p62/sequestosome-1 as a severity-reflecting plasma biomarker in Charcot-Marie-Tooth disease type 1A.

Autophagy is a self-degradation system for recycling to maintain homeostasis. p62/sequestosome-1 (p62) is an autophagy receptor that accumulates in neuroglia in neurodegenerative diseases. The objective of this study was to determine the elevation of plasma p62 protein levels in patients with Charcot-Marie-Tooth disease 1A (CMT1A) for its clinical usefulness to assess disease severity. We collected blood samples from 69 CMT1A patients and 59 healthy controls. Plasma concentrations of p62 were analyzed by ELISA, and we compared them with Charcot-Marie-Tooth neuropathy score version 2 (CMTNSv2). A mouse CMT1A model (C22) was employed to determine the source and mechanism of plasma p62 elevation. Plasma p62 was detected in healthy controls with median value of 1978 pg/ml, and the levels were significantly higher in CMT1A (2465 pg/ml, p < 0.001). The elevated plasma p62 levels were correlated with CMTNSv2 (r = 0.621, p < 0.0001), motor nerve conduction velocity (r = - 0.490, p < 0.0001) and disease duration (r = 0.364, p < 0.01). In C22 model, increased p62 expression was observed not only in pathologic Schwann cells but also in plasma. Our findings indicate that plasma p62 measurement could be a valuable tool for evaluating CMT1A severity and Schwann cell pathology.

Impact of COVID-19 Infection and Its Association With Previous Vaccination in Patients With Myasthenia Gravis in Korea: A Multicenter Retrospective Study.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, patients with myasthenia gravis (MG) were more susceptible to poor outcomes owing to respiratory muscle weakness and immunotherapy. Several studies conducted in the early stages of the COVID-19 pandemic reported higher mortality in patients with MG compared to the general population. This study aimed to investigate the clinical course and prognosis of COVID-19 in patients with MG and to compare these parameters between vaccinated and unvaccinated patients in South Korea. METHODS: This multicenter, retrospective study, which was conducted at 14 tertiary hospitals in South Korea, reviewed the medical records and identified MG patients who contracted COVID-19 between February 2022 and April 2022. The demographic and clinical characteristics associated with MG and vaccination status were collected. The clinical outcomes of COVID-19 infection and MG were investigated and compared between the vaccinated and unvaccinated patients. RESULTS: Ninety-two patients with MG contracted COVID-19 during the study. Nine (9.8%) patients required hospitalization, 4 (4.3%) of whom were admitted to the intensive care unit. Seventy-five of 92 patients were vaccinated before contracting COVID-19 infection, and 17 were not. During the COVID-19 infection, 6 of 17 (35.3%) unvaccinated patients were hospitalized, whereas 3 of 75 (4.0%) vaccinated patients were hospitalized (P < 0.001). The frequencies of ICU admission and mechanical ventilation were significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.019 and P = 0.032, respectively). The rate of MG deterioration was significantly lower in the vaccinated patients than in the unvaccinated patients (P = 0.041). Logistic regression after weighting revealed that the risk of hospitalization and MG deterioration after COVID-19 infection was significantly lower in the vaccinated patients than in the unvaccinated patients. CONCLUSION: This study suggests that the clinical course and prognosis of patients with MG who contracted COVID-19 during the dominance of the omicron variant of COVID-19 may be milder than those at the early phase of the COVID-19 pandemic when vaccination was unavailable. Vaccination may reduce the morbidity of COVID-19 in patients with MG and effectively prevent MG deterioration induced by COVID-19 infection.

Clinical and laboratory findings in scrub typhus associated Guillain-Barré syndrome in South Korea.

BACKGROUND AND AIMS: Scrub typhus is an endemic disease in the fall season that occurs in a limited number of places known as the Tsutsugamushi Triangle. Peripheral neuropathy is a common complication of scrub typhus. Herein, we encountered several patients with ascending paralysis after scrub typhus infection, who were diagnosed with Guillain-Barré syndrome (GBS). We aimed to investigate the clinical and laboratory characteristics of patients who developed GBS after scrub typhus. METHODS: Patients were retrospectively recruited from six nationwide tertiary centers in South Korea from January 2017 to December 2021. Patients who had been clinically diagnosed with GBS and confirmed to have scrub typhus via laboratory examination and/or the presence of an eschar before the onset of acute limb paralysis were included. The GBS-associated clinical and electrophysiological characteristics, outcomes, and scrub typhus-associated features were collected. RESULTS: Of the seven enrolled patients, six were female and one was male. The median time from scrub typhus infection to the onset of limb weakness was 6 (range: 2-14) days. All patients had eschar on their bodies. Four patients (57.1%) were admitted to the intensive care unit and received artificial ventilation for respiratory distress. At 6 months, the median GBS disability score was 2 (range, 1-4) points. INTERPRETATION: Patients with scrub typhus-associated GBS have a severe clinical presentation and require intensive treatment with additional immunotherapies. Therefore, GBS should be included in the differential diagnosis when peripheral neuropathies develop during scrub typhus treatment. Notably, scrub typhus is associated to GBS.

A Case of Transverse Myelitis Following Treatment with Atezolizumab for Advanced Hepatocellular Carcinoma.

The results of the IMbrave150 study have led to widespread use of the combination therapy of atezolizumab and bevacizumab as a first-line treatment for unresectable or metastatic hepatocellular carcinoma (HCC). Compared to traditional cytotoxic chemotherapy agents, immune checkpoint inhibitors show a spectrum of side effects ranging from mild side effects such as skin rash to potentially severe systemic effects such as myocarditis. We present a case of transverse myelitis diagnosed during the treatment of HCC with atezolizumab and bevacizumab combination therapy.

Early rituximab treatment reduces long-term disability in aquaporin-4 antibody-positive neuromyelitis optica spectrum.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) causes relapsing inflammatory attacks in the central nervous system, leading to disability. As rituximab, a B-lymphocyte-depleting monoclonal antibody, is an effective in preventing NMOSD relapses, we hypothesised that earlier initiation of rituximab can also reduce long-term disability of patients with NMOSD. METHODS: This multicentre retrospective study involving 19 South Korean referral centres included patients with NMOSD with aquaporin-4 antibodies receiving rituximab treatment. Factors associated with the long-term Expanded Disability Status Scale (EDSS) were assessed using multivariable regression analysis. RESULTS: In total, 145 patients with rituximab treatment (mean age of onset, 39.5 years; 88.3% female; 98.6% on immunosuppressants/oral steroids before rituximab treatment; mean disease duration of 121 months) were included. Multivariable analysis revealed that the EDSS at the last follow-up was associated with time to rituximab initiation (interval from first symptom onset to initiation of rituximab treatment). EDSS at the last follow-up was also associated with maximum EDSS before rituximab treatment. In subgroup analysis, the time to initiation of rituximab was associated with EDSS at last follow-up in patients aged less than 50 years, female and those with a maximum EDSS score ≥6 before rituximab treatment. CONCLUSIONS: Earlier initiation of rituximab treatment may prevent long-term disability worsening in patients with NMOSD, especially among those with early to middle-age onset, female sex and severe attacks.

Clinical significance of anti-NT5c1A autoantibody in Korean patients with inflammatory myopathies.

To explore the clinical significance of anti-cytosolic 5'-nucleoditase 1A (NT5c1A) antibody seropositivity in inflammatory myopathies, we measured anti-NT5c1A antibodies and analyzed their clinical features. Anti-NT5c1A antibodies were measured in the sera of 103 patients with inflammatory myopathies using an enzyme-linked immunosorbent assay. Positivity for anti-NT5c1A antibody was found in 13 (12.6%) of 103 patients with inflammatory myopathy. Anti-NT5c1A antibody was most frequently identified in patients with inclusion body myositis (IBM) (8/20, 40%), followed by dermatomyositis (2/13, 15.4%), immune-mediated necrotizing myopathy (2/28, 7.1%), and polymyositis (1/42, 2.4%). In eight patients with the anti-NT5c1A antibody-seropositive IBM, the median age at symptom onset was 54 years (interquartile range [IQR]: 48-57 years), and the median disease duration was 34 months (IQR: 24-50 months]. Knee extension weakness was greater than or equal to hip flexion weakness in eight (100%) patients, and finger flexion strength was less than shoulder abduction in three (38%) patients. Dysphagia symptoms were found in three (38%) patients. The median serum CK level was 581 IU/l (IQR: 434-868 IU/L]. Clinically significant differences were not found between anti-NT5c1A antibody-seropositive and seronegative IBM groups with respect to gender, age at symptom onset, age at diagnosis, disease duration, serum CK values, presence of other autoantibodies, dysphagia, and the pattern of muscle impairment. Although anti-NT5c1A antibody is known to be associated with IBM, seropositivity has also been noted in non-IBM inflammatory myopathies, and is insufficient to have clinical significance by itself. These findings have important implications for interpreting anti-NT5c1A antibody test results as the first study in Korea.

Neural cell adhesion molecule 1 is a cellular target engaged plasma biomarker in demyelinating Charcot-Marie-Tooth disease.

BACKGROUND AND PURPOSE: Elevated plasma concentrations of neural cell adhesion molecule 1 (NCAM1) and p75 neurotrophin receptor (p75) in patients with peripheral neuropathy have been reported. This study aimed to determine the specificity of plasma concentration elevation of either NCAM1 or p75 in a subtype of Charcot-Marie-Tooth disease (CMT) and its correlation with pathologic nerve status and disease severity. METHODS: Blood samples were collected from 138 patients with inherited peripheral neuropathy and 51 healthy controls. Disease severity was measured using Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), and plasma concentrations of NCAM1 and p75 were analyzed by enzyme-linked immunosorbent assay. Eight sural nerves from CMT patients were examined to determine the relation of histopathology and plasma NCAM1 levels. RESULTS: Plasma concentration of NCAM1, but not p75, was specifically increased in demyelinating subtypes of CMT (median = 7100 pg/mL, p < 0.001), including CMT1A, but not in axonal subtype (5964 pg/mL, p > 0.05), compared to the control (3859 pg/mL). CMT1A patients with mild or moderate severity (CMTNSv2 < 20) showed higher levels of plasma NCAM1 than healthy controls. Immunofluorescent NCAM1 staining for the sural nerves of CMT patients showed that NCAM1-positive onion bulb cells and possible demyelinating Schwann cells might be associated with the specific increase of plasma NCAM1 in demyelinating CMT. CONCLUSIONS: The plasma NCAM1 levels in demyelinating CMT might be a surrogate biomarker reflecting pathological Schwann cell status and disease progression.

Clinical and Radiological Features of Korean Patients With Anti-HMGCR Myopathy.

BACKGROUND AND PURPOSE: To understand the characteristics of Korean patients with anti-3-hydroxy-3-methylglutaryl-coenxyme A reductase (HMGCR) myopathy, we measured anti-HMGCR antibodies and analyzed the clinical, radiological, and pathological features of patients with anti-HMGCR myopathy. METHODS: We measured titers of anti-HMGCR antibodies in the sera of 99 patients with inflammatory myopathy, 36 patients with genetic myopathy, and 63 healthy subjects using an enzyme-linked immunosorbent assay. We tested 16 myositis-specific autoantibodies (MSAs) in all patients with anti-HMGCR myopathy. RESULTS: Positivity for the anti-HMGCR antibody was observed in 17 (4 males and 13 females) of 99 patients with inflammatory myopathy. The median age at symptom onset was 60 years. Ten (59%) of the patients with anti-HMGCR positivity had taken statins. The titer of anti-HMGCR antibodies was significantly higher in the statin-naïve group (median=230 U/mL, interquartile range=170-443 U/mL) than in the statin-exposed group (median=178 U/mL, interquartile range=105-210 U/mL, p=0.045). The most common symptom was proximal muscle weakness in 15 patients (88%), followed by myalgia in 9 (53%), neck weakness in 4 (24%), dysphagia in 3 (18%), and skin lesions in 2 (12%). The median titer of anti-HMGCR antibody was 202 U/mL. We found eight different MSAs in nine (53%) patients. The median disease duration from symptom onset to diagnosis was significantly shorter in the MSA-positive group than in the MSA-negative group (p=0.027). CONCLUSIONS: Our study was the first to measure anti-HMGCR antibodies in inflammatory myopathy. It has provided new findings, including the suggestion of the coexistence of other MSAs in Korean patients.

Bilateral Facial Weakness with Distal Paresthesia Following COVID-19 Vaccination: A Scoping Review for an Atypical Variant of Guillain-Barré Syndrome.

Background and Purpose: Recent population-based studies from the US and UK have identified an increase in the occurrence of Guillain-Barré syndrome (GBS) following coronavirus disease 2019 (COVID-19) vaccination. However, the localized variant of GBS might be underestimated due to its rarity and atypical features. We aimed to identify and characterize bilateral facial weakness with distal paresthesia (BFWdp) as a GBS variant following COVID-19 vaccination. Materials and Methods: Relevant studies published during the COVID-19 pandemic were searched and identified in the MEDLINE, Embase, and other databases. Results: This review found that 18 BFWdp cases presented characteristics similar to previous BFWdp cases as defined in the literature: male dominance, frequent albuminocytological dissociation, and acute inflammatory demyelinating neuropathy pattern. In contrast, facial nerve enhancement on brain MRI and antiganglioside antibody positivity were often observed in BFWdp following COVID-19 vaccination. Conclusions: The mechanism of BFWdp following COVID-19 vaccination appears to be somewhat different from that of sporadic BFWdp. Neurological syndromes with rare incidence and difficulty in diagnosis should be considered adverse events of COVID-19 vaccination.

Miller Fisher syndrome following COVID-19 vaccines: A scoping review.

BACKGROUND AND PURPOSE: Miller Fisher syndrome (MFS), a variant of Guillain-Barré Syndrome (GBS), could be underestimated in evaluations of its adverse events (AEs) following COVID-19 vaccination. We aimed to identify and characterize MFS following COVID-19 vaccination. MATERIALS AND METHODS: Relevant studies reported on during the COVID-19 pandemic were identified in the MEDLINE, Embase, and other databases. RESULTS: Nine cases of MFS following COVID-19 vaccination from various regions were included. Unlike MFS following COVID-19 infection, patients with MFS following COVID-19 vaccination frequently presented with anti-GQ1b antibody positivity (44%, 4/9). Unlike GBS following COVID-19 vaccination, only two of nine (22%) cases of MFS following COVID-19 vaccination had developed after viral-vector-related vaccine administration. CONCLUSIONS: Miller Fisher syndrome following COVID-19 vaccination seems to have a different pathophysiology from MFS following COVID-19 infection and GBS following COVID-19 vaccination. This neurological syndrome with a rare incidence and difficulty in diagnosis should be considered an AE of COVID-19 vaccination.

Necrotizing myopathy presenting as congestive heart failure and life-threatening ventricular arrhythmias: a case report.

BACKGROUND: Necrotizing autoimmune myopathy is a rare subtype of idiopathic inflammatory myopathy; however, it can be associated with fatal cardiac manifestations. CASE SUMMARY: A 58-year-old female patient was referred for congestive heart failure with dysrhythmia. Electrocardiograms showed ventricular arrhythmias of various QRS complex morphologies and coupling intervals with beat-to-beat differences. Despite optimal medical therapy for heart failure, the patient was admitted for the progression of dyspnoea and generalized motor weakness. The burden of non-sustained ventricular tachycardia gradually increased, and ventricular fibrillation eventually occurred. In view of a differential diagnosis of an inflammatory myocardial diseases such as sarcoidosis, a cardiac biopsy was performed. However, pathologic examinations revealed only necrotic muscle fibres without granuloma. Further examinations revealed proximal dominant motor weakness, an elevated serum creatinine-phosphokinase level, myogenic potentials on needle electromyography, and biceps muscle biopsy findings that were compatible with necrotizing autoimmune myopathy. High-dose steroid therapy improved the patient's motor weakness, including her respiratory impairment, and successfully suppressed ventricular arrhythmias. DISCUSSION: This case suggests that intensive immunosuppressive therapy with high-dose steroid could be useful in the necrotizing autoimmune myopathy manifested as congestive heart failure and life-threatening ventricular arrhythmias.

Atrial Cardiopathy Biomarkers and MRI-Based Infarct Patterns in Patients with Embolic Strokes of Undetermined Source.

OBJECTIVES: The study aimed to investigate whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration and/or left atrial volume index (LAVI), as atrial cardiopathy biomarkers, were associated with infarct patterns on diffusion-weighted imaging in patients with embolic strokes of undetermined source (ESUS). MATERIALS AND METHOD: We retrospectively evaluated patient with ESUS from our stroke registry between January 2018 and November 2019. Cut-off values for atrial cardiopathy biomarkers were defined as >250 pg/mL for NT-proBNP and >34 mL/m2 for LAVI. Eligible patients were then assigned to 3 groups and infarct patterns were compared according to their atrial cardiopathy markers: Group 1 (no atrial cardiopathy markers), Group 2 (one marker), and Group 3 (both markers). RESULTS: Among 194 eligible patients with ESUS (76 women; mean age, 69.2 years), simultaneous increases of NT-proBNP concentration and LAVI were identified in 39 (20.1%). Group 3 had a significantly larger infarct volume, relative to Group 1 and Group 2 (P=0.043) Multivariable logistic regression analyses revealed that these patients (Group 3) were significantly more likely to have multi-territorial infarcts (adjusted odds ratio [aOR]: 3.03, 95% confidence interval [CI]: 1.05-8.72; P=0.04), a maximal lesion diameter >15mm (aOR: 4.51, 95% CI: 1.70-11.93; P=0.001), and large cortical infarctions (aOR: 4.17, 95% CI: 1.75-9.96; P=0.001). CONCLUSION: We found that simultaneously increased values for NT-proBNP concentration and LAVI were independently associated with multi-territorial and large cortical infarct patterns in patients with ESUS. These findings suggest that NT-proBNP and LAVI may be useful biomarkers for identifying cardioembolic subtypes and guiding treatment selection in patients with ESUS.

Finger drop sign as a new variant of acute motor axonal neuropathy.

We propose the finger drop sign as a new clinical variant of acute motor axonal neuropathy (AMAN) defined by immunological and radiological evidence. We identified eight consecutive patients who had AMAN. All of them developed prominent involvement of the finger extensors. We performed magnetic resonance imaging (MRI) of the extremity muscles and serological assays for antiganglioside antibodies and Campylobacter jejuni. Patients with AMAN showed characteristic and a markedly sustained weakness of the finger extensors with a distinctive pattern of the finger drop sign. Limb MRI revealed unevenly distributed abnormal signals in the muscles mainly innervated by the posterior interosseous nerve. All tested patients showed positivity for immunoglobulin G antibody against ganglioside complex of GM1 and phosphatidic acid. A pathophysiological understanding of this unique syndrome can provide further insight into antiganglioside-antibody-mediated axonal injury in Guillain-Barré syndrome.

Relationship between the washout rate of I-123 MIBG scans and autonomic function in Parkinson's disease.

PURPOSE: We have evaluated the clinical significance of the washout rate (WR) on I-123 MIBG scans through the analysis of the relationship between the I-123 MIBG scans and autonomic status in patients with Parkinson's disease (PD). MATERIALS AND METHODS: Sixty patients with clinical PD who had decreased HMR were enrolled. An autonomic symptom was evaluated using a head-up tilt test and the Composite Autonomic Severity Score (CASS). An I-123 MIBG scan and F-18 FP-CIT positron emission tomography (PET) were performed. All of the patients were classified into three groups according to the WR. The differences in patient characteristics and the imaging parameters among the three groups were evaluated, and a correlation analysis was also performed. RESULTS: The frequency of orthostatic hypotension was significantly different among the three groups. The difference in systolic pressure (dSysPr) and the difference in diastolic pressure (dDiaPr) of group 3 was significantly larger than those of groups 1 and 2. From the correlation analysis, it can be seen that age, Hoehn and Yahr (H&Y) stage, dSysPr, and dDiaPr had a weak positive correlation with the WR. The total CASS score was significantly higher in group 3 compared with groups 1 and 2. The WR had a moderate positive correlation with the cardiosympathetic score and the total CASS score. CONCLUSION: The WR is related to autonomic dysfunction. An I-123 MIBG cardiac scan is considered to be a good method to evaluate not only the differential diagnosis of Parkinson's disease but also the degree of autonomic dysfunction.

Serum CXCL13 reflects local B-cell mediated inflammatory demyelinating peripheral neuropathy.

Immune damages on the peripheral myelin sheath under pro-inflammatory milieu result in primary demyelination in inflammatory demyelinating neuropathy. Inflammatory cytokines implicating in the pathogenesis of inflammatory demyelinating neuropathy have been used for the development of potential biomarkers for the diagnosis of the diseases. In this study, we have found that macrophages, which induce demyelination, expressed a B-cell-recruiting factor CXC chemokine ligand 13 (CXCL13) in mouse and human inflammatory demyelinating nerves. The serum levels of CXCL13 were also higher in inflammatory demyelinating neuropathic patients but not in acute motor axonal neuropathy or a hereditary demyelinating neuropathy, Charcot-Marie-Tooth disease type 1a. In addition, CXCL13-expressing macrophages were not observed in the sciatic nerves after axonal injury, which causes the activation of innate immunity and Wallerian demyelination. Our findings indicate that the detection of serum CXCL13 will be useful to specifically recognize inflammatory demyelinating neuropathies in human.

Pattern of Extraocular Muscle Involvements in Miller Fisher Syndrome.

BACKGROUND AND PURPOSE: The most-common initial manifestation of Miller Fisher syndrome (MFS) is diplopia due to acute ophthalmoplegia. However, few studies have focused on ocular motility findings in MFS. This study aimed to determine the pattern of extraocular muscle (EOM) paresis in MFS patients. METHODS: We consecutively recruited MFS patients who presented with ophthalmoplegia between 2010 and 2015. The involved EOMs and the strabismus pattern in the primary position were analyzed. Antecedent infections, other involved cranial nerves, and laboratory findings were also reviewed. We compared the characteristics of the patients according to the severity of ophthalmoplegia between complete ophthalmoplegia (CO) and incomplete ophthalmoplegia (IO). RESULTS: Twenty-five patients (15 males and 10 females) with bilateral ophthalmoplegia were included in the study. The most-involved and last-to-recover EOM was the lateral rectus muscle. CO and IO were observed in 11 and 14 patients, respectively. The patients were aged 59.0±18.4 years (mean±SD) in the CO group and 24.9±7.4 years in the IO group (p<0.01), and comprised 63.6% and 21.4% females, respectively (p=0.049). Elevated cerebrospinal fluid protein was identified in 60.0% of patients with CO and 7.7% of patients with IO (p=0.019) for a mean follow-up time from the initial symptom onset of 3.7 days. CONCLUSIONS: The lateral rectus muscle is the most-involved and last-to-recover EOM in ophthalmoplegia. The CO patients were much older and were more likely to be female and have an elevation of cerebrospinal fluid protein than the IO patients.

p75 and neural cell adhesion molecule 1 can identify pathologic Schwann cells in peripheral neuropathies.

OBJECTIVE: Myelinated Schwann cells (SCs) in adult peripheral nerves dedifferentiate into immature cells in demyelinating neuropathies and Wallerian degeneration. This plastic SC change is actively involved in the myelin destruction and clearance as demyelinating SCs (DSCs). In inherited demyelinating neuropathy, pathologically differentiated and dysmyelinated SCs constitute the main nerve pathology. METHODS: We investigated whether this SC plastic status in human neuropathic nerves could be determined by patient sera to develop disease-relevant serum biomarkers. Based on proteomics analysis of the secreted exosomes from immature SCs, we traced p75 neurotrophin receptor (p75) and neural cell adhesion molecule 1 (NCAM) in the sera of patients with peripheral neuropathy. RESULTS: Enzyme-linked immunosorbent assay (ELISA) revealed that p75 and NCAM were subtype-specifically expressed in the sera of patients with peripheral neuropathy. In conjunction with these ELISA data, pathological analyses of animal models and human specimens suggested that the presence of DSCs in inflammatory neuropathy and of supernumerary nonmyelinating or dysmyelinating SCs in inherited neuropathy could potentially be distinguished by comparing the expression profiles of p75 and NCAM. INTERPRETATION: This study indicates that the identification of disease-specific pathological SC stages might be a valuable tool for differential diagnosis of peripheral neuropathies.