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

Neuro-ophthalmic Consultants Northwest

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

Steven R. Hamilton, M.D.


Seattle Neuroscience Institute

Seattle, WA


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


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


Structure of the Neuromuscular Junction



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



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


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


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


“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



Pseudo-INO of OMG


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


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


Diagnostic Test SensitivitiesTest Ocular MG Generalized

MG

AChR Ab 50% 90%

edrophonium 60-95% 70-95%

Repetitive nerve stim.

10-17% 53-100%

Single fiber EMG

82-99% 82-99%

Ice Test 89%


Edrophonium Test


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


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


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


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


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


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


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


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


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


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)


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


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


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


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


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)


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


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


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


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


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)


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


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


Bryce Canyon,Utah

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

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