REVIEW ARTICLE
Treatment of Ocular Myasthenia Gravis
Wayne T. Cornblath, MD
Abstract: Myasthenia gravis is a relatively common neuromuscular
disorder, with ocular myasthenia gravis being a subset defined as myas-
thenia gravis limited to the orbicularis, levator, and extraocular muscles.
Patients with ocular myasthenia gravis can have disabling diplopia or
functional blindness from ptosis and in most cases treatment is required.
Like generalized myasthenia gravis, there are a variety of treatments
available that include pyridostigmine, immunosuppression, intravenous
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immunoglobulin, plasmapheresis, thymectomy, lid crutches, ptosis sur-
gery, and extraocular muscle surgery. Unfortunately, there is limited data
on the use of individual treatments in ocular myasthenia gravis and no
data comparing treatments. Using a combination of available data on
treatment of generalized myasthenia gravis, data on treatment of ocular
myasthenia gravis, best practices, and clinical experience we will provide
a rational framework for treatment of ocular myasthenia gravis.
Key Words: ocular myasthenia gravis, treatments
(Asia-Pac J Ophthalmology 2018;7:257–259)
I n discussing treatment choices for disease, physicians favor
evidence-based medicine and use of randomized clinical trials
(RCT) to pick treatments proven to work with acceptable and
known adverse effects and risk. Unfortunately, in the arena of
treatments for ocular myasthenia gravis (OMG) there are essen-
tially no RCTs to guide therapy when discussing single drugs and
no RCTs comparing treatment choices (ie, azathioprine versus
prednisone). Although there are RCTs for generalized myasthe-
nia gravis (GMG), such as the recent work showing the benefit
of thymectomy, this data does not directly apply to OMG given
the different risk-benefit calculations between a life-threatening
disease, GMG, and OMG, which is not life-threatening. Given
the lack of evidence we must rely on the “art” of medicine while
employing as much of the science of medicine as is available.
Current treatment options for the diplopia and/or ptosis of ocular
myasthenia gravis are 1) no treatment; 2) mechanical treatments:
lid crutches for ptosis or patching for diplopia; 3) anticholinester-
ase therapy, primarily pyridostigmine; 4) oral immunosuppres-
sive therapy: prednisone, azathioprine, mycophenolate mofetil,
cyclophosphamide, cyclosporine, tacrolimus; 5) intravenous im-
munoglobulin (IVIG); 6) plasmapheresis; 7) surgical therapy in
the form of thymectomy; 8) monoclonal antibody therapy: eculi-
zumab and rituximab; and 9) surgical therapy in the form of ptosis
surgery and/or eye muscle surgery. We will review who would
From the Departments of Ophthalmology & Visual Sciences and Neurology, W.K.
Kellogg Eye Center, University of Michigan, MI.
Received for publication July 3, 2018; accepted July 23, 2018.
The author has no conflicts of interest to declare.
Reprints: Wayne T. Cornblath, MD, Departments of Ophthalmology & Visual
Sciences and Neurology, W.K. Kellogg Eye Center, University of Michigan,
1000 Wall Street, Ann Arbor, MI 48105. Email: wtc@med.umich.edu.
Copyright © 2018 by Asia Pacific Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.22608/APO.2018301
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018
Copyright © 2018 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
qualify for each therapy and a stepwise protocol to using therapy.
TREATMENT OPTIONS
On rare occasion patients with OMG will have either episod-
ic symptoms (ie, a few weeks a year) or very intermittent symp-
toms, such as ptosis at the end of the day. In this setting where the
morbidity of the symptoms is minimal, then observation only is a
reasonable option.
In patients with diplopia only, patching an eye will eliminate
the diplopia. Although most patients prefer to use both eyes with
resultant depth perception and increased side vision, occasionally
patients will prefer monocular vision and no medications with
their accompanying side effects, costs, and so on. At times a pa-
tient with diplopia and unilateral ptosis will patch themselves and
not complain of symptoms. Lid crutches, metal wire placed on
glasses frames that elevate the lids, can reduce ptosis as can sim-
ple tape. Although not used commonly these can provide symp-
tom relief to the occasional patient who does not want to use other
therapies.
Pyridostigmine is a mainstay of therapy for OMG, typically
being tried first in all patients who desire treatment beyond patch-
ing. The advantages of pyridostigmine are safety, variable dosing,
and relative quickness in determining efficacy. Pyridostigmine
typically is more effective for ptosis than diplopia.1 We recom-
mend a trial of pyridostigmine before using immunosuppressive
treatment in all patients desiring medical therapy. Our practice is
to start with 60 mg of pyridostigmine once a day, increasing the
dose to as many as six to eight 60 mg pills once the patient notes
what effect the first doses have. Increasing pyridostigmine is done
using 2 metrics: 1) how long a single dose lasts; 2) how effectively
a 60 mg dose eliminates symptoms. If a 60 mg dose eliminates all
symptoms and lasts 6 hours, we instruct the patient to take 60 mg
every 5 hours to allow for absorption of the next dose. If a 60 mg
dose does not eliminate symptoms entirely we instruct the patient
to try a 90 mg dose, increasing in 30 mg increments until symp-
toms are adequately improved or 180 mg is reached. Patients are
generally instructed in these principles and then followed up by
phone or with an office visit to discuss response to therapy and
any additional fine-tuning of dose needed. Abdominal cramping
and diarrhea are idiosyncratic responses to pyridostigmine that
can limit its use. Fortunately, concomitant use of glycopyrrolate
can eliminate the adverse effects. In using glycopyrrolate, dosage
adjustment is also needed. Some patients use 1 mg of glycopyrro-
late a day with their first dose of pyridostigmine and are symptom
free the rest of the day. Other patients require glycopyrrolate with
every other dose of pyridostigmine or with every dose of pyr-
idostigmine. Some patients find they need to take glycopyrrolate
an hour before their pyridostigmine to eliminate adverse effects.
Finally, some patients will require 2 mg of glycopyrrolate versus
the standard 1 mg starting dose. Again, this will require extensive
discussion with the patient and careful follow-up to monitor suc-
cess. Success is defined by the patient being happy with reduction
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Cornblath
of symptoms. Some patients require elimination of all symptoms,
but others are happy with a partial reduction in symptoms. In gen-
eral, in 2 to 4 weeks the success or failure of pyridostigmine can
be determined.
Oral immunosuppressive therapy is the next step in treat-
ment if a patient fails pyridostigmine. There are no RCTs proving
the efficacy of any of the common immunosuppressive therapies
in OMG. The recent EPITOME trial published results but as
only 9 patients completed 16 weeks of therapy compared with
a planned 88, no clear conclusions can be drawn.2 However,
multiple retrospective series, clinical experience, and experience
with GMG all lead to a reasonable conclusion that immunosup-
pressive therapy (prednisone, mycophenolate mofetil, cyclospo-
rine, cyclophosphamide, azathioprine, rituximab, and so on) is
effective in OMG. As there are no head-to-head trials comparing
immunosuppressive therapy in OMG, then other factors must be
used to decide which immunosuppressive therapy to use in what
order. Factors to be considered include age of the patient, medical
comorbidities, side effect profile of the agent selected, monitoring
requirements, speed of onset of action, cost of drug, and need
for years of treatment. Generally, prednisone is a commonly used
first choice of oral immunosuppressive.3 Advantages of predni-
sone include wide availability, low cost, well-known side effect
profile with significant experience in use in multiple other con-
ditions, and reasonable efficacy.4,5 Disadvantages of prednisone
include worsening of disease in patients with preexisting diabetes
mellitus, hypertension, and osteoporosis. Another issue in the use
of prednisone is the starting dose. Two dose regimens are typical-
ly used, either starting at a high dose, 60 mg of prednisone, and
then tapering down after symptoms resolve6 or starting at a low
dose and slowly tapering up until symptoms resolve.2 Although
we tend to favor starting at a low dose and tapering up, there are
no studies comparing the 2 methods in OMG.
There has been a fair amount of discussion regarding the use
of immunosuppressive treatment in patients with OMG to prevent
the progression of OMG to GMG. Given the relatively low rate
of progression of OMG to GMG of 15–21%7,8 and the risk of
immunosuppressive treatment, we generally feel the use of im-
munosuppressive treatment should be predicated on eliminating
symptoms of OMG, not preventing GMG.9
In patients who either fail prednisone or who are felt to be at
high risk for prednisone adverse effects (ie, elderly diabetics with
preexisting osteoporosis), then mycophenolate mofetil would be
our next drug of choice. Advantages to mycophenolate mofetil
include ease of use given a single standard starting dose of
1000 mg 2 times per day, minimal adverse effects, and a study of
its use in OMG. Disadvantages include monthly monitoring of
complete blood count, greater cost than prednisone, and longer
time needed for improvement than prednisone.10
If mycophenolate mofetil is not an option due to cost or
failure, then azathioprine is our next choice. Advantages to
azathioprine include cost, long-term experience with excellent
knowledge of adverse effects, and a study of its use in OMG. Dis-
advantages include long time to onset.11 Cyclosporine, cyclophos-
phamide, or tacrolimus are the next options. These drugs have all
been used in GMG with success, so their use in OMG is likely
also to be successful.12 Again, there are no head-to-head trials of
these drugs, so the risk-benefit of each drug in an individual pa-
tient along with the practitioner’s experience with the drugs must
be taken into account.
258 | www.apjo.org
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Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018
Intravenous IG and plasmapheresis are both mainstays of
treatment in GMG. In 1 study 17 patients with OMG did not show
improvement with IVIG.13 There are no studies concerning plas-
mapheresis in OMG patients. Use of these treatments in patients
who have failed other treatments is not unreasonable but must be
done on a case-by-case basis.
Thymectomy has been used to treat GMG for many years
with a recent RCT showing efficacy14 along with a meta-
analysis showing efficacy.15 A recent meta-analysis of thymec-
tomy in OMG notes a remission rate of 50% and recommends
thymectomy be considered in patients with OMG.16 Other authors
feel thymectomy is not an option in OMG.17,18 We agree with
these authors that thymectomy in the absence of thymoma should
generally not be used to treat OMG.
Eculizumab has been recently approved for use in GMG,
whereas rituximab has been used in both GMG and OMG.19,20
The advantages of these drugs are relative ease of use given the
infrequent dosing, whereas the disadvantages are very high cost.
As with plasmapheresis and IVIG, use of these treatments in pa-
tients who have failed other treatments is not unreasonable but
must be done on a case-by-case basis.
Occasionally, patients with OMG will develop a fixed, not
variable, ptosis that does not improve despite maximal medical
treatment of their OMG. In this setting ptosis surgery by a sur-
geon experienced in operating on patients with OMG can be suc-
cessful in eliminating the ptosis.21 Similarly, while most of the
time the diplopia in OMG is variable, on occasion the diplopia
does not vary and eye muscle surgery is an option. In this setting
careful evaluation by an ophthalmologist experienced in ocular
motility evaluation is needed to demonstrate stability of measure-
ments for at least 6 months.22
CONCLUSIONS
The treatment of OMG is an area where we are guided more
by logic and work on GMG than by specific RCTs in OMG pa-
tients. A great number of questions remain in elucidating the best
treatment for OMG. Perhaps the first question is, how do we mea-
sure OMG and results of treatment? Unfortunately there is not yet
a comprehensive validated scale for OMG, as there is for GMG.23
There is a consensus that immunosuppressive therapy is effec-
tive in OMG but no consensus on dosing regimens with pred-
nisone, or comparisons of efficacy and adverse effects between
prednisone and mycophenoate mofetil or other commonly used
immunosuppressive agents. The role of thymectomy could also
be explored in treating OMG. Hopefully, the future will bring ad-
ditional knowledge in our goal of treating this disabling disease.
REFERENCES
1. Kupersmith MJ, Ying G. Ocular motor dysfunction and ptosis in ocular
myasthenia gravis: effects of treatment. Br J Ophthalmol. 2005;89:
1330–1334.
2. Benatar M, Mcdermott MP, Sanders DB, et al. Efficacy of prednisone for
the treatment of ocular myasthenia (EPITOME): a randomized controlled
trial. Muscle Nerve. 2016;53:363–369.
3. Kerty E, Elsais A, Argov Z, et al. EFNS/ENS guidelines for the treatment of
ocular myasthenia. Eur J Neurol. 2014;21:687–693.
4. Kupersmith MJ, Moster M, Bhuiyan S, et al. Beneficial effects of
corticosteroids on ocular myasthenia gravis. Arch Neurol. 1996;53:802–804.
© 2018 Asia-Pacific Academy of Ophthalmology
Asia-Pacific Journal of Ophthalmology • Volume 7, Number 4, July/August 2018
5. Bruce BB, Kupersmith MJ. Safety of prednisone for ocular myasthenia
gravis. J Neuroophthalmol. 2012;32:212–215.
6. Kupersmith MJ. Ocular myasthenia gravis: treatment successes and
failures in patients with long-term follow-up. J Neurol. 2009;256:
1314–1320.
7. Nagia L, Lemos J, Abusamra K, et al. Prognosis of ocular myasthenia
gravis: retrospective multicenter analysis. Ophthalmology. 2015;122:
1517–1521.
8. Mazzoli M, Ariatti A, Valzania F, et al. Factors affecting outcome in ocular
myasthenia gravis. Int J Neurosci. 2017;128:15–24.
9. Wong SH, Plant G, Cornblath W. Does treatment of ocular myasthenia
gravis with early immunosuppressive therapy prevent secondarily
generalization and should it be offered to all such patients. J
Neuroophthalmol. 2016;36:98–102.
10. Chan CW. Mycophenolate mofetil for ocular myasthenia. J Neurol. 2008;
255:510–513.
11. Sommer N, Sigg B, Melms A, et al. Ocular myasthenia gravis: response to
long term immunosuppressive treatment. J Neurol Neurosurg Psychiatry.
1997;62:156–162.
12. Lee JI, Jander S. Myasthenia gravis: recent advances in immunopathology
and therapy. Expert Rev Neurother. 2017;17:287–299.
13. Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia
gravis: a randomized controlled trial. Neurology. 2007;68:837–841.
14. Wolfe GI, Kaminski HJ, Aban IB, et al. Randomized trial of thymectomy in
myasthenia gravis. N Engl J Med. 2016;375:511–522.
© 2018 Asia-Pacific Academy of Ophthalmology
Copyright © 2018 Asia-Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.
Treatment of OMG
15. Cataneo AJM, Felisberto G Jr, Cataneo DC. Thymectomy in
nonthymomatous myasthenia gravis - systematic review and meta-analysis.
Orphanet J Rare Dis. 2018;13:99.
16. Zhu K, Li J, Huang X, et al. Thymectomy is a beneficial therapy for patients
with non-thymomatous ocular myasthenia gravis: a systematic review and
meta-analysis. Neurol Sci. 2017;38:1753–1760.
17. Al-Haidar M, Benatar M, Kaminski HJ. Ocular myasthenia. Neurol Clin.
2018;36:241–251.
18. Smith SV, Lee AG. Update on ocular myasthenia gravis. Neurol Clin. 2017;
35:115–123.
19. Howard JF Jr, Utsugisawa K, Benatar M, et al. Safety and efficacy of
eculizumab in anti-acetylcholine receptor antibody-positive refractory
generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-
blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16:
976–986.
20. Iorio R, Damato V, Alboini PE, et al. Efficacy and safety of rituximab for
myasthenia gravis: a systematic review and meta-analysis. J Neurol. 2015;
262:1115–1119.
21. Litwin AS, Patel B, McNab AA, et al. Blepharoptosis surgery in patients
with myasthenia gravis. Br J Ophthalmol. 2015;99:899–902.
22. Peragallo JH, Velez FG, Demer JL, et al. Long-term follow-up of
strabismus surgery for patients with ocular myasthenia gravis. J
Neuroophthalmol. 2013;33:40–44.
23. Wong SH. Rating scale for ocular myasthenia gravis: a call to action! J
Neuroophthalmol. 2018;38:138–139.
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