Myasthenia Gravis 101Myasthenia Gravis 101

Decontee “Dr. Dee” Jimmeh, MDDecontee “Dr. Dee” Jimmeh, MD

Norwood Clinic NeurologyNorwood Clinic Neurology

September 13, 2014September 13, 2014

OutlineOutline

BackgroundBackground

PathogenesisPathogenesis

DiagnosisDiagnosis

TreatmentTreatment

Special considerationsSpecial considerations

HistoryHistory

Early descriptions (1600s)Early descriptions (1600s) ““spurious palsy of her members but also in her tongue spurious palsy of her members but also in her tongue

as she speaks long or eagerly, she becomes mute as as she speaks long or eagerly, she becomes mute as as a fish…unable recover her voice for an hour or as a fish…unable recover her voice for an hour or two.” –Sir Thomas Willis two.” –Sir Thomas Willis

““The excessive fatigue he encountered wrecked his The excessive fatigue he encountered wrecked his constitution…and his eyelids were so heavy that he constitution…and his eyelids were so heavy that he could not see unless they were lifted up by his could not see unless they were lifted up by his attendants.” –Chief Openchancanoughattendants.” –Chief Openchancanough

HistoryHistory

1800s –modern descriptions published1800s –modern descriptions published

1930s- rational treatments began1930s- rational treatments began Mary WalkerMary Walker Alfred BlalockAlfred Blalock

1960s- disease of autoimmunity1960s- disease of autoimmunity Simpson and NastuckSimpson and Nastuck

MyastheniaMyasthenia GravisGravis (MG)(MG)

Myasthenia (Greek for Muscle/Weakness) Myasthenia (Greek for Muscle/Weakness) Gravis (Latin for severe) Gravis (Latin for severe) Most commonly muscles of the face/eyes/extremities; Most commonly muscles of the face/eyes/extremities;

and can affect the diaphragm (breathing muscle)and can affect the diaphragm (breathing muscle)

MG is rareMG is rare New cases: 10-20 per million each yearNew cases: 10-20 per million each year Prevalence: 150-200 per million each yearPrevalence: 150-200 per million each year

Affects people in 2 age groupsAffects people in 2 age groups 15 -30 yrs of age (usually Women)15 -30 yrs of age (usually Women) 60 – 75 yrs of age (usually Men)60 – 75 yrs of age (usually Men)

MG (continued)MG (continued)

Prior to development of treatments 20-30% of Prior to development of treatments 20-30% of people with MG died within 3 years (due to people with MG died within 3 years (due to respiratory failure)respiratory failure)

Today, with treatment, the vast majority of Today, with treatment, the vast majority of people with MG can people with MG can expectexpect to live normal lives to live normal lives and continue and continue allall the activities they enjoy the activities they enjoy

Recognition and Diagnosis are the key factors in Recognition and Diagnosis are the key factors in getting treatment; and thus good outcomegetting treatment; and thus good outcome RecognitionRecognitionDiagnosisDiagnosisTreatmentTreatmentgood good

outcomeoutcome

DiagnosisDiagnosis

Early referral to neurologist is keyEarly referral to neurologist is key

Often takes patients years to get right diagnosis Often takes patients years to get right diagnosis Eye problemsEye problems Chronic FatigueChronic Fatigue Heart and Lung problemsHeart and Lung problems Depression (other psychiatric disorders)Depression (other psychiatric disorders)

Obstacles to DiagnosisObstacles to Diagnosis

Lack of disease awarenessLack of disease awareness

Late neurology referralLate neurology referral

Symptoms fluctuate/vague (Fatigue; Symptoms fluctuate/vague (Fatigue; weakness)weakness) Patients ignore/dismiss symptomsPatients ignore/dismiss symptoms Doctors attribute to something elseDoctors attribute to something else

Difficult Disease to UnderstandDifficult Disease to Understand

What is Myasthenia?What is Myasthenia?

Myasthenia Gravis is an Myasthenia Gravis is an AutoimmuneAutoimmune disorder of the disorder of the Neuro-Muscular Junction Neuro-Muscular Junction that is characterized by that is characterized by fatigable/ fluctuating strengthfatigable/ fluctuating strength

To understand MG, you must understand the following To understand MG, you must understand the following concepts:concepts: Neuro-Muscular Junction (NMJ)Neuro-Muscular Junction (NMJ) Autoimmune DiseaseAutoimmune Disease

Where’s the Problem?Where’s the Problem?

Brain

Muscle

Spinal chord

Nerve

**NMJ

AchAch

Ach

NMJNerve Muscle

Ach

ACH-R

AchStrongContraction !!

Impulse

+StrongContraction(Reinforcement)

Ach

Ach

Degraded

What is the Problem?What is the Problem?

Autoimmune diseaseAutoimmune disease Antibodies attack and block the Ach receptors Antibodies attack and block the Ach receptors

at the NMJat the NMJ

Ach

AchAch

Ach

NMJ Nerve Muscle

ImpulseACH-R

+

No signalNo contractionNo Strength

Recognition of MGRecognition of MG

Patient HistoryPatient History

Physical Exam/ObservationsPhysical Exam/Observations

Ancillary TestsAncillary Tests Blood testsBlood tests Bedside testsBedside tests Electrophysiology studiesElectrophysiology studies

SymptomsSymptoms

Muscles that are easily fatigable cause Muscles that are easily fatigable cause symptomssymptoms Complaints of double vision (diplopia) and droopy Complaints of double vision (diplopia) and droopy

eyelid (ptosis)- presenting symptoms in 2/3 of patientseyelid (ptosis)- presenting symptoms in 2/3 of patients

Difficulty in chewing, talking, and swallowing-Difficulty in chewing, talking, and swallowing-presenting symptom in 15% of patientpresenting symptom in 15% of patient

Arm weakness- presenting symptom in 10% of Arm weakness- presenting symptom in 10% of patientspatients

Less common presentation-Shortness of BreathLess common presentation-Shortness of Breath

SymptomsSymptoms

Listening to the Patient’s symptoms gives Listening to the Patient’s symptoms gives important cluesimportant clues ““I am weaker during activities”I am weaker during activities” ““I am weaker in the evening, but I feel great in the I am weaker in the evening, but I feel great in the

morning” morning” ““I feel weaker in the heat”I feel weaker in the heat” ““My strength gets better after I rest a while”My strength gets better after I rest a while”

Lack of certain symptoms also importantLack of certain symptoms also important ““No, Doc, I don’t have any tingling or numbness”No, Doc, I don’t have any tingling or numbness”

ObservationObservation

Simply, looking at the patient can give Simply, looking at the patient can give clues to the Diagnosisclues to the Diagnosis

ExamExam

Exploit the fatigability of muscles in MG Exploit the fatigability of muscles in MG patientspatients Unable to maintain upward gaze of eyesUnable to maintain upward gaze of eyes Weakness increases with repeated “strength Weakness increases with repeated “strength

testing”testing”

Weakness Weakness limitedlimited to the eyes is called to the eyes is called ocular myasthenia (10%), otherwise called ocular myasthenia (10%), otherwise called generalized MGgeneralized MG

Antibody TestingAntibody Testing

Blood test drawn to isolate the Auto-immune Blood test drawn to isolate the Auto-immune Antibodies directed at the Ach-R of the NMJAntibodies directed at the Ach-R of the NMJ

80% of patients with generalized MG have Ab; 50% of 80% of patients with generalized MG have Ab; 50% of ocular MG patients have Absocular MG patients have Abs

Presence of Abs in the appropriate clinical context Presence of Abs in the appropriate clinical context confirmsconfirms the diagnosis of MG the diagnosis of MG

If MG still suspected, other tests are needed (e.g. If MG still suspected, other tests are needed (e.g. MuSK antibody)MuSK antibody)

Ach

AchAch

Ach

NMJ Nerve Muscle

ImpulseACH-R

+

No signalNo contractionNo Strength

Bedside TestsBedside Tests

Tensilon Test- Tensilon Test- Drug injected IV that transiently increases the amount of Ach Drug injected IV that transiently increases the amount of Ach

available to the muscleavailable to the muscle Tensilon prevents Ach breakdownTensilon prevents Ach breakdown If positive test, strength (i.e. ptosis) improvesIf positive test, strength (i.e. ptosis) improves Tensilon Test positive in 90% of MG patientsTensilon Test positive in 90% of MG patients

Cold Pack TestCold Pack Test Cold Pack placed over an eye with PtosisCold Pack placed over an eye with Ptosis Cold Temperature transiently prevents Ach breakdownCold Temperature transiently prevents Ach breakdown If positive, ptosis improvesIf positive, ptosis improves (Explains why MG patients are so sensitive to the heat!)(Explains why MG patients are so sensitive to the heat!)

Diagnostic TestingDiagnostic Testing

EMG/Nerve ConductionEMG/Nerve Conduction Rapid stimulation of weak muscle causes Rapid stimulation of weak muscle causes

decremented (fatigable) responsedecremented (fatigable) response

• Repetitive Nerve Stimulation (RNS) - aka Jolly Test: test the nerve supplying a symptomatic muscle. Positive Test is a 10% decrement in size of response. Stimulated Ulnar Nerve

and recorded over thumb muscle

Additional TestingAdditional Testing

Single Fiber EMG (SFEMG)Single Fiber EMG (SFEMG)

Most sensitive test for diagnosing MGMost sensitive test for diagnosing MG Can detect very subtle NMJ abnormalitiesCan detect very subtle NMJ abnormalities If SFEMG is Negative, then the patient does not have If SFEMG is Negative, then the patient does not have

MGMG An operator dependent testAn operator dependent test

Thymus GlandThymus Gland

•Thought to be important Thought to be important in antibody production in antibody production through regulation of B through regulation of B and T cellsand T cells

•10% have 10% have thymic tumorthymic tumor 70% have hyperplasia70% have hyperplasia

•Removal in such cases Removal in such cases remains standard remains standard treatment. Removal treatment. Removal without evidence of a without evidence of a mediastinal mass is mediastinal mass is controversialcontroversial

Thymoma on chest X-rayThymoma on chest X-ray

Thymoma on chest CTThymoma on chest CT

ThymectomyThymectomy

Should be considered in all people diagnosed with MGShould be considered in all people diagnosed with MG Early surgery is best; but Early surgery is best; but NEVERNEVER an emergency an emergency Good response has been reported, but variableGood response has been reported, but variable

Twice as likely to be medication free after removalTwice as likely to be medication free after removal

Caution in the following:Caution in the following: Patients older than 55-60 yr oldPatients older than 55-60 yr old Patients who have not gone through pubertyPatients who have not gone through puberty

TreatmentTreatment

Goal of Treatment is to treat symptoms while addressing Goal of Treatment is to treat symptoms while addressing the underlying cause of the disease (autoimmunity)the underlying cause of the disease (autoimmunity)

Patient –specific regimenPatient –specific regimen

Side effects vs. desired clinical responseSide effects vs. desired clinical response

With proper treatment and patience most people achieve With proper treatment and patience most people achieve excellent outcomesexcellent outcomes

TreatmentTreatment

Treatment Options: (current arsenal)Treatment Options: (current arsenal) Medicines that improve NMJ functionMedicines that improve NMJ function

Mestinon (pyridostigmine), NeostigmineMestinon (pyridostigmine), Neostigmine ImmunosuppressantsImmunosuppressants

Steroids, Cyclosporine, Imuran, CellCeptSteroids, Cyclosporine, Imuran, CellCept Chemotherapeutics Chemotherapeutics

CyclophosphamideCyclophosphamide Antibody removalAntibody removal

Plasma Exchange, IVIgPlasma Exchange, IVIg ThymectomyThymectomy

TreatmentTreatment

Mestinon- helps with symptomsMestinon- helps with symptoms Modifies the NMJ the same way Tensilon does; helps Modifies the NMJ the same way Tensilon does; helps

facilitate nerve to muscle transmissionfacilitate nerve to muscle transmission

Inhibits Ach breakdown- inhibits Ach esteraseInhibits Ach breakdown- inhibits Ach esterase

Helps eliminate the symptoms of weakness very Helps eliminate the symptoms of weakness very rapidlyrapidly

Usually the first medicine that is startedUsually the first medicine that is startedStart 30 to 60 mg every 4-8 hrs- titrate to effectStart 30 to 60 mg every 4-8 hrs- titrate to effect

TreatmentTreatment

Steroids (Prednisone)Steroids (Prednisone) Work quicklyWork quickly

““Dampens” the over-active immune system- make person less Dampens” the over-active immune system- make person less auto-immuneauto-immune

Most patients started on a high dose (60-100mg) and then Most patients started on a high dose (60-100mg) and then tapered down slowlytapered down slowly

Most patients will always require some amount of steroids in Most patients will always require some amount of steroids in their treatment regimen for MGtheir treatment regimen for MG

Limited mainly because of side effects (DM; weight gain; Limited mainly because of side effects (DM; weight gain; infection risk)infection risk)

ImmunosuppressantsImmunosuppressants

CellCept, Imuran, Prograf, CyclosporineCellCept, Imuran, Prograf, Cyclosporine Work to inhibit T and B cell activityWork to inhibit T and B cell activity

Usually these agents are added after steroids have achieved Usually these agents are added after steroids have achieved maximal effectmaximal effect

Take much longer to take effect than steroids (2-12 months)Take much longer to take effect than steroids (2-12 months)

Used to limit steroid useUsed to limit steroid use

Most require lab work for side effect monitoring ( CBC, LFTs)Most require lab work for side effect monitoring ( CBC, LFTs)

TreatmentTreatment

Chemotherapeutics (Cytoxan)Chemotherapeutics (Cytoxan) Go a step further than immunosuppressants in Go a step further than immunosuppressants in

modifying the immune systemmodifying the immune systemActually “kill” existing T and B cellsActually “kill” existing T and B cells

Very powerful drugs that should be used with Very powerful drugs that should be used with extreme caution and in limited situationsextreme caution and in limited situations

Some use the these drugs to “Re-boot” the patient’s Some use the these drugs to “Re-boot” the patient’s immune system- usually when all other treatment immune system- usually when all other treatment options have failed to achieve desired outcome of options have failed to achieve desired outcome of symptom remissionsymptom remission

TreatmentTreatment

Plasma ExchangePlasma Exchange Effectively siphons out “bad antibodies” from the bloodEffectively siphons out “bad antibodies” from the blood Usually receive 5-6 “Exchanges” over a 10 day periodUsually receive 5-6 “Exchanges” over a 10 day period Requires hospitalization; and a large IVRequires hospitalization; and a large IV

IVIgIVIg Infusion of Immunoglobulins into the bloodInfusion of Immunoglobulins into the blood Thought to “displace” the “bad antibodies” or prevent the B-cells Thought to “displace” the “bad antibodies” or prevent the B-cells

from producing the “bad antibodies”from producing the “bad antibodies” Can be used as maintenance or rescue therapyCan be used as maintenance or rescue therapy

Special conditions in MGSpecial conditions in MG

Myasthenic CrisisMyasthenic Crisis

Pregnancy Pregnancy

Neonatal MGNeonatal MG

Hospitalization and MGHospitalization and MG

Myasthenic CrisisMyasthenic Crisis

Defined by Respiratory failure in MG patientDefined by Respiratory failure in MG patient Can be presenting symptom or can be incited by Can be presenting symptom or can be incited by

infection/medication infection/medication

Patients often require ventilator supportPatients often require ventilator support

Patients need Patients need rapidrapid treatment treatment

IVIG or Plasma exchange IVIG or Plasma exchange

MG and PregnancyMG and Pregnancy

Effects can be unpredictable on MomEffects can be unpredictable on Mom 1/3 with increased symptoms1/3 with increased symptoms 1/3 with improvement in symptoms1/3 with improvement in symptoms 1/3 with no effect1/3 with no effect

Labor can be longer due to fatigue and Labor can be longer due to fatigue and weaknessweakness Increased C-sectionsIncreased C-sections

Increased rate of preterm laborIncreased rate of preterm laborNo long term effects on the course of MGNo long term effects on the course of MG

Treatment and PregnancyTreatment and Pregnancy

Some treatments can still be used during Some treatments can still be used during pregnancypregnancy MestinonMestinon Steroids (if needed)Steroids (if needed) IVIgIVIg Plasma exchangePlasma exchange

Some medications are avoided if possibleSome medications are avoided if possible

PregnancyPregnancy

Be preparedBe prepared NeurologistNeurologist Maternal-Fetal Medicine Specialist (High-risk Maternal-Fetal Medicine Specialist (High-risk

OB)OB) NeonatologistNeonatologist

Pay attention to fetal movementsPay attention to fetal movements

MG and the BabyMG and the Baby

Majority of babies have no problemsMajority of babies have no problems

Approx 12-15% can have “neonatal MG”Approx 12-15% can have “neonatal MG” Usually mildUsually mild

Poor suckPoor suck

Weak cryWeak cry

Decreased muscle toneDecreased muscle tone Usually resolve within the first few weeksUsually resolve within the first few weeks

If hospitalized…If hospitalized…

Real caseReal case

MG flares can be triggeredMG flares can be triggered HeatHeat InfectionsInfections MedicationsMedications

AntibioticsAntibiotics

BP medicationsBP medications

SedativesSedatives

AnesthesiaAnesthesia

What to rememberWhat to remember

Myasthenia symptoms will worsen from other Myasthenia symptoms will worsen from other medical illnessmedical illness

Request neurology consultation Request neurology consultation

Know what medications are being given to youKnow what medications are being given to you

Maintain close outpatient follow-up appointment Maintain close outpatient follow-up appointment after dischargeafter discharge

ResearchResearch

ThymectomyThymectomy

Guided missile cell therapy Guided missile cell therapy Johns Hopkins 2012Johns Hopkins 2012

Stem cell researchStem cell research

Take Home PointsTake Home Points

Early recognition and diagnosis is key to better Early recognition and diagnosis is key to better outcomes.outcomes.

Several treatments are available. Each regimen Several treatments are available. Each regimen is patient specific.is patient specific.

Can have a relatively normal lifeCan have a relatively normal life

More research is neededMore research is needed

Special Thanks to Myasthenia Gravis Special Thanks to Myasthenia Gravis SocietySociety

??? Questions?????? Questions???

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