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

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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

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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
• 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 5743
• 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

• 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 lt 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 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
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Edrophonium Test
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Caveats on Diagnostic Tests

• AChR Antibody (Ab) tests
• If negative binding AChR Ab level
• lt4 positive modulating Ab
• lt1 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
  Feb60(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
  15217(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
  Feb62(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
  Dec23(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

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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)
• 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 GMGAspreva sponsored trial (Donald
Sanders _at_ 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 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

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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 198314661
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Indications for Thymectomy

• Ocular only
• Thymoma
• All generalized
• Selected generalized
• Young onset
• Disabling MG
• Unresponsive to pyridostigmine
• Recent onset only (lt 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)
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Thymectomy for Ocular MG

• Roberts et al. J Thorac Cardiovasc Surg
  2001122562-8
• 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 patients quality of
  life and prevent long-term generalization and
  disability

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