Ocular Myasthenia Treatment Review 2007 PDF

SPECIAL ARTICLE Evidence report: The medical treatment of ocular myasthenia (an evidence-based review) Report of the Quality Standards Subcommittee of the American...

SPECIAL ARTICLE Evidence report: The medical treatment of ocular myasthenia (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology Michael Benatar, ABSTRACT Objective: To perform a systematic review of the relevant literature and to provide MBChB, MS, DPhil evidence-based guidelines for the medical treatment of ocular myasthenia. Methods: Medline, Henry J. Kaminski, EMBASE, and the Cochrane Neuromuscular Disease Group Register were searched for articles of MD, FAAN possible relevance to the medical treatment of ocular myasthenia. The titles and abstracts of all arti- cles, as well as the full texts of all potentially relevant manuscripts, were read by both reviewers. Experts in the field were also contacted to identify other published or unpublished literature. All arti- Address correspondence and reprint requests to the American cles were evaluated using predefined criteria to evaluate their methodologic quality. Data from these Academy of Neurology, 1080 articles were extracted to address two questions: 1) Are there any effective treatments for symptoms Montreal Ave., St. Paul, MN of ocular myasthenia? 2) Are there any treatments that reduce the risk of progression from ocular to 55116 [email protected] generalized myasthenia gravis (MG)? Results: A single randomized controlled trial compared the effi- cacy of intranasal neostigmine to placebo for the treatment of ocular symptoms. Methodologic limita- tions of this study preclude any firm conclusions. A second randomized controlled trial compared the efficacy of corticotropin with placebo, but outcome was reported in terms of a quantification of the range of eye movements. For this reason, the results of the second study could not be used to address the issues of improvement in ocular symptoms or the risk of progression to generalized MG. This review did not identify any randomized controlled trials addressing the risk of progression to general- ized MG but did identify five observational studies reporting the effects of corticosteroids on progres- sion to generalized MG, two of which also reported the effects of azathioprine. Recommendations: The absence of high-quality evidence means that it is not possible to make any evidence-based recommen- dations regarding the effects of cholinesterase inhibitors, corticosteroids, or other immunosuppres- sive agents with respect to improvement of ocular symptoms. There is similarly an absence of evidence regarding the effects of cholinesterase inhibitors on the risk of progression to generalized myasthenia gravis (MG). Based on data from several observational studies, corticosteroids and aza- thioprine are of uncertain benefit in terms of their effect on the risk of progression to generalized MG. NEUROLOGY 2007;68:2144–2149 INTRODUCTION Background and justification. erase inhibitors, blepharoplasty, and lid crutches for Myasthenia gravis (MG) is an uncommon neuro- relief of symptoms as well as immunosuppressive logic disorder with an estimated prevalence of ap- therapy with corticosteroids and/or a range of proximately 5 to 15 per 100,000.1-7 Approximately corticosteroid-sparing immunosuppressive agents 50% of patients present with purely ocular symp- to prevent progression to generalized MG. Oppo- toms (ptosis, diplopia), so-called ocular myasthe- nents of immunosuppressive therapy argue that oc- nia.7,8 Between 50% and 60% of those who present ular myasthenia is not life-threatening and, with purely ocular symptoms will progress to de- therefore, that symptoms may not justify the poten- velop generalized disease,7,8 and the vast majority tial for significant adverse effects associated with will do so within the first 1 to 2 years.7,8 immunosuppressive drugs, that symptoms may be The treatment of ocular myasthenia, with the alleviated via other means such as a lid crutches or goals of alleviating symptoms and preventing pro- eye patching, and that there is little evidence to sup- gression to generalized MG, is a subject of port the use of immunosuppressive therapy either in debate.9-11 Options for treatment include cholinest- terms of permanent relief of ocular symptoms or Supplemental data at www.neurology.org This article was previously published in electronic format as an Expedited E-Pub on April 25, 2007, at www.neurology.org. From the Department of Neurology, Emory University School of Medicine (M.B.), and Department of Neurology, Case Western Reserve University, Louis Stokes Cleveland VA Medical Center (H.J.K.), Cleveland, OH. Approved by the Quality Standards Subcommittee on July 29, 2006; by the Practice Committee on March 15, 2007; and by the AAN Board of Directors on April 5, 2007. Disclosure: The authors report no conflicts of interest. 2144 Copyright © 2007 by AAN Enterprises, Inc. with regard to the risk of progression to generalized server blinding, explicit inclusion/exclusion criteria, disease.9 The proponents of immunosuppressive and completeness of follow-up— using a set of pre- therapy, on the other hand, argue that the symp- defined criteria. The quality of observational toms of ocular myasthenia (diplopia and ptosis) studies was similarly evaluated in three domains— may impair vision sufficiently to interfere with control for confounding, completeness of follow- work and quality of life and that such treatment of- up, and observer blinding— using predefined ten eliminates symptoms. Further, the initial presen- criteria. The method of randomization was graded tation with ocular myasthenia affords the as adequate (computer-generated random numbers, opportunity to intervene therapeutically to reduce tables of random numbers, coin toss), unclear the likelihood of progression to generalized MG.10 (statement made that trial is randomized but method not described), or inadequate (quasi- Clinical questions. Because the primary goals of randomized). Allocation concealment was graded treatment for ocular myasthenia are 1) to alleviate as adequate (identical prenumbered containers pre- the symptoms of ocular myasthenia and 2) to pre- pared by an independent pharmacy of central ran- vent or limit the severity of the generalization of the domization unit or sequentially numbered opaque disease, this review was performed to address these sealed envelopes), unclear (no details given of how two specific questions: the next assignment in the sequence was concealed), 1. Does pharmacologic treatment lead to an im- inadequate (open allocation schedule, unsealed or provement in ocular symptoms (diplopia and nonopaque envelopes, alternation, days of week, ptosis)? etc.), or not done. Patient and observer blinding were graded as adequate (method of blinding de- 2. Is pharmacologic treatment associated with a scribed and thought to be sufficient to ensure that reduced risk of progression from ocular to gen- the investigator was unaware of the treatment re- eralized MG? ceived at the time outcome evaluation was per- The question of the role of thymectomy in the formed), unclear (authors state that study was treatment of ocular myasthenia was not addressed blinded, but details not provided), inadequate by this review given that the general issue of the (some method used to blind investigators, but tech- benefits of thymectomy in MG has been the subject nique was unreliable), or not done. Completeness of of a previous practice parameter.12 follow-up was graded as adequate (analysis per- formed with ⬎80% of patients), unclear (insuffi- Description of the analytical process. Panel selection cient details provided on withdrawals, dropouts, and literature review process. Two neurologists with ex- etc.), inadequate (⬍80% of patients included in the perience in the evaluation and treatment of patients analysis), or not done. Finally, control for con- with MG were appointed by the American Academy founding was graded as adequate (multivariate of Neurology Quality Standards Subcommittee to analysis that included at least two factors—age, du- prepare this review. The Cochrane Neuromuscular ration of ocular symptoms before initiation period Disease Group Register was searched for random- of follow-up, concomitant immunosuppressive ized controlled trials; Medline (1966 to 2004) and therapy, duration of follow-up after entry into the EMBASE (1980 to 2004) were also searched for ran- study, antibody status, presence of abnormalities on domized controlled trials, case– control studies, and repetitive nerve stimulation or single fiber electro- cohort studies. Search terms included myasthenia myography— or data presented showing that the gravis, eye, ocular, and vision, as well as a series of treatment groups were comparable at baseline with terms describing specific therapies and specific types respect to this same set of factors), unclear (authors of clinical studies. To be included in the review, state that they controlled for confounding, but details studies had to meet three criteria: 1) randomized (or not given), inadequate (some effort made to control quasi-randomized) controlled trial or observational for confounding, but insufficient number of relevant (cohort or case– control) study design; 2) active factors were considered in the analysis), or not done. treatment compared with placebo, no treatment, or some other treatment; and 3) results reported sepa- ANALYSIS OF EVIDENCE Are cholinesterase inhib- rately for patients with ocular myasthenia (Grade 1) itors, corticosteroids, or other immunosuppressive as defined by the Myasthenia Gravis Foundation of agents effective in improving visual symptoms in ocu- America.13 Studies reporting outcome in children lar myasthenia? Evidence. Two randomized con- and adults were considered. trolled trials that included patients with ocular The quality of randomized controlled trials was myasthenia were identified.14,15 The methodological evaluated in six domains—method of randomiza- quality and results of these studies are summarized tion, allocation concealment, patient blinding, ob- in table 1 and table E-1 (at www.neurology.org). Neurology 68 June 12, 2007 2145  Table 1 Design characteristics and outcome of randomized controlled trials in ocular myasthenia Follow-up Author Treatment Treatment Method of Allocation Patient Observer duration (year) Class n Participants modality schedule randomization concealment blinding blinding (proportion) RR* (95% CI) Mount II 43 Age and sex ACTH 290 U Unclear Adequate Adequate Adequate 12 months No data for (1964) not reported over 8 (72%) symptomatic days improvement Badrising III 3 Age not Intranasal 4.5 mg Unclear Unclear Unclear Unclear 2 weeks 3 (1996) reported; neostigmine TID (100%) (0.17–53.7) 60% male *Risk ratio (RR) comparing improvement in ocular symptoms amongst those receiving active treatment compared with those receiving control treatment. ACTH ⫽ corticotropin. The first study included 43 patients with ocular my- III).15 No firm conclusions can be drawn from this asthenia who were randomly assigned to receive ei- study given the extremely small sample size (n ⫽ 3) ther an 8-day course of corticotropin or placebo in a and other methodologic limitations of the study. parallel group design (Class II).14 The range of ocu- There are no studies that examined the efficacy of lar movement was determined from projections of pyridostigmine (Mestinon), corticosteroids, or photographic negatives of each eye in different posi- other immunosuppressive agents in improving the tions of gaze. By marking the midpoint of the pupil symptoms of ocular myasthenia. with the eye deviated to the left, to the right, up- Recommendations. Given the absence of evidence, ward, and downward and then connecting these it is not possible to make any evidence-based recom- four points with an elliptical curved line, the investi- mendations regarding the effects of cholinesterase gators estimated the area of eye movement. The ef- inhibitors, corticosteroids, or other immunosup- fectiveness of therapy was determined by pressive agents in improving the symptoms of ocu- comparing the area of eye movement between base- lar myasthenia. line and post-treatment time points (10 days, 1 month, and 3 months). Results were reported sepa- Are cholinesterase inhibitors, corticosteroids, or other immunosuppressive agents effective in reducing the rately for each eye. There was improvement in the risk of progression from ocular to generalized MG? area of movement of 10 of 15 right eyes and 14 of 17 Evidence. Neither of the two randomized con- left eyes among subjects who received corticotro- trolled trials identified by this review reported out- phin. In the placebo-treated patients, there was im- come in terms of the risk of progression to provement in 8 of 14 right eyes and 11 of 16 left eyes. generalized MG. The review did identify five obser- There was no evaluation of ocular symptoms or the vational studies that reported the impact of cortico- risk of progression to generalized disease. Because steroids on the risk of progression from ocular to this study did not report outcome in terms of either generalized MG,16-20 two of which also examined of the two clinical questions this evidence-based re- the effect of azathioprine on the risk of developing port aimed to answer, it was not possible to include generalized MG.17,20 The methodologic quality of the results in this evidence-based report. The second study included only three patients these studies (table 2) was fairly uniform with ade- with ocular myasthenia (and seven patients with quate follow-up in most, and adequate control for generalized myasthenia) who were randomly as- confounding but lack of independent assessment of signed to receive a 2-week course of either intrana- outcome (Class IV). The point estimates of the risk sal neostigmine or placebo in a crossover study ratios and odds ratios in the studies that examined design without a washout period (Class III).15 No the effects of oral corticosteroids showed a benefit primary outcome measure was specified, but the au- in terms of reducing the risk of progression to gener- thors reported that ptosis was improved in one of alized MG in three studies17,18,20 (Class IV), with the the patients during treatment with neostigmine. The confidence interval (CI) spanning unity in two stud- review did not identify any observational studies ies,16,19 only one of which did not show a benefit that reported outcome in terms of improvement in (Class IV)16 (table 2). The two studies that examined ocular symptoms. the effects of azathioprine similarly showed a bene- Conclusions. There is only a single randomized ficial effect on the risk of progression to generalized controlled trial that has examined the question of MG with CIs that did not span unity (Class IV)17,20 whether pharmacotherapy improves symptoms in (table 2). ocular myasthenia. This study compared the effi- Conclusions. There are no randomized controlled cacy of intranasal neostigmine to placebo (Class trials that have examined the efficacy of cholinester- 2146 Neurology 68 June 12, 2007  Table 2 Design characteristics and outcome of observational studies in ocular myasthenia Treatment Control for Completeness Patient OR†/RR‡ Author (year) Class n Participants modality Treatment schedule confounding of follow-up blinding* (95% CI) Papapetropoulos IV 28 Mean age Corticosteroids Gradual titration to Adequate Adequate;100%; Not done 4.3 (2003), case– 49 y (range 60 mg QOD and ⱖ8 y (0.7–25.9) control 15–80); then tapered to 61% male lowest dose required (5–10 mg QOD) Mee (2003), IV 34 Mean age Corticosteroids 25 mg QD (mean Adequate Adequate; Not done 0.02 case–control 55 y (range duration of therapy 100%; mean (0.001–0.16) 18–87); 33.5 months) 4.2 y 56% male Kupersmith IV 147 Mean age Corticosteroids 10 mg QD for 2 Adequate Inadequate; Not done 0.19 (2003), 50 y (range days, 20 mg QD for 64%; mean (0.07–0.54) cohort 2–80); 57% 2 days, dose 3.6 y; range male increased to 50–60 1⁄2–16 y mg QD for 4–5 days, 40 mg QD for 1 week, 30 mg QD for 1 week, 20 mg QD for 1 week, 10 mg/ 20 mg alternating QD for 1 week, dose further reduced by 2.5 mg QD each week Monsul IV 56 Mean age Corticosteroids 40–60 mg QD Adequate Adequate; Not done 0.32 (2004), 53 y; sex tapered to 2.5–10 100% ⱖ2 y (0.1–1.05) cohort not reported mg QD over 3–6 months Sommer IV 78 Mean age Corticosteroids Maximum dose 52 Inadequate Adequate; Not done 0.19 (1997), 51 y (range mg QD (mean 100% (0.08–0.46) cohort 10–84); duration of therapy 49% male 32 months) Mee (2003), IV 34 Mean age Azathioprine Dose not specified Adequate Adequate; Not done 0.04 case–control 55 y (range (mean duration of 100%; mean (0.002–0.72) 18–87); therapy 24 months) 3.6 y 56% male Sommer IV 78 Mean age Azathioprine Maximum dose 145 Inadequate Adequate; Not done 0.27 (1997), 51 y (range mg QD (mean 100% (0.09–0.82) cohort 10–84); duration of therapy 49% male 44 months) *Blinding was not the only factor used to determine whether outcome assessment was regarded as independent (see Appendix 1, Classification of Evidence) †Exposure odds ratio (OR) comparing those progressing to generalized myasthenia gravis (MG) with those who do not progress, where exposure represents treat- ment with corticosteroids or azathioprine (OR reported for case– control studies). ‡Risk ratio (RR) comparing risk of progression to generalized MG amongst those on active rather than control therapy (RR reported for cohort studies). ase inhibitors, corticosteroids, or other immunosup- to the question of whether cholinesterase inhibitors pressive agents in reducing the risk of progression to have any effect in reducing the risk of progression to generalized MG. The available studies that have ex- generalized MG. Recommendations cannot be amined this question are all observational and of made because of an absence of evidence. limited quality (Class IV). Three of the five observa- tional studies that examined the efficacy of cortico- RECOMMENDATIONS FOR FUTURE RESEARCH steroids and both observational studies that There is a need for well-designed, randomized, examined the efficacy of azathioprine suggest that placebo-controlled studies of the efficacy of cho- these agents may be effective in reducing the risk of linesterase inhibitors, corticosteroids, and other im- progression from ocular to generalized MG (Class munosuppressive agents. These studies should use IV). clinically relevant outcome measures such as im- Recommendations. For patients with ocular myas- provement or resolution of ocular symptoms and thenia, the evidence does not support or refute the the risk of progression to generalized MG. These use of corticosteroids and/or azathioprine to reduce studies should carefully document the frequency the risk of progression to generalized MG (Level U). and severity of treatment-related side effects be- The decision to use such agents should be weighed cause this information will be critical to any cost– against the potential for harmful side effects of these benefit analysis of immunosuppressive treatment in medications. Furthermore, it is not possible to make ocular myasthenia. any evidence-based recommendations with regard In the absence of randomized controlled trials, Neurology 68 June 12, 2007 2147  well-designed observational studies may shed light John D. England, MD, FAAN; Gary M. Franklin, MD, MPH on the efficacy of cholinesterase inhibitors, cortico- (ex-officio); Gary H. Friday, MD, MPH, FAAN; Larry B. Gold- stein, MD, FAAN; Deborah Hirtz, MD (ex-officio); Robert G. steroids, and other immunosuppressive agents. Holloway, MD, MPH, FAAN; Donald J. Iverson, MD, FAAN; These studies should adequately control for poten- Leslie A. Morrison, MD; Clifford J. Schostal, MD; David J. tially confounding factors (age, the use of concomi- Thurman, MD, MPH; William J. Weiner, MD, FAAN; Samuel tant therapy, the duration of ocular symptoms Wiebe, MD before entry into the study, the duration of follow-up following entry into the study, antibody APPENDIX 2 status, and the presence of systemic abnormalities AAN classification of therapeutic evidence Class I: Prospective, randomized, controlled clinical trial with of repetitive nerve stimulation or single fiber elec- masked outcome assessment, in a representative population. tromyography), should assess adverse effects, and The following are required: should ensure that the outcome measure is ascer- a) primary outcome(s) clearly defined; b) exclusion/inclu- tained in a blinded fashion to minimize bias. sion criteria clearly defined; c) adequate accounting for drop- outs and cross-overs with numbers sufficiently low to have ACKNOWLEDGMENT minimal potential for bias; d) relevant baseline characteristics This evidence-based report is based, in part, on a Cochrane are presented and substantially equivalent among treatment review performed by the authors. The authors are grateful to groups or there is appropriate statistical adjustment for Christopher Bever, Jr., MD, MBA, FAAN, the QSS facilitator differences. for this project, as well as the other members of the QSS for Class II: Prospective matched group cohort study in a represen- their advice and assistance in the preparation of this report. tative population with masked outcome assessment that meets a– d above OR a RCT in a representative population that lacks MISSION STATEMENT OF QSS one criteria a– d. The Quality Standards Subcommittee (QSS) of the AAN seeks to de- Class III: All other controlled trials (including well-defined nat- velop scientifically sound, clinically relevant Practice Parameters for the ural history controls or patients serving as own controls) in a practice of neurology. Practice Parameters are strategies for patient man- representative population, where outcome is independently as- agement that assist physicians in clinical decision making. A Practice sessed, or independently derived by objective outcome Parameter is one or more specific recommendations based on analysis of measurement.* evidence of a specific clinical problem. These might include diagnosis, Class IV: Evidence from uncontrolled studies, case series, case symptoms, treatment, or procedure evaluation. reports, or expert opinion. *Objective outcome measurement: an outcome measure that is DISCLAIMER unlikely to be affected by an observer’s (patient, treating physi- This statement is provided as an educational service of the American cian, investigator) expectation or bias (e.g., blood tests, admin- Academy of Neurology (AAN). It is based on an assessment of current istrative outcome data). scientific and clinical information. It is not intended to include all possi- ble proper methods of care for a particular neurologic problem or all APPENDIX 3 legitimate criteria for choosing to use a specific procedure. Neither is it Classification of recommendations intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative A ⫽ Established as effective, ineffective, or harmful for the of the patient and the physician caring for the patient, based on all of the given condition in the specified population. (Level A rat- circumstances involved. ing requires at least two consistent Class I studies.) B ⫽ Probably effective, ineffective, or harmful for the given CONFLICT OF INTEREST STATEMENT condition in the specified population. (Level B rating re- The American Academy of Neurology is committed to producing inde- quires at least one Class I study or at least two consistent pendent, critical and truthful clinical practice guidelines (CPGs). Signifi- Class II studies.) cant efforts are made to minimize the potential for conflicts of interest to C ⫽ Possibly effective, ineffective, or harmful for the given influence the recommendations of this CPG. To the extent possible, the condition in the specified population. (Level C rating re- AAN keeps separate those who have a financial stake in the success or quires at least one Class II study or two consistent Class III failure of the products appraised in the CPGs and the developers of the studies.) guidelines. Conflict of interest forms were obtained from all authors and U ⫽ Data inadequate or conflicting; given current knowledge, reviewed by an oversight committee prior to project initiation. AAN treatment is unproven. limits the participation of authors with substantial conflicts of interest. The AAN forbids commercial participation in, or funding of, guideline projects. Drafts of the guideline have been reviewed by at least three Received December 27, 2006. Accepted in final form March 2, AAN committees, a network of neurologists, Neurology peer reviewers, 2007. and representatives from related fields. The AAN Guideline Author Conflict of Interest Policy can be viewed at www.aan.com. With regards REFERENCES to this specific report, all authors have stated that they have nothing to 1. Ferrari G, Lovaste M. Epidemiology of myasthenia gravis disclose. in the province of Trento (northern Italy). Neuroepidemi- ology 1992;11:135–142. APPENDIX 1 2. Phillips LH, Torner JC, Anderson MS, Cox GM. The ep- Quality Standards Subcommittee members: Jacqueline French, idemiology of myasthenia gravis in central and western MD, FAAN (Co-chair); Gary S. Gronseth, MD (Co-chair); Virginia. Neurology 1992;42:1888–1893. Charles E. Argoff, MD; Stephen Ashwal, MD, FAAN (ex- 3. Robertson N, Deans J, Compston D. Myasthenia gravis: a officio); Christopher Bever Jr., MD, MBA, FAAN (facilitator); population based epidemiological study in Cam- 2148 Neurology 68 June 12, 2007  bridgeshire, England. J Neurol Neurosurg Psychiatry clinical research standards. Task Force of the Medical Sci- 1998;65:492–496. entific Advisory Board of the Myasthenia Gravis Founda- 4. Somnier F, Keiding N, Paulson O. Epidemiology of myas- tion of America. Neurology 2000;55:16–23. thenia gravis in Denmark. Arch Neurol 1991;48:733–739. 14. Mount F. Corticotropin in treatment of ocular myasthenia: a 5. Storm-Mathisen A. Epidemiology of myasthenia gravis in controlled clinical trial. Arch Neurol 1964;11:114–124. Norway. Acta Neurol Scand 1984;70:274–284. 15. Badrising U, Brandenburg H, van Hilten J, Brietl P, Wint- 6. Yu Y, Hawkins B, Ip M, Wong V, Woo E. Myasthenia in zen A. Intranasal neostigmine as add-on therapy in myas- Hong Kong Chinese: 1. Epidemiology and adult disease. thenia gravis. J Neurol 1996;243:S59. Acta Neurol Scand 1992;86:113–119. 16. Papapetropoulos TH, Ellul J, Tsibri E. Development of 7. Oosterhuis HJ. The natural course of myasthenia gravis: generalized myasthenia gravis in patients with ocular my- a long term follow-up study. J Neurol Neurosurg Psychi- asthenia gravis. Arch Neurol 2003;60:1491–1492. atry 1989;52:1121–1127. 17. Mee J, Paine M, Byrne E, King J, Reardon K, O’Day J. 8. Bever CT, Aquino AV, Penn AS, Lovelace RE, Rowland Immunotherapy of ocular myasthenia gravis reduces con- LP. Prognosis of ocular myasthenia. Ann Neurol 1983;14: version to generalized myasthenia gravis. J Neurooph- 516–519. thalmol 2003;23:251–255. 9. Kaminski H, Daroff R. Treatment of ocular myasthenia: ste- 18. Kupersmith MJ, Latkany R, Homel P. Development of roids only when compelled. Arch Neurol 2000;57:752–753. generalized disease at 2 years in patients with ocular my- 10. Agius M. Treatment of ocular myasthenia with cortico- asthenia gravis. Arch Neurol 2003;60:243–248. steroids: yes. Arch Neurol 2000;57:750–751. 19. Monsul NT, Patwa HS, Knorr AM, Lesser RL, Goldstein 11. Hachinski V. Treatment of ocular myasthenia. Arch Neu- JM. The effect of prednisone on the progression from oc- rol 2000;57:753. ular to generalized myasthenia gravis. J Neurol Sci 2004; 12. Gronseth G, Baroh R. Practice parameter: thymectomy 217:131–133. for autoimmune myasthenia gravis (an evidence-based re- 20. Sommer N, Sigg B, Melms A, Weller M, Schepelmann K, view). Neurology 2000;55:636–643. Herzau V, et al. Ocular myasthenia gravis: response to 13. Jaretzki A, Barohn R, Ernstoff R, Kaminski H, Keesey J, long-term immunosuppressant treatment. J Neurol Neu- Penn A, et al. Myasthenia gravis: recommendations for rosurg Psychiatry 1997;62:156–162. Neurology 68 June 12, 2007 2149