Clinical Reasoning: Two Patients Presenting with Neuropathic Pain in Lower limbs

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Evaluating an In-House Cell-Based Assay for Detecting Antibodies Against Muscle-Specific Tyrosine Kinase in Myasthenia Gravis

Background and purpose: Detecting antibodies against muscle-specific tyrosine kinase (MuSK Abs) is essential for diagnosing myasthenia gravis (MG). We applied an in-house cell-based assay (CBA) to detect MuSK Abs. Methods: A stable cell line was generated using a lentiviral vector, which allowed the expression of MuSK tagged with green fluorescent protein in human embryonic kidney 293 (HEK293) cells. Serum and anti-human IgG antibody conjugated with red fluorescence were added. The presence of MuSK Abs was determined based on the fluorescence intensity and their colocalization in fluorescence microscopy. Totals of 218 serum samples collected from 177 patients with MG, 31 with other neuromuscular diseases, and 10 healthy controls were analyzed. The CBA results were compared with those of a radioimmunoprecipitation assay (RIPA) and an enzyme-linked immunosorbent assay (ELISA). Results: The MuSK-HEK293 cell line stably expressed MuSK protein. The CBA detected MuSK Abs in 34 (19.2%) of 177 samples obtained from patients with MG and in none of the participants having other neuromuscular diseases or in the healthy controls. The clinical characteristics of the patients with MuSK MG determined based on the CBA were strongly correlated with known clinical features of MuSK MG. There was an almost perfect agreement between the results of the CBA and those of the RIPA (Cohen's kappa=0.880, p<0.001) and ELISA (Cohen's kappa=0.982, p<0.001). Conclusions: The results of the in-house CBA showed excellent agreement with both the RIPA and ELISA. Our in-house CBA can be considered a reliable method for detecting MuSK Abs.ope

Safety and Temporal Pattern of the Lymphocyte Count During Fingolimod Therapy in Patients With Multiple Sclerosis: Real-World Korean Experience

Background and purpose: Fingolimod (FTY) inhibits lymphocyte egress from lymphoid organs to cause lymphopenia, but the clinical implications of FTY-induced lymphopenia are not fully understood. We aimed to determine the frequency and severity of lymphopenia during FTY treatment among Korean patients with multiple sclerosis (MS), and its association with infections. Methods: We retrospectively reviewed the medical records of patients with MS treated using FTY from 12 referral centers in South Korea between March 2013 and June 2021. Patients were classified according to their nadir absolute lymphocyte count (ALC) during treatment: grade 1, 800-999/µL; grade 2, 500-799/µL; grade 3, 200-499/µL; and grade 4, <200/µL. Results: FTY treatment was administered to 69 patients with a median duration of 18 months (range=1-169 months), with 11 patients being treated for ≥7 years. During FTY treatment, mean ALCs were reduced after the first month (653.0±268.9/µL, mean±standard deviation) (p<0.0001) and remained low during treatment lasting up to 84 months. During follow-up, 41 (59.4%) and 7 (10.1%) patients developed grade-3 and grade-4 lymphopenia, respectively. No significant difference was found in age at FTY initiation, sex, baseline ALC, body mass index, or prior disease-modifying treatment between patients with and without grade-4 lymphopenia. Infections were observed in 11 (15.9%) patients, and the frequencies of patients with and without grade-4 lymphopenia were similar. Conclusions: FTY treatment induced grade-4 lymphopenia in 10% of South Korean patients with MS, but did not appear to be associated with an increased infection risk.ope

Autoantibody Testing in Neuromuscular Disorders

Autoantibodies are present in many autoimmune disorders, including diseases impacting the peripheral nerve, neuromuscular junction, and muscle. Some of these autoantibodies play a vital role in pathogenesis, whereas others are unlikely to be directly pathogenic, but may be useful biomarkers. The identification of autoantibodies is valuable in diagnosis, as well as in establishing a treatment plan in antibody-mediated neuromuscular disorders. This review briefly summarizes antibody, autoantibody, and methods of autoantibody testing for clinicians who treat patients with neuromuscular disorders.ope

Clinical Classification and Scales for Myasthenia Gravis

The variable predominance of the affected muscle groups and the fluctuating severity and extent of myasthenia gravis (MG) makes it difficult to assess and classify these patients. With new treatments being developed and applied, it has become more important to properly classify MG patients and objectively evaluate the results of treatment. So far, a number of clinical classification and assessment systems have been proposed and used individually. However, for the comparative analysis, a uniform set of classifications and reliable measurement methods of muscle impairment are necessary. In this article, MG-clinical classification and several MG-specific assessment tools that are widely used are mentioned.ope

Traumatic Basilar Artery Dissection with Acute Pontine Infarction

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Anti-titin antibody is associated with more frequent hospitalization to manage thymoma-associated myasthenia gravis

Background and purpose: Anti-titin antibodies are antistriational antibodies associated with thymoma-associated myasthenia gravis (MG). We evaluated whether the patients with anti-titin antibody are more frequently hospitalized to manage thymoma-associated MG than those patients without anti-titin antibody. Methods: Patients with thymoma-associated MG who conducted the serological test for anti-titin antibody were retrospectively included. Disease severity, treatments, MG-related annual hospitalization rate, and MG-related emergency room (ER) visit rate were compared between the patients with anti-titin antibody and those patients without anti-titin antibody. Multivariate analysis was conducted to analyze the association between anti-titin antibody serostatus and multiple admissions (hospitalization or ER visit of ≥2 times). Results: Of the 64 included patients, 31 (48.4%) patients were positive for anti-titin antibody (titin+ group) and 33 (51.6%) patients were negative for anti-titin antibody (titin- group). Both the annual rate of MG-related hospitalization and ER visit were significantly higher in the titin+ group [0.2 (0.1-0.6) and 0.1 (0-0.2) per year, respectively] than those in the titin- group [0 (0-0.2) and 0 (0-0) per year, p = 0.004 and p = 0.006, respectively]. In multivariate analysis, positive anti-titin antibody was still significantly associated with multiple admissions [odds ratio (OR) 4.11, 95% CI 1.05-16.03] compared to the titin- group as a reference after adjusting for sex, follow-up duration, age at onset, systemic chemotherapy, and the Masaoka staging. Conclusion: The presence of anti-titin antibody is associated with more frequent hospital utilization. Personalized explanation and careful monitoring strategy could be required in patients with thymoma-associated MG with anti-titin antibody for the timely detection of relapses.ope

Value of Area Postrema Syndrome in Differentiating Adults With AQP4 vs. MOG Antibodies

Objectives: To compare the frequency of area postrema syndrome (APS) in adults with anti-aquaporin-4 (AQP4) and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. Methods: APS is defined as acute or subacute, single or combined, episodic or constant nausea, vomiting, or hiccups, persisting for at least 48 h, which cannot be attributed to any other etiology. The presence of APS was investigated in 274 adults with AQP4 antibodies and 107 adults with MOG antibodies from 10 hospitals. Results: The study population comprised Korean adults (≥18 years). At the time of disease onset, 14.9% (41/274) adults with AQP4 antibodies had APS, while none of the participants with MOG antibodies developed APS (p < 0.001). During the course of the disease, 17.2% (47/274) adults with AQP4 antibodies had APS in contrast to 1.9% (2/107) adults with MOG antibodies with APS (p < 0.001). Conclusions: APS, one of the core clinical characteristics of individuals with AQP4 antibodies, is an extremely rare manifestation in Korean adults with MOG antibodies.ope

Factors affecting the intention of COVID-19 vaccination in Korean patients with myasthenia gravis: A survey-based study

Objective: To investigate the intention of coronavirus disease 2019 (COVID-19) vaccination in Korean patients with myasthenia gravis (MG) and to determine the factors that influence their attitude toward COVID-19 vaccination. Materials and methods: We conducted a questionnaire survey of 160 Korean patients with MG. The questionnaire consisted of five categories, including vaccination status, willingness to get vaccinated, general concerns over vaccination, impact of MG diagnosis on vaccination decision, and MG-specific concerns over vaccination. The responses were rated from 1 (no intention or influence) to 5 (significant intention or influence). We compared the clinical factors between patients willing to get vaccinated (willing group) and those who were neutral or unwilling (hesitant group). Results: The average score of willingness to get vaccinated was 4.1 ± 1.2 (Likert score, 1-5). The hesitant group demonstrated higher proportions of women, patients with MG Foundation of America (MGFA) classification ≥III at nadir, and those who had experienced myasthenic crisis than the willing group (women, p = 0.027; MGFA classification≥III, p = 0.018; myasthenic crisis, p = 0.027). Scores for the willingness to get vaccinated (Likert score, 1-5) were negatively correlated with the MGFA classification at nadir (r = -0.235, p = 0.003), degree of general concern about vaccination (r = -0.362, p < 0.001), and impact of MG diagnosis on vaccination decision (r = -0.365, p < 0.001). In the path analysis, the MGFA classification at nadir was negatively associated with the willingness to get vaccinated by increasing the impact of MG diagnosis on vaccination decision. Conclusion: MG diagnosis, maximum disease severity, and general concerns about vaccination influenced the intention to get vaccinated.ope

Initial Repetitive Nerve Stimulation Test Predicts Conversion of Ocular Myasthenia Gravis to Generalized Myasthenia Gravis

Background and purpose: A major concern with ocular myasthenia gravis (MG) is the potential conversion to generalized MG. This study was conducted to determine if the repetitive nerve stimulation (RNS) test could predict the conversion from ocular to generalized MG. Methods: The RNS test was conducted in a consistent manner on five muscles in the face and limbs in every patient. Subjects were divided into those who remained as ocular MG (ROMG group) and those who experienced conversion to generalized MG during follow-up (GOMG group). Results: Conversion to generalized MG occurred in 24 (21.4%) of 112 MG patients with ocular onset. The proportion of patients displaying abnormal decreases in responses in the trapezius, abductor digiti minimi, or flexor carpi ulnaris muscles on the RNS test was higher in the GOMG group (p<0.001, p=0.002, and p<0.001, respectively). The Cox proportional-hazards model revealed that an abnormal result on the RNS test was significantly associated with conversion to generalized MG [hazard ratio (HR)=3.13, 95% confidence interval (CI)=1.18-8.32]. Notably, the HR was higher for abnormal results on the RNS test for the limb muscles, at 5.19 (95% CI=2.09-12.90). Conclusions: An abnormal result on the RNS test, especially in the limb muscles, is an independent predictor of the conversion from ocular to generalized MG. Applying the RNS test to limb muscles could be useful for predicting the conversion to generalized MG in patients with ocular onset.ope