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Current Treatment Options in Neurology (2012) 14:103–112 DOI 10.

1007/s11940-011-0151-8

Neurologic Ophthalmology and Otology (RK Shin, Section Editor)

Treatment of Ocular Myasthenia Gravis
Scott 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: shaines@mcvh-vcu.edu 2 Department of Ophthalmology, Virginia Commonwealth University, Richmond, VA 23298-0599, USA 3 Department of Ophthalmology and Visual Sciences, University of Iowa, 200 Hawkins Drive, PFP Iowa City, IA 52242-1091, USA Email: matthew-thurtell@uiowa.edu 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 I Diplopia 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 variable weakness and fatigability. Often, MG presents with only ocular symptoms such as ptosis and diplopia. Treatment of ocular MG is aimed at relieving the symptoms of ptosis and diplopia, as well as preventing the development of generalized MG symptoms. Immune suppression with steroids is often the main therapy. Steroid doses must be increased slowly because of a risk of precipitating myasthenic crisis. After achieving the highest target dose, steroids are then slowly tapered down to the lowest effective dose. Often, acetylcholinesterase inhibitors such as pyridostigmine and neostigmine are also employed to help control symptoms. When steroids are contraindicated, acetylcholinesterase inhibitors can be tried as the primary therapy. Steroid-sparing agents such as azathioprine and mycophenolate may also have a role in treating ocular MG. Other treatments for MG include plasmapheresis, intravenous immunoglobulin, and other immunosuppressive agents, but these are rarely required for ocular MG. Patients should also be evaluated for thymoma. Thymoma should be resected surgically. Ocular MG without thymoma is not usually treated with thymectomy. Topical agents may be useful as additional therapy for mild or moderate ptosis. Nonpharmacologic treatments include 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 classic example of autoimmune disease. The syndrome is characterized by variable weakness and fatigability that results from disruption of neuromuscular trans-

Of those who present with only ocular symptoms. it overshoots and then twitches as it settles back into its resting position. Elevation of the more ptotic lid may unmask ptosis of the fellow eye. The extraocular muscles are commonly affected. and a total of 80% will develop generalized symptoms in 2 years. randomized study has been performed to investigate whether generalized disease can be prevented. or central ocular motor disorders such as internuclear ophthalmoplegia or skew deviation. The edrophonium (Tensilon) or neostigmine tests can be considered positive with an objective change in the ocular misalignment or ptosis [8]. Steroid-sparing agents may also be used as a second-line therapy. Class IV]. The amount of ptosis may improve with rest. it is unusual for them to occur later [3]. Of patients who did not receive prednisone. which include ptosis and diplopia. but there is some evidence that early treatment with steroids can be effective [9••]. Any skeletal muscle can potentially be affected. or acetylcholinesterase inhibitors such as edrophonium (Tensilon) [5] or neostigmine [6]. mission. 55 patients were treated with steroids and 32 were not. Prevention of generalized disease is a significant clinical concern. Treatment Pharmacologic treatment & Goals of therapy include minimizing symptoms of diplopia and ptosis and preventing progression to generalized MG. and then back up to primary position. especially in patients (such as those with diabetes mellitus) for whom corticosteroids are relatively contraindicated.8 mg. The treatment of ocular MG has two goals: Besides the immediate goal of improving symptoms of ptosis and diplopia [4]. Ocular symptoms of MG. The patients were observed for 4 years or more. such as pupil-sparing 3rd nerve palsy or 4th nerve palsy. there is also an objective of reducing the chance of developing generalized MG. Kupersmith performed a retrospective analysis of 87 patients treated with a tapered dose of oral steroid or pyridostigmine alone [9••. Section Editor) About 65% of patients with MG initially present with ocular symptoms [9••]. In many cases. this pattern should raise a suspicion of thyroid eye disease. Cogan’s lid twitch is seen when looking down. compared with 14% of the treated patients. Acetylcholinesterase inhibitors can be used in conjunction with immune suppression or as an alternative first-line therapy. may be the only manifestation of the disease [3. Examination may reveal fatigability with prolonged upgaze and a Cogan’s lid twitch. 4]. If a patient goes 2 years without developing generalized symptoms. which can co-exist with MG [7. Immune suppression with prednisone is often considered a first-line therapy. and recommendations are made on the basis of retrospective data and clinical experience [12]. about half will develop generalized symptoms within 6 months. The subjects were not randomized. controlled trials to guide treatment do not exist. as the eyelid elevates. as most of the morbidity and mortality of MG comes from generalized disease. There has been a call for a large-scale randomized trial to confirm these results [11]. the average daily dose of prednisone in the treated patients was 4. and treatment was based on comorbid conditions and patient preference. Both groups were also treated with pyridostigmine. After the first year of therapy. Although an esotropia or “cross-eyed” pattern is also possible. Class III]. and there is considerable heterogeneity in disease expression [2•]. Ptosis is often variable and asymmetric. No placebo-controlled. The ophthalmoparesis of ocular MG is also variable and can mimic almost any pattern of ocular misalignment from cranial neuropathies. & & & . ice. 50% developed generalized MG. MG more often causes an exotropia or “wall-eyed” ocular deviation. The disrupted nerve-muscle communication is typically due to autoantibodies against skeletal muscle acetylcholine receptors [1]. The role of medical treatments in preventing generalization remains controversial [10].104 Neurologic Ophthalmology and Otology (RK Shin.

the INR should be checked frequently in patients using warfarin. gastrointestinal ulcers. such as a patient who is closely monitored in the hospital while receiving plasma exchange or intravenous immunoglobulin (IVIG). osteoporosis. Drugs that require monitoring should be followed closely during prednisone dose changes. and psychosis. but no convincing evidence-based recommendation can be made for this treatment [11].Treatment of Ocular Myasthenia Gravis Haines and Thurtell 105 Prednisone Corticosteroids have long been considered a mainstay of treatment for ocular MG. such as tuberculosis. Some clinicians advocate the use of prednisone as first-line therapy for MG. but this approach remains controversial. and increased dose or “stress dosing” is an important consideration at the time of surgical procedures. Corticosteroids are relatively contraindicated in patients with diabetes or hypertension. avascular necrosis of the hip. and then slowly tapered back down to the minimum effective dose. Corticosteroids are especially contraindicated for patients with chronic infectious disease. Prednisone is a pregnancy category C drug. whether titrating up or tapering down. including diabetes. If the patient’s symptoms return. then increase to the previously effective dose. Changes in steroid dosing can precipitate a myasthenic crisis. then the dose may be increased to 25 mg and slowly tapered again [9••]. and others advocate trying symptomatic treatment before using immune therapy. hypertension. Corticosteroids can cause or exacerbate multiple medical conditions. should be made in small increments. If there is a flare-up of previously treated disease. and all changes. A rapid increase of the dose is acceptable in a controlled setting. Doses are generally started low. immune suppression and infection. adrenal insufficiency. similar to the body’s normal peak of endogenous steroid [3]. Maintain the dose at 60 mg per day for 1 week and then begin to taper down by decreasing the dose by 10 mg every week. Standard dosage Contraindications Main drug interactions Main side effects Special points Cost Cholinesterase inhibitors (pyridostigmine and neostigmine) Cholinesterase inhibitors act on the enzyme responsible for breakdown of acetylcholine. congestive heart failure. For example. A sample dosing schedule might be as follows: Start with prednisone 10 mg daily for 2 days. thus increasing the availability of acetylcholine in the neuromuscular junction and facilitating muscle activation. Cushing syndrome. Prednisone can interact with multiple medications and potentially alter the drug levels. These medi- . Once the dose is back down to 10 mg daily. the specific cost varies depending on the final dosing regimen. myopathy. titrated up gradually to reduce the risk of precipitating myasthenic crisis. proceed with weekly dose reductions at intervals of 2. up to a goal of 60 mg daily. to try to minimize long-term adverse effects. glaucoma. Low cost. Doses should be given only once per day in the morning. and every 2 days increase the dose by an additional 10 mg. Sudden withdrawal could lead to hypoadrenergic crisis. Sometimes the final dosing regimen is administered every other day.5 mg.

No large randomized study has been performed to investigate the use of cholinesterase inhibitors in MG. but the response in observational studies is substantial and obviates the need for further investigation [13]. It requires monitoring of blood counts and liver function. Section Editor) cations may be used as an adjunctive therapy to immunosuppression with corticosteroids or as an alternative first-line therapy. Doses need to be adjusted for renal failure. The advantage of cholinesterase inhibitors is that they are fast-acting. but this is seldom seen in clinical practice. The maximum dose is generally determined by adverse effects. Some physicians start azathioprine when steroid doses cannot be successfully lowered to a satisfactory level. Azathioprine can be used in combination with prednisone as a steroid-sparing agent. azathioprine is used without steroid. and others start azathioprine at the same time that steroids are initiated. diarrhea. lymphopenia. Pyridostigmine is usually started at 60 mg three times daily and can be titrated to higher doses. Pyridostigmine is often better tolerated than neostigmine. and muscle twitches or cramps. There is risk of hepatotoxicity. These are relatively inexpensive and are available as generics. High doses theoretically could cause cholinergic crisis. These include abdominal cramps. Standard dosage Contraindications Main drug interactions Main side effects . Neostigmine is usually started at 15 mg three times per day and can be similarly titrated. sweating. It acts on proliferating lymphocytes and induces both B-cell and T-cell lymphopenia [14]. Blood analysis should be performed at baseline and rechecked after 1 month and then every 6 months. Angiotensin-converting enzyme (ACE) inhibitors increase the risk of pancytopenia. and pancytopenia. Cholinesterase inhibitors should be avoided when there is gastrointestinal obstruction. and free from long-term adverse effects. The combination of prednisone and azathioprine can allow the use of lower doses of prednisone. Standard dosage Contraindications Main drug interactions Main side effects Special points Cost Azathioprine Azathioprine is a purine analogue that inhibits nucleic acid synthesis. Bradycardia is also a relative contraindication. and it has been found to be as effective as prednisone alone. Allopurinol increases levels of azathioprine. Opioids and beta-blockers may increase the risk of bradycardia. as well as some concern about increased risk of malignancies. Azathioprine affects levels of warfarin. Class II]. or it may even extend the remission period longer than prednisone alone [14. safe. Azathioprine is a pregnancy category D drug. Typically begin at 50 mg per day and increase the dose by 50 mg per day at weekly intervals until reaching a target of 2 to 3 mg/kg per day. The gastrointestinal effects can sometimes be overcome with diphenoxylate-atropine. Occasionally.106 Neurologic Ophthalmology and Otology (RK Shin. with the decision depending on potential contraindications to steroid therapy and on patient and physician preferences. nausea. Flu-like symptoms may occur at initiation. increased secretions. Cholinergic side effects are common. bradycardia. Pyridostigmine and neostigmine are both pregnancy category C drugs.

500 mg twice daily. 90 tablets of 50 mg cost about $90. 120 tablets of 500 mg cost about $1. The effectiveness of this treatment varies considerably. 18–22]. and the maximal effect occurs at 6 to 24 months after beginning treatment [16].Treatment of Ocular Myasthenia Gravis Haines and Thurtell 107 Special points There have been reports of effectively using lower doses of azathioprine. Class III]. There is a delay in therapeutic response. This is a pregnancy category D medication. with a goal between 1. Cost Mycophenolate mofetil Mycophenolate is metabolized in the liver to its active form. naphazoline was also reported to be effective for ptosis due to MG [17. such as 50 mg per day [15. with 70% of patients studied considering it to be useful. mycophenolic acid. Class IV]. Standard dosage Contraindications Main drug interactions Main side effects Special points Cost Naphazoline When ptosis is the only symptom of MG or when it is the only residual symptom after systemic therapy. Acute angle-closure glaucoma is a consideration.05% used as needed every 3 or 4 h. Recently. Mycophenolate has a shorter time until clinical benefit than azathioprine. topical treatment can be considered. through stimulation of Mueller’s muscle. Generic formulations are available and it can be obtained without a prescription.000 mg twice daily. 0. Renal failure is a relative contraindication. Gastrointestinal effects are common. Begin at 500 mg twice daily for 4 weeks and then increase the dose to 1. No significant interactions have been reported. which inhibits nucleic acid synthesis and preferentially inhibits replication of B lymphocytes and T lymphocytes [14]. Bone marrow suppression is a rare but serious adverse effect. It has previously been reported to be effective for improving ptosis in Horner’s syndrome. Naphazoline could cause central nervous system depression in very young children. but many are rarely used for ocular MG: – Cyclosporine – Tacrolimus – Cyclophosphamide – Rituximab . as the combination could lead to bone marrow suppression. This medication should not be used in combination with other immunosuppressants such as azathioprine.000 and 1.200. Standard dosage Contraindications Main drug interactions Main side effects Special points Cost Other treatments & A number of other treatments are available for the treatment of MG [1. Naphazoline is an alpha-2 agonist that is commonly used for red eye.

Depending on the ocular deviation. The most common eyelid elevation surgeries are external levator advancements and frontalis slings. This elective intervention is contraindicated for any patient with a high risk of surgical morbidity. Strabismus surgery is relatively benign. it should be removed [12]. extraocular muscle tendons are lengthened or shortened to change the mechanical advantage of the extraocular muscles. If a thymoma is detected. this type of procedure is performed only when the ocular deviation appears to be stable over a period of at least 6 months [25]. and worsening of diplopia Adjustable sutures are advisable. (Thymoma associated with MG is considered to have a more favorable prognosis than thymoma not associated with MG [23. Thymectomy Standard procedure Contraindications Complications Strabismus surgery Strabismus surgery can be used to minimize ocular misalignment causing diplopia. Patients with MG should be evaluated for thymoma. Eyelid surgery is relatively benign. but bleeding disorders and immune suppression are relative contraindications. stable ptosis [26]. 16]. bronchopneumonia. but there is evidence that purely ocular MG may not benefit from thymectomy [10. but bleeding disorders and immune suppression are relative contraindications. strabismus surgery to correct ocular misalignment in certain cases. sternum instability. Standard procedure Contraindications . Wound healing disorders. Thymectomy can be performed by full or partial sternotomy or by transcervical or thoracoscopic approaches. Infection. Strabismus surgery is more difficult in patients who have had previous strabismus surgery. to allow for correction of eye position.108 Neurologic Ophthalmology and Otology (RK Shin. Section Editor) – – – – Methotrexate Etanercept Intravenous immunoglobulin Plasmapheresis Surgery & Surgical options can include thymectomy (used as a nonpharmacologic treatment to modify the course of disease in MG). and eyelid surgery to correct ptosis. Generally. patients should be cautioned about the high risk of failure. ocular ischemia.) Thymectomy also can be considered in nonthymomatous MG. 24]. Standard procedure Contraindications Complications Special points Eyelid elevation surgery Surgical eyelid elevation can be an option for medically refractory. Given the variability of MG. and phrenic nerve damage.

Prisms are also ineffective when there is significant variability of the diplopia. Mechanical support is an effective treatment for ptosis. occlusive devices. diplopia was successfully treated by fitting the patient with contact lens monovision [28. Monovision is an option used for presbyopic patients: one eye is given a prescription for distance viewing and the other eye has a different prescription for reading. Very low cost. Special points Cost Prisms Usage Prisms can be an effective solution for patients with stable ocular misalignment. Prolonged eyelid support can result in exposure keratopathy. and eyelid support should not be used by patients with altered eye sensation or impaired level of consciousness. A need for repeat surgery is not uncommon (2 of 16 patients in one study) [26. but they can be used in several ways [27]. Contact lenses can even be made with small vertical prism power (up to 4 prism diopters).Treatment of Ocular Myasthenia Gravis Haines and Thurtell 109 Complications Special points Infections and exposure keratopathy Given the variability of MG. Generally very low cost. Applying semitransparent tape (such as Scotch tape or Micropore medical tape (3M)) provides sufficient blur to effectively occlude one eye. Fresnel prisms cost about $20 Special points Cost Contact lenses Usage Contact lenses are not often considered in the management of diplopia. or tape can be used to elevate the lids. They can successfully occlude by fogging one eye with unneeded spherical power or with an opaque optical center. It is useful to determine the better-seeing or dominant eye and to occlude the other eye. when the deviation is not too great. In one case. eyeglass prisms. Class IV]. patients should be cautioned about the high risk of failure. but custom eyeglasses can vary greatly. Patches are commonly used. Prisms are not effective when there is a torsional component to the diplopia. . or prisms can be ground into the prescription lens. It is sometimes difficult to find optical shops that can accommodate eyelid crutch requests. or one lens of eyeglasses may be fogged. Eyelid supports Usage Special points Cost Occlusive device Usage The simplest solution to diplopia is to cover one eye. Assistive devices & Nonpharmacologic methods to correct diplopia and ptosis include eyelid supports. Class III]. and contact lenses. Prisms are available as a Fresnel stick-on for regular glasses. Eyelid crutches can be fitted into glasses.

This nucleotide is stable for oral administration. who account for 10% to 15% of cases. this therapy effectively improved muscle strength in 14 of 16 patients [30]. Clinical development for treatment of MG is ongoing in the UK [22]. The labor and cost of this treatment were the evident disadvantages [29. Children younger than 10 years of age need to be monitored especially closely because of the potential to develop amblyopia [32]. Juvenile MG should not be confused with congenital MG. which is soluble in the synaptic cleft and not tethered to the postsynaptic membrane. or neonatal MG. Spontaneous remission is more likely to occur in juvenile MG than in adult MG [31]. using plasmapheresis and high-dose intravenous steroids followed by lowdose oral steroids for maintenance. Similar to adults. Antisense therapy MG has been shown to be associated with expression of a less typical isoform of the acetylcholinesterase enzyme (AchE-R). Pediatric considerations & & & & & MG is relatively uncommon among the pediatric population. unlike the typical isoform (AchE-S). 10% to 15% of patients with juvenile MG will have only ocular symptoms. Custom contact lenses are more expensive than most of the assistive devices listed above. Emerging therapies Early aggressive therapy A strategy of early aggressive treatment has been investigated. In early studies. which is caused by exposure to maternal antibodies in utero. which is caused by genetic mutations. EN101 (Monarsen) is an antisense oligonucleotide that blocks conversion of RNA into the AchE-R protein. Disclosure No potential conflicts of interest relevant to this article were reported. Class II]. Section Editor) Special points Cost The use of contact lenses is a particularly good option for patients who are already accustomed to wearing them.110 Neurologic Ophthalmology and Otology (RK Shin. This strategy allowed for lower doses of maintenance oral steroids and decreased chronic steroid complications. .

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