MG 101: The MG 101: The BasicsBasics
Matthew N. Meriggioli, Matthew N. Meriggioli, M.D.M.D.
MG 101: CurriculumMG 101: Curriculum1.1. History of Myasthenia Gravis (MG)History of Myasthenia Gravis (MG)2.2. What goes wrong?What goes wrong?
Problems with the immune systemProblems with the immune system Normal muscle functionNormal muscle function Muscle function in MGMuscle function in MG
3.3. How is MG diagnosed?How is MG diagnosed?4.4. How is MG treated?How is MG treated?5.5. Living with MG.Living with MG.6.6. The FutureThe Future
1. History of MG1. History of MG
MyastheniaMyasthenia (Greek – (Greek – muscle illness)muscle illness)
Gravis Gravis (Latin – “grave or (Latin – “grave or serious”)serious”)
First description in the 17First description in the 17thth centurycentury Sir Thomas WillisSir Thomas Willis
““a woman who spoke a woman who spoke freely and readily freely and readily enough for a while, but enough for a while, but after a long period of after a long period of speech was not able to speech was not able to speak a word for one speak a word for one or two hours”or two hours”
‘On the palsy’, persons who (translated) in the morning are able to walk firmly, to fling about their Arms hither and thither, or to take up any heavy thing, before noon the stock of Spirits being spent, which had flowed into the Muscles, they are scarce able to move Hand or Foot.
Walker MB. Lancet 1934;1:1200-1
““Treatment of myasthenia gravis with physostigmineTreatment of myasthenia gravis with physostigmine” ”
““Mrs. M.”Mrs. M.”
First thymectomy, 1939First thymectomy, 1939 Alfred BlalockAlfred Blalock 21 year old woman with “cystic thymic 21 year old woman with “cystic thymic
tumor” and MGtumor” and MG Able to stop prostigmin Able to stop prostigmin No recurrence of symptoms over 3 year follow-No recurrence of symptoms over 3 year follow-
up periodup period ““We wish to emphasize again the absence of We wish to emphasize again the absence of
conclusive proof that the improvement noted conclusive proof that the improvement noted in our patient is due to removal of the tumor..”in our patient is due to removal of the tumor..”
Ann Surg 1939;110:544Ann Surg 1939;110:544
““Guessing it Right”Guessing it Right” John A. Simpson, April 28, 1960John A. Simpson, April 28, 1960 "Myasthenia gravis: a new hypothesis""Myasthenia gravis: a new hypothesis"
“…“…the ‘competitive-blocking’ substance must have the ‘competitive-blocking’ substance must have the the unusual property of persistence in the myasthenic baby for unusual property of persistence in the myasthenic baby for several weeksseveral weeks ... Where, then, are we to look for a blocking ... Where, then, are we to look for a blocking substance which must be of competitive type, substance which must be of competitive type, transmissible transmissible through the placenta, with persistence in the child for a few through the placenta, with persistence in the child for a few weeks onlyweeks only, but not transmissible to another adult? , but not transmissible to another adult? If one If one looks at the mechanism of attachment of acetylcholine to looks at the mechanism of attachment of acetylcholine to receptor protein one is immediately reminded of the Ehrlich receptor protein one is immediately reminded of the Ehrlich theory of antibody actiontheory of antibody action. Let us suppose that antibody was . Let us suppose that antibody was developed against the "receptor substance" of the end-plate developed against the "receptor substance" of the end-plate protein. Would not this substance have exactly the protein. Would not this substance have exactly the properties described?6 properties described?6
Simpson JA. Myasthenia gravis: a new hypothesis. Scot Med J. 1960; 5: 419–436.
2. What goes wrong?2. What goes wrong?
1.1. Normal Nerve-muscle triggering Normal Nerve-muscle triggering (neuromuscular junction)(neuromuscular junction)
2.2. The neuromuscular junction in MGThe neuromuscular junction in MG
3.3. Immune system abnormalityImmune system abnormality
The Neuromuscular The Neuromuscular Junction (1)Junction (1)
The Neuromuscular The Neuromuscular Junction (2)Junction (2)
Nerve
Muscle
Why does MG cause muscle weakness?
NT NT
A.
B.
MG Damages the Muscle EndplateMG Damages the Muscle Endplate
The Immune System and MG
The Immune System’s Job:The Immune System’s Job:The body’s The body’s homeland defense.homeland defense.
Must correctly recognize potential Must correctly recognize potential threats and distinguish “good” from threats and distinguish “good” from “bad”“bad”
The The Neuromuscular JunctionNeuromuscular Junction: Target of : Target of the immune system in MGthe immune system in MG
AChR
MG is an autoimmune MG is an autoimmune diseasedisease
Autoimmune Disease: occurs when the immune system loses tolerance to self tissues
Normal Immune system: Protects against foreign invaders
The Problem
Nature Immunology (9): 759-761 (2001)
Why do people get Why do people get autoimmune disease?autoimmune disease?
Why do people get Why do people get MG?MG?
Probably same reasons as previous Probably same reasons as previous slideslide
We don’t really knowWe don’t really know Thymus glandThymus gland
What is happening in the What is happening in the immune system in people with immune system in people with
MG?MG?
Anti-AChRAbs
TT
TT
TT
TT
BB
Plasma cellPlasma cellAPC
Nerve Terminal
Postsynaptic membrane
AChR
MuSK
Rapsyn
AChase
ACh
Voltage-gated Na+ channelVoltage-gated Ca+ channel
Ca++Ca++
AChR
MuSK
The Thymus Gland and The Thymus Gland and the Origin of MGthe Origin of MG
Thymic hyperplasiaThymic hyperplasia
AChR
AChRAChR
Tumor cellTumor cell
ThymomaThymomaTT
The Thymus Gland and The Thymus Gland and the Origin of MGthe Origin of MG
The thymus gland is abnormal in The thymus gland is abnormal in many MG patientsmany MG patients
Thymectomy makes MG better (we Thymectomy makes MG better (we think)think)
Muscle-like cells express AChRMuscle-like cells express AChR BUT- What triggers immune attack?BUT- What triggers immune attack?
Abnormal AChR?Abnormal AChR? Viral infectionViral infection
3. How is MG diagnosed?3. How is MG diagnosed?
Clinical featuresClinical features Tensilon testTensilon test Antibody testsAntibody tests Electrical testsElectrical tests
Clinical features of MGClinical features of MG
Muscle weakness - fluctuatingMuscle weakness - fluctuating Fatigue with muscle useFatigue with muscle use Double vision, droopy eyelids, Double vision, droopy eyelids,
trouble swallowing/chewingtrouble swallowing/chewing Facial weaknessFacial weakness Shortness of breathShortness of breath No pain, numbnessNo pain, numbness
MG weaknessMG weakness
Farouk D, 2000
MG: Initial presentation MG: Initial presentation and progressionand progression
Initial symptomsInitial symptoms Eye muscle weaknessEye muscle weakness 75%75% Head/neck weaknessHead/neck weakness 15%15% Limb weaknessLimb weakness 10%10%
Within first yearWithin first year ~75% develop head/neck +/- limb weakness~75% develop head/neck +/- limb weakness ~67% reach maximum MG severity~67% reach maximum MG severity ~20% experience severe exacerbation/MG ~20% experience severe exacerbation/MG
crisiscrisis
Tensilon TestTensilon Test
Before After
AChR antibody testAChR antibody test
Positive in 85% of MG patientsPositive in 85% of MG patients Antibody level does NOT correlate Antibody level does NOT correlate
with disease severity between with disease severity between patientspatients
In an individual patient, changes in In an individual patient, changes in antibody levels do correlateantibody levels do correlate
““Antibody negative” MGAntibody negative” MG
40-50% of patients with ocular MG40-50% of patients with ocular MG MuSK antibodies in 40% of AChR MuSK antibodies in 40% of AChR
negative, generalized MGnegative, generalized MG ““Low-affinity” antibodies in “double Low-affinity” antibodies in “double
negatives” ?? negatives” ??
Electrical testsElectrical tests
Repetitive nerve Repetitive nerve stimulation (RNS)stimulation (RNS)
Single fiber EMGSingle fiber EMG
4. How is MG treated?4. How is MG treated?
Non-immune treatments Non-immune treatments Mestinon, etc.Mestinon, etc. ““Band-aid” Band-aid”
Immune-directed treatmentsImmune-directed treatments Short-termShort-term
Plasmapheresis, IVIgPlasmapheresis, IVIg Long-termLong-term
CorticosteroidsCorticosteroids Immunosuppressive drugsImmunosuppressive drugs Thymectomy?Thymectomy?
Thymectomy?Thymectomy?
Does it Work?Does it Work? In which patients?In which patients?
ThymomaThymoma How old/young?How old/young?
Ongoing international trial Ongoing international trial
Treatment must be Treatment must be individualizedindividualized
Based on:Based on: Age of onsetAge of onset Status of thymus (CT scan)Status of thymus (CT scan)
ThymomaThymoma Thymic hyperplasiaThymic hyperplasia
Antibody statusAntibody status Severity/distribution of diseaseSeverity/distribution of disease Other medical problemsOther medical problems
5. Living with MG5. Living with MG
Prognosis Prognosis Most patients do well with treatmentMost patients do well with treatment Little/no functional limitationsLittle/no functional limitations Your MG will likely not go away or be Your MG will likely not go away or be
“cured”“cured” You will probably need some drugs to You will probably need some drugs to
control your MG (all have potential side control your MG (all have potential side effects)effects)
Factors affecting MGFactors affecting MG
ExerciseExercise Body TemperatureBody Temperature Illness, infections, stress Illness, infections, stress Menstrual cycleMenstrual cycle Less when MG controlledLess when MG controlled
What can you do?What can you do?
Avoid overexertionAvoid overexertion Avoid catching infectionsAvoid catching infections Avoid certain drugsAvoid certain drugs Eat a well-balanced diet and get Eat a well-balanced diet and get
plenty of rest, and some exerciseplenty of rest, and some exercise
What about exercise?What about exercise?
Guided by your own strength / enduranceGuided by your own strength / endurance Stop if you are fatigued, continue as you Stop if you are fatigued, continue as you
are if you are feeling goodare if you are feeling good The bottom line is that exercise is good The bottom line is that exercise is good
within sensible guidelineswithin sensible guidelines During “stable times,” you can follow as During “stable times,” you can follow as
active a regime as anyone elseactive a regime as anyone else During a exacerbation ease off, and titrate During a exacerbation ease off, and titrate
your level of exercise the point at which your level of exercise the point at which you feel most comfortable. you feel most comfortable.
Everyone’s differentEveryone’s different
Auburn's starting Auburn's starting Quarterback from Quarterback from 2005-2007, he 2005-2007, he guided the Tigers guided the Tigers to a 29-9 record to a 29-9 record
117.58 passer 117.58 passer rating rating
Brandon Cox
QuestionsQuestions
Is MG inherited?Is MG inherited? Is MG contagious?Is MG contagious? Why did I get MG?Why did I get MG? Will my MG go away?Will my MG go away? Will I be able to continue working?Will I be able to continue working?
QuestionsQuestions
Can vaccination trigger or worsen Can vaccination trigger or worsen MG?MG?
Are there vaccines that MG patients Are there vaccines that MG patients should not have?should not have?
What is MG crisis?What is MG crisis?
Outlook is improving in Outlook is improving in MG!MG!
Grob D (1999)
6. The future6. The future
CurrentCurrent Best-Best-
characterized characterized autoimmune autoimmune diseasedisease
Treatment is Treatment is effective in most effective in most (but non-(but non-specific)specific)
The futureThe future What triggers MG?What triggers MG? What keeps it What keeps it
going?going? What are the What are the
genetic factors?genetic factors? Design a more Design a more
specific treatment specific treatment – CURE?– CURE?
How is research in MG How is research in MG carried out?carried out?
Experimental MGExperimental MG Patient-related researchPatient-related research
Experimental MGExperimental MG
Rabbits, rats, mice, etc.Rabbits, rats, mice, etc. Immunize with AChR from electric Immunize with AChR from electric
organs of electric eels or fish.organs of electric eels or fish. Weakness, Antibody responsesWeakness, Antibody responses
Experimental MGExperimental MG
εα α
δ β
Muscle
Acetylcholine
Torpedo Californica AChR
Baseline
After neostigmine
MG – Clinical TrialsMG – Clinical Trials
PHASE I TRIALS: PHASE I TRIALS: Initial studies to determine Initial studies to determine the metabolism and pharmacologic actions of the metabolism and pharmacologic actions of drugs in humans, the side effects, early drugs in humans, the side effects, early evidence of effectiveness; may include healthy evidence of effectiveness; may include healthy participants and/or patients.participants and/or patients.
PHASE II TRIALS: PHASE II TRIALS: Controlled clinical studies Controlled clinical studies conducted to evaluate the effectiveness and conducted to evaluate the effectiveness and safety of the drug in patients.safety of the drug in patients.
PHASE III TRIALS: PHASE III TRIALS: Expanded controlled trials Expanded controlled trials provide and adequate basis for FDA labelingprovide and adequate basis for FDA labeling
What would be the ideal What would be the ideal treatment for MG?treatment for MG?
Treatment applied for a short time Long-lived result Target effects to autoreactive cells
(Antigen-specific) No side-effects
Immune Tolerance
AutoReactiveTreatment ImmuneTolerance
The ideal immunotherapyThe ideal immunotherapy
ObstaclesObstacles Treatment of autoimmune disease Treatment of autoimmune disease
occurs months or even years after occurs months or even years after the onset of the disease processthe onset of the disease process
Autoimmune response becomes Autoimmune response becomes more complex as disease progressesmore complex as disease progresses
Benefit achieved by interfering with Benefit achieved by interfering with the immune system’s defense the immune system’s defense mechanismsmechanisms
MG upsets the balance in the immune system
MG
No MG
““The art of medicine consists The art of medicine consists in amusing the patient while in amusing the patient while
nature cures the disease”nature cures the disease”
Voltaire (1694 - 1778)Voltaire (1694 - 1778)
How do we restore the balance?
How do we restore the How do we restore the balance?balance?
Expand regulatory immune cellsExpand regulatory immune cells Use agents (drugs) that promote Use agents (drugs) that promote
their mobilization and growththeir mobilization and growth ?Grow them in culture ?Grow them in culture
Make them AChR-specific Make them AChR-specific ? Stem cells? Stem cells
SummarySummary MG is caused by an abnormal immune MG is caused by an abnormal immune
response targeting the muscle (AChR, MuSK)response targeting the muscle (AChR, MuSK) Most people with MG do well with the right Most people with MG do well with the right
treatment (treatment must be treatment (treatment must be individualized).individualized).
You can live a normal life with MG.You can live a normal life with MG. We know a lot about the immune system We know a lot about the immune system
defect in MG, but there are key questions defect in MG, but there are key questions that remain unansweredthat remain unanswered
Thank YouThank You