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Ocular Myasthenia Gravis: Diagnostic Studies and Long Term Impact of Treatment

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. Overview of Myasthenia Gravis (MG). Definition

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Ocular Myasthenia Gravis: Diagnostic Studies and Long Term Impact of Treatment

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  1. 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 Neuro-ophthalmic Consultants Northwest

  2. 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 Neuro-ophthalmic Consultants Northwest

  3. 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 Neuro-ophthalmic Consultants Northwest

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

  5. Neuro-ophthalmic Consultants Northwest

  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 Neuro-ophthalmic Consultants Northwest

  7. Neuro-ophthalmic Consultants Northwest

  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 Neuro-ophthalmic Consultants Northwest

  9. 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 Neuro-ophthalmic Consultants Northwest

  10. 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 Neuro-ophthalmic Consultants Northwest

  11. “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 Neuro-ophthalmic Consultants Northwest

  12. Neuro-ophthalmic Consultants Northwest

  13. Pseudo-INO of OMG Neuro-ophthalmic Consultants Northwest

  14. 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 Neuro-ophthalmic Consultants Northwest

  15. 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 2nd and 3rd years Grob et al, Annals NY Acad Sci 1987, 505: 472 Neuro-ophthalmic Consultants Northwest

  16. Diagnostic Test Sensitivities Neuro-ophthalmic Consultants Northwest

  17. Edrophonium Test Neuro-ophthalmic Consultants Northwest

  18. 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 Caveats on Diagnostic Tests Neuro-ophthalmic Consultants Northwest

  19. 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 Treatment of OMG Neuro-ophthalmic Consultants Northwest

  20. 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 The Dangers of Patching ocular MG Patients Neuro-ophthalmic Consultants Northwest

  21. 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 Pyridostigmine Therapy of ocular MG Neuro-ophthalmic Consultants Northwest

  22. 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 Immunosuppressive Therapies for Ocular MG Neuro-ophthalmic Consultants Northwest

  23. 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 Corticosteroids for Ocular MG Neuro-ophthalmic Consultants Northwest

  24. 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 Corticosteroid Therapy for ocular MG Neuro-ophthalmic Consultants Northwest

  25. 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 Combined Therapies for Ocular MG Neuro-ophthalmic Consultants Northwest

  26. 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 Combined Therapies for OMG Neuro-ophthalmic Consultants Northwest

  27. 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) Neuro-ophthalmic Consultants Northwest

  28. 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 Neuro-ophthalmic Consultants Northwest

  29. 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 Neuro-ophthalmic Consultants Northwest

  30. MM Trials for GMGAspreva 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 Neuro-ophthalmic Consultants Northwest

  31. Treatment of ocular MG with MMHamilton 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 Neuro-ophthalmic Consultants Northwest

  32. 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) Neuro-ophthalmic Consultants Northwest

  33. 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 Neuro-ophthalmic Consultants Northwest

  34. 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 Neuro-ophthalmic Consultants Northwest

  35. 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 Neuro-ophthalmic Consultants Northwest

  36. 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 Neuro-ophthalmic Consultants Northwest

  37. 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% Indications for Thymectomy From a poll of 56 neurologists on the Med Adv Board of the MGF (Lanska 1990) Neuro-ophthalmic Consultants Northwest

  38. 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 Thymectomy for Ocular MG Neuro-ophthalmic Consultants Northwest

  39. 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 Neuro-ophthalmic Consultants Northwest

  40. BryceCanyon,Utah Neuro-ophthalmic Consultants Northwest

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