1. Neuro-ophthalmic Consultants Northwest Ocular Myasthenia Gravis: Diagnostic Studies and Long Term Impact of Treatment Steven R. Hamilton, M.D. Neuro-ophthalmic Consultants Northwest Seattle Neuroscience Institute Seattle, WA

2. Neuro-ophthalmic Consultants Northwest Overview of Myasthenia Gravis (MG) Definition –A neuromuscular disorder manifested by weakness and fatigability of voluntary muscles Prevalence –50-125 cases per million population –25,000 affected persons in the United States History of MG –First described in 1672 by Thomas Willis

3. Neuro-ophthalmic Consultants Northwest Physiology of MG Acetylcholine (Ach) packaged in vesicles on presynaptic neuron Ach receptors (AchR) opposite the neuron in the muscle endplate Action potential  end plate potential Ach degraded by acetylcholinesterase

4. Neuro-ophthalmic Consultants Northwest Structure of the Neuromuscular Junction

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6. Immunopathogenesis of MG MG is the prototypical autoimmune disease Animal model –Rabbits and the electric eel (Torpedo californica) Action of AChR antibodies –Reversible blockade of receptors –Conformation changes of the receptors –Inflammation and destruction of receptors (primarily through complement cascade) –Atrophy of receptor membranes with loss of folds

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8. Epitope Spreading Concept During an autoimmune attack, the response begins to be directed against other antigenic regions (epitopes) on the original target or on neighboring antigens on the target Results in a widened autoimmune attack and increased damage of the target receptors Concept has radically changed treatment regimen of rheumatoid arthritis patients –Early aggressive intervention with anti-TNF (tumour necrosis factor) drugs in RA has been proven to prevent permanent joint damage

9. Neuro-ophthalmic Consultants Northwest Osserman Classification Group I-ocular MG Group Ia-ocular MG with physiologic evidence of dissemination Group IIa-mild generalized MG (no respiratory) Group IIb-mild generalized MG + respiratory Group III-acute fulminant MG (thymomas) Group IV-late severe MG from groups I or II after 2 years

10. Neuro-ophthalmic Consultants Northwest Ocular Myasthenia Gravis Variable ptosis and diplopia –Presenting symptoms in 50-70% of patients –Eventually present in 90% of MG patients Lid twitch and enhanced ptosis Weakness of orbicularis oculi muscles Pseudo-internuclear ophthalmoplegia Normal pupils

11. Neuro-ophthalmic Consultants Northwest “My left eyelid droops” 66-year-old man with thyroidectomy 40 years earlier Residual proptosis without diplopia Droopy left lid for one month, worse at night Transient double vision recently

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13. Pseudo-INO of OMG

14. Neuro-ophthalmic Consultants Northwest Ocular MG Demographics 14% (2021/1,487 patients) with localized ocular MG followed a mean of 18 years Male: female ratio = 57:43 Age of onset: male (43 yrs), female (32 yrs) Maximum level of severity reached within 3 yrs in 85% Grob et al, Annals NY Acad Sci 1987, 505: 472

15. Neuro-ophthalmic Consultants Northwest Generalized MG Demographics Bulbar, extremity, or trunk weakness plus ocular 86% (1,285/1,487 patients) with generalized MG Male to female ratio = 41: 59 Age of onset: male (41 yrs), female (28 yrs) Onset time from ocular to generalized MG: –58% < 6 months –20% within first year –7% during 2 nd and 3 rd years Grob et al, Annals NY Acad Sci 1987, 505: 472

16. Neuro-ophthalmic Consultants Northwest Diagnostic Test Sensitivities TestOcular MGGeneralized MG AChR Ab50%90% edrophonium60-95%70-95% Repetitive nerve stim. 10-17%53-100% Single fiber EMG 82-99% Ice Test89%

17. Neuro-ophthalmic Consultants Northwest Edrophonium Test

18. Neuro-ophthalmic Consultants Northwest Caveats on Diagnostic Tests AChR Antibody (Ab) tests –If negative binding AChR Ab level <4% positive modulating Ab <1% positive blocking Ab –50% of AchR Ab-negative patients have Ab to MuSK (muscle specific kinase) (rare in OMG) SF(single fiber) EMG –100% sensitive in SR-LP muscle groups –62% sensitive in OO group alone

19. Neuro-ophthalmic Consultants Northwest Treatment of OMG Two potential goals –Return the person to a state of clear vision –Prevent or limit the severity of generalized MG Treatment options –Mechanical (patching) or strabismus surgery –Medical therapy Symptomatic (pyridostigmine bromide) Immunosuppression –Thymectomy

20. Neuro-ophthalmic Consultants Northwest The Dangers of Patching ocular MG Patients Too often patients are abandoned to poor quality of life without the chance of binocular vision An easy fix for the treating neurologist without consideration of the long-term implications for quality of life and the risk of generalization of the disease

21. Neuro-ophthalmic Consultants Northwest Pyridostigmine Therapy of ocular MG Improves visual disability in 20-40% of OMG patients Most effective for isolated variable ptosis No immunomodulatory effect to prevent generalization of disease May actually mask underlying progression of disease or even permit epitope spreading

22. Neuro-ophthalmic Consultants Northwest Immunosuppressive Therapies for Ocular MG Cochrane Review 2006 –“There are no data from randomized controlled trials on the impact of any form of treatment on the risk of progression from ocular to generalized myasthenia gravis.” Observational studies (cohort and case studies) suggest corticosteroids and azathioprine may reduce the risk of generalization of ocular MG

23. Neuro-ophthalmic Consultants Northwest Corticosteroids for Ocular MG Kupersmith et al. Arch Neurol. 2003 Feb;60(2):243-8 –147 pts with ocular MG –Treated with 6 weeks of 40-60 mg prednisone per day with gradual taper to once-a-day or alternate-day low-dose therapy (2.5-10 mg) –2 years follow-up data –7% vs. 36% development of generalized MG

24. Neuro-ophthalmic Consultants Northwest Corticosteroid Therapy for ocular MG Monsul et al. J Neurol Sci. 2004 Feb 15;217(2):131-3 –56 ocular MG patients Treated patients received 60 mg prednisone per day with slow taper over 3-6 months 2 year follow-up 11% vs. 35% development of generalized MG

25. Neuro-ophthalmic Consultants Northwest Combined Therapies for Ocular MG Sommer et al. J Neurol Neurosurg Psychiatry. 1997 Feb;62(2):156-62 –78 pts with ocular MG with mean duration of disease of 8 years –Only12% generalized if on corticosteroids (45), azathioprine (27), or both (23) –64% generalized if on no immunosuppression Thymectomy for abnormal chest CT also correlated with good outcome

26. Neuro-ophthalmic Consultants Northwest Combined Therapies for OMG Mee et al. J Neuro-ophthalmol. 2003 Dec;23(4):249- 50 –Retrospective review of 34 patients who are positive for AChR Antibodies –Treatment with corticosteroids and/or azathioprine –2 years of follow-up –21/34 (62%) patients generalized 9% of those on immunomodulatory therapy generalized 86% of those on pyridostigmine alone generalized

27. Neuro-ophthalmic Consultants Northwest Mycophenolate mofetil Pro-drug of mycophenolic acid – first isolated in 1898 from Penicillium Inhibits lymphocyte purine synthesis by reversibly and noncompetitively blocking inosine monophosphate dehydrogenase. Highly specific for lymphocytes Side effects: gastrointestinal upset, increased liver function tests. Rare bone marrow suppression. Better tolerated than azathioprine and cyclosporine (less nephrotoxic)

28. Neuro-ophthalmic Consultants Northwest Mycophenolate mofetil (MM) for MG Faster onset of action than azathioprine –2-4 months average 250 mg/day for 1 week, then 250 mg twice a day for 1 week, increasing gradually to 1-2 gms/day in twice a day schedule Take on an empty stomach Avoid pregnancy (class C drug) Check complete blood count, liver function tests every 4 months

29. Neuro-ophthalmic Consultants Northwest MM Trials for Generalized MG Meriggioli et al. (Neurology 2003) –Retrospective review of 85 patients –28 seronegative –Dosages ranged from 1-3g/day –56% with prior thymectomy –73% achieved pharmacologic remission or significant improvement –Maximal benefit at 26 weeks; 6% discontinued due to side effects

30. Neuro-ophthalmic Consultants Northwest MM Trials for GMG Aspreva sponsored trial (Donald Sanders @ Duke) 80 patient double-blind, placebo-controlled trial 12 week duration MM plus prednisone vs prednisone alone (20 mg dose) No significant difference in outcomes MM well tolerated

31. Neuro-ophthalmic Consultants Northwest Treatment of ocular MG with MM Hamilton et al. Retrospective review of 14 patients with ocular MG treated with Mycophenolate mofetil –Demographics Gender: 9 Men, 5 Women Average age at presentation: 52 (23-77) Average Follow up on MM: 17 months (6-41) –Diagnostic Tests 9/14 AchR Ab+, 1 MuSK + edrophonium test 4/7 tested +; 7 not performed CT chest – 9/10 negative, 1 thymic hyperplasia

32. Neuro-ophthalmic Consultants Northwest Study Design Patients were started on MM for one of three reasons –Primary agent besides pyridostigmine (3/14) –Worsening symptoms on other immunosuppressives (8/14) –Tapering off other immunosuppressives (3/14)

33. Neuro-ophthalmic Consultants Northwest Study Design Starting dose MM 250mg daily with gradual increase to target dose of 1 gm twice a day. Minimum duration of treatment for at least 6 months. Blood monitoring of complete blood count with differential and liver function tests. –Initially every 2 weeks –Quarterly when patient reached maintenance

34. Neuro-ophthalmic Consultants Northwest Results 13/14 patients were able to reach a maintenance dose of 1g twice a day. 1 patient reached 1,750 mg daily 2 patients discontinued the medication –1 due to development of cellulitis –1 due to lack of response

35. Neuro-ophthalmic Consultants Northwest Results Based on MGFA assessment: –8/14 in pharmacologic remission –4/14 improved –2/14 no change or worse Mean time to objective improvement: –2 months Side effects: 4/14 had mild liver enzyme abnormalities; 1 patient discontinued due to development of cellulitis No patients converted to generalized MG

36. Neuro-ophthalmic Consultants Northwest Thymectomy Introduced for thymoma, later for weakness Mulder et al series –249/781 patients with moderate-severe MG had thymectomy –87% benefited with supplemental medication –51% achieved remission –Patients with thymoma responded least well –Onset to improvement may take months-years Mulder et al. Am J Surg 1983;146:61

37. Neuro-ophthalmic Consultants Northwest Indications for Thymectomy Ocular only Thymoma All generalized Selected generalized –Young onset –Disabling MG –Unresponsive to pyridostigmine –Recent onset only (< 5 yrs) “few” 100% 5% –57% –38% –25% –21% From a poll of 56 neurologists on the Med Adv Board of the MGF (Lanska 1990)

38. Neuro-ophthalmic Consultants Northwest Thymectomy for Ocular MG Roberts et al. J Thorac Cardiovasc Surg 2001;122:562-8 –61 patients with Ocular MG only underwent thymectomy –Mean follow-up of 9 years –12 patients received anticholinesterase and steroids –51% cured, 20% improvement, 26% no change, 3% worsening –70% were cured or improved post thymectomy

39. Neuro-ophthalmic Consultants Northwest Conclusions Ocular MG can usually be accurately diagnosed in patients presenting with diplopia and/or ptosis Ocular MG has a high spontaneous rate of conversion to generalized MG over 3 years There are strong immunological reasons to seriously consider early immunosuppression of ocular MG to optimize the patient’s quality of life and prevent long-term generalization and disability

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