MG Handout

8/14/2019 MG Handout

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MYASTHENIA GRAVIS

Pakamas Pasogpakdee,MD6/28/09

Introduction

The most common primary disorder of neuromusculartransmission

Usual cause is an acquired immunological abnormality , somecases result from genetic abnormality at the NMJ

Women : 2nd and 3rd decades , Men : 6th decadesUSA : M>F (5th decades)

Neurology in Clinical Practice , 5th Edition , 20086/28/09

Immunopathology of MG

LEMS6/28/09

80% of MG pts. , weakness result from the effects ofcirculating anti-AChR Ab (T cell dependent)

destruction of the folds , accelerated internalization &destruction of AChR , block Ach-AchR binding

10% of MG pts. have circulating Ab to MuSKRemaining = seronegative

Neurology in Clinical Practice , 5th Edition , 2008


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AChR Ab +ve

AChR Ab neg

AntiMUSK

AntititinAb to ryanodine receptor

AntiRapsyn

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Clinical Presentation

65% ptosis & diplopia15% difficult chewing , swallowing , talking10% limb weakness rare single muscle group weaknessTypically fluctuates during the day , usually being least in themorning and worse as the day progresses , esp. after prolongeduse of affected muscles



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Clinical Presentation

Careful questioning often reveals evidence of earlier myasthenicmanifestration

- frequent purchases of new eyeglasses - avoidance of foods that became difficult to chew or swallow - cessation of activities that require prolonged use of specificm.

- friends may have noted a sleepy or sad facial appearance caused by ptosis or facial weakness


Physical Findings

pattern of muscle involvement Ocular muscle - eye movements - Eye lid Oropharyngeal muscle - "myasthenic snarl - nasal speech , difficulty chewing , difficulty swallowing

choking on liquids Limb muscle - Limb muscle weakness , Fatiguability


EYE & MG

Ptosis - usually asymmetrically - allow soap or water in the eyes during bathingDiplopia - Asymmetric weakness of several muscle in both eyes - Pattern of weakness is not characteristic of lesions of

one or more nerves

- Pupillary responses are normal - Weakness is most frequent & usually most severe in MRshould raise suspicion of MG in the combination of ptosis ,ophthalmoparesis , weak eye closure


Eyelid manifestation

Levator palpebrae - Ptosis - Upper eyelid retraction - Lid fatigue test - Enhancing ptosis - Cogan lid twitch sign - Ice test - Sleep test - Rest testOrbicularis oculi muscle - Forced eye closure: buried eyelashes

- Open the eyes against forced eyelid closure

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Upper eyelid retraction

Left upper eyelid retraction contralateral to a ptotic rightupper eyelid

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Lid fatigue test

(A) On initial upgaze, minimal left upper eyelid ptosis is evident(C) After 2 minutes of sustained upgaze, the degree of left

upper eyelid ptosis is significantly increased owing to levatormuscle fatigue

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Cogan lid twitch sign

looks down for at least 10 to 20 seconds makesan upward saccade back to primary gaze

transient overshoot of the upper eyelid , which maybe followed by nystagmoid twitches of the uppereyelid and then downward drifting of the eyelid to anormal or ptotic position

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Ice test

Preceding the test

An ice pack is applied to theclosed left eye for 2 minutes

Right upper eyelid ptosis issignificantly improved

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Sleep test

(A) before the test (B) After 30 minutes of sleep(lying down in a quiet and dimlylit room), the ptosis isnoticeably improved in botheyes

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Rest test

(A) Before rest (B) After only 5 minutes ofgentle eye closure, the ptosisis much improved in both eyes

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bilateral lagophthalmos

Not bury the eyelashes duringforced eye closure

Orbicularis oculi muscle

severe bilateral orbicularis weaknesssecondary lower eyelid retraction

weak orbicularis muscle in the right eye duringforced eye closure

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Ocular finding in myasthenia gravis

Weakness usually involves one or more ocular muscles w/o overt pupillary abnormality

Weakness is typically variable , fluctuating , fatigable

Ptosis that shifts from one eye to the other is virtually pathognomonic of MG

With limited ocular excursion , saccades are superfast , producing ocular quiver

After downgaze , upgaze produces lid overshoot lid twitch

Pseudo-internuclear ophthalmoplegia-limited adduction is present w/ nystagmoid jerks inabducting eye

In asymmetrical ptosis , covering the eye w/ the ptotic lid may relieve contraction of theopposite frontalis

Passively lifting a ptotic lid may cause the opposite lid to fall

Edrophonium may improve only one of several weak ocular muscle , other may becomeweaker

Edrophonium may relieve asymmetric ptosis & produce retraction of the opposite lid fromfrontalis contraction

The opposite lid may droop further as the more involved lid strengthens after edrophonium

Cold applied to the eye may improve lid ptosis Neurology in Clinical Practice , 5th Edition , 20086/28/09

Oropharyngeal Muscles

Changes in voice - nasal voice - asking high-pitched EEEEEEEEE sound Difficulty chewing and swallowing Inadequate maintenance of the upper airway Alter facial appearance

- myasthenic snarl


Myasthenic Snarl

Corner of mouthdroop downward

Rest Smile

Contraction of medial

portion of upper lip

No upward curling

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Trunk & limb muscles

Neck muscleUpper extremities

- Out stretched arms test - Grip fatigue can be measured with a dynamometer thatthe patient grasps repetitively - Repetitive exercise test

Lower extremity - step up and down from a footstool as if climbing stairs - progressively more difficult and the patient begins topush off their knee with their arm in order to help theweakening quadriceps

* Neck flexors , Deltoids , Triceps , WE , FE , ankledorsiflexors *

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Diagnostic test

Clinical diagnosis Investigation

Anticholinesterase test Autoantibodies Electridiagnosting Testing

repetitive nerve stimulation single-fibre electromyography

Neurology in Clinical Practice , 5th Edition , 20086/28/09 6/28/09


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Diagnostic test

1. Anticholinesterase test

Edrophonium Chloride (Tensilon) Test- Rapid onset(30sec), short duration(5min)

- 2 mg IV if no change add 8 mg IV

Neostigmine test

- Neostigmine 1-2 mg,IM- Effects seen within 20-40 min

- Should have measurable parameter eg. P tosis


Diagnostic test

1. Anticholinesterase test

False positive Edrophonium test

- Lambert-Eaton syndrome (37%positive)

- Botulism (27% positive)

- Congenital end-plate acetylcholine receptor deficiency

- Guillain-Barr syndrome

- Amyotrophic lateral sclerosis

- Brain stem glioma


Diagnostic test

2. Auto- Ab

serum antibodies that bind human AChR 70-90% generalized myasthenia 50-75% ocular myasthenia

AChR binding antibodies conc. sometimes increased inpatients w/

SLE , inflammatory neuropathy , ALS , RA taking D-penicillamine , thymoma w/o MG , normal relatives ofpatients with MG


Diagnostic test

2. Auto-Ab

Positive AChR Ab plus clinical = confirm diagnosis Negative AChR Ab can not be rule out no correlation between disease severity and antibody titre clinical improvement: associated with a fall in Ab titre

Biodrugs 2001 March; 15 (3): 173-83N Engl J Med 1994; 330 (25): 1797-810

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Diagnostic test

2. Auto-Ab

Anti-MUSK Ab Antistriational muscle Ab : predicting thymoma (60% of

pts. w/ MG w/ onset before age 50 have thymoma)

Others : Antititin Ab Anti ryanodine Ab


Diagnostic test

3. Electrodiagnostic test

Repetitive Nerve Stimulation (RNS) - Decrement of > 10% at 3 Hz: highly probable - more often in proximal muscles, such as

the facial muscles, biceps, deltoid, and trapezius than inhand muscles

- Anti-ChE medications should withheld 12hours (24 hours) prior to testing

- Yield of RNS : Ocular MG 30-40% Generalized MG 70-80%



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Diagnostic test

3. Electrodiagnostic test

Single Fiber EMG (SFEMG) - most sensitive clinical test of neuromuscular

transmission

- shows increased jitter in some muscles inalmost all patients with myasthenia gravis

- positive in 95-99% of pts. with generalized MG


Diagnostic test

Anticholinesterase test : often Dx in pts. w/ ptosis orophthalmoparesis , less useful in assessing other muscles

Autoantibodies : presence of AChR-Ab , anti-MUSK Ab ensuresthe Dx of MG , but absence dose not exclude

Electrodiagnosting Testing repetitive nerve stimulation : confirm impaired

neuromuscular transmission , but frequently normal inmild or purely ocular disease

single-fibre electromyography : normal jitter in weakmuscle excludes MG

Neither EDx is specific for MGNeurology in Clinical Practice , 5th Edition , 20086/28/09

Sensitivity of tests in MG

Tests Ocular MG Generalized MG

Edrophonium test 80-90% 80-90%

Ice pack / sleep test Criteria poorly defined Criteria poorly defined

AChR Ab 30-50% 80-90%

MuSK Ab Rare 30-40% of seronegative

Antistriatal Ab 80% in pt. w/ thymoma

30% in pt. w/o thymoma

80% in pt. w/ thymoma

30% in pt. w/o thymoma

RNS 30-60% 90%

Single fiber EMG 90-95% 90-95%

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DDx : Ocular MG

Mitochondrial disorder : CPEOOculopharyngeal muscular dystrophyThyroid ophthalmopathyBrainstem lesionLocal eyelid disorder

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DDx : Generalized MG

NMJ disorder - LEM - Congenital myasthenic syndrome - Neurotoxins eg. BotulismMyopathiesDemyelinating polyneuropathies

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Assessment

Associated disorder - Disorder of thymus : Thymoma , Hyperplasia - Other autoimmune disorder : Hashimoto thyroiditis ,

Graves disease , RA , SLE

Disorder or circumstance that may exacerbate MG - Hyperthyroidism , Occult infection - Medical Rx of other condition (aminoglycoside,

quinidine, antiarrhythmic drug)

Disorder that may interfere therapy - TB , DM , PU , GI bleed , Asthma , osteoporosis

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Classification (modifications of Osserman)

Class I - Ocular myasthenia

Class IIA - Mild generalized myasthenia with slow progression;no prominent bulbar signs; no crisis; drug responsive

Class IIB - Moderate generalized myasthenia; severe skeletaland bulbar involvement but no crisis;

drug response than satisfactory

Class III - Acute fulminating myasthenia; rapid progression ofsevere symptoms with respiratory crisis and poor

drug response; high incidence of thymoma; high mortality

Class IV - Late severe myasthenia; same as III but progress

over two years from class I to II6/28/09

Class I - Any ocular muscle weakness- May have weakness of eye closure- All other muscle strength is normal

Class II - Mild weaknessaffecting other than ocular muscles- May also have ocular muscle weakness of any severity

IIa - Predominantly affecting limb , axial muscles , or both- May also have lesser involvement of oropharyngeal

IIb - Predominantly affecting oropharyngeal ,respiratorymuscles or both

- May also have lesser or equal involvement of limb , axial

muscles or both

Classification (MGFA)

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Class III-Moderate weaknessaffecting other than ocular muscles- May also have ocular muscle weakness of any severity

IIIa - Predominantly affecting limb , axial muscles , or both- May also have lesser involvement of oropharyngeal

IIIb - Predominantly affecting oropharyngeal ,respiratorymuscles or both

- May also have lesser or equal involvement of limb , axialmuscles or both


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Class IV- Severe weaknessaffecting other than ocular muscles- May also have ocular muscle weakness of any severity

IVa - Predominantly affecting limb , axial muscles , or both- May also have lesser involvement of oropharyngeal

IVb - Predominantly affecting oropharyngeal ,respiratorymuscles or both


Class V - Defined by intubation, w/ or w/o mechanical ventilationexcept when employed during routine postoperativemanagement

The use of a feeding tube w/o intubation places the patients in class IVb


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Class IV- Severe weaknessaffecting other than ocular muscles- May also have ocular muscle weakness of any severity

IIIa - Predominantly affecting limb , axial muscles , or both- May also have lesser involvement of oropharyngeal

IIIb - Predominantly affecting oropharyngeal ,respiratorymuscles or both


Class V - Defined by intubation, w/ or w/o mechanical ventilationexcept when employed during routine postoperativemanagement

The use of a feeding tube w/o intubation places the patients in class IVb

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Clinical subtypes

Early onset cases Late onset cases Ocular myasthenia Seronegative MG

Thymoma associated MG Positive antititin antibodies

Neonatal MG

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Early onset cases

Female Onset before age 40 AChR Ab-positive Usually do not Ab to muscle Ag Hyperplasia of thymus gland 60% of cases : HLA-D8 , HLA-DRw3

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Late onset cases

Men slightly more than female Onset after age 40 Associated with HLA-B7 , HLA-DRw2

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Ocular myasthenia

AChR Ab positive only 40-60% of cases Represent mild cases of autoimmune generalized MG 50-60% develop generalized weakness in 1-2 years 40% remain ocular MG Pts. w/ pure ocular symptoms for 2 yrs. have less

chance to develop generalized MG

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Seronegative MG

Clinicla similar to MG with AChR Ab Many evidence suggest autoimmune in origin

Development of neonatal MG in babies born toseronegative mother

Response to plasma exchange A good proportion of cases have autoantibodies to a

muscle specific receptor tyrosine kinase (MuSK)

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Thymus & MG

more mature T cells than normal Thymus70% of pt. have lymphoid follicular hyperplasia> 10% of pt. have a thymoma3060% of thymomas associated with MG


TREATMENT

Controlled clinical trials : rareObjectives :

Directly target autoimmune responseModify Ab production or modify immune mediated damageto NMJ

Modify natural history of diseaseStrategy : induce remission , maintain remission

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TREATMENT

CSR: no s/s of MG 1 yr. & has received no therapy for MGduring that time , isolated weakness of eyelid closure is accept

PR: same criteria of CSR except that the pts. continue to takesome from of therapy of MG. Pts. taking

cholinesterase inh. are excluded from this category because theiruse suggests the presence of weakness

CSR = complete stable remission , PR = pharmacologic remission

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TREATMENT

MM : no symptoms of functional limitation from MG , someweakness on examination of some muscles

MM-0 : no MG treatment 1 yr.MM-1 : receive some form of immunosuppression , no ChE

inhibitor or other symptomatic therapy

MM-2 : receive low dose of ChE inhibitor(


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SYMPTOMATIC TREATMENTS

Pharmacologic treatmentCholinesterase inhibitor (first line medication)

Muscle training , weight control , lifestyle modification

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Cholinesterase inhibitor

retard the enzymatic hydrolysis of ACh at cholinergicsynapses ACh accumulates at NMJ prolonged effects

diagnostic testearly treatment , symptomatic treatment response usually becomes less w/ chronic use

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Pyridostigmine bromide (Mestinon) & neostigmine bromide(Prostigmine)

initial oral dose = 30-60 mg every 4-6 hrs.mestinon 60 mg , oral = neostigmine methylsulfate 0.5mg , IV

no fixed dosage schedule suits all patientsvaries from day to day & during the same daydifferent muscles response differently

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Drugs schedule should be titrated to produce an optimalresponse in muscles causing the greatest disability

Attempts to eliminate all weakness by increasing thedose or shortening the interval causes overdose at the timeof peak effect

keep the dose low enough to provide definiteimprovement in the most important muscle groupsw/in 30-45 min , expect the effect to wear offbefore the next dose

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Adverse effect : muscarinic receptor on smooth muscle &autonomic glands

nicotinic receptor on skeletal musclecommon : GI queasiness , nausea , vomiting ,abdominal cramp , loose stool , diarrhea

suppress with loperamide hydrochloride(Imodium) ,propantheline bromide(Pro-Banthine) ,glycopyrrolate(Robinul) diphenoxylate hydrochloride w/atropine(Lomotil)

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Corticosteroids Immunosuppressant drugsPlasma exchange Intravenous immunoglobulinThymectomy

IMMUNOMODULATION

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G0=dormant phase

G1= resting phase

M= mitotic ph ase

G2= perimitotic phase

S= DNA synthesisphase

CY

CY

CY

CY , AZAMMF , MTX

CY , AZAMMF , MTX

Cell cycle

IMMUNOMODULATION

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T cellNucleus

T-cell receptor

T-cell receptorMacrophage

Extracellular

Intracellular

S

S

CSA

TAC

IMMUNOMODULATION

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Corticosteroids

Mechanism :Blocking Ag processingDecrease number of circulating T cellsReducing trafficking of inflammatory cellsReduce expression of inflammatory cytokines and adhesionmolecules

Never been studied in large RCT marked improvement orcomplete relief of symptoms > 75% of pts.onset : 6-8 weeks remission : 3 monthsgood response : pts w/ recent onset of symptoms

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Corticosteroids

1.5-2.0 mg/kg/day until sustained improvement (2 wks.)EOD

reduced 20 mg/mo. 60 mg , EOD reduced 10 mg/mo. 20 mg , EOD reduced 5 mg q 3 mo 10 mg , EODnot reduce the dose further than this unless anotherimmunosuppressant being given

weakness returns increased dosage or addimmunosuppressant

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Corticosteroids

1/3 of pts. become weaker temporarily , usually in first 7-10days

managed w/ ChE inhibitorsoropharyngeal weakness or respiratory insufficiency : plasmaexchange before started prednisone

should be hospitalized to start this treatment

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Corticosteroids

start 20 mg/day increase 10 mg q 1-2 wks. maximumimprovement

reduced as above reduced frequency or severity of corticosteroid-inducedexacerbations

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Corticosteroids

SE : hypercorticism , weight gain , HT , diabetes ,anxiety / depression / insomnia steroid psychosis ,glaucoma , osteoporosis , cataracts , ulcer/GI perforations ,myopathy , opportunistic infections , avascular necrosis oflarge joints

SE increased when high daily dose > 1 mo.SE resolved when taper dose , 2x discontinue restart when values become normalpancreatitis : rarepotentially mutagenic adequate contraception

Azathioprine

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Cyclosporine (CYA)

Retrospective analyses :

improvement in most pts. taking CYA w/ or w/ocorticosteroids

Ciafaloni et al. 20006/28/09

inhibits predominantly T-lymphocyte dependent immuneresponse

start at 5-6 mg/kg/day (divided 12 hr. apart)measured serum level at 1 mo.keep trough serum CYA concentration 75-150 ng/mLmonitor serum creatinine q 2-3 mo.

Cyclosporine (CYA)

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SE : renal toxicity , HTN improve 1-2 mo. , maximum improvement after 6 mo.after maximum response gradually reduced CYA tominimum that maintain improvement

Cyclosporine (CYA)

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Cyclophosphamide

given IV in monthly pulsed doses has been used

effectively in severe , generalized MG that is refractory to

other therapy

De Feo et al ,2002 Drachman et al,20026/28/09

IV : 500 mg/m2oral : 150-200 mg/day total dose 5-10 gSE : alopecia , cystitis , nausea , vomiting , anorexia ,discoloration of nail & skin

Cyclophosphamide

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Mycophenolate mofetil (MM)

inhibits the proliferation of B & T-lymphocyte clones ,responding to antigenic stimulation

suppresses the formation of Ab active in complement-dependent lysis & cell-mediated cytotoxicity

2 g/day in divided 12 hr. apartonset action : 2 wks.SE : leukopenia , diarrhea refractory MG , as corticosteroid sparing agent whenazathioprine has produced intolerable SE or has not beeneffective

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Plasma Exchange

sudden worsening of myasthenic symptoms for any reason rapidly improve strength before surgeryconcomitantly w/ starting high dose corticosteroidschronic intermittent treatment for refractory MG

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Plasma Exchange

remove 2-3 Liters of plasma , 3 times a wk. untilimprovement , usually 5-6 exchanges

improvement usually begin after 2nd or 3rd exchange improvement last for wks or months repeated exchange not produce a cumulative benefitSE : cardiac arrythmias , nausea , lightheadedness , chills ,obscured vision , pedal edema

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Intravenous Immunoglobulin

2 g/kg (0.4 g/kg/day) infused over 2-5 days improvement 50-100% , begin in 1 wk. , lasting for severalwks. or mo.

SE : headache , chills , fever , alopecia , aseptic meningitis ,leukopenia , retinal necrosis , renal failure , cerebralinfarction , myocardial infarction

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Intravenous Immunoglobulin

C/I : selective IgA deficiency because may develop anaphylaxis to IgA in IVIg preperation A multicenter , randomized , controlled s tudy comparingplasmapheresis with IVIg has demonstrated equal efficacy butsignificanly fewer and less severe SE for IVIg

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Thymectomy

classic long-term treatmenteffect is usually not apparent until after 1 yr , and the fulleffect is not felt for 5 yr

never been demonstrated to be effective in a prospective ,controlled study

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Thymectomy

Controversies

Effectiveness in late onset pts. (>50 year old)Reduced effectiveness in MuSK +ve patientsCost effectivenessWhen to performed thymectomyWhich surgical techniques

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Thymectomy

American Academy of Neurology : medication free remission : 2x

asymptomatic : 1.6x show improvement : 1.7x For pts. w/ nonthymomatous autoimmune MG ,thymectomy is recommended as an option to increase theprobability of remission or improvement

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Thymectomy

recommended thymectomy for most pts. w/ MG whosesymptoms begin before age 60

good response : young people , women , early in course ofdisease

advantage : induce sustained , drug-free remission , removethymoma

transthoracic approach

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Thymectomy

repeat thymectomy :chronic refractory diseaseall thymic tissue not removed at prior surgerygood response to original surgery

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Ocular MG

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MG (II,III,IV)

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Factor that worsen myasthenic symptoms

emotional upsetsystemic illness (esp. viral respiratory infections)

hypothyroidism or hyperthyroidismpregnancymenstrual cycle

DrugsFever

Neurology in Clinical Practice , 5th Edition , 2008

Special situations

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Special situations

Surgery : spinal block avoidance neuromuscular blocking agentPregnancy :

improve-stable-worse ChE inhibitor induce uterine contraction

immunosuppressant : only corticosteroids transient neonatal myasthenia

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Special situations

Avoidance of situations in which neuromuscular transmissionmay be compromised

Penicillamine , amiodarone , aminoglycosides

thyroid dysfunction may have direct effect on the NMJ

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Prognosis

course of disease : variable but usually progressiveocular myasthenia generalized myasthenia (2 years) , 1st yearmaximum weakness (65%)

active stage : symptoms fluctuate over a relatively short period andthen become more severe

burnt-out stage : after 15-20 years , untreated weakness becomefixed , muscle atrophy

remission : may occur early on but rarely permanentNeurology in Clinical Practice , 5th Edition , 20086/28/09

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