May 22, 대한흉부외과학회 제 24 차 춘게학술대회 Pathophysiology, Diagnosis and...

May 22, 대한흉부외과학회 제 24 차 춘게학술대회

Pathophysiology, Diagnosis and Medical Management of Myasthenia G

ravis

Jung-Joon Sung MDDepartment of Neurology

Seoul National University Hospital

대한흉부외과학회 제 24 차 춘계학술대회 May 22, 2008


Introduction

Anatomy of neuromuscular junction

Pathophysiology of exertional weakness

Etiology of myasthenia gravis

Clinical features of myasthenia gravis

Diagnosis & treatment of myasthenia gravis

Presurgical preparation

Agenda


Repetitive Nerve Stimulation Test (RNST, Jolly test)

Exertional WeaknessExertional Weakness


Myasthenia Gravis (MG)

MG vs PBP


Myasthenia gravis pseudoparalytica


Neuromuscular Junction in MG

Normal vs MG

A) B)


Myasthenia Gravis


Neuromuscular Junction


• MUSK and rapsyn : clusting of AchRs

• Neuregulin (or ARIA, acetylcholine receptor-inducing activity): regulate expression of AchR


Physiology of NMJ Primary (immediately available) store

1,000 quanta Beneath presynapticnerve terminal

Secondary (mobilization) store 10,000 quanta Re-supply after a few seconds

Tertiary (reserve) store 100,000 quanta Distant axon and cell body


Action Potential in NMJ


Physiologic modeling of RNS

Number of quanta released during each stimulation (m) = Probability of release (p) X Number of quanta in the immediately available store (n) *p; effectively proportional to the concentration of calcium, 0.2 in no

rmal n; 1000 in baseline

“Mobilization store” replenishes after 1-2 sec

100ms is required to pump Ca out of presynaptic terminal. *If stimulation rate >10 Hz , Ca conc increases


Physiologic modeling of RNS - Low Rate stimulation

Threshold : 15mV

stimulus No. of quanta stored

No. of quanta

released

EPP SFAP CMAP

1 1000 200 40 + Normal

2 800 160 32 + n/c

3 640 128 26 + n/c

4 512 102 20 + n/c

5 640 128 26 + n/c



-- Myasthenia Gravis

stimulus No. of quanta stored

No. of quanta

released

EPP SFAP CMAP

1 1000 200 20 + Normal

2 800 160 16 + n/c

3 640 128 13 - decrement

4 512 102 10 - decrement

5 640 128 13 - Decrement(repaired)



Normal MG LEMS


Etiology and pathogenesis Destructive autoantibodies to AChR Evidence:

Immunization with purified AChR would induce autoantibodies to AChR

Autoantibodies to AChR are found in human MG

Features of MG could be induced by passive transfer of autoantibodies to mice

Plasmapheresis improve S/S in MG


Etiology and pathogenesis Antigen presenting cells->

CD4+ T cells-> B cells-> autoantibodies-> attack AChR

Hyperplastic thymus:Myoid cells: surface AChR,

muscle proteins In patients, the thymus gland

is almost always abnormal.70% hyperplasia10% thymoma

Genetics: HLA B8, DR3, DQB1

Leite MI, et al. Ann Neurol 2005


Pathogenic Mechanism in MG

Blocking antibody

Increased acetylcholine recpetor (AChR) degradation

Complement-mediated damage of post-synaptic membrane


Incidence

Prevalence: 50/1,000,000 More prevalent in female Bimodal peak in Incidence

female incidence peaks in the 3rd decademale incidence peaks in the 6-7th decade

anti-AChR Ab: 85-90% in generalized MG50-60% in ocular MG10-20%: seronegative MG


Clinical Features Fluctuating nature: exertional weakness Distribution of weakness

Ocular: pure in only 15-20% • Diplopia & ptosis: extraocular muscles (EOM) and l

evator palpabrae (LP)• 90% generalization occurred in 13 months

Facial and oropharyngeal musclesRespiratoryLimbs, never affected alone

Response to cholinergic drugs


Clinical Features

Crisis:Respiratory muscles involvementMore likely in oropharyngeal or

respiratory muscle involvementDue to infection, surgery, emotional

stress, systemic disease, aspirationSome are spontaneous.Vs. cholinergic crisis


Diagnostic Tests Repetitive nerve stimulation(Jolly test)

3-5 HZ, more than 10 % decremental responsepositive in 90% generalized type

Single-fiber EMG: increased jitterpresence of block

Antibodies to AChR:no false-positive except Lambert-Eaton

syndrome or thymoma without MGtiter is not related to severity

Response to cholinergic drugs: Tensilon (Edrophonium) test, Neostigmine test


Discrepancy btw severity and AChR Ab titer

Vincent A. Semin Neurol 2004


Laboratory data, others

Antibodies to myofibrillar proteinsTitin, Ryanodine receptor85-95% in MG with thymoma

Anti-MuSK (muscle specific tyrosine kinase)0-70% in patients without anti-AChR Ab

Other autoimmune disease: hyperthyroidism (5%)

Chest CT: thymic hyperplasia, 15% thymoma


Vincent A, et al. Lancet Neurol 2003

Pathogenic mechanisms in SNMG


SNMG in Korea

85.1

14.9SNMGSPMG

MuSK Ab Pos

4

0

FemaleMale

MuSK Ab Neg

7

4

FemaleMale

Generalized SNMG4

11

MuSK AbNegMuSK AbPos

Sung JJ, et al. Journal of Clinical Neuroscience 2005


MuSK-antibody-positive SNMG

0

5000

10000

15000

20000

25000

Ocular SNMG (n=8) Generalized SNMG (n=15)

Group

MuS

Kan

tibod

y tit

er (

cpm

125I-

MuS

K

prec

ipita

ted

per

5 L

ser

um)

IgG MuSK antibodies assayed by immunoprecipitation Vincent A, et al. Lancet Neurol 2003

Sung JJ, et al. Journal of Clinical Neuroscience 2005


Clinical features of MuSK-antibody-negative and –positive SNMG patients in Korea

Clinical features

No. of patients

MuSK positive 　MuSK ne

gative

(n=4) 　 (n=19)

MuSK antibodies (cpm precipitated/5 ul serum)

>17,000 cpm

< 400 cpm

Most disabling symptoms

ocular 0 9

pharyngeal 2 4

respiratory 2 2

limb weakness 0 4

axial weakness 0 0

Other autoimmune disease 3 4

Other autoantibodies 1 　 1


Clinical features

No. of patients

MuSK positive 　MuSK ne

gative

(n=4) 　 (n=19)

Immunosuppresive treatment

4(100%) 4(21%)

Thymectomy 1 1

Change in status

improved 4 13

unchanged 0 6

Treatment response (PIS)

CSR 0 2

PR 1 4

MM-0 0 1

MM-1 0 1

MM-2 0 4

MM-3 3 7PIS= postintervention status; CSR = complete stable remission;

PR = pharmacological remission; MM = minimal manifestations


SPMGAChR antibody onlyAChR antibody + titin, ryanodine receptor antibody

SNMG (Ocular SNMG)MuSK antibodyUndefined SNMG

Suggested Four Types in MG


Evoli A. Acta Neurol Scand 2006


Treatment(1) Symptomatic treatments

Anticholinergics (anti-AChE drugs): pyridostigmine (Mestinon)

Plasmapheresis Intravenous immunoglobulin (IVIg)

Alter clinical courseThymectomySteroidsother immunosupressive drugs

• Azathioprine(Imuran), cyclophosphamide, cyclosporin, Mycophenolate mofetil


Treatment(2) Cholinergics: anti-AChE drugs

Side effects: due to muscarinic effects• Tearing, salivatoin, secretion, diarrhea, GI

cramps, meiosis, bradykardia, hypotension

Cholinergic crisis: Overdosage of anti-AChE drugsDesensitization of AChR result in

weaknessMuch salivation, meiosisTx: decrease dosage, atropine


ImmunosuppressionTherapy Route Dose Side effects Monitor or prevention Prednisolone/prednisone

PO 1mg/kg for 2- 6 weeks, tapering by 5-10mg/week to alternate- day regimen (1mg/kg qod), then taper slowly to the minimum maintenance dose

hypertension, weight gain, hyperglycemia, hypokalemia, cataracts, glaucoma, gastric ulcer, osteoporosis, infection, aseptic femoral necrosis

weight, blood pressure, serum glucose/potassium, DEXA opthalmic exam, antiulcer drug, calcium & vitamin D or biphosphonates, low- sodium low- cabohydrate high- protein diet, exercise

IV/IM 20- 50 mg; weekly one-day- a- week dosing

same as PO except gastric irritation

same as PO

Azathioprine PO 50 mg/day single AM dose increase to 2- 3 mg/kg/day over 2- 3 months

flulike illness, hepatotoxicity, pancreatitis, leukopenia, macrocytosis, oncogenicity, infection, teratogenicity

monthly blood cell count, liver enzymes

Cyclophosphamide

PO 1.5- 2.0 mg/kg/day; single AM dose

bone marrow suppression, infertility, hemorrhagic cystitis, alopecia, infections, oncogenicity, teratogenicity

monthly blood cell count, urinalysis

IV 0.5- 1 g/m2 smae as PO weekly blood cell count, urinalysis

cyclosporine PO 4- 6 mg/kg/day split into two daily doses

nephrotoxicity, hypertension, infection, hepatotoxicity, hirsuitism, tremor, gum hyperplasia, teratogenicity

blood pressure, monthly cyclosporine level, creatine/BUN, liver enzymes

IVIg IV 2 g/kg over 2- 5 days; then every 4- 8 잔 as needed

hypotension, arrhythmia, diaphoreisis, flushing, nephrotoxicity, headache, aseptic meningitis, anaphylaxis, stroke

heart rate, blood pressure, creatine/BUN


Presurgical Preparation (I) Risk factors in difficult ventilator weaning

MGFA classification II or higher Duration for more than 6 yearsHistory of steroid requirementPrior history of respiratory insufficiencyVital capacity less than 2.9 LPyridostigmine dose greater than 750

mg/d 48 hours before surgeryMaximal expiratory force less than 40 to

50 cm H2OKernstine KH. Thorac Surg Clin 2005


Presurgical Preparation (II) After appropriate management, unless emergent

surgery

If unable to decrease AChEIs in order to reduce respiratory complication, change to IV form of AChEIs (1/30 of oral dose in pyridostigmine)

Plasmapheresis, reduce requisite dose of AChEIs


Presurgical Preparation (III)

Steroid, increase post-op complication

Oral steroid, change to IV steroids, and consider stress dosage (eg. Methylprednisolone 500 mg IV on OP day)


Drugs with Adverse Effects on MG depolarizing muscle relaxant: succinylcholine aminoglycoside:

block presynaptic calcium currentsdecreased release of Ach

ampicillin erythromycin chlorpromazine quinidine procainamide beta blockers calcium channel blockers Tetracycline Magnesium penicillamine interferon

May 22, 대한흉부외과학회 제 24 차 춘게학술대회 Pathophysiology, Diagnosis and...

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