Journal of Neuro-Ophthalmology, December 2003, Volume 23, Issue 4

Immunotherapy of Ocular Myasthenia Gravis Reduces Conversion to Generalized Myasthenia Gravis

BACKGROUND: Several retrospective studies have suggested that immunotherapy, including prednisolone, azathioprine and thymectomy, reduces progression of ocular myasthenia gravis to generalized myasthenia gravis. This study examines the effect of immunotherapy on generalization rates in ocular myasthenia patients who are acetylcholine receptor (AChR) antibody-positive. METHODS: Retrospective record review of 34 patients from three university-based hospitals with neurology and neuro-ophthalmology services in Australia. In all patients, positive AChR antibodies were recorded, the initial symptoms were purely ocular, and all had at least 2 years of follow-up. The patients who developed generalized myasthenia gravis were compared with those who remained purely ocular. RESULTS: There were 21 patients who developed generalized myasthenia gravis. Of these 21, only 2 (9.5%) had received prior immunotherapy. Among the 13 patients whose symptoms remained purely ocular, 10 (76.9%) had received prior immunotherapy. CONCLUSIONS: In this study, most of the patients who progressed from ocular myasthenia to generalized myasthenia had not received prior immunotherapy. This study adds weight to the call for a prospective trial of early immunotherapy in patients with ocular myasthenia.

ORIGINAL CONTRIBUTION Immunotherapy of Ocular Myasthenia Gravis Reduces Conversion to Generalized Myasthenia Gravis JaredMee, MB, BS, Mark Paine, MB, BS, Edward Byrne, MD, DSC, John King, MB, BS, Katrina Rear don, MB, BS, PhD, and Justin O ' Day, MB, BS Abstract Background: Several retrospective studies have sug­gested that immunotherapy, including prednisolone, aza-thioprine and thymectomy, reduces progression of ocular myasthenia gravis to generalized myasthenia gravis. This study examines the effect of immunotherapy on generaliza­tion rates in ocular myasthenia patients who are acetylcho­line receptor ( AChR) antibody- positive. Methods: Retrospective record review of 34 patients from three university- based hospitals with neurology and neuro-ophthalmology services in Australia. In all patients, posi­tive AChR antibodies were recorded, the initial symptoms were purely ocular, and all had at least 2 years of follow- up. The patients who developed generalized myasthenia gravis were compared with those who remained purely ocular. Results: There were 21 patients who developed general­ized myasthenia gravis. Of these 21, only 2 ( 9.5%) had re­ceived prior immunotherapy. Among the 13 patients whose symptoms remained purely ocular, 10 ( 76.9%) had received prior immunotherapy. Conclusions: In this study, most of the patients who pro­gressed from ocular myasthenia to generalized myasthenia had not received prior immunotherapy. This study adds weight to the call for a prospective trial of early immuno­therapy in patients with ocular myasthenia. ( JNeuro- Ophthalmol 2003; 23: 251- 255) yasthenia gravis is an autoimmune condition in which antibodies to the acetylcholine receptor ( AChR) cause weakness of somatic musculature. In ocular myasthenia, the weakness is limited to the extraocular, levator, and orbicularis oculi muscles. Progression to gen­eralized myasthenia occurs in about 50%>, usually within 2 From the Royal Victorian Eye and Ear Hospital ( JM, MP, JK, JO), and St Vincent's Hospital ( MP, EB, KR), Melbourne, Australia Address correspondence to Justin O'Day, MB BS, FRANZCO, Level 1, 55 Victoria Pde, Fitzroy, Melbourne, Australia, 3065; E- mail: JustinODay@ bigpond. com or 3 years ( 1,2). Ocular myasthenia is treated according to symptoms with pyridostigmine and immunotherapies such as prednisolone, azathioprine, and thymectomy. Predniso­lone and azathioprine doses are minimized to limit side ef­fects. Thymectomy is used to treat younger patients with thymic enlargement noted on computed tomography ( CT). Studies by Sommer et al ( 3) and Kupersmith et al ( 4) suggest that immunotherapy may reduce the risk of gener­alization in ocular myasthenia. Studies of ocular myasthe­nia can, however, be compromised by vague diagnostic cri­teria in seronegative patients, inadequate follow- up times, or selection bias from the inclusion of patients presenting with many years of purely ocular symptoms. In this study, we reviewed 34 AchR- positive patients to find the effect of immunotherapy on generalization. METHODS Patients were identified from a central database of AChR antibody tests. Ethical approval was obtained from all three involved hospitals to access the AChR database and to view medical records with consent from the patient. All patients had been examined by neurologists or neuro-ophthalmologists between January 1990 and January 2002. Most patients had presented between 1998 and 2002. Using the AChR database and medical records, we found 44 patients who were AchR- positive on first or sub­sequent testing and whose initial symptoms were purely ocular. We excluded four patients who had less than 2 years of follow- up from their initial symptoms, to reduce selec­tion bias, three patients who had more than 2 years of ocular symptoms before their first presentation were also ex­cluded. Three patients were excluded because it could not be determined whether they had received significant immu­notherapy. One excluded patient had only 1 month of pred­nisolone and the other two patients had developed systemic myasthenia at 3 and 6 months post- thymectomy, given that this procedure generally takes 6 months to 3 years to have its effect. The treatment approach of different physicians varied slightly. The general approach was to treat first with an an­ticholinesterase and then introduce prednisolone 25mg Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. J Neuro- Ophthalmol, Vol. 23, No. 4, 2003 251 JNeuro- Ophthalmol, Vol. 23, No. 4, 2003 Mee et al daily if the symptoms were troublesome. If the predniso­lone could not be tapered over the following months, then azathioprine might be prescribed. Videoscopic thymec­tomy was considered in patients with an enlarged thymus onCT. Generalization was determined from the patient records, based on the opinion of the treating neurologists or neuro- ophthalmologists. Antibodies to AChR were measured by radioimmu­noassay according to the method of Vincent and Newsom- Davis ( 5). The source of antigen was receptor protein from cell line TE671, a subline of the rhabdomyosarcoma cell line. TE671- sourced AChR receptors labeled with I125 Al­pha bungarotoxin were incubated with patient specimens and then immunoprecipitated with anti- human IgG. After centrifugation, the labeled AChRautoantibody- bound com­plex was counted in a gamma counter. RESULTS Patient Characteristics There were 34 AChR - positive patients with only ocular myasthenic manifestations on initial evaluation. These included diplopia or ptosis that were diurnal or worse after exercise, weak orbicularis oculi function with fatiga­bility, and Cogan's lid twitch. Age at onset ranged from 18 to 87 years and averaged 55.1 years. Nineteen patients were male and 15 were female. Three patients had concomitant thyroid disease. Twenty- three patients underwent single-fiber electromyography ( SFEMG) of orbicularis oculi, frontalis, or extensor digitorum communis; 16 ( 70%) of these tests were positive. Of 21 patients who underwent in­travenous edrophonium chloride ( Tensilon) testing, 18 ( 86%) were positive. All five patients who underwent the ice test were positive. Two AChR- positive patients had clinical features of ocular myasthenia but negative Tensilon and SFEMG tests. The patients were divided into two groups. The first group contained 21 patients who progressed to generalized myasthenia (" generalized group"); the second group con­tained 13 patients whose manifestations remained purely ocular at final follow- up (" ocular group"). The two patient groups were compared ( Table 1). There were 11 men and 10 women in the generalized group, and 8 men and 5 women in the ocular group. The time from initial symptoms to first presentation was 7.90 ± 7.85 months in the generalized group and 5.58 ± 7.13 months in the ocular group. Follow-up time was 50.38 ± 43.18 months in the generalized group and 50.61 ± 33.84 months in the ocular group. Age at onset averaged 48.62 ± 18.42 years in the generalized group and 65.46 ± 12 in the ocular group. This difference in age was statistically significant ( t- test, P. = 0 .0029). AChR anti­body titer averaged 51.65 in the generalized group and TABLE 1. Comparison of generalized and ocular myasthenic patient groups Generalized Ocular Received immunotherapy No prior immunotherapy Average age ( years) Male/ female Prior symptom duration* ( months) Follow- up time** ( months) Average AChR titer 2 19 49 1/ 10 7.9 50.4 51.6 10 3 65 8/ 5 5.6 50.6 50.9 * The average time from symptom onset to first presentation. ** The average time from symptom onset to last follow- up appointment. 50.87 in the ocular group. SFEMG tests were positive more frequently in the generalized group ( 12/ 16, or 75%) than in the ocular group ( 4/ 8, or 50%). This difference was not sta­tistically significant ( P = 0.36, Fisher exact test). Treatment Characteristics There were 21 patients who progressed from ocular to generalized myasthenia; only 2 ( 9.5%) of these patients had received immunotherapy prior to generalizing ( Fig. 1). One patient generalized 15 months after thymectomy and the other 14 months after being started on treatment with pred­nisolone. The remaining 19 patients had received pyrido­stigmine or no treatment prior to generalization ( Table 2). Ten ( 76.9%) of the 13 patients who remained purely ocular had received immunotherapy ( Fig. 1). All 10 had re­ceived prednisolone. The maximum dose received was Generali/. ed Purely Ocular Outcomes FIGURE 1. Outcomes in 34 patients with acetylcholine re­ceptor antibody- positive myasthenia gravis presenting with purely ocular manifestations. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 252 © 2003 Lippincott Williams & Wilkins Ocular Myasthenia: Immunotherapy Reduces Generalization JNeuro- Ophthalmol, Vol. 23, No. 4, 2003 TABLE 2. Age/ gender 77/ M 58/ M 47/ M 59/ F 31/ F 45/ M 66/ M 50/ M 70/ M 18/ F 74/ M 39/ F 62/ M 44/ F 20/ M 20/ F 59/ M 21/ M 50/ F 45/ F 66/ F Patients who progressed to generalized myasthenia. Clinical features and treatment Symptom duration* ( months) 16 4 8 1 4 12 7 24 2 1 1 6 2 6 2 24 4 12 24 5 1 AChR** 46 6.9 47 47 110 91 69 8 92 22 71 77 3.6 4 93 140 4.4 8.4 70 74 0.4 Pyridostigmine therapy No Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No No No No No No Adverse effects Immunotherapy o f therapy Prednisolone Cushing's Thymectomy Time to generalization ( months) 24 23 8 40 20 22 8 29 18 7 31 1 3 6 55 12 3 12 21 59 5 Follow- up ( months) 30 24 23 183 64 122 24 64 73 8 36 32 9 41 60 82 4 62 26 84 7 * From initial symptoms to first presentation. ** Acetylcholinesterase Receptor Antibody titer. 25mg/ d for eight. The other two patients had had a maxi­mum dose of 15mg/ d and 3 7. 5mg/ d. The treatment duration ranged from 1 to 92 months ( average 33.5 months) and 9 patients had received more than 12 months of treatment. The patient who received only 1 month of predmsolone had been treated with azathioprine for 5 months and underwent thymectomy for thymoma soon after initial presentation. Four other patients also received azathioprine and two un­derwent thymectomy ( Table 3). Three patients in the ocular group received no immunotherapy at all. The difference between the proportion of those who generalized after receiving immunotherapy versus no im­munotherapy was statistically significant ( PE = 0.00011, Fisher exact test) ( 6). Overall, 61.8% of the patients devel­oped generalized myasthenia gravis. Of those who general­ized, 76% did so by 2 years. The generalized manifestations developed from 1 to 59 months after the initial ocular mani­festations ( average 19.4 ± 16.3 months). Adverse treatment effects were noted in four patients. Two patients developed a Cushingoid appearance, one de­veloped diabetes, and another became obese. DISCUSSION We have studied 34 AchR- positive patients with over 2 years' follow- up and less than 2 years of ocular myas­thenic manifestations prior to presentation. Of 21 who gen­eralized, only 2 ( 9.5% i) had received immunotherapy prior to generalization. By comparison, of the 13 who remained ocular, 10 ( 76.9% o) had received immunotherapy. The gen­eralized and ( purely) ocular groups were similar in duration of symptoms prior to first presentation, and in follow up times. The ocular group was, on average, 15 years older. This may suggest that older patients are less likely to gen­eralize. However, previous authors have found no associa­tion between age of onset and generalization ( 3,7). In one study, patients aged over 50 years actually had a higher risk of generalization and respiratory crisis ( 8). This is opposite to the trend in our study. Some retrospective studies have indicated that immu­notherapy might lower the rate of generalization, but the evidence is inconclusive. Kupersmith et al ( 4) treated 32 ocular myasthenia patients with prednisolone and found that only 9%> generalized. Most patients presented within a Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 253 JNeuro- Ophthalmol, Vol. 23, No. 4, 2003 Mee et al TABLE 3 Age/ gender 56/ M 51/ F 74/ M 53/ M 66/ M 87/ F 67/ M 63/ F 87/ F 59/ M 74/ M 55/ M 59/ F . Patients who did not progress to generalized myasthenia Symptom duration ( months)* 5 12 1 24 < 1 < 1 5 2 3 12 1 2 < 1 AChR*" 81 200 14 90 55 27 17 65 5.6 5.8 39 26 36 Prednisolone dose ' range ( mg) 5- 25 6- 25 2- 20 None 15 None 11- 25 2- 25 None 1- 25 10- 37 5- 25 12- 25 Duration of prednisolone therapy ( months) 43 14 92 1 50 36 31 21 18 29 ( ocular group). Clinical features Adverse effects of prednisone therapy Cushing's obesity None None None None None None None diabetes Duration of azathioprine therapy ( months) 5 27 18 46 24 and treatment Thymectomy ( months) 1 32 4 Follow- up ( months) 49 24 153 26 33 67 56 48 40 52 24 57 29 * From initial symptoms to first presentation. ** Acetylcholinesterase Receptor Antibody titer. *** Time from initial symptoms to thymectomy. few months of symptom onset and all had at least 2 years' follow- up. Only 10 of 28 were seropositive and 3 lof 32 had a positive Tensilon test. Sommer et al ( 3) reviewed 78 ocu­lar myasthenics. Among 50 patients receiving immuno­therapy, only 12% generalized, whereas among 28 patients who had not received immunotherapy, 64% generalized. The diagnoses were made an average of 40 months after symptom onset, so that this study may have selected late-presenting patients who were unlikely to generalize. In the Sommer et al ( 3 study, there was no analysis of the differ­ences between the groups. Schumm et al ( 9) performed thymectomy on 18 ocular myasthenics at an average of 40 months after symptom onset. All improved, three achieved full remission, and none generalized. However, at 40 months from symptom onset, few ocular myasthenics would be expected to generalize even without treatment. Immunosuppressants were used in parallel and may have contributed to the results. Oosterhuis ( 10) reviewed patients managed from 1925 to 1965 without immunotherapy and found that 69% developed generalized myasthenia. This is a higher rate than in more recent studies of patients who do receive immunotherapy; for example, Sommer et al ( 3) found a 31% conversion rate. Early immunotherapy might be expected to prevent generalization of ocular myasthenia. Prednisolone has been shown to increase the incidence of remission and symptomatic improvement. ( 2) Myasthenia is an autoim­mune condition and prednisolone suppresses antibody production ( 11) and specifically T lymphocyte responses ( 12). In a study of over 750 ocular myasthenics, Grob et al ( 2) found that 66% of the patients developed generalized disease. Of the patients whose symptoms were purely ocu­lar after 1 year, 84% remained purely ocular. Perhaps early immunotherapy in the first 1 to 2 years might get patients through this period without having them generalize. It may be time for a prospective trial of early prednis­olone use or thymectomy to prevent generalization of ocu­lar myasthenia. Such a trial will expose patients to increased treatment side effects and risks, so existing studies need to indicate a likely benefit to the patient. A prospective trial would also require definite diagnoses in all patients. The existing retrospective studies are few in number and weakened by the inclusion of patients presenting with several years of purely ocular symptoms who are therefore unlikely to generalize no matter what treatment they re­ceive. If follow- up times are short or unstated, patients may be counted as having remained ocular yet generalize after the study period has ended. Another weakness of the existing studies is the inclu­sion of many seronegative patients, some of whom may not have myasthenia. The lack of a gold standard diagnos­tic test makes it difficult to get a definite diagnosis in AChR- negative ocular myasthenia patients. The Tensilon test and SFEMG are not entirely specific for myasthenia ( 13,14,15). Depending on what diagnostic criteria are used, Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 254 © 2003 Lippincott Williams & Wilkins Ocular Myasthenia: Immunotherapy Reduces Generalization JNeuro- Ophthalmol, Vol. 23, No. 4, 2003 studies with a large proportion of seronegative patients are likely to contain varying numbers of patients with the wrong diagnosis and this will influence the quoted general­ization rates. If AChR antibodies, which are highly specific ( 99%) for myasthenia ( 13,16) are present, then the diagno­sis is fairly certain. The strengths of our study are that the diagnosis of ocular myasthenia is fairly certain in all patients and that latency times from symptom onset to presentation and fol­low- up times are appropriate and comparable in the two pa­tient groups. However, the study has the inherent weak­nesses of a retrospective review. The age difference be­tween the two groups may also be a confounding factor. 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