10/16/2012

1

TREATMENT OPTIONS IN

B . J A N E D I S T A D , M D1 3 O C T O B E R 2 0 1 2

TREATMENT OPTIONS IN MYASTHENIA GRAVIS

OUTLINE

• Anatomy/physiology• Pathophysiology • Electrophysiology

• RNS• SFEMG

• Presentation• Treatment

• Acetylcholinesterase inhibition• Immune modulation• Immune suppression

• Corticosteroids• Long-term

• Thymectomy• Future

• Other neuromuscular junction disorders

ANATOMY/PHYSIOLOGY

ACTIVITY – NORMAL NMJ1. Depolarization

2. Activation of voltage gated Cachannels 3. Calcium influx

4. Acetylcholine release

5. ACh binds receptors5. ACh binds receptors

Presynaptic

Postsynaptic6. Ion channels open

7. Local depolarization=EPP

6. Ion channels open

8. EPP is proportional to amount of ACh

9. depolarization above threshold-> all-

or-none MFAP

10. safety factor

PATHOPHYSIOLOGY

Incidence 3-4/million

PROTOTYPICAL AUTOIMMUNE DISORDER

Antibodies to nicotinic acetylcholine receptor (AChR) cause the disease Specific T cells permit and modulate the synthesis of

high affinity antibodies that cause AChR loss, NMJ damage, failed NMJ transmission Reduced number of receptors at the motor endplates Reduced number of receptors at the motor endplates

of patients Disease can be transferred to mice if inject IgG of MG

patient Active animal immunization w/ purified AChR caused

experimental autoimmune myasthenia gravis Procedures to reduce AChR antibodies improve

symptoms Thymus

10/16/2012

2

THYMUS AND MG

• T cells reactive to AChR found in blood and thymus

• thymus contains 1) muscle cells w/ AChR ag, 2)apc, 3) T cells

• Thymic lymphocytes can produce antibodyy y p y p y• Abnormal thymus in MG

• 10-15% tumor• 70% have hyperplastic changes

• Thymectomy causes decrease in reactive T cells

TESTING THE NEUROMUSCULAR JUNCTION

REPETITIVE NERVE STIMULATION REPETITIVE NERVE STIMULATION

RNS-DECREMENTAL RESPONSE

• Baseline-• 32% decrease compound muscle action

potential (CMAP) amplitude

• Post exercise facilitation-• 8% decrease

• Post exercise exhaustion• Post exercise exhaustion-• 44% decrease

• 2 minutes p-• 56 % decrease

• 3 minutes p-• 69% decrease

SINGLE FIBER EMG BASICS

• Study 2 adjacent single muscle fibers, “pair”, from same motor unit

• all muscle fibers within one motor unit fire at approximately same time, following motor axon depolarizationaxon depolarization

• Variation in time interval b/t firing of adjacent single muscle fibers from same motor unit = jitter

10/16/2012

3

SFEMG

• Sensitive• Not specific

• ALS, polymyositis with abnormal jitter• Neurogenic or myopathic conditions with abnormal fiber density

img.medscape.com/.../1134815-1141438-295.jpg

SFEMG SENSITIVITY

Authors N [EDC] abnormal EDC + additional

Published

Sanders & Stalberg

788 85% 98% 1996

Oh et al 120 92% 1992 Gil h i t & 10 90% (ADQ) 1987 Gilchrist & Sanders

10 90% (ADQ) 1987

Sanders & Howard

127 85% (any one muscle – usually EDC)

99% (any 2 mm –usually frontalis)

1986

SENSITIVITY

SFEMG

Any muscle

SFEMG

EDC

RNS

Any muscle

AChR antibody any

timeMG Gen Ocul Gen Ocul Gen Ocul Gen Ocultype

% abn 99 97 89 63 76 48 80 55

Modified from Bromberg MB, “Myasthenia Gravis and Myasthenic Syndromes”, in MotorDisorders, ed: David S. Younger, Lippincott Williams & Wilkins, 1999, 177-178.

BRIEF PRESENTATION BRIEF PRESENTATION REVIEW

PRESENTATION

• EYE - >90%• Diplopia• Ptosis

• LIMB 10-25% at onset• Proximal weakness (initially present w/)

• BULBAR 17-23% at onset• Dysarthria• Dysphagia• Facial

• RESPIRATORY• FATIGUABLE

10/16/2012

4

EVALUATION-GENERAL

• Endurance testing• Exertional activities• Ice pack-may block AChE activity

• Laboratory • AcetylCholine receptor antibodiesAcetylCholine receptor antibodies• MuSK antibodies• Voltage-gated calcium channel Ab

• “Tensilon” test-edrophonium

ANTIBODIES

ANTIBODIES – ACETYLCHOLINE RECEPTOR

• Binding• High specificity• 80-90% of generalized MG (15% seroconversion 12 mos)• Seen in ALS, PM, LEMS

• Blocking• Fewer than 1% of pts have these w/o binding ab

• Modulating• Increase AChR degradation by cross-linking receptors• 8/508 (Chan et al 2007) [1.6%]

• Striational• Lack specificity• Seen in 10-15% of LEMs• 90% of thymoma patients

MUSCLE SPECIFIC KINASE ANTIBODIES (MUSK)

• Receptor tyrosine kinase that causes auto-phosphorylation followed by phosphorylation of rapsyn and AChR

• Up to 40-70% of “seronegative” MG • Cranial and bulbar muscles more involved or mainly • Cranial and bulbar muscles more involved or mainly

neck, shoulder• Involvement of limb muscles less severe, inconsistent• High frequency of respiratory crises

TENSILON (EDROPHONIUM CHLORIDE) TEST

• Before

• After 8 mg TREATMENT

10/16/2012

5

TREATMENT TIERS

• Acetylcholinesterase inhibitor – pyridostigmine– eg(60 Q4-6h)

• Immune modulation• Plasma exchange• IVIg

• Immune suppression• Prednisone• Other

• Thymectomy

COST

• Prednisone 20mg #90 - $10.70• Azathioprine 50mg #90 - $21.55• Neoral, Cyclosporine 100mg #60 - $159.60• Cellcept, Mycophenolate 500mg #120 - $351.75 p , y p g $

(brand), $117.80 (generic)

• 2006:Prednisone 20mg #90 - $9.10 • Azathioprine 50mg #90 - $22.45 • Neoral, Cyclosporine 100mg #60 - $369.10 • Cellcept, Mycophenolate 500mg #120 - $686.10

HIGHER END PRODUCTS

• IVIG, Flebogamma 30g/600mL - $6,896.34• Plasma exchange• Rituximab

IMMUNE SUPPRESSION

• Prednisone• 1 – 1 ½ mg/kg/day or QOD until improvement/ambulation

• Long-term immune suppression• Azathioprine (2-3 mg/kg/d)

M th t t ( t 15 / k)• Methotrexate (up to 15 mg/wk)• Cyclosporine (dose per trough level <200)• Cyclophosphamide (0.7-1 mg/m2)• Mycophenolate mofetil (2-3 g/d)• Tacrolimus• Rituximab

MONITORING

• Clinical response• Adverse effects

• CBC• LFT – azathioprine and MTX• Renal function – CyA, cytoxan• Mg – cyclosporine (CyA)• Trough levels – cyclosporine

• Antibody level

PLASMA EXCHANGE

• Removes antibodies• Response within days• Lasts only several weeks• 4-6 exchanges, removing 3-5 L of plasma each

treatment• Hypotension• MI in patients at risk• plasma exchange shown as a treatment (Newsom-

Davis et al., 1978), confirmed myasthenia is antibody-mediated

10/16/2012

6

IVIG

• May neutralize autoantibodies, • attenuate complement-mediated tissue damage, • block Fc receptors on macrophages, • modulate cytokines60 70 % t• 60-70 % response rate

• 2 g/kg over days• Headache, myalgias• Renal failure, MI, stroke reported• Possible longer ventilation/prolonged respiratory

recovery

IVIG VS PLEX

• Previous trials underpowered• 84 patients randomized• Close to 70% patients improved at 2 weeks• Higher AChR antibody and worse at presentation g y p

predicted better outcome• Treatments comparable in moderate to severe MG

CORTICOSTEROIDS

• Suppress humoral, cell-mediated and nonspecific arms of the immune system

• High dose initially then reduce to QOD• Improvement over 10-30 days or more

E ti t d 90% t• Estimated 90% response rate• May precipitate weakness• Multiple side effects• Calcium +/- vitamin D

EPITOME

• Prednisone vs. pyridostigmine in ocular MG• Modest dose prednisone• Over 4 months• Double blind• Prednisone may reduce risk of progressing to

generalized• Record review*

• 87 patients, 55 were in the prednisone-treated and 32 were in the untreated groups

• GMG developed in 13% of the prednisone-treated and 50% of the untreated patients

*Kupersmith MJ. Ocular myasthenia gravis: treatment successes and failures in patients with long-term follow-up. J Neurol. 2009 Aug;256(8):1314-20.

AZATHIOPRINE

• Blocks cell proliferation; inhibition of T lymphocytes presumed mechanism for benefit

• Goal 2-3 mg/kg• Up to 20 % cannot tolerate• Hepatic toxicity• Leukopenia• Weekly to monthly CBC, LFTs

CYCLOSPORINE

• Inhibits T lymphocyte-dependent immune responses by suppressing IL2 activity

• Response w/in 1-2 months• Cost

R l t i it • Renal toxicity • Hypertension• 5-6 mg/kg/day divided BID• Goal level ~100-150 ng/L trough• Monitor Mg, Cr• Multiple drug interactions

10/16/2012

7

CYCLOPHOSPHAMIDE

• Nitrogen mustard alkylating agent, blocks B and T cell proliferation

• Myelosuppression• Hemorrhagic cystitis• Increased risk of malignancy• For resistant MG

MYCOPHENOLATE MOFETIL

• Suppresses T and B cell proliferation via selective block of purine synthesis

• Target 2000-3000 mg/day, divided BID• Mean time to improvement 10 weeks• Side effects GI• Myelosuppression potential• 2 recent trials – negative results (Siddique 2012)

• 68% attained remission/minimal manifestation at mean 16 mos

• Of remaining 32%, greater than half showed 50% improvement

• Mean time onset definite improvement 6 months• A few pts worsened after treatment cessation

THYMECTOMY

Jaretzki

PAST DATA

• Comparison of unrelated statistical techniques• Life table analysis, using the Kaplan–Meier method, is considered the preferred statistical technique for the

analysis of remissions following thymectomy.• It provides comparative analysis using all follow-up information accumulated to the date of assessment, including

information on patients subsequently lost to follow up and on those who have not yet reached the date of assessment.

• uncorrected crude rates have been primary form of analysis in the comparative evaluation of remissions and improvement following thymectomy. Uncorrected crude rates consist simply of the number of remissions divided p g y y p yby the number of patients operated upon or sometimes divided only by the number of patients followed (potentially a very different denominator). This form of analysis does not include in the evaluation all the follow-up information accumulated to the date of assessment, including the length of follow. As a result, patients evaluated many years after surgery may incorrectly appear to do as well or better

• reported studies are usually retrospective,

FIGURE 2. COMPARATIVE KAPLAN–MEIER REMISSION RATES OF SIX THYMECTOMY TECHNIQUES. KAPLAN–MEIER LIFE TABLE ANALYSIS REMISSION RATES OF SIX THYMECTOMY TECHNIQUES EMPLOYED IN THE TREATMENT OF

NONTHYMOMATOUS MG ARE COMPARED

• . The Kaplan–Meier spontaneous remission rate in children is also recorded because no comparative life table analysis data is available for adults. These data suggest that the more extensive the resection, the better the results. In addition, contrary to the oft-repeated statements to the contrary, the results of all forms of thymectomy appear to be far from being equal. Statistical confirmation requires the data be available for co-analysis. Cervical + Sternal, combined transcervical and transsternal thymectomy (T-4)17; VATET (T-2b Extend), video-assisted thoracoscopic extended thymectomy94Sternal (T-3b Extend), extended transsternal thymectomy94; Cervical (T-1b Extend), “extended”transcervical thymectomy47; Cervical (T-1a Basic), original “basic” transcervical thymectomy95; VATS(T-2a), “classic” video-assisted thoracic surgery thymectomy96; Spontaneous, spontaneous remissions in children.80 (Reprinted with permission.82)

FUTURE THERAPIES

10/16/2012

8

ECULIZUMAB

• Complement activation at NMJ associated with AChR loss and NMJ transmission failure

• Humanized monoclonal Ab blocks formation of terminal complement complex by selectively

ti ti l f C5preventing enzymatic cleavage of C5• Randomized, double-blind, placebo-controlled,

crossover, phase II trial • 6/7 pts improved by 3 pts on QMG scale at 16 weeks• 4/7 had 8 pt improvement

ANTISENSE TREATMENT

• EN101• EN101 is a synthetic 20-base antisense oligodeoxy-

nucleotide directed against the human AChE gene• Phase II double-blind crossover • Decreases AChE activity• Decreases AChE activity• All doses showed decrease in symptoms• Can suppress pro-inflammatory function

METHOTREXATE

• Selective inhibitor of dihydrofolate reductase and lymphocyte proliferation

• Effective immunosuppressive medication for autoimmune disease

• Randomized, double-blind, placebo-controlled multicenter trial

• Up to 20 mg• 37 enrolled• Anticipated completion in one year

RITUXIMAB

• Anti-CD20 monoclonal antibody• Targets circulating B cells• Feasibility trial• 7 patientsp• Well-tolerated• All scores improved at 12 weeks

DRUGS TO MINIMIZE

Katirji (ed)

10/16/2012

9

MGTX

• A multi-center, single-blind, randomized study comparing Thymectomy to No Thymectomy• In non-thymomatous MG individuals• On prednisone

T t i l • Two-arm trial

REFERENCES

• Berman SA. Assessment of Neuromuscular Transmission . http://www.emedicine.com/neuro/TOPIC23.HTM. Sept 2008.

• Bromberg MB, “Myasthenia Gravis and Myasthenic Syndromes”, in Motor Disorders, ed: David S. Younger, Lippincott Williams & Wilkins, 1999, 177-178.

• Cherington M. Clinical spectrum of botulism. Muscle and Nerve. 1998;21:701-710.• Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin

Invest. 2006 Nov;116(11):2843-54. • Daube JR (ed). Clinical Neurophysiology. Philadelphia: FA Davis & Co, 1996.• Gilchrist JM Sanders DB Double step repetitive stimulation in Kaminski HJ (ed) • Gilchrist JM, Sanders DB. Double-step repetitive stimulation in Kaminski HJ (ed).

Myasthenia Gravis and Related Disorders. New Jersey: Humana Press, 2003.• Chan KH, Lachance DH, Harper CM, Lennon VA. Frequency of seronegativity in adult-

acquired generalized myasthenia gravis. Muscle Nerve. 2007;36(5):651-8• Kupersmith MJ. Ocular myasthenia gravis: treatment successes and failures in patients

with long-term follow-up. J Neurol. 2009 Aug;256(8):1314-20.• Myasthenia Gravis Meeting at the New York Academy of Sciences, 2012.• Oh SJ, Doo EM, Kuruoglu R et al. Diagnostic sensitivity of the laboratory tests in myasthenia

gravis. Muscle Nerve. 1992;155:720-724.

• O’Neill JH, Murray NMF, Newsom-Davis J. THE LAMBERT-EATON MYASTHENIC SYNDROME A REVIEW OF 50 CASES. Brain. 1988; 111 (3): 577-596.

• Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders. Boston: Butterworth-Heinemann, 1998.

• Sanders DB, Stalberg EV. AAEM minimonography #25: Single fiber Electromyography. Muscle Nerve 1996;19:1069-1083.

• Titulaer MJ, Wirtz PW, Willems LN, van Kralingen KW, Smitt PA, Verschuuren JJ.Screening for small cell lung cancer: a follow up study of patients with LambertScreening for small-cell lung cancer: a follow-up study of patients with Lambert-Eaton myasthenic syndrome. J Clin Oncol. 2008 10;26(26):4276-81.

• Wirtz PW, van Dijk JG, van Doorn PA, et al. The epidemiology of the Lambert-Eaton myasthenic syndrome in the Netherlands. Neurology 2004;63:397–398.

• Wolfe GI, Barohn RJ, Galetta SL. Drugs for the diagnosis and treatment of myasthenia gravis. In: Zimmerman TJ, ed. Textbook of Ocular Pharmacology. Philadelphia: Lippincott-Raven Publishers 1997.

• Zivković SA, Shipe C. Use of repetitive nerve stimulation in the evaluation of neuromuscular junction disorders. Am J Electroneurodiagnostic Technol. 2005;45(4):248-61.

CASE 1

• 42 yo male with subtle leg weakness for 2 years; 2 months of double vision, subtle swallowing difficulties

EXAM AND CONDUCTION FINDINGS

• Decreased left eye abduction• Inability to maintain upgaze• Neck flexion, hip flexion weakness

• What type of testing?• What area?

EXAM AND CONDUCTION FINDINGS

• Normal standard nerve conduction studies and EMG

• 2-3 hz RNS 50% decrement CMAP amplitude

10/16/2012

10

CASE 2

• A 59 yo woman with an 8 month history of progressive weakness of legs (climbing stairs)

• Dry mouth

EXAM & CONDUCTION FINDINGS

• Proximal arm and leg weakness• Decreased reflexes• Normal sensation• NCS - Small amplitude motor responses onp p• Normal sensory responses• Normal needle exam (EMG)• Additional testing? What would it show?

REPETITIVE NERVE STIMULATION IN LEMS

CASE 3

A 50 year old woman presented to the clinic with acute trouble swallowing and speaking, eyelid drooping, and moderate generalized weakness. Her symptoms seemed to fluctuate throughout the day.

Her examination revealed bilateral ptosis, mild tachypnea, dysarthria, and moderate proximal>distal weakness of both arms and legs symmetrically. She had no sensory loss.

REPETITIVE NERVE STIMULATION (RADIAL MOTOR) – MYASTHENIA GRAVIS

BaselineBaseline Postexercise facilitationPostexercise facilitation

10/16/2012

11

REPETITIVE NERVE STIMULATION (RADIAL MOTOR)

Postexercise exhaustion Recovery

JITTER

• Also called “mean consecutive difference”• Variation in the “interpotential interval”

between two time locked muscle fiber action potentials

• Increased in myasthenia gravis 92-95% of the titime

NormalNormal IncreasedIncreased

LAMBERT EATON LAMBERT EATON MYASTHENIC SYNDROME

-Reduced release of ACh-IgG antibodies to voltage gated calcium

LEMS -MECHANISM

voltage-gated calcium channel-Interferes with calcium-dependent release of ACh-Causes reduced end-plate potential

VOLTAGE GATED CALCIUM CHANNEL ANTIBODY

• P/Q type identified in 90%• 1/3 also have N type• P/Q type reported in SCLC, PCD• ~20% misdiagnosed as MG*g

*O’Neill. Brain 1988Katirji B in Myasthenia Gravis and Related Disorders.

10/16/2012

12

TREATMENT

• Pyridostigmine• Guanidine

• increases intracellular calcium through inhibition of mitochondrial calcium uptake

• increased intracellular calcium enhances • increased intracellular calcium enhances neurotransmitter release.

• bone marrow suppression, nephrotoxicity, hepatotoxicity

• 3,4 diaminopyridine (DAP)• blocks potassium channels in nerve terminals

resulting in prolonged nerve action potentials with increased calcium entry into presynaptic neurons.

CONGENITAL MYASTHENIC CONGENITAL MYASTHENIC SYNDROMES

Defective synthesis or packaging of acetylcholineDeficiency of acetylcholinesteraseDeficiency of acetylcholine receptorsSlow postsynaptic ion channel

Review

Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders. Boston: Butterworth-Heinemann, 1998.