Low-Density Lipoprotein Receptor-Related Protein 4-Positive Myasthenia Gravis in a Double-Seronegative, Electromyography-Negative Patient

We describe a patient with ocular myasthenia gravis, where single-fiber electromyography and testing for acetylcholine receptor and muscle-specific kinase antibodies were negative. However, antibodies to low-density lipoprotein receptor-related protein 4 (LRP4) were positive, and this prompted appropriate management. We recommend that testing for LRP4 antibodies be considered when the clinical suspicion for myasthenia gravis is high despite negative conventional diagnostic tests.

Clinical Observation Low-Density Lipoprotein Receptor-Related Protein 4-Positive Myasthenia Gravis in a Double-Seronegative, Electromyography-Negative Patient Joshua M. Kruger, MD, PhD, Dimitrios Karussis, MD, PhD, Paraskevi Zisimopoulou, PhD, Panayiota Petrou, MD Abstract: We describe a patient with ocular myasthenia gravis, where single-fiber electromyography and testing for acetylcholine receptor and muscle-specific kinase antibodies were negative. However, antibodies to low-density lipoprotein receptor-related protein 4 (LRP4) were positive, and this prompted appropriate management. We recommend that testing for LRP4 antibodies be considered when the clinical suspicion for myasthenia gravis is high despite negative conventional diagnostic tests. Journal of Neuro-Ophthalmology 2017;37:285-286 doi: 10.1097/WNO.0000000000000499 © 2017 by North American Neuro-Ophthalmology Society T he diagnosis of ocular myasthenia gravis can be challenging because of the limited sensitivity of serological testing and other diseases that can have a similar clinical presentation (1). We describe a patient who presented with ptosis and diplopia. Single-fiber electromyography (EMG) and acetylcholine receptor and muscle-specific kinase (MuSK) antibodies were all negative. Antibodies to (LRP4), however, were positive establishing the correct diagnosis of ocular myasthenia gravis. Department of Ophthalmology (JMK), Hadassah Medical Center, Kiryat Hadassah, Jerusalem, Israel; Neuroimmunology and Cell Therapy Unit (DK, PP), Neurology Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; and Department of Neurobiology (PZ), Hellenic Pasteur Institute, Greece and Tzartos NeuroDiagnostics, Athens, Greece. P. Zisimopoulou is coinventor in a patent related to myasthenia gravis therapy and diagnosis, and is an employee of Tzartos Neurodiagnostics. The remaining authors report no conflicts of interest. Address correspondence to Joshua M. Kruger, MD, PhD, Department of Ophthalmology, Hadassah Medical Center, Kiryat Hadassah, PO Box 12000, Jerusalem, 91120, Israel; E-mail: dr.joshua.kruger@ gmail.com Kruger et al: J Neuro-Ophthalmol 2017; 37: 285-286 CASE REPORT A 46-year-old man with a history of insulin-dependent diabetes mellitus, hypertension, and hypercholesterolemia developed headaches, left ptosis, and diplopia. Examination revealed limited adduction, elevation, and depression of the left eye and bilateral abduction weakness. There was no anisocoria. Computed tomography (CT) angiography and MRI of the brain were unremarkable, as were orbital studies with CT and MRI. Lumbar puncture was significant for only mildly elevated protein of 772 mg/L (normal range 150-450 mg/ L). Chest CT showed no evidence of thymoma. An edrophonium test demonstrated improvement in left ptosis. Empiric treatment with IV methylprednisolone was associated with clinical improvement but was discontinued because of difficulty in managing his diabetes mellitus. Treatment with pyridostigmine provided limited benefit in low doses, but higher doses were not tolerated by the patient because of persistent diarrhea and excessive salivation. The diagnosis of myasthenia gravis was doubted when single-fiber EMG of the frontalis and testing for antibodies against acetylcholine receptor and MuSK were negative. Results were positive for antibodies against thyroid peroxidase (217 IU/mL; normal range 0-35 IU/mL) and thyroglobulin (126 IU/mL; normal range 0-40 IU/mL). With discontinuing pyridostigmine, the patient's symptoms worsened, particularly muscle fatigue and diplopia. Treatment with plasmapheresis was initiated with dramatic improvement in ptosis, diplopia, and muscle weakness. Testing for antibodies against LRP4 was positive (moderate-strong signal on cellbased assay) (2). Treatment with azathioprine was initiated, with improvement in left ptosis and minimal intermittent diplopia with full extraocular movements. DISCUSSION A substantial proportion of patients with myasthenia gravis have no detectable antibodies to acetylcholine receptor or 285 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation MuSK (double seronegative), particularly when they present with only ocular symptoms or mild systemic disease (3,4). A subgroup of these patients who were seronegative have been identified as having antibodies to LRP4 (4,5). Zhang et al (6) detected anti-LRP4 antibodies in 9.2% of patients with myasthenia who were double seronegative. Our case is particularly notable because the single-fiber EMG study also was negative. Single-fiber EMG of the frontalis is highly sensitive for ocular myasthenia gravis, but false negatives do occur. Testing of the orbicularis oculi muscles increases sensitivity (6,7). Without a firm diagnosis, the decision to treat with immunosuppression was delayed in our patient. However, because of a high clinical suspicion for myasthenia gravis, we proceeded with testing for LRP4. Similar to MuSK, LRP4 is a membrane protein responsible for clustering of the acetylcholine receptor (8). Zisimpoulou et al (2) detected LRP4 autoantibodies in 18.7% of 635 patients with double-seronegative myasthenia gravis, whereas the autoantibody was undetectable in 56 healthy controls. The presence of antibodies to thyroglobulin and thyroid peroxidase in our patient raised the suspicion of thyroid eye disease. However, orbital imaging showed no evidence of enlarged extraocular muscles, and the presence of ptosis (vs lid retraction) did not support that diagnosis. In addition, approximately 11% of the general population carries autoantibodies against thyroglobulin (9); up to 25% of normal individuals have autoantibodies against thyroid peroxidase (10). In addition, patients with myasthenia gravis are more likely to have antithyroid antibodies (11). We recommend that testing for LRP4 antibodies be considered when the clinical suspicion for myasthenia gravis is high despite negative conventional diagnostic tests. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. M. Kruger, D. Karussis, P. Zisimopoulou, and P. Petrou; b. Acquisition of data: J. M. Kruger, D. Karussis, P. Zisimopoulou, and P. Petrou; c. Analysis and interpretation of data: J. M. Kruger, D. Karussis, P. Zisimopoulou, and P. Petrou. Category 2: a. Drafting the manuscript: J. M. Kruger, 286 D. Karussis, P. Zisimopoulou, and P. Petrou; b. Revising it for intellectual content: J. M. Kruger, D. Karussis, P. Zisimopoulou, and P. Petrou. Category 3: a. 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