Lambert-Eaton Myasthenia Syndrome Initial Presentation Mimicking Myasthenia Gravis

The neuromuscular junction disorders myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) both present with muscle weakness but usually have clinical features that distinguish the 2 disorders (1-3).

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Lambert‒Eaton Myasthenia Syndrome Initial Presentation Mimicking Myasthenia Gravis So Yeon Uhm, BS, Huy Nguyen, MD, Kunal P. Kanakia, MD, John E. Carter, MD T he neuromuscular junction disorders myasthenia gravis (MG) and Lambert‒Eaton myasthenic syndrome (LEMS) both present with muscle weakness but usually have clinical features that distinguish the 2 disorders (1– 3). We present a case demonstrating unique features in that isolated ocular manifestations led to an initial diagnosis of ocular MG that seemed to be confirmed by also showing a response to ice pack testing and pyridostigmine treatment, however, was later confirmed to be a case of LEMS with positive voltage-gated calcium channel (VGCC) antibodies and characteristic electromyogram (EMG) findings. We highlight a scenario where pyridostigmine was selected over the usual medication, 3,4-diaminopyridine, for the treatment of LEMS symptoms (4,5). In addition, we highlight the diagnostic utility of chest computed tomography (CT) because both diseases have different chest-associated neoplasms (6,7). CASE REPORT A 62-year-old man presented with 5 months of intermittent but progressively more frequent horizontal and vertical diplopia producing imbalance and a gait disturbance. Two weeks before presentation, he noticed that the intermittent double vision was worst with leftward gaze and left eye drooping and became more persistent as the day progressed. He also had left upper and left lower-extremity numbness and 15-pound weight loss. The patient had a history of 70 pack-year tobacco use and cervical degenerative disease. Initial examination showed the following left eye abnormalities: near complete abduction deficit (see Supplemental Digital Content 1, Video E1, http://links.lww. com/WNO/A491), impaired spontaneous blink (see SuppleDepartments of Ophthalmology (HN, JEC), University of Texas Health Science Center at San Antonio, San Antonio, Texas; Departments of Neurology (KPK, JEC), University of Texas Health Science Center at San Antonio, San Antonio, Texas; the Joe R. and Teresa Lozano Long School of Medicine (SU), San Antonio, Texas. mental Digital Contents 2 and 3, Video E2,E3, http://links. lww.com/WNO/A492, http://links.lww.com/WNO/A493), and brow ptosis (see Supplemental Digital Content 3, Video E3, http://links.lww.com/WNO/A493). There was also a low amplitude and low frequency nystagmoid movement of both eyes in the primary position (see Supplemental Digital Content 3, Video E3, http://links.lww.com/WNO/A493). Left orbicularis oculi showed marked fatigability with sustained upgaze (see Supplemental Digital Content 4, Video E4, http://links.lww.com/WNO/A494). Left brow ptosis and weakened voluntary eyelid closure was partially reversible by a brief interval of relaxed eye closure. A 2-minute ice pack test demonstrated subjective improvement of diplopia in primary gaze. Pupillary and intraocular examination findings were normal. A general neurologic examination result was normal except for decreased left-sided extremity sensation to soft touch and pinprick. The patient had normal strength and intact deep tendon reflexes. He received a working diagnosis of MG because of variation of ocular symptoms and improvement of diplopia after the ice pack test. Extremity numbness was attributed to previously diagnosed radiculopathy from degenerative disk disease. Although antiacetylcholine receptor (antiAChR) antibodies were sent (binding, blocking, and modulating), the patient was started on pyridostigmine 30 mg 3 times daily that led to symptomatic improvement of diplopia. The patient underwent chest CT to evaluate for thymic hyperplasia or mass and was found instead to have large necrotic hilar lymph nodes that were highly suspicious for malignancy. Ultrasound-guided endobronchial biopsy yielded small-cell lung carcinoma with characteristic immunohistochemical staining (CD56, AE1/AE3, TTF-1, synaptophysin, chromogranin, and Ki-67) (8). The small-cell carcinoma of the lungs raised concern for LEMS. An EMG showed characteristic neuromuscular potentiation after exercise. Serum antibodies against P/Q VGCC eventually proved to be positive while binding, blocking, and modulating anti-AChR antibodies were negative. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Huy Nguyen, MD, Department of Ophthalmology, University of Texas Health Science Center of San Antonio, 7703 Floyd Curl Drive—MSC 6230, San Antonio, TX 78229-3900; E-mail: [e-mail] Uhm et al: J Neuro-Ophthalmol 2023; 43: e47-e49 DISCUSSION Lambert‒Eaton myasthenic syndrome and MG are both characterized by muscle weakness from acquired autoantibodies against neuromuscular junction targets (presynaptic voltage-gated calcium channels in LEMS and postsynaptic AChR in MG). However, the distribution of weakness at e47 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence initial presentation and at the point of maximum disease severity is usually distinct. In MG, 50% of patients present with ocular symptoms and signs, 15% with bulbar symptoms and signs, and only 5% present solely with limb weakness with the remainder showing a mixture of muscular symptoms and signs. Conversely, LEMS usually presents with symmetric weakness of proximal limb weakness, predominantly in the lower extremities. The patient’s asymmetrical left-sided decreased sensation is therefore better explained by radiculopathy due to degenerative disk disease than LEMS. Ocular involvement as a presenting sign of LEMS is rare, although disease course may progress to include ocular weakness. Even at the point of maximal disease severity, purely ocular involvement without limb weakness is rare. In addition, the pattern of diurnal variation differs between the 2 conditions. Patients with LEMS experience peak muscle weakness in the morning that progressively improves through the day with exercise, whereas the opposite is true for patients with MG (9). This is reflected by EMG findings that show potentiation of compound muscle action potential (CMAP) with exercise or high frequency (10–50 Hz) repetitive nerve stimulation (RNS) in LEMS, whereas the opposite finding is seen with MG. A increase in CMAP amplitude of 60%–100% after RNS or isometric exercise is strongly suggestive of presynaptic neuromuscular junction disorder (10). Our patient showed symptoms and signs of ocular involvement at initial presentation. Initial manifestations mimicked MG with fatigable ocular muscle weakness presenting as brow ptosis and diplopia. Weakness in the extremities was not present, which does not fit the common initial presentation of LEMS. The ice pack test is used frequently as a quick, noninvasive method of evaluating the blepharoptosis and diplopia in MG, with reported sensitivity of 70%– 96% and specificity of 88%–98.3% (11,12). Our patient with LEMS had subjective improvement of diplopia after ice pack application for 2 minutes. There are few case reports that describe response to ice packs in LEMS (13). Our patient also demonstrated improvement in his diplopia with pyridostigmine monotherapy before chemotherapy was initiated. Pyridostigmine is reported not to be efficacious as monotherapy nor synergistic with the established treatment with 3,4-diaminopyridine in LEMS. He remained on pyridostigmine monotherapy even after LEMS was diagnosed because of subjective response and to avoid known side effects of hepatotoxicity and seizure exacerbation. His chemotherapy regiment placed him at risk for hepatoxicity, and he demonstrated new onset seizure-like activity later in his course, thus establishing a scenario where pyridostigmine was preferred over the standard treatment in terms of risk and benefits. Other immunosuppressive therapy options were not used because they are reserved for refractive or nonneoplastic cases and there is little evidence to suggest e48 their efficacy (3,4). Although the patient’s response to ice pack testing and pyridostigmine is unexpected for LEMS, nerve conduction studies (NCSs) and serum studies were diagnostic. Our hospital policy only allows for testing of anti-MUSK after binding, blocking, and modulating anti-AChR results are negative, but EMG/NCS had already yielded diagnostic results by that point. The ocular presentation, response to MG therapy in combination with LEMS serology, and NCS results may indicate the presence of myasthenia gravis Lambert‒Eaton overlap syndrome, but the existence of this syndrome is debated (3,14). Up to 70% of MG have thymus hyperplasia and 15% thymoma, whereas 60% of LEMS have a paraneoplastic disorder most commonly in association with small-cell lung carcinoma (2,15). Both neoplastic associations are detected with chest CT with high sensitivity and specificity (16,17). Our case demonstrates how chest CT evaluation for MG thymic involvement serves dual purpose in also evaluating for cancer-associated LEMS in someone with an extensive smoking history. STATEMENT OF AUTHORSHIP Conception and design: H. Nguyen; Acquisition of data: H. Nguyen; Analysis and interpretation of data: H. Nguyen, K. P. Kanakia. Drafting the manuscript: H. Nguyen, K. P. Kanakia, S. Uhm; Revising it for intellectual content: H. Nguyen, K. P. Kanakia, J. E. Carter. Final approval of the completed manuscript: H. Nguyen, K. Kanakia, S. Uhm, and J. E. Carter. REFERENCES 1. Nicolle MW. Myasthenia gravis and lambert-eaton myasthenic syndrome. Contin Lifelong Learn Neurol. 2016;22:1978–2005. 2. Schoser B, Eymard B, Datt J, Mantegazza R. Lambert–Eaton myasthenic syndrome (LEMS): a rare autoimmune presynaptic disorder often associated with cancer. J Neurol. 2017;264:1854–1863. 3. Oh SJ. Myasthenia gravis Lambert-Eaton overlap syndrome. Muscle Nerve. 2016;53:20–26. 4. 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