Ocular Myasthenia Gravis:
Diagnostic Studies and Long
Term Impact of Treatment
Steven R. Hamilton, M.D.
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Seattle Neuroscience Institute
Seattle, WA
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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
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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
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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 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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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
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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
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Ocular Myasthenia Gravis
• Variable ptosis and diplopia
– Presenting symptoms in 50-70% of patients
– Eventually present in 90% of MG patients
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Lid twitch and enhanced ptosis
Weakness of orbicularis oculi muscles
Pseudo-internuclear ophthalmoplegia
Normal pupils
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“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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Pseudo-INO of OMG
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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
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Generalized MG Demographics
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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
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Diagnostic Test Sensitivities
Test
Ocular MG
AChR Ab
50%
Generalized
MG
90%
edrophonium
60-95%
70-95%
Repetitive
nerve stim.
Single fiber
EMG
Ice Test
10-17%
53-100%
82-99%
82-99%
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89%
Edrophonium Test
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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
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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
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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
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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
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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
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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
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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
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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
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Combined Therapies for OMG
• Mee et al. J Neuro-ophthalmol. 2003 Dec;23(4):24950
– 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
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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)
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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
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MM Trials for Generalized MG
• Meriggioli et al. (Neurology 2003)
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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
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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
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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
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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)
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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
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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
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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
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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
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Indications for Thymectomy
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Ocular only
Thymoma
All generalized
Selected generalized
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• “few”
• 100%
• 5%
Young onset
Disabling MG
Unresponsive to pyridostigmine
Recent onset only (< 5 yrs)
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57%
38%
25%
21%
From a poll of 56 neurologists on the Med Adv Board
of the MGF (Lanska 1990)
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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
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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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