Ocular Myasthenia Gravis Diagnostic Studies and Long Term

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

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

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

Structure of the Neuromuscular Junction

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Immunopathogenesis of MG • MG is the prototypical autoimmune disease • Animal model – Rabbits and the electric eel (Torpedo californica) • Action of ACh. R 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

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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

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

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

“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

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Pseudo-INO of OMG 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 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 Neuro-ophthalmic Consultants Northwest

Diagnostic Test Sensitivities Test Ocular MG ACh. R Ab 50% Generalized MG 90% edrophonium 60 -95% 70 -95% Repetitive nerve stim. Single fiber EMG Ice Test 10 -17% 53 -100% 82 -99% Neuro-ophthalmic Consultants Northwest 89%

Edrophonium Test Neuro-ophthalmic Consultants Northwest

Caveats on Diagnostic Tests • ACh. R Antibody (Ab) tests – If negative binding ACh. R Ab level • <4% positive modulating Ab • <1% positive blocking Ab – 50% of Ach. R Ab-negative patients have Ab to Mu. SK (muscle specific kinase) (rare in OMG) • SF(single fiber) EMG – 100% sensitive in SR-LP muscle groups – 62% sensitive in OO group alone 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 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 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 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 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 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 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 – Only 12% 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 Neuro-ophthalmic Consultants Northwest

Combined Therapies for OMG • Mee et al. J Neuro-ophthalmol. 2003 Dec; 23(4): 24950 – Retrospective review of 34 patients who are positive for ACh. R 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 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) 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 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 -3 g/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

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 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 at presentation: 52 (23 -77) • Average Follow up on MM: 17 months (6 -41) – Diagnostic Tests • 9/14 Ach. R Ab+, 1 Mu. SK + • edrophonium test 4/7 tested +; 7 not performed • CT chest – 9/10 negative, 1 thymic hyperplasia 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) Neuro-ophthalmic Consultants Northwest

Study Design • Starting dose MM 250 mg 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

Results • 13/14 patients were able to reach a maintenance dose of 1 g 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

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

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

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

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