Lambert-Eaton Myasthenic Syndrome: Ocular Signs and Symptoms

The demographic associations among patients presenting with myasthenia gravis with only ocular manifestations (OMG) is not clear.; ; In this 5-center case series, we collected the race, gender, and age at diagnosis of patients diagnosed with myasthenia gravis who had no signs or symptoms of generalized myasthenia gravis (GMG). An a priori sample size calculation determined that 140 patients were required to accept that there was a ≤10-year difference in mean age (equivalence testing: power 90%, α = 0.05). Robust Bayesian analysis and linear regression were applied to evaluate whether age differed by gender or race.; ; Of 433 patients included, 258 (60%) were men. Mean age among men was 57 years (SD = 19) and 52 years (SD = 21) among women. The 95% credible interval (CI) (Bayesian equivalent of confidence interval) was 0.8-8.7 years for mean age, and there was a 99.6% probability that the mean difference in age between sexes was <10 years. Race was documented in 376 (68 [18%] non-Caucasian). Caucasians were 17.3 years older than non-Caucasians at diagnosis (95% CI, 12.2-22.3 y; P < 0.001) controlling for gender. There was no additive interaction of gender and race (P = 0.74). There was a bimodal distribution for women peaking around 30 and 60 years. Men had a left skewed unimodal age distribution peaking at age 70.; ; The distribution of age at presentation in patients with OMG is different between men and women, similar to GMG. Non-Caucasian patients tend to develop OMG at a younger age.

Original Contribution Lambert-Eaton Myasthenic Syndrome: Ocular Signs and Symptoms Jeffery D. Young, MD, Jacqueline A. Leavitt, MD Background: To evaluate ocular signs and symptoms in Lambert-Eaton myasthenic syndrome (LEMS) and determine the frequency of ophthalmic involvement. Methods: A retrospective review of the medical records of all patients diagnosed with LEMS at the Mayo Clinic in Rochester, MN, from January, 1976, to December, 2010, was performed with special attention to ophthalmic symptoms and signs. Results: One hundred seventy-six patients met the inclusion criteria. Ophthalmic symptoms included ptosis in 41 (23%), diplopia in 36 (20.5%), decreased vision in 24 (14%), and dry eye complaints in 12 (7%). Ophthalmic signs included ptosis in 45 (26%), abnormal ocular motility in 15 (8.5%), strabismus in 14 (8%), pupillary dysfunction in 12 (7%), and findings consistent with dry eyes in 4 (2%). Conclusions: A significant number of patients reported ophthalmic symptoms, and many had objective findings on clinical examination consistent with these symptoms. To our knowledge, this is the largest case series of ophthalmic findings in patients with LEMS and indicates that these patients warrant a complete ophthalmic examination. Journal of Neuro-Ophthalmology 2016;36:20-22 doi: 10.1097/WNO.0000000000000258 © 2015 by North American Neuro-Ophthalmology Society T he first known case of myasthenic syndrome in association with lung cancer was published by Anderson Department of Surgery (JDY), Division of Ophthalmology, University of Vermont College of Medicine, Burlington, Vermont; and Department of Ophthalmology (JAL), Mayo Foundation, Mayo Clinic, Rochester, Minnesota. Supported in part by an unrestricted grant from Research to Prevent Blindness, New York and The Robert R. Waller Career Development Award. The authors report no conflicts of interest. This study was reviewed and approved by the Institutional Review Boards of the Mayo Clinic and Olmsted Medical Group. This study was performed in accordance with HIPAA regulations and was in adherence with the tenets of the Declaration of Helsinki. Address correspondence to Jeffery D. Young, MD, University of Vermont Medical Center, 58 E. View Lane, Berlin, VT 05641; E-mail: [e-mail] 20 et al (1) while Lambert et al (2) characterized the electrophysiologic pattern of this syndrome. Further research led to the discovery of the autoantibodies thought to be responsible for the characteristic clinical findings. Lambert-Eaton myasthenic syndrome (LEMS), which includes both paraneoplastic and autoimmune etiologies, commonly involves weakness of the proximal muscles, autonomic symptoms (e.g., decreased sweating and dry mouth), and reduced deep tendon reflexes. Involvement of the visual system is less well characterized. Ophthalmic symptoms, generally mentioned in other studies, have been reported with a prevalence ranging from 0% to 80% (3,4). The aim of our study was to further elucidate the ophthalmic symptoms and findings of LEMS. METHODS The records of all patients with the diagnosis of LEMS from January 1, 1976, to December 31, 2010, were reviewed. Inclusion criteria were clinical features including reduced deep tendon reflexes, autonomic symptoms (dry mouth, constipation, impaired sweating, and impotence), and proximal muscle weakness. In addition, we required a diagnostic electromyography (EMG) (consisting of .10% decrement of compound muscle action potentials at 2 Hz stimulation and facilitation of .100% after brief exercise or 50 Hz stimulation) and/or the presence of voltage-gated calcium channel antibodies, N-type or P/Qtype. Historical information and examination findings were obtained from the medical record. Each patient's record was reviewed with special attention to ophthalmologic and neurologic examination findings. At a minimum, each patient had a neurologic examination, which included a basic eye examination including eyelid position, ocular motility, and pupillary testing. RESULTS The diagnosis of LEMS was mentioned in 241 records, and 176 met our inclusion criteria. Men represented 53.3% of Young and Leavitt: J Neuro-Ophthalmol 2016; 36: 20-22 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution the patients, and mean age at diagnosis was 60.3 years (range: 7-83 years). Malignancy was diagnosed either before diagnosis or during the follow-up period in 79 patients (44.9%), 65 of which were found to have small cell lung carcinoma. Forty-two patients (24%) had an examination by an ophthalmologist at the time of presentation or during the follow-up period (up to 14.5 years). Twenty-five patients (14%) had onset of ophthalmic symptoms coincident with onset of systemic symptoms. Six patients (3%) had ophthalmic symptoms (3 with ptosis, 2 with diplopia, and 1 with decreased/blurred vision) before systemic symptoms. The most common ophthalmic complaints were ptosis and diplopia with 41 patients (23%) and 36 patients (20.5%), respectively. Less frequently, 24 patients (14%) reported decreased vision, and 12 patients had symptoms of dry eye. Ophthalmic signs included ptosis in 45 patients (26%), which was asymmetric in 21 patients. Two patients each had fatigable ptosis and Cogan lid twitch. Motility dysfunction was noted in 15 cases (8.5%). Two patients had generalized decrease in motility, and 2 had eye movements described as dysconjugate. One patient was noted to have slow horizontal saccades, and 1 patient had findings of bilateral adduction weakness. Fourteen cases (8%) had some form of strabismus: esodeviation (4-18 prism diopters), exodeviation (4-10 prism diopters), and hyperdeviation (2-12 prism diopters). Additionally, 2 patients showed signs of convergence insufficiency. Pupillary abnormalities were detected in 12 patients (7%), including 7 with sluggish pupils. Anisocoria was noted in 4. One patient was noted to have Horner syndrome, and another showed hypersensitivity to 0.125% pilocarpine. Clinical signs of dry eye (staining with vital dyes or superficial punctate keratitis) were seen in 4 patients (2%). Because of lack of standardized best-corrected visual acuity data, findings of blurred or decreased vision could not be accurately analyzed. Two patients also were diagnosed with myasthenia gravis (MG). One of these patients had a positive edrophonium test before confirming the diagnosis of LEMS with an EMG. The second patient had acetylcholine receptor binding antibodies detected at the same time of LEMS diagnosis and subsequently had a positive edrophonium test. DISCUSSION Previous studies have shown that eyelid findings in LEMS are quite common with a range of 28%-54% of patients (5-7). Ptosis was the most common finding in our cohort and was generally mild. Brazis (8) identified enhanced ptosis in 1 patient with LEMS. Breen et al (9) reported a case of lid elevation on sustained upgaze and suggested that this may represent facilitation of the levator, similar to the facilitation seen in other muscle groups in LEMS. Young and Leavitt: J Neuro-Ophthalmol 2016; 36: 20-22 Cogan lid twitch seen in 2 of our patients is likely nonspecific (10,11). Abnormalities in eye movements in our patients were generally mild and did not seem to have common pattern. Findings ranged from an isolated functional deficit to dysconjugate eye movements. Using quantitative oculography, Cruciger et al (12) and Dell'Osso et al (13) showed that facilitation can occur in extraocular muscles. Three studies (4-6) comprising 170 patients with LEMS documented ocular motility abnormalities in up to 30% of patients. Individual case reports are rare. Kanzato et al (14) described a 57-year-old man with bilateral ophthalmoparesis sparing abduction in both eyes. Rudnicki (15) reported a 52-year-old woman who noted diplopia on lateral gaze, but a clear description of her eye movements was lacking. Diplopia as a symptom of LEMS has been reported in 21%-52% of patients (4,5,7,16-19). Objective signs of ocular misalignment have been reported to occur in 12%-50% in studies with 227 and 10 patients, respectively (4-7). Our data showed a lower prevalence with objective findings. Krieger and Goldchmit (20) reported 2 patients with isolated medial rectus weakness as the only ocular manifestation of LEMS. Both were successfully treated with strabismus surgery. None of our patients required strabismus surgery to treat their deviation. Pupillary dysfunction in LEMS is an indicator of intraocular autonomic dysfunction. The most common sign of pupillary dysfunction in our study was sluggish pupils. O'Neill et al (5) reported that 6 of their 50 patients had sluggish pupillary light response, and 2 were noted to have postganglionic denervation hypersensitivity with response to dilute cholinergic agonists indicating parasympathetic dysfunction. The patient with LEMS described by Kanzato et al (14) exhibited Horner syndrome with hypersensitivity to alpha agonist drops demonstrating involvement of the sympathetic pupillary pathway. Clark et al (21) prospectively evaluated 13 eyes of patients with LEMS and found evidence of both sympathetic and parasympathetic denervation hypersensitivity in 4 of 7 patients, indicating generalized autonomic dysfunction. They additionally found abnormal pupil cycle time, a nonspecific indicator of pupillary reflex arc dysfunction, in 9 of 13 eyes. Another ocular indicator of autonomic function is ocular surface lubrication. Dry eye is difficult to quantify as some patients exhibiting subjective symptoms have no objective findings on clinical examination. Previous studies indicate that between 4% and 29% of patients complain of symptoms of dry eye (7,17,19). Clark et al (21) prospectively tested the reflex tear production in 7 patients with LEMS (13 eyes) and found that 9 eyes had abnormal results. LEMS and MG may occur in the same patient, and there can be considerable overlap in the clinical eye findings (22-25). The distribution of muscle weakness in LEMS is certainly different from MG; in MG, weakness develops in 21 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution a craniocaudal direction and in the opposite direction in LEMS (3). Although extraocular motor symptoms are more common in MG, autonomic symptoms (specifically pupillary involvement and dry eye) are not a part of the MG symptom complex (26). Our study is limited by its retrospective nature, and most of the patients were examined by a specialist in neurology and not ophthalmology. As a tertiary medical center, the studied patient population may have been biased. Followup was also limited. This is the largest single-institution series of patients with LEMS and to the best of our knowledge, the only large series focusing on ophthalmic symptoms and findings. Patients with LEMS may present with ophthalmic symptoms as part of the initial symptom complex and can very rarely manifest with ophthalmic symptoms before the onset of systemic symptoms (15,27). Titulaer et al (17) showed that ophthalmic findings occur soon after the diagnosis but not necessarily as soon as other symptoms such as proximal weakness. Some of our patients had been followed elsewhere before definitive diagnosis at our institution, resulting in their presentation later in the clinical course. Therefore, we could not further define ocular manifestations based on the chronicity of the disease. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. D. Young and J. A. Leavitt; b. Acquisition of data: J. D. Young; c. Analysis and interpretation of data: J. D. Young. Category 2: a. Drafting the article: J. D. Young; b. Revising it for intellectual content: J. D. Young and J. A. Leavitt. Category 3: a. Final approval of the completed article: J. D. Young and J. A. Leavitt. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. REFERENCES 1. Anderson HJ, Churchill-Davidson HC, Richardson AT. 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