10.1007_s11940-011-0151-8_2

8/3/2019 10.1007_s11940-011-0151-8_2

1/10

Current Treatment Options in Neurology (2012) 14:103112

DOI 10.1007/s11940-011-0151-8

Neurologic Ophthalmology and Otology (RK Shin, Section Editor)

Treatment of Ocular

Myasthenia GravisScott R. Haines, MD

1*, 2

Matthew J. Thurtell, MBBS

Address

*,1Department of Neurology, Virginia Commonwealth University,

P.O. Box 980599, Richmond, VA 23298-0599, USA

Email: [email protected] of Ophthalmology, Virginia Commonwealth University, Richmond,

VA 23298-0599, USA3Department of Ophthalmology and Visual Sciences, University of Iowa,

200 Hawkins Drive, PFP Iowa City, IA 52242-1091, USAEmail: [email protected]

Published online: 26 October 2011

* Springer Science+Business Media, LLC 2011

Keywords Ocular myasthenia gravis I Treatment I Prednisone I Steroids I Pyridostigmine I Ptosis IDiplopia I Acetylcholinesterase inhibitors I Steroid-sparing agents I Surgery I Thymectomy I Contact lenses

Opinion statement

Myasthenia gravis (MG) is an autoimmune disorder that is characterized by variableweakness and fatigability. Often, MG presents with only ocular symptoms such as ptosisand diplopia. Treatment of ocular MG is aimed at relieving the symptoms of ptosis anddiplopia, as well as preventing the development of generalized MG symptoms. Immunesuppression with steroids is often the main therapy. Steroid doses must be increasedslowly because of a risk of precipitating myasthenic crisis. After achieving the highesttarget dose, steroids are then slowly tapered down to the lowest effective dose. Often,acetylcholinesterase inhibitors such as pyridostigmine and neostigmine are alsoemployed to help control symptoms. When steroids are contraindicated, acetylcholin-esterase inhibitors can be tried as the primary therapy. Steroid-sparing agents such asazathioprine and mycophenolate may also have a role in treating ocular MG. Othertreatments for MG include plasmapheresis, intravenous immunoglobulin, and other im-munosuppressive agents, but these are rarely required for ocular MG. Patients shouldalso be evaluated for thymoma. Thymoma should be resected surgically. Ocular MG

without thymoma is not usually treated with thymectomy. Topical agents may be usefulas additional therapy for mild or moderate ptosis. Nonpharmacologic treatments in-clude occlusive devices, prisms, eyelid supports, contact lenses, and (in long-standing,stable cases) strabismus surgery or eyelid elevation surgery.

Introduction

Myasthenia gravis (MG) is often considered a classicexample of autoimmune disease. The syndrome is

characterized by variable weakness and fatigabilitythat results from disruption of neuromuscular trans-

8/3/2019 10.1007_s11940-011-0151-8_2

2/10

mission. The disrupted nerve-muscle communicationis typically due to autoantibodies against skeletal mus-cle acetylcholine receptors [1]. Any skeletal muscle canpotentially be affected, and there is considerable het-erogeneity in disease expression [2]. The extraocularmuscles are commonly affected. Ocular symptoms ofMG, which include ptosis and diplopia, may be theonly manifestation of the disease [3, 4].

Ptosis is often variable and asymmetric. Examina-tion may reveal fatigability with prolonged upgazeand a Cogans lid twitch. Cogans lid twitch is seen

when looking down, and then back up to primary po-sition; as the eyelid elevates, it overshoots and thentwitches as it settles back into its resting position. Ele-

vation of the more ptotic lid may unmask ptosis of thefellow eye. The amount of ptosis may improve withrest, ice, or acetylcholinesterase inhibitors such asedrophonium (Tensilon) [5] or neostigmine [6].

The ophthalmoparesis of ocular MG is also var-

iable and can mimic almost any pattern of ocularmisalignment from cranial neuropathies, such aspupil-sparing 3rd nerve palsy or 4th nerve palsy,or central ocular motor disorders such as internu-clear ophthalmoplegia or skew deviation. MG moreoften causes an exotropia or wall-eyed ocular de-

viation. Although an esotropia or cross-eyed pat-tern is also possible, this pattern should raise asuspicion of thyroid eye disease, which can co-exist

with MG [7, Class IV]. The edrophonium (Tensi-lon) or neostigmine tests can be considered positive

with an objective change in the ocular misalign-ment or ptosis [8].

About 65% of patients with MG initially presentwith ocular symptoms [9]. Of those who presentwith onlyocular symptoms, about half will develop gen-eralized symptoms within 6 months, and a total of 80%

will develop generalized symptoms in 2 years. If a pa-tient goes 2 years without developing generalized symp-toms, it is unusual for them to occur later [3].

The treatment of ocular MG has two goals: Besidesthe immediate goal of improving symptoms of ptosisand diplopia [4], there is also an objective of reducingthe chance of developing generalized MG. The role ofmedical treatments in preventing generalization remainscontroversial [10], but there is some evidence that earlytreatment with steroids can be effective [9].

Prevention of generalized disease is a significant clin-ical concern, as most of the morbidity and mortality ofMG comes from generalized disease. No placebo-con-trolled, randomized study has been performed to inves-tigate whether generalized disease can be prevented.

Kupersmith performed a retrospective analysis of 87patients treated with a tapered dose of oral steroid or pyr-idostigmine alone [9, Class III]. The subjects were notrandomized, and treatment was based on comorbid con-ditions and patient preference; 55 patients were treated

with steroids and 32 were not. Both groups were alsotreated with pyridostigmine. After the first year of thera-py, the average daily dose of prednisone in the treatedpatients was 4.8 mg. The patients were observed for4 years or more. Of patients who did not receive predni-sone, 50% developed generalized MG, compared with14% of the treated patients. There has been a call for alarge-scale randomizedtrial to confirm these results[11].

Treatment

Pharmacologic treatment

& Goals of therapy include minimizing symptoms of diplopia and ptosisand preventing progression to generalized MG. In many cases, con-trolled trials to guide treatment do not exist, and recommendations aremade on the basis of retrospective data and clinical experience [ 12].

& Immune suppression with prednisone is often considered a first-linetherapy.

& Acetylcholinesterase inhibitors can be used in conjunction with im-mune suppression or as an alternative first-line therapy, especially inpatients (such as those with diabetes mellitus) for whom cortico-steroids are relatively contraindicated.

& Steroid-sparing agents may also be used as a second-line therapy.

104 Neurologic Ophthalmology and Otology (RK Shin, Section Editor)

8/3/2019 10.1007_s11940-011-0151-8_2

3/10

Prednisone

Corticosteroids have long been considered a mainstay of treatment forocular MG, but no convincing evidence-based recommendation can bemade for this treatment [11]. Some clinicians advocate the use of pred-nisone as first-line therapy for MG, but this approach remains contro-

versial, and others advocate trying symptomatic treatment before using

immune therapy.Standard dosage Doses are generally started low, titrated up gradually to reduce the risk of

precipitating myasthenic crisis, and then slowly tapered back down to theminimum effective dose. A sample dosing schedule might be as follows: Startwith prednisone 10 mg daily for 2 days, and every 2 days increase the doseby an additional 10 mg, up to a goal of 60 mg daily. Maintain the dose at60 mg per day for 1 week and then begin to taper down by decreasing thedose by 10 mg every week. Once the dose is back down to 10 mg daily,proceed with weekly dose reductions at intervals of 2.5 mg. If the patientssymptoms return, then increase to the previously effective dose. If there is aflare-up of previously treated disease, then the dose may be increased to25 mg and slowly tapered again [9]. Sometimes the final dosing regimen isadministered every other day, to try to minimize long-term adverse effects.

Doses should be given only once per day in the morning, similar to thebodys normal peak of endogenous steroid [3].

Contraindications Corticosteroids are relatively contraindicated in patients with diabetes orhypertension. Corticosteroids are especially contraindicated for patients withchronic infectious disease, such as tuberculosis. Prednisone is a pregnancycategory C drug.

Main drug interactions Prednisone can interact with multiple medications and potentially alter thedrug levels. Drugs that require monitoring should be followed closely duringprednisone dose changes. For example, the INR should be checked fre-quently in patients using warfarin.

Main side effects Corticosteroids can cause or exacerbate multiple medical conditions, in-cluding diabetes, hypertension, congestive heart failure, immune suppres-

sion and infection, Cushing syndrome, adrenal insufficiency, osteoporosis,avascular necrosis of the hip, gastrointestinal ulcers, myopathy, glaucoma,and psychosis.

Special points Changes in steroid dosing can precipitate a myasthenic crisis, and allchanges, whether titrating up or tapering down, should be made insmall increments. A rapid increase of the dose is acceptable in a con-trolled setting, such as a patient who is closely monitored in the hos-pital while receiving plasma exchange or intravenous immunoglobulin(IVIG). Sudden withdrawal could lead to hypoadrenergic crisis, and in-creased dose or stress dosing is an important consideration at the timeof surgical procedures.

Cost Low cost; the specific cost varies depending on the final dosing regimen.

Cholinesterase inhibitors (pyridostigmineand neostigmine)

Cholinesterase inhibitors act on the enzyme responsible for breakdownof acetylcholine, thus increasing the availability of acetylcholine in theneuromuscular junction and facilitating muscle activation. These medi-

Treatment of Ocular Myasthenia Gravis Haines and Thurtell 105

8/3/2019 10.1007_s11940-011-0151-8_2

4/10

cations may be used as an adjunctive therapy to immunosuppression with corticosteroids or as an alternative first-line therapy, with the deci-sion depending on potential contraindications to steroid therapy and onpatient and physician preferences. The advantage of cholinesteraseinhibitors is that they are fast-acting, safe, and free from long-term ad-

verse effects. Pyridostigmine is often better tolerated than neostigmine.No large randomized study has been performed to investigate the use ofcholinesterase inhibitors in MG, but the response in observationalstudies is substantial and obviates the need for further investigation [13].

Standard dosage Pyridostigmine is usually started at 60 mg three times daily and can be ti-trated to higher doses. The maximum dose is generally determined by ad-verse effects. Neostigmine is usually started at 15 mg three times per day andcan be similarly titrated.

Contraindications Cholinesterase inhibitors should be avoided when there is gastrointestinalobstruction. Bradycardia is also a relative contraindication. Pyridostigmineand neostigmine are both pregnancy category C drugs.

Main drug interactions Opioids and beta-blockers may increase the risk of bradycardia.

Main side effects Cholinergic side effects are common. These include abdominal cramps,

nausea, diarrhea, increased secretions, sweating, bradycardia, and muscletwitches or cramps. The gastrointestinal effects can sometimes be overcomewith diphenoxylate-atropine.

Special points High doses theoretically could cause cholinergic crisis, but this is seldomseen in clinical practice.

Cost These are relatively inexpensive and are available as generics.

Azathioprine

Azathioprine is a purine analogue that inhibits nucleic acid synthesis. It actson proliferating lymphocytes and induces both B-cell and T-cell lympho-penia [14]. Azathioprine can be used in combination with prednisone as asteroid-sparing agent. Some physicians start azathioprine when steroid

doses cannot be successfully lowered to a satisfactory level, and others startazathioprine at the same time that steroids are initiated. Occasionally,azathioprine is used without steroid. The combination of prednisone andazathioprinecan allow the use of lower doses of prednisone, and it has beenfound to be as effective as prednisone alone, or it may even extend the re-mission period longer than prednisone alone [14, Class II].

Standard dosage Typically begin at 50 mg per day and increase the dose by 50 mg per day atweekly intervals until reaching a target of 2 to 3 mg/kg per day. Doses needto be adjusted for renal failure.

Contraindications Azathioprine is a pregnancy category D drug. It requires monitoring of bloodcounts and liver function. Blood analysis should be performed at baselineand rechecked after 1 month and then every 6 months.

Main drug interactions Angiotensin-converting enzyme (ACE) inhibitors increase the risk of pancy-topenia. Allopurinol increases levels of azathioprine. Azathioprine affectslevels of warfarin.

Main side effects Flu-like symptoms may occur at initiation. There is risk of hepatotoxicity,lymphopenia, and pancytopenia, as well as some concern about increasedrisk of malignancies.


8/3/2019 10.1007_s11940-011-0151-8_2

5/10

Special points There have been reports of effectively using lower doses of azathioprine, suchas 50 mg per day [15, Class IV]. There is a delay in therapeutic response, andthe maximal effect occurs at 6 to 24 months after beginning treatment [16].

Cost 90 tablets of 50 mg cost about $90.

Mycophenolate mofetil

Mycophenolate is metabolized in the liver to its active form, mycophe-nolic acid, which inhibits nucleic acid synthesis and preferentiallyinhibits replication of B lymphocytes and T lymphocytes [14].

Standard dosage Begin at 500 mg twice daily for 4 weeks and then increase the dose to1,000 mg twice daily, with a goal between 1,000 and 1,500 mg twice daily.

Contraindications This is a pregnancy category D medication. Renal failure is a relativecontraindication.

Main drug interactions This medication should not be used in combination with other immuno-suppressants such as azathioprine, as the combination could lead to bonemarrow suppression.

Main side effects Gastrointestinal effects are common. Bone marrow suppression is a rare butserious adverse effect.

Special points Mycophenolate has a shorter time until clinical benefit than azathioprine.

Cost 120 tablets of 500 mg cost about $1,200.

Naphazoline

When ptosis is the only symptom of MG or when it is the only residualsymptom after systemic therapy, topical treatment can be considered.Naphazoline is an alpha-2 agonist that is commonly used for red eye. It haspreviously been reported to be effective for improving ptosis in Hornerssyndrome, through stimulation of Muellers muscle. Recently, naphazoline

was also reported to be effective for ptosis due to MG [ 17, Class III].

Standard dosage 0.05% used as needed every 3 or 4 h.

Contraindications Acute angle-closure glaucoma is a consideration.

Main drug interactions No significant interactions have been reported.

Main side effects Naphazoline could cause central nervous system depression in very youngchildren.

Special points The effectiveness of this treatment varies considerably, with 70% of patientsstudied considering it to be useful.

Cost Generic formulations are available and it can be obtained without aprescription.

Other treatments

& A number of other treatments are available for the treatment of MG

[1, 1822], but many are rarely used for ocular MG:


Cyclosporine

Tacrolimus

Cyclophosphamide

Rituximab

8/3/2019 10.1007_s11940-011-0151-8_2

6/10

Surgery

& Surgical options can include thymectomy (used as a nonpharmaco-logic treatment to modify the course of disease in MG), strabismussurgery to correct ocular misalignment in certain cases, and eyelidsurgery to correct ptosis.

Thymectomy

Patients with MG should be evaluated for thymoma. If a thymoma isdetected, it should be removed [12]. (Thymoma associated with MG isconsidered to have a more favorable prognosis than thymoma not as-sociated with MG [23, 24].) Thymectomy also can be considered innonthymomatous MG, but there is evidence that purely ocular MG maynot benefit from thymectomy [10, 16].

Standard procedure Thymectomy can be performed by full or partial sternotomy or by trans-cervical or thoracoscopic approaches.

Contraindications This elective intervention is contraindicated for any patient with a high riskof surgical morbidity.

Complications Wound healing disorders, sternum instability, bronchopneumonia, andphrenic nerve damage.

Strabismus surgery

Strabismus surgery can be used to minimize ocular misalignment causingdiplopia. Generally, this type of procedure is performed only when theocular deviation appears to be stable over a period of at least 6 months [25].

Standard procedure Depending on the ocular deviation, extraocular muscle tendons are length-

ened or shortened to change the mechanical advantage of the extraocularmuscles.

Contraindications Strabismus surgery is relatively benign, but bleeding disorders and immunesuppression are relative contraindications. Strabismus surgery is more diffi-cult in patients who have had previous strabismus surgery.

Complications Infection, ocular ischemia, and worsening of diplopia

Special points Adjustable sutures are advisable, to allow for correction of eye position.Given the variability of MG, patients should be cautioned about the high riskof failure.

Eyelid elevation surgery

Surgical eyelid elevation can be an option for medically refractory, stableptosis [26].

Standard procedure The most common eyelid elevation surgeries are external levator advance-ments and frontalis slings.

Contraindications Eyelid surgery is relatively benign, but bleeding disorders and immunesuppression are relative contraindications.


Methotrexate

Etanercept

Intravenous immunoglobulin

Plasmapheresis

8/3/2019 10.1007_s11940-011-0151-8_2

7/10

Complications Infections and exposure keratopathy

Special points Given the variability of MG, patients should be cautioned about the high riskof failure. A need for repeat surgery is not uncommon (2 of 16 patients inone study) [26, Class III].

Assistive devices

& Nonpharmacologic methods to correct diplopia and ptosis includeeyelid supports, occlusive devices, eyeglass prisms, and contactlenses.

Eyelid supports

Usage Mechanical support is an effective treatment for ptosis. Eyelid crutches can befitted into glasses, or tape can be used to elevate the lids.

Special points Prolonged eyelid support can result in exposure keratopathy, and eyelidsupport should not be used by patients with altered eye sensation orimpaired level of consciousness.

Cost Generally very low cost, but custom eyeglasses can vary greatly. It is some-times difficult to find optical shops that can accommodate eyelid crutch

requests.

Occlusive device

Usage The simplest solution to diplopia is to cover one eye. Patches are commonlyused, or one lens of eyeglasses may be fogged. Applying semitransparent tape(such as Scotch tape or Micropore medical tape (3M)) provides sufficientblur to effectively occlude one eye.

Special points It is useful to determine the better-seeing or dominant eye and to occlude theother eye.

Cost Very low cost.

Prisms

Usage Prisms can be an effective solution for patients with stable ocular misalign-ment, when the deviation is not too great. Prisms are available as a Fresnelstick-on for regular glasses, or prisms can be ground into the prescriptionlens.

Special points Prisms are not effective when there is a torsional component to the diplopia.Prisms are also ineffective when there is significant variability of the diplopia.

Cost Fresnel prisms cost about $20

Contact lenses

Usage Contact lenses are not often considered in the management of diplopia,but they can be used in several ways [27]. They can successfully occludeby fogging one eye with unneeded spherical power or with an opaqueoptical center. Contact lenses can even be made with small verticalprism power (up to 4 prism diopters). In one case, diplopia was suc-cessfully treated by fitting the patient with contact lens monovision [ 28,Class IV]. Monovision is an option used for presbyopic patients: one eyeis given a prescription for distance viewing and the other eye has adifferent prescription for reading.


8/3/2019 10.1007_s11940-011-0151-8_2

8/10

8/3/2019 10.1007_s11940-011-0151-8_2

9/10

References and Recommended Reading

Papers of particular interest, published recently, have been

highlighted as: Of importance Of major importance

1. Jani-Acsadi A, Lisak R. Myasthenia gravis. Curr TreatOptions Neurol. 2010;12:23143.

2. Pal J, Rozsa C, Komoly S et al. Clinical and biologicalheterogeneity of autoimmune myasthenia gravis. JNeuroimmunol. 2011;231:4354.

This is an excellent review of the biologic basis of MG. Thereis a brief discussion of the unique immunologic propertiesof extraocular muscles.

3. Luchanok U, Kaminski H. Ocular myasthenia: diag-nostic and treatment recommendations and the evi-dence base. Curr Opin Neurol. 2008;21:815.

4. Porter N, Salter B. Ocular myasthenia gravis. Curr Treat Options Neurol. 2005;7:7988.

5. Benatar M. A systematic review of diagnostic studies

in myasthenia gravis. Neuromuscul Disord.2006;16:45967.

6. Miller N, Morris J, Maquire M. Combined use ofneostigmine and ocular motility measurements inthe diagnosis of myasthenia gravis. Arch Ophthal-mol. 1982;100:7613.

7. Zouvelou V, Potagas C, Karandreas N, et al. Con-current presentation of ocular myasthenia and eu-thyroid graves ophthalmopathy: a diagnosticchallenge. J Clin Neurosci. 2008;15:71820.

8. Daroff B. The office tensilon test for ocular myas-thenia gravis. Arch Neurol. 1986;43:8434.

9. Kupersmith MJ. Ocular myasthenia gravis: treatmentsuccesses and failures in patients with long-term

follow-up. J Neurol 2009;256:1314

20.This was a retrospective review of 87 patients with ocular MGtreated with prednisone or with pyridostigmine only. Thepatients treated with prednisone showed a delayed onset anda reduced incidence of generalized MG.

10. Gilbert M, De Sousa E, Savino P. Ocular myas-thenia gravis treatment: the case against predni-sone therapy and thymectomy. Arch Neurol.2007;64:17902.

11. Benatar M, Kaminski H. Evidence report: the medicaltreatment of ocular myasthenia (an evidence review).Neurology. 2007;68:21449.

12. Kumar V, Kaminski H. Treatment of myastheniagravis. Curr Neurol Neurosci Rep. 2011;11:8996.

13. Mehndiratta M, Pandey S, Kuntzer T. Acetylcholin-esterase inhibitor treatment for myasthenia gravis(review). Cochrane Libr. 2011;2:116.

14. Diaz-Manera J, Rojas-Garcia R, Illa I. Treatmentstrategies for myasthenia gravis. Expert Opin Phar-macother. 2009;10:132942.

15. Finsterer J, Frank M, Krexner E. Low-dose azathio-prine effectively suppresses clinical and immuno-logical manifestations of generalized myasthenia.South Med J. 2010;103:1824.

16. Skeie G, Apostolski S, Evoli A, et al. Guidelinesfor treatment of autoimmune neuromusculartransmission disorders. Eur J Neurol.2010;17:893902.

17. Nagane Y, Utsugisawa K, Suzuki S, et al. Topicalnaphazoline in the treatment of myasthenic ble-pharoptosis. Muscle Nerve. 2011;44:414.

18. Antonio-Santos A, Eggenberger E. Medical treatmentoptions for ocular myasthenia gravis. Curr OpinOphthalmol. 2008;19:46878.

19. Cortese I, Chaudry V, So Y, et al. Evidence basedguideline update: plasmapheresis in neurologicdisorders: report of the Therapeutics and Tech-nology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2011;76:294300.

20. Ibrahim H, Dimachkie M, Shaibani A. A review:the uses of rituximab in neuromuscular diseases. JClin Neuromuscul Dis. 2010;12:91102.

21. Mandawat A, Kaminski H, Cutter G, et al. Compar-ative analysis of therapeutic options used for myas-thenia gravis. Ann Neurol. 2010;68:797805.

22. Angelini C. Diagnosis and management of autoim-mune myasthenia gravis. Clin Drug Investig.2011;31:114.

23. Zielinksi M. Management of myasthenic patients with thymoma. Thorac Surg Clin. 2011;21:4757.

24. Chen Z, Luo H, Peng Y, et al. Comparative clinicalfeatures and immune responses after extended thy-mectomy for myasthenia gravis in patients withatrophic versus hyperplastic thymus. Ann ThoracSurg. 2011;91:2128.

25. Morris OC, ODay J. Strabismus surgery in the man-agement of diplopia caused by myasthenia gravis. BrJ Ophthalmol. 2004;88:832.

26. Bradley E, Bartley G, Chapman K, et al. Surgicalcorrection of blepharoptosis in patients withmyastheniagravis. Ophthal Plast Recons. 2001;17:10310.

27. Evans B. Orthoptic indications for contact lens wear.Cont Lens Anterior Eye. 2006;29:17581.

28. Migneco M. Alleviating vertical diplopia throughcontact lenses without the use of prism. Eye ContactLens. 2008;34:2978.


8/3/2019 10.1007_s11940-011-0151-8_2

10/10

29. Nagane Y, Suzuki S, Suzuki N, et al. Early aggressivetreatment strategy against myasthenia gravis. EurNeurol. 2011;65:1622.

30. Sussman J, Argov Z, McKee D, et al. Antisense treat-ment for myasthenia gravis: experience with mon-arsen. Ann NY Acad Sci. 2008;1132:28390.

31. Hennessey I, Long A, Hughes I, et al. Thymectomy forinducing remission in juvenile myasthenia gravis.Pediatr Surg Int. 2011;27:5914.

32. Pineles S, Avery R, Moss H, et al. Visual and systemicoutcomes in pediatric ocular myasthenia gravis. Am JOphthalmol. 2010;15:4539.


10.1007_s11940-011-0151-8_2

Documents

Transcript of 10.1007_s11940-011-0151-8_2