Comitant Ocular Deviation in Myasthenia Gravis

Occurrence of comitant ocular deviation in myasthenia gravis (MG) is not well described.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Comitant Ocular Deviation in Myasthenia Gravis Tiffany Pike-Lee, MD, Jeremy Hill, MD, Jianbo Li, PhD, Gregory S. Kosmorsky, DO, Yuebing Li, MD, PhD Background: Occurrence of comitant ocular deviation in myasthenia gravis (MG) is not well described. Methods: A retrospective analysis of patients with ocular or generalized MG evaluated at a neuro-ophthalmology clinic for a 6-year period. Comitant ocular deviation was defined as magnitude of deviations in all planes varying by ,20% from the measurement in the primary position. Results: Among the 120 patients included, 89 patients had ocular and 31 patients generalized MG. At the initial strabismus testing, comitant ocular deviation was present in 27 (22.5%) patients. Among the 16 patients who had a follow-up, ocular deviation remained comitant in 6 patients and converted to incomitant or no ocular deviation in 10 patients. An additional 7 patients demonstrated comitant ocular deviation at follow-up. Brain MRI was performed in 18 patients with comitant ocular deviation, and none showed abnormalities in the brainstem or cerebellum. Conclusion: Comitant ocular deviation can be an ocular manifestation of MG. Its presence does not necessarily indicate a central etiology in patients with MG neither excluding a MG diagnosis. Journal of Neuro-Ophthalmology 2021;41:e619–e621 doi: 10.1097/WNO.0000000000001056 © 2020 by North American Neuro-Ophthalmology Society O cular deviation (strabismus) is often classified as being comitant or incomitant based on its variation with the gaze position. Incomitant ocular deviation is present when the degree of deviation changes with directions of gaze. Classical etiologies for incomitant ocular deviation include cranial nerve mononeuropathy, neuromuscular junctional disorder, ocular myopathy, or orbital structural anomalies. A comitant ocular deviation is equal in all gaze directions Neuromuscular Center (TP-L, JH, YL), Neurological Institute, Cleveland Clinic Foundation, Cleveland, Ohio; Department of Quantitative Health Sciences (JL), Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; and Cole Eye Institute (GSK), Cleveland Clinic Foundation, Cleveland, Ohio. The authors report no conflicts of interest. Address correspondence to Yuebing Li, MD, PhD, Neuromuscular Center, Desk S90, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; E-mail: [e-mail] Pike-Lee et al: J Neuro-Ophthalmol 2021; 41: e619-e621 regardless of the eye used for fixation and is usually observed in congenital or acquired disorders of the brainstem or cerebellum (1–3). Double vision due to ocular deviation is one of the most common presentations in myasthenia gravis (MG) secondary only to ptosis (4). The intrinsic properties of extraocular muscles render them to high risk for neuromuscular junction transmission dysfunction (4). It is traditionally believed that MG is associated with incomitant ocular deviation. Occurrence of comitant ocular deviation in MG is not well established, thus the focus of our study. Because a comitant deviation might exclude the possibility of MG for some practitioners, it is helpful to know that this possibility exists so as not to automatically reject the MG diagnosis in favor of other possibilities known to be associated with comitant deviation. METHODS The study was approved by our institutional review board. All patients carrying a diagnosis of ocular or generalized MG who were evaluated at the neuro-ophthalmology clinic at our institution between 2012 and 2017 were screened. MG diagnoses were confirmed by antibody measurement, edrophonium testing, electrophysiological studies, or treatment responses. All patients had strabismus examination by neuro-ophthalmologists. Patients without detailed motility examination were excluded. Comitant ocular deviation was defined as magnitude of deviations in all horizontal and vertical planes varying by ,20%, and incomitant ocular deviation was defined when deviation varied by $20% (Fig. 1). Data on demographics, results from the first and last strabismus examinations, antibody status, and brain imaging findings were collected. Results are given as means for continuous variables and percentages and counts for categorical variables. For continuous variables, 3-group comparisons were made using the Kruskal– Wallis rank sum test and when significant then using the Wilcoxon rank sum test for pairwise comparisons. e619 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Examples of comitant (A) and incomitant (B) ocular deviation in 2 patients with myasthenia gravis. Measurement of ocular deviations at 9 different gaze positions are shown. RHT, right hypertropia. For categorical variables, the Fisher exact test was used for both 3-group comparisons and when significant then pairwise comparisons. RESULTS A total of 167 patients were initially reviewed, and 47 patients were excluded because of incomplete data. Among the 120 patients included in the final evaluation, 55 were women. The mean age at the time of neuro-ophthalmology examination was 63.7 years old (range: 26–87 years). Thirty one (25.8%) had generalized MG and 89 (74.2%) ocular. The diagnosis of MG were made based on positivity of the following testing: acetylcholine receptor (AChR) antibody (N = 78), muscle-specific tyrosine kinase antibody (N = 1), single-fiber electromyography (N = 37), repetitive nerve stimulation (N = 1), edrophonium testing (N = 2), or clinical course including treatment responses (N = 1). Seventyfour (61.7%) patients were MG-treatment naïve at the initial visit. At the initial strabismus testing, comitant ocular deviation was present in 27 (22.5%) patients and 18 (67%) of whom were treatment naive. Incomitant ocular deviation was seen in 28 (23.3%) patients 23 (82%) of whom were treatment naive. No ocular deviation was seen in 65 (54.2%) patients and 33 (51%) of whom were treatment naive. Ptosis was present in 51 (42.5%) patients. Table 1 lists several important features of the 3 patient subgroups. No significant difference was observed between subgroups of patients with comitant and incomitant ocular deviations. When compared with the subgroup of patients with comitant or incomitant ocular deviations, the subgroup of patients with no ocular deviations have a longer disease duration and are more likely to be seropositive for AChR antibodies. A total of 74 (61.7%) patients had follow-up neuroophthalmologic evaluation with strabismus testing, with a mean follow-up period of 11.4 months (range: 0–60 months). The ocular deviation at the initial and final follow-up visits was compared for all 74 patients. Among the 16 patients initially presenting with comitant ocular deviation, ocular deviation remained comitant in 6 patients, converted to incomitant ocular deviation in 3 patients, and improved to no deviation in 7 patients. In 18 patients initially presenting with incomitant ocular deviation, ocular deviation remained incomitant in 7 patients, converted to comitant in 4 patients, and improved to no deviation in 7 patients. In the remaining 40 patients with no ocular deviation, incomitant deviation developed in 4 patients and comitant deviation in 3 patients. Brain MRI was performed in 18 of 34 (52.9%) patients with comitant ocular deviation at the initial presentation and during the course, revealing no abnormalities in the brainstem or the cerebellum, except that a small vestibular schwannoma was observed in 1 patient. In all patients with TABLE 1. Comparison of patients with comitant, incomitant, and no ocular deviations at the initial examination Features Female sex (%) Ocular MG (%) Duration #12 months (%) AChR antibody (+) (%) Ptosis (%) Comitant (N = 27) 11 21 19 17 10 (41) (78) (70) (63) (37) Incomitant (N = 28) 16 21 20 12 15 (57) (75) (71) (43) (54) No Ocular Deviations (N = 65) 28 46 28 49 26 (43) (71) (43)* (75)† (40) *P ,0.05 when comparing with comitant and incomitant subgroups. † P , 0.01 when comparing with the incomitant subgroup. AChR, acetylcholine receptor; MG, myasthenia gravis. e620 Pike-Lee et al: J Neuro-Ophthalmol 2021; 41: e619-e621 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution comitant ocular deviation, MG remains the final diagnosis, and the only diagnosis accounting for the occurrence of ocular deviation. DISCUSSION Extraocular muscle weakness with symptoms of ptosis and double vision are the initial manifestation in approximately 75% of patients with MG and eventually appear in more than 90% patients (4). The typical ocular findings of MG are asymmetric ptosis and/or ocular deviation with variability throughout the day. Cranial nerve palsies of 3, 4, and 6 have characteristic patterns enabling differentiation. When such characteristic patterns are present, the diagnosis of MG is easily suspected and readily diagnosed through confirmatory testing. A pattern of variable incomitant ocular deviation is usually observed in MG. Only 1 patient with MG with comitant ocular deviation was previously described (5). Our report is the first in revealing the frequent presence of comitant ocular deviation in approximately a quarter of patients with MG with ocular presentations. Our data also suggest that ocular deviation in MG can evolve interchangeably from being comitant to being incomitant or vice versa or improving to no deviation. The conversion between comitant, incomitant, and no ocular deviation could be related to MG disease evolution or treatment effect. More than half of the patients with comitant ocular deviation underwent brain imaging, with no abnormalities found in the majority, indicating a coexisting central nervous system disorder is unlikely the explanation for the presence of ocular comitance. At follow-up, MG diagnoses remained the only explanation for ocular deviation in all patients with comitant ocular deviation. It has been stated that ocular deviation in MG may present with any combination of muscle involvement, ranging from individual muscle palsy to complete external ophthalmoplegia. Ocular MG may mimic extraocular nerve palsies or a variety of central disorders of ocular motility such as unilateral or bilateral internuclear ophthalmoplegia, one-and-a-half syndrome, double elevator palsy, or divergence or convergence insufficiency (6–8). Hypermetric saccades and supernormal saccadic velocities have been observed in MG, perhaps because of increased central compensatory impulses to overcome peripheral weakness (9). Ocular symptoms in MG results from the combination of muscle weakness and central adaptive mechanisms (10,11). Our speculation is that the comitant ocular deviation is likely a result of central adaption (spread of comitance) in MG in response to peripheral weakness. Given the retrospective nature of this study, there were a few limitations to consider, including nonstandardized MG treatment before initial strabismus testing and lack of follow-up strabismus testing in some patients. In addition, Pike-Lee et al: J Neuro-Ophthalmol 2021; 41: e619-e621 we cannot totally exclude the presence of a previously unrecognized small-angle misalignment as the cause of ocular comitance in the portion of patients with MG who had comitant deviation throughout the course. In these instances, the evolving nature of ocular deviation would be a valuable clue to investigate for an MG diagnosis. In conclusion, the presence of a comitant ocular deviation does not necessarily indicate a central etiology in MG nor does it exclude an MG diagnosis. Neuroimaging studies should be considered to exclude an intracranial lesion in those with comitant deviation as disorders such as multiple sclerosis, brainstem lesions, and other pathologies are in the differential diagnosis. However, should neuroimaging be normal, the diagnosis of MG should be entertained in patients with comitant ocular deviation? STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: T. Pike-Lee, G. Kosmorsky, and Y. Li; b. Acquisition of data: T. Pike-Lee, J. Hill, and Y. Li; c. Analysis and interpretation of data: T. Pike-Lee, J. Li, G. Kosmorsky, and Y. Li. Category 2: a. Drafting the manuscript: T. Pike-Lee and Y. Li; b. Revising it for intellectual content: G. Kosmorsky and Y. Li. Category 3: a. Final approval of the completed manuscript: Y. Li. REFERENCES 1. Borchert MS. Principles and techniques of the examination of ocular motility and alignment. In: Miller NR, Newman NJ, Biousse V, Kerrison JB, eds. Walsh & Hoyt’s Clinical NeuroOphthalmology, 6th Edition. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:887–905. 2. Martin TJ, Corbett JJ. Examination of the visual motor system. In: Martin TJ, Corbett JJ, eds. Practical Neuroophthalmology. New York, NY: McGraw-Hill, 2013:185–200. 3. Wray SH. The extraocular muscles and diplopia. In: Wray SH, ed. Eye Movement Disorders in Clinical Practice. New York, NY: Oxford University Press; 2014:124–161. 4. Barton JJ, Fouladvand M. Ocular aspects of myasthenia gravis. Semin Neurol. 2000;20:7–20. 5. Colavito J, Cooper J, Ciuffreda KJ. Non-ptotic ocular myasthenia gravis: a common presentation of an uncommon disease. Optometry. 2005;76:363–375. 6. Acers TE. Ocular myasthenia gravis mimicking pseudointernuclear ophthalmoplegia and variable esotropia. Am J Ophthalmol. 1979;88(3 pt 1):319–321. 7. Lepore FE. Divergence paresis: a nonlocalizing cause of diplopia. J Neuroophthalmol. 1999;19:242–245. 8. Bandini F, Faga D, Simonetti S. Ocular myasthenia mimicking a one-and-a-half syndrome. J Neuroophthalmol. 2001;21:210– 211. 9. Oohira A, Goto K, Sato Y. Saccades of supernormal velocity: adaptive response to ophthalmoplegia in a patient with myasthenia gravis. Neuroophthalmol. 1987;7:203–209. 10. Schmidt D, Dell’osso LF, Abel LA, Daroff RB. Myasthenia gravis: saccadic eye movement waveforms. Exp Neurol. 1980;68:346–364. 11. Kaminski HJ, Maas E, Spiegel P, Ruff RL. Why are eye muscles frequently involved in myasthenia gravis? Neurology. 1990;40:1663–1669. e621 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.