Treatment of Ocular Myasthenia Gravis

Abstract

Myasthenia gravis is a relatively common neuromuscular disorder, with ocular myasthenia gravis being a subset defined as myasthenia 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 immunoglobulin, plasmapheresis, thymectomy, lid crutches, ptosis surgery, 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.

In 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 essentially 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 myasthenia 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) anticholinesterase therapy, primarily pyridostigmine; 4) oral immunosuppressive therapy: prednisone, azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine, tacrolimus; 5) intravenous immunoglobulin (IVIG); 6) plasmapheresis; 7) surgical therapy in the form of thymectomy; 8) monoclonal antibody therapy: eculizumab and rituximab; and 9) surgical therapy in the form of ptosis surgery and/or eye muscle surgery. We will review who would qualify for each therapy and a stepwise protocol to using therapy.

TREATMENT OPTIONS

On rare occasion patients with OMG will have either episodic symptoms (ie, a few weeks a year) or very intermittent symptoms, 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 patient 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 simple tape. Although not used commonly these can provide symptom 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 patching. 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 recommend 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 symptoms 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 glycopyrrolate 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 pyridostigmine. 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 success. Success is defined by the patient being happy with reduction of symptoms. Some patients require elimination of all symptoms, but others are happy with a partial reduction in symptoms. In general, in 2 to 4 weeks the success or failure of pyridostigmine can be determined.

Oral immunosuppressive therapy is the next step in treatment 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 immunosuppressive therapy (prednisone, mycophenolate mofetil, cyclosporine, 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 prednisone include wide availability, low cost, well-known side effect profile with significant experience in use in multiple other conditions, 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 typically 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 immunosuppressive 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. Disadvantages include long time to onset.¹¹ Cyclosporine, cyclophosphamide, 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 patient along with the practitioner's experience with the drugs must be taken into account.

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 plasmapheresis 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 thymectomy 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 patients 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 surgeon experienced in operating on patients with OMG can be successful 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 measurements 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 patients. A great number of questions remain in elucidating the best treatment for OMG. Perhaps the first question is, how do we measure 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 effective in OMG but no consensus on dosing regimens with prednisone, 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 additional knowledge in our goal of treating this disabling disease.