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