne State University 7. Tensilon test pictures http://www.neuro.wustl.edu/neuromuscular/mtime/mgdx.html

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