myasthenia gravis victor politi,m.d. medical director, svcmc school of allied health, physician...

Myasthenia GravisMyasthenia Gravis

Victor Politi,M.D.Victor Politi,M.D.

Medical Director, SVCMC Medical Director, SVCMC School of Allied Health, School of Allied Health, Physician Assistant ProgramPhysician Assistant Program

PathophysiologyPathophysiology

The underlying defect is a The underlying defect is a decrease in the number of decrease in the number of available Ach receptors at available Ach receptors at neuromuscular junctions due to an neuromuscular junctions due to an antibody mediated autoimmune antibody mediated autoimmune attackattack


PathophysiologyPathophysiology• ACh synthesized in the motor nerve ACh synthesized in the motor nerve

terminal and stored in vesicles terminal and stored in vesicles • ACh released causes miniature end plate ACh released causes miniature end plate

potentialspotentials• Action potential release ACh and combined Action potential release ACh and combined

with postsynaptic receptorswith postsynaptic receptors• Postsynaptic channels are open allowing Postsynaptic channels are open allowing

entry of sodium producing depolarization entry of sodium producing depolarization of muscle fiberof muscle fiber


A process is terminated by hydrolysis A process is terminated by hydrolysis of ACh by AChEof ACh by AChE

The fundamental defect is a decrease The fundamental defect is a decrease in the number of ACh receptors at the in the number of ACh receptors at the postsynaptic muscle membrane, postsynaptic muscle membrane, therefore, although ACh is released therefore, although ACh is released normally it produces small end plate normally it produces small end plate potentials which fail to trigger muscle potentials which fail to trigger muscle action potentialsaction potentials

MG- Autoantibodies protect against the MG- Autoantibodies protect against the postsynaptic acetylcholine receptorspostsynaptic acetylcholine receptors


The neuromuscular abnormalities The neuromuscular abnormalities caused by an autoimmune caused by an autoimmune response mediated by specific anti response mediated by specific anti AChR antibodiesAChR antibodies

These antibodies reduce the These antibodies reduce the available AChR’s at neuromuscular available AChR’s at neuromuscular junctionsjunctions

Myasthenia gravis (MG)Myasthenia gravis (MG)

Neuromuscular disorder Neuromuscular disorder characterized by weakness and characterized by weakness and fatigability of skeletal musclesfatigability of skeletal muscles

There is no cure for MG but There is no cure for MG but treatment is highly effectivetreatment is highly effective

PathologyPathology

The neuromuscular abnormalities in The neuromuscular abnormalities in MG are brought about by an MG are brought about by an autoimmune response mediated by autoimmune response mediated by specific anti-AChR antibodiesspecific anti-AChR antibodies

the thymus is abnormal in the thymus is abnormal in approximately 75% of patients with approximately 75% of patients with MGMG

In 65% of patients the thymus is In 65% of patients the thymus is hyperplastichyperplastic

Clinical FeaturesClinical Features

Prevalence rate 1 in 10,000 peoplePrevalence rate 1 in 10,000 people Can affect any age groupCan affect any age group

• women - peak incidence 20’s-30’swomen - peak incidence 20’s-30’s• men - peak incidence 50’s-60’smen - peak incidence 50’s-60’s

Women affected more than menWomen affected more than men Cardinal features - weakness and Cardinal features - weakness and

fatigabilityfatigability


Weakness typically increases Weakness typically increases during repeated use (fatigue) and during repeated use (fatigue) and may improve during rest or sleepmay improve during rest or sleep

Course of MG - variableCourse of MG - variable Remissions - rarely complete or Remissions - rarely complete or

permanentpermanent


Unrelated infections or systemic Unrelated infections or systemic disorders may lead to increased disorders may lead to increased myasthenic weakness and may myasthenic weakness and may precipitate a “crisis”precipitate a “crisis”

A crisis is if weakness in A crisis is if weakness in respiration or swallowing becomes respiration or swallowing becomes severe and respiratory assistance severe and respiratory assistance or intubation is necessaryor intubation is necessary


Characteristic pattern of muscle Characteristic pattern of muscle weaknessweakness

early involvement -lids and early involvement -lids and extraocular musclesextraocular muscles

diplopia and ptosis common initial diplopia and ptosis common initial complaintscomplaints

Difficulty in swallowing may occurDifficulty in swallowing may occur


In 85% of cases, weakness In 85% of cases, weakness becomes generalized, affecting becomes generalized, affecting limb muscles as welllimb muscles as well

Limb weakness is often proximal Limb weakness is often proximal and may be asymmetricand may be asymmetric

deep tendon reflexes are deep tendon reflexes are preservedpreserved

Diagnosis and EvaluationDiagnosis and Evaluation

Suspect on basis of weakness and Suspect on basis of weakness and fatigability as previously describedfatigability as previously described

No loss of reflexes or impairment of No loss of reflexes or impairment of sensation or other neurologic functionsensation or other neurologic function

Edrophonium- initial dose 2mg IV, Edrophonium- initial dose 2mg IV, second dose 8mg IVsecond dose 8mg IV

ACh receptor antibody detectable in ACh receptor antibody detectable in 80% of all myosthenic patients80% of all myosthenic patients

Differential DiagnosisDifferential Diagnosis

Several other conditions that cause Several other conditions that cause weakness or the cranial and/or somatic weakness or the cranial and/or somatic musculature must be considered in the musculature must be considered in the differential diagnosis of MG:differential diagnosis of MG:• drug induced myasthenia, Lambert-Eaton drug induced myasthenia, Lambert-Eaton

myasthenic syndrome,neurastheniamyasthenic syndrome,neurasthenia• hyperthyroidism, botulism, intracranial hyperthyroidism, botulism, intracranial

mass lesions and progressive external mass lesions and progressive external ophthalmoplegia ophthalmoplegia

Differential DiagnosisDifferential Diagnosis

Drugs that may exacerbate MGDrugs that may exacerbate MG• penicillaminepenicillamine• aminoglycoside antibioticsaminoglycoside antibiotics• procainamideprocainamide

Lambert-Eaton myasthenic Lambert-Eaton myasthenic syndromesyndrome

Presynaptic disorder of Presynaptic disorder of neuromuscular junction - causes neuromuscular junction - causes muscle weakness similar to MGmuscle weakness similar to MG

proximal muscles of lower limbs proximal muscles of lower limbs most commonly affectedmost commonly affected

ptosis of the eyelids and diplopia in ptosis of the eyelids and diplopia in up to 70% of patientsup to 70% of patients

LES- Autoantibodies against the presynaptic voltage-gated calcium channels


MG and Lambert-Eaton myasthenic MG and Lambert-Eaton myasthenic syndrome are readily distinguished syndrome are readily distinguished

patients with Lambert-Eaton patients with Lambert-Eaton syndrome have depressed or syndrome have depressed or absent reflexes, autonomic absent reflexes, autonomic changes (dry mouth, impotence) changes (dry mouth, impotence) and show incremental responses and show incremental responses on repetitive nerve stimulationon repetitive nerve stimulation


LES is caused by auto antibody LES is caused by auto antibody directed against calcium channels directed against calcium channels on the motor nerve terminals on the motor nerve terminals resulting in impaired release of resulting in impaired release of AChACh


Majority of patients with this Majority of patients with this syndrome have an associated syndrome have an associated malignancy - most commonly small malignancy - most commonly small cell carcinoma of the lungcell carcinoma of the lung

The diagnosis of Lambert-Eaton The diagnosis of Lambert-Eaton may signal the presence of the may signal the presence of the tumor long before it would tumor long before it would otherwise be detectedotherwise be detected


Treatment involves Treatment involves plasmapheresis and plasmapheresis and immunosuppression, as for MGimmunosuppression, as for MG

Myasthenic patients have an Myasthenic patients have an increased incidence of several increased incidence of several associated disordersassociated disorders

Thymic abnormalities - 75% of casesThymic abnormalities - 75% of cases• thymoma thymoma

Hyperthyroidism - 3-8% of casesHyperthyroidism - 3-8% of cases• may worsen the myasthenic weaknessmay worsen the myasthenic weakness

other autoimmune disordersother autoimmune disorders• blood tests for rheumatoid factor, blood tests for rheumatoid factor,

antinuclear antibodiesantinuclear antibodies

Thymoma on CT of chestThymoma on CT of chest

Chronic infection of any kind can Chronic infection of any kind can exacerbate MGexacerbate MG

measurements of ventilatory measurements of ventilatory function are valuable because of function are valuable because of the frequency and seriousness of the frequency and seriousness of respiratory impairment in respiratory impairment in myasthenic patientsmyasthenic patients

Because of the side effects of Because of the side effects of glucocorticoids and other glucocorticoids and other immunosuppressive agents used in immunosuppressive agents used in the treatment of MG, a through the treatment of MG, a through medical history/exam should be medical history/exam should be mademade

Particular attention should be paid to Particular attention should be paid to evidence of chronic or latent evidence of chronic or latent infection (tuberculosis/hepatitis), infection (tuberculosis/hepatitis), HTN, diabetes, renal impairment, HTN, diabetes, renal impairment, and glaucomaand glaucoma

TherapyTherapy

The prognosis has improved The prognosis has improved greatly for MG cases due to greatly for MG cases due to advances in treatmentadvances in treatment

virtually all MG patients can be virtually all MG patients can be returned to productive lives with returned to productive lives with proper therapyproper therapy

TherapyTherapy

Anticholinesterase medicationsAnticholinesterase medications• pyridostigminepyridostigmine

immunosuppressive agentsimmunosuppressive agents• glucocorticoids, azathioprianeglucocorticoids, azathiopriane

thymectomythymectomy plasmapheresisplasmapheresis

Management of Management of myasthenic crisismyasthenic crisis

Exacerbation of weakness sufficient to Exacerbation of weakness sufficient to endanger lifeendanger life• respiratory failurerespiratory failure• aspirationaspiration

The possibility that the deterioration The possibility that the deterioration should be due to excessive anti -ChE should be due to excessive anti -ChE medication (cholinergic crisis) is best medication (cholinergic crisis) is best excluded by temporarily stopping anti-excluded by temporarily stopping anti-ChE drugsChE drugs

Management of Management of myasthenic crisismyasthenic crisis

The most common cause of crisis is The most common cause of crisis is intercurrent infectionintercurrent infection

The myasthenic patient with fever The myasthenic patient with fever and early infection should be treated and early infection should be treated like other immunocompromised like other immunocompromised patients with early antibiotic patients with early antibiotic therapy, respiratory assistance, and therapy, respiratory assistance, and pulmonary physiotherapy. pulmonary physiotherapy. Plasmapheresis is frequently helpful Plasmapheresis is frequently helpful in hastening recoveryin hastening recovery

Questions ??Questions ??

myasthenia gravis victor politi,m.d. medical director, svcmc school of allied health, physician...

Documents

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basis of weakness

increased myasthenic

postsynaptic muscle

autoimmune response

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