Clinical Features, Treatment, and Prognostic Factors of Childhood-Onset Myasthenia Gravis in a Large Chinese Cohort.

BACKGROUND: To describe the clinical features of patients with childhood-onset myasthenia gravis (MG) (CMG) and explore predictors affecting the treatment outcomes. METHODS: A retrospective observational cohort analysis of 859 patients with CMG with disease onset before age 14 years was performed at Tongji Hospital. RESULTS: Patients in the pubertal-onset group (n = 148) had a worse disease course than those in the prepubertal group (n = 711), including a higher incidence of generalized MG (GMG) at presentation, generalization of ocular MG (OMG), and more severe Myasthenia Gravis Foundation of America (MGFA) classification. All patients were initially treated with pyridostigmine, 657 with prednisone, and 196 with immunosuppressants (ISs). However, 226 patients were resistant to prednisone treatment. Multivariate analysis revealed that thymic hyperplasia, higher MGFA class, disease duration before prednisone administration, and thymectomy before prednisone administration were independent predictors of prednisone resistance. At the last visit, 121 of the 840 patients with OMG had developed GMG after a median of 10.0 years from symptom onset and 186 patients (21.7%) achieved complete stable remission (CSR). In multivariable analysis, age at onset, thymic hyperplasia, prednisone, and IS treatment were associated with generalization, whereas age at onset, disease duration, anti-acetylcholine receptor antibodies (AChR-ab), MGFA class II, short-term prednisone treatment, and IS treatment were associated with CSR. CONCLUSIONS: The majority of patients with CMG have mild clinical symptoms and favorable outcomes, especially those with earlier onset age, shorter disease duration, and negative AChR-ab. In addition, early prednisone and ISs are shown to be effective and safe for most patients with CMG.

Clinical and immune-related factors associated with exacerbation in adults with well-controlled generalized myasthenia gravis.

Objectives: To describe the clinical predictors and immune-related factors for exacerbation in adults with well-controlled generalized myasthenia gravis (GMG). Methods: We conducted a retrospective analysis of 585 adults with well-controlled GMG from our institution to explore the risk factors for exacerbation. Furthermore, propensity score matching (PSM) was used to compare the proportions of lymphocyte subsets, and the levels of immunoglobulin, complement, and anti-acetylcholine receptor antibody (AChR-ab) in the peripheral blood of 111 patients with exacerbations and 72 patients without exacerbations. Results: A total of 404 patients (69.1%) experienced at least one exacerbation, and the median (interquartile range) time to the first exacerbation was 1.5 years (0.8-3.1 years). Multivariable Cox regression analysis showed that age at onset, disease duration before enrollment, Myasthenia Gravis Foundation of America classification (MGFA) class III vs. class II, MGFA class IV-V vs. class II, AChR-ab levels, anti-muscle specific kinase antibody levels, thymus hyperplasia, prednisone plus immunosuppressants vs. prednisone treatment, and thymectomy were independent predictors for exacerbations [hazard ratio (HR) = 1.011, 1.031, 1.580, 1.429, 2.007, 2.033, 1.461, 0.798, and 0.651, respectively]. Propensity-matched analysis compared 51 patient pairs. After PSM, the peripheral blood proportions of CD3-CD19+ B cells, ratios of CD3+CD4+/CD3+CD8+ T cells, and AChR-ab levels were significantly increased, and the peripheral blood proportions of CD3+CD8+ T and CD4+CD25+CD127low+ regulatory T cells (Tregs) were significantly lower in patients with exacerbation than in those without exacerbation (all p < 0.05). Conclusion: Myasthenia gravis (MG) exacerbations were more frequent in those patients with older onset age, longer disease duration, more severe MGFA classification, positive AChR-ab, and lack of combined immunotherapy or thymectomy treatment. On the other hand, CD3-CD19+ B cells, CD3+CD8+ T cells, Tregs, and AChR-ab in peripheral blood may be involved in the course of GMG exacerbation.

Increased expression of cell adhesion molecules in myofasciitis.

Background: Myofasciitis is a heterogeneous group of diseases pathologically characterized by inflammatory cell infiltration into the fascia. Endothelial activation plays a critical role in the pathogenesis of the inflammatory response. However, the expression of cellular adhesion molecules (CAMs) in myofasciitis has not been investigated. Methods: Data on clinical features, thigh magnetic resonance imaging, and muscle pathology were collected from five patients with myofasciitis. Immunohistochemical (IHC) staining and Western blot (WB) of the muscle biopsies from patients and healthy controls were performed. Results: Increased levels of serum pro-inflammatory cytokines, including IL-6, TNF-α, and IL-2R, were detected in four patients. IHC staining and WB indicated significantly increased expression of cell adhesion molecules in blood vessels or inflammatory cells within the perimysium in muscle and fascia tissues of patients with myofasciitis compared to controls. Conclusion: The up-regulation of CAMs in myofasciitis indicates endothelial activation, which may be potential therapy targets for the treatment of myofasciitis.

TWEAK and Fn14 are overexpressed in immune-mediated necrotizing myopathy: implications for muscle damage and repair.

OBJECTIVES: TNF-like weak inducer of apoptosis (TWEAK) and its sole receptor fibroblast growth factor-inducible 14 (Fn14) are involved in various inflammatory conditions. This study was performed to investigate the potential role of TWEAK/Fn14 in immune-mediated necrotizing myopathy (IMNM). METHODS: Muscle biopsies from patients with IMNM (n = 37) and controls (n = 11) were collected. Human muscle cells were treated with TWEAK in vitro. Muscle biopsies and cultured muscle cells were analysed by immunostaining and quantitative PCR. Serum levels of TWEAK and Fn14 were detected by ELISA. RESULTS: TWEAK and Fn14 were overexpressed in IMNM muscle biopsies. The percentage of Fn14-positive myofibers correlated with disease severity, myonecrosis, regeneration and inflammation infiltrates. Fn14-positive myofibers tended to be surrounded or invaded by CD68+ macrophages. TWEAK treatment had a harmful effect on cultured muscle cells by inducing the production of multiple chemokines and pro-inflammatory cytokines. Serum Fn14 levels were increased in patients with IMNM and correlated with muscle weakness. CONCLUSIONS: TWEAK/Fn14 signalling was activated in IMNM, most likely aggravating muscle damage via amplifying inflammatory response and macrophages chemotaxis. Fn14 seems to be a biomarker for assessing disease severity in IMNM. In addition, Fn14 may also contribute to muscle injury repair.

Dynamic nomogram for predicting generalized conversion in adult-onset ocular myasthenia gravis.

PURPOSE: To explore the factors and risk mapping model of progression from ocular myasthenia gravis (OMG) to generalized myasthenia gravis (GMG) in adult-onset patients. METHODS: A retrospective, observational cohort study was performed for 435 OMG patients with onset age older than 14 years old. Multivariate Cox regression was used to identify the independent factors affecting generalized conversions that then were incorporated into the construction of the nomogram. RESULTS: Two hundred thirty-seven patients (54.5%) had transformed into GMG after a median of 1.1 years (range 0.1--9.1 years). The 6-, 12-, and 24-month generalized conversion rates were 31.7%, 49.8%, and 65.4%, respectively. Multivariable analysis showed that the early-onset age, male sex, concomitant autoimmune diseases (AID), positive results of anti-acetylcholine receptor antibodies, repetitive nerve stimulation abnormalities, the presence of thymoma, and prednisone treatment were significantly associated with the generalized conversions (hazard ratio [HR] = 0.598, 0.686, 1.554, 1.541, 2.020, 2.510, and 0.556, respectively). A nomogram was established to predict the possibility of generalization-free survival (GFS) in adult-onset OMG patients, and the model demonstrated good predictive performance with a C-index of 0.736 (95% confidence interval 0.703 ~ 0.769). Moreover, subgroup analyses were performed based on the presence or absence of prednisone therapy, and the results indicated that prednisone therapy has better prevention of generalized conversions in male, non-thymoma patients, and patients without other AID. CONCLUSION: A new predictive nomograph and web-based survival calculator we developed show favorable applicability and accuracy in predicting long-term GFS in adult-onset OMG patients.

Polymorphisms in drug metabolism genes predict the risk of refractory myasthenia gravis.

Background: Nearly 10% to 20% of myasthenia gravis (MG) patients are refractory to conventional treatment for unclear reasons. The study aimed to explore the relationship between drug metabolism gene polymorphisms and refractory MG. Methods: One hundred and thirty-one MG patients (33 in the refractory group; 98 in the non-refractory group) admitted to Tongji Hospital were included in this retrospective study. Improved multiplex ligation detection reaction (iMLDR) was used to genotype 13 polymorphisms (NR3C1 rs17209237, rs9324921; FKBP5 rs1360780, rs4713904, rs9296158; HSP90AA1 rs10873531, rs2298877, rs7160651; MDR1 rs1045642, rs1128503, rs2032582; CYP3A4 rs2242480; and CYP3A5 rs776746). We applied multivariable logistic regression to investigate the association between refractory MG and nucleotide polymorphisms. Generalized multifactor dimensionality reduction (GMDR) was used to examine gene-gene interactions. Results: CC genotype of HSP90AA1 rs7160651 was associated with the increased risk of refractory MG than CT genotype [odds ratio (OR) =0.26; P=0.041] and CT + TT genotype (dominant model, OR =0.24; P=0.022). For CYP3A5 rs776746, AA genotype was associated with refractory MG compared with AG genotype (OR =0.11; P=0.017), GG genotype (OR =0.18; P=0.033), and AG + GG genotype (dominant model, OR =0.16; P=0.020). The frequency of CAT haplotype of HSP90AA1 rs10873531, rs2298877, rs7160651 was less common in refractory patients (OR =0.33; P=0.044). No significant gene-gene interactions were observed. Conclusions: HSP90AA1 rs7160651 and CYP3A5 rs776746 were significantly associated with refractory MG. Further studies are warranted to confirm the results and investigate the use of polymorphisms for treatment individualization.

The accumulation of muscle RING finger-1 in regenerating myofibers: Implications for muscle repair in immune-mediated necrotizing myopathy.

Background: Muscle RING finger-1 (MuRF-1) plays a key role in the degradation of skeletal muscle proteins. We hypothesize the involvement of MuRF-1 in immune-mediated necrotizing myopathy (IMNM). Methods: Muscle biopsies from patients with IMNM (n = 37) were analyzed and compared to biopsies from patients with dermatomyositis (DM, n = 13), dysferlinopathy (n = 9) and controls (n = 7) using immunostaining. Results: MuRF-1 staining could be observed in IMNM, DM and dysferlinopathy biopsies, whereas the percentage of MuRF-1 positive myofibers was significantly higher in IMNM than in dysferlinopathy (p = 0.0448), and positively correlated with muscle weakness and disease activity in IMNM and DM. Surprisingly, MuRF-1 staining predominantly presented in regenerating fibers but not in atrophic fibers. Moreover, MuRF-1-positive fibers tended to be distributed around necrotic myofibers and myofibers with sarcolemma membrane attack complex deposition. Abundant MuRF-1 expression in IMNM and DM was associated with rapid activation of myogenesis after muscle injury, whereas relatively low expression of MuRF-1 in dysferlinopathy may be attributed to damaged muscle regeneration. Conclusions: MuRF-1 accumulated in regenerating myofibers, which may contribute to muscle injury repair in IMNM and DM. MuRF-1 staining may help clinicians differentiate IMNM and dysferlinopathy.

Remission and relapses of myasthenia gravis on long-term tacrolimus: a retrospective cross-sectional study of a Chinese cohort.

Objective: To identify the factors that predict the remission and relapses in myasthenia gravis (MG) patients improved by prednisone and tacrolimus treatment. Methods: A retrospective, observational cohort analysis of MG patients who achieved remission after receiving prednisone and tacrolimus were performed at Tongji Hospital. The main outcome measures were the time to remission, prednisone discontinuation, tacrolimus reduction-associated relapse, and treatment outcome. Results: After adding tacrolimus, 256 patients were able to achieve remission with a mean time to remission of 2.1 ± 1.4 months. After a median follow-up of 2.9 years, 167 patients (65.2%) discontinued prednisone, and 20 patients (7.8%) achieved complete stable remission. Moreover, 53 of the 109 patients who were tapering tacrolimus experienced relapses. In multivariable analysis, female sex, low tacrolimus concentrations, and quantitative myasthenia gravis (QMG) scores have a positive correlation with the time to remission; concomitant additional autoimmune disease (AID) and high anti-acetylcholine receptor antibody (AChR-ab) levels were significantly associated with low probabilities of prednisone discontinuation [odds ratio (OR) = 0.312-0.912, respectively]; rapid tacrolimus decrement speed (⩾0.76 mg/year) was an independent predictor for the development of relapse during tapering tacrolimus (OR = 5.662). Conclusion: Sex, tacrolimus concentrations, and QMG scores can be used as potential predictors of the time to remission in MG patients treated with tacrolimus and prednisone. Prednisone should be tapered slowly, especially in patients with additional AID or high serum titers of AChR-ab. To avoid symptoms recurrence, the dose of tacrolimus should reduce slowly, not exceeding 0.76 mg/year.

Childhood-Onset Myasthenia Gravis Patients Benefited from Thymectomy in a Long-Term Follow-up Observation.

INTRODUCTION: The effect of thymectomy on the treatment of childhood-onset myasthenia gravis (CMG) remains debatable. The objective of this study was to evaluate the clinical outcome and relevant prognostic factors of thymectomy for CMG patients. MATERIALS AND METHODS: A total of 32 CMG patients who underwent thymectomy before 18 years of age were included in this retrospective study. Clinical state following thymectomy was assessed by quantified myasthenia gravis (QMG) scores, myasthenia gravis-related activities of daily living (MG-ADL) scores, and Myasthenia Gravis Foundation of America postintervention status. Repeated-measures analysis of variance (ANOVA) examined the changes in postoperative scores during the 5-year follow-up. Univariate logistic regression was applied to identify factors associated with short-term (1-year postoperation) and long-term (5-year postoperation) clinical outcomes. RESULTS: Repeated-measures ANOVA showed that QMG scores (F = 6.737, p < 0.001) and MG-ADL scores (F = 7.923, p < 0.001) decreased gradually with time. Preoperative duration (odds ratio [OR] = 0.85, 95% confidence interval [CI]: 0.73-1.00, p = 0.043), gender (OR = 0.19, 95% CI: 0.04-0.94, p = 0.041), and MG subgroup (OR = 13.33, 95% CI: 1.43-123.99, p = 0.023) were predictors for 1-year postoperative prognosis. Shorter disease duration (OR = 0.82, 95% CI: 0.70-0.97, p = 0.018) and generalized CMG (OR = 6.11, 95% CI: 1.06-35.35, p = 0.043) were found to have more favorable long-term results. CONCLUSION: Our results suggest that thymectomy is effective in treating CMG. Thymectomy could be recommended for CMG patients, especially for patients in the early course of GMG.

Endoplasmic Reticulum Stress Is Involved in Muscular Pathogenesis in Idiopathic Inflammatory Myopathies.

Objectives: Endoplasmic reticulum (ER) stress plays pivotal roles in the regulation of skeletal muscle damage and dysfunction in multiple disease conditions. We postulate the activation of ER stress in idiopathic inflammatory myopathies (IIM). Methods: Thirty-seven patients with immune-mediated necrotizing myopathy (IMNM), 21 patients with dermatomyositis (DM), 6 patients with anti-synthetase syndrome (ASS), and 10 controls were enrolled. The expression of ER stress-induced autophagy pathway was detected using histological sections, Western blot, and real-time quantitative Polymerase Chain Reaction. Results: ER stress-induced autophagy pathway was activated in biopsied muscle of patients with IMNM, DM, and ASS. The ER chaperone protein, glucose-regulated protein 78 (GRP78)/BiP expression in skeletal muscle correlated with autophagy, myofiber atrophy, myonecrosis, myoregeneration, and disease activity in IMNM. Conclusion: ER stress was involved in patients with IIM and correlates with disease activity in IMNM. ER stress response may be responsible for skeletal muscle damage and repair in IIM.

Long-Term Improvement in a Chinese Cohort of Glucocorticoid-Resistant Childhood-Onset Myasthenia Gravis Patients Treated With Tacrolimus.

OBJECTIVES: To evaluate the long-term outcome of tacrolimus for childhood-onset myasthenia gravis (CMG) with an inadequate response to glucocorticoids, and investigate factors associated with favorable outcomes following tacrolimus treatment. METHODS: A retrospective, observational cohort study was performed for CMG patients who had not improved satisfactorily after sufficient prednisone therapy for at least 8 weeks. All patients were given tacrolimus in doses of 2-3 mg for more than 6 months. The primary efficacy outcome was assessed using the prednisone dose, quantitative MG (QMG), and MG-activity of daily living (ADL) scores. The participants were divided into improved and unimproved groups based on changes in QMG scores to investigate the risk factors that affected tacrolimus efficacy. RESULTS: A total of 149 glucocorticoid resistant CMG patients were finally enrolled in our study, with 113 (75.8%) responding well to tacrolimus (defined as minimal manifestation status or better). One month after initiating tacrolimus, there was a noticeable improvement in prednisone dose, QMG, and ADL scores, which continued to improve throughout the study. More importantly, the prednisone was eventually stopped in 89 of the patients (78.8%). Thymus type [odds ratio (OR) = 3.156, 95% confidence interval (CI) 1.427-6.978; P = 0.005] and pre-intervention status (OR = 0.284, 95%CI 0.109-0.741; P = 0.010) were independent predictors of tacrolimus efficacy after controlling for confounding factors in multiple logistic regression. CONCLUSION: The majority of glucocorticoid-resistant CMG patients have a good long-term prognosis after adding tacrolimus. Thymus type and pre-intervention status can serve as potential predictors affecting the efficacy of tacrolimus.

Differences in immunophenotypes between myasthenia gravis patients with and without thyroid antibodies.

INTRODUCTION/AIMS: Immunophenotypes are related to the therapeutic efficacy of specific immunomodulating agents in patients with myasthenia gravis (MG), but the relationship of immunophenotype to the presence or absence of thyroid antibodies is unknown. This study aims to evaluate differences in the immunophenotypes between MG patients with and without thyroid antibody (TAb) positivity to provide insight for future targeted immunotherapies. METHODS: This retrospective observational study included 48 MG patients with acetylcholine receptor antibody (AchR-Ab), of which 15 (31.25%) were TAb positive. Ocular MG (OMG) was defined as ocular-only manifestations for the duration for which records were available. Peripheral lymphocyte subpopulations were measured by flow cytometry. RESULTS: TAb positive patients appeared to have a higher prevalence of OMG than TAb negative patients (53.33% vs. 24.24%, p  = .048). Percentages of B cells (mean difference (MD) = 6.16, 95% confidence interval (CI): 1.91-10.40, p = .007) and CD8 + CD28+ cells (MD = 15.14, 95%CI: 5.17-25.11, p  = .013) were higher in TAb positive patients than those in TAb negative patients, while AChR-Ab titers (MD = -6.49 nmol/L, 95%CI: -9.29 to -3.70, p  < .001), percentages of T cells (MD = -6.43, 95%CI: -11.92 to -0.94, p = .023), CD3 + HLA-DR+ cells (MD = -6.47, 95%CI: -12.31 to -0.63, p  = .031) and CD8+ T cells (MD = -6.60, 95%CI: -9.86 to -3.34, p < .001) were lower. DISCUSSION: The immunophenotypes of MG patients with and without TAb positivity were significantly different, suggesting that their sensitivity to immunotherapy may be different. Further studies focused on differences between TAb positive and TAb negative MG patients in their responses to specific immunotherapies are needed to support our exploratory findings.

Efficacy of tacrolimus as long-term immunotherapy for neuronal surface antibody-mediated autoimmune encephalitis.

AIMS: We aimed to verify the efficacy and safety of tacrolimus as long-term immunotherapy for the treatment of neuronal surface antibody-mediated autoimmune encephalitis (AE) during the first attack. METHODS: In this retrospective observational cohort study, patients with neuronal surface antibody-mediated AE who experienced the first attack were enrolled. We compared the outcomes of 17 patients who received tacrolimus with those of 47 patients treated without tacrolimus. Patients were assessed at onset and 3, 6, and 12 months, as well as at the last follow-up, by using the modified Rankin scale (mRS) and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The efficacy of tacrolimus was also compared in a subgroup of patients with anti-NMDA receptor encephalitis. RESULTS: Among all patients with neuronal surface antibody-mediated AE, those receiving tacrolimus had lower median mRS scores [1 (IQR = 0-1) versus 2 (IQR = 1-3) in controls, p = 0.001)], CASE scores [2 (IQR = 1-3) versus 3 (IQR = 2-7), p = 0.006], and more favorable mRS scores (94.1% versus 68.1%, p = 0.03) at the 3-month follow-up. No difference was found at the last follow-up. There was no significant difference in the occurrence of relapse and adverse events between the two groups (11.8% versus 14.9%, p = 0.75). In the subgroup of patients with anti-NMDA receptor encephalitis, patients treated with tacrolimus had a lower median mRS score at the 3-month follow-up [1 (IQR = 0-2) versus 2 (IQR = 1-3), p = 0.03]; however, no difference in the outcome was detected at the last follow-up. CONCLUSION: Tacrolimus can be used as long-term immunotherapy in patients with neuronal surface antibody-mediated AE during the first attack. Treatment with tacrolimus appears to accelerate the clinical improvement of neuronal surface antibody-mediated AE.

Hemorrhagic transformation after acute ischemic stroke caused by polycythemia vera: Report of two case.

BACKGROUND: Polycythemia vera (PV) is a chronic myeloproliferative disorder characterized by an increase in red blood cells in the peripheral blood. Previous work has reported the occurrence of thrombosis or hemorrhage arising in the cerebral vasculature secondary to PV. However, hemorrhagic transformation after PV-associated acute ischemic stroke has not been previously described. CASE SUMMARY: We herein present two cases of PV where hemorrhagic transformation occurred after an acute ischemic stroke. Case 1 was a 57-year-old woman with a history of hypertension who was admitted for left-sided weakness. Case 2 was a 68-year-old man who was admitted for a 10-d sudden left arm weakness. Imaging examinations for the two patients revealed hemorrhagic transformation after acute ischemic stroke. Both patients had JAK-2-V617F mutation and received antiplatelet therapy. Both of them had a good prognosis during the follow-up. CONCLUSION: This report suggested that hemorrhagic transformation may occur in acute ischemic stroke caused by PV. Antiplatelet drugs do not seem to influence the long-term outcomes in such patients. Future research should focus on establishing a standard antiplatelet treatment strategy for this condition.

Overlapping syndrome mimicking infectious meningoencephalitis in a patient with MOG and GFAP IgG.

BACKGROUND: Central nervous system overlapping autoimmune syndromes are uncommon, especially with the coexistence of MOG-IgG and GFAP-IgG. CASE PRESENTATION: A 23-year-old woman presented with transient convulsions, a loss of consciousness, persistent fever, headache, and vomiting. Cerebrospinal fluid (CSF) analysis revealed elevated cellularity, and magnetic resonance imaging (MRI) showed diffuse leptomeningeal enhancement. She had fever and headache with antiviral and antibiotic treatment for 2 weeks, and she had empirical anti-tuberculosis treatment and oral prednisolone therapy. She was followed for 3 months after presentation with improved symptoms and normal CSF analysis. A 3-month follow-up MRI showed asymmetric lesions in the cerebellum, corona radiata, and white matter with enhancement. The anti-tuberculosis treatment was continued, and steroid therapy was discontinued. After she stopped taking prednisolone, an interrupted headache gradually appeared. MRI at 4 months after presentation revealed a partial reduction in lesions but enlarged areas in the left cerebellum and right parietal white matter and a new lesion in the region of the right ependyma with linear enhancement. Her CSF was positive for anti-myelin oligodendrocyte glycoprotein (MOG) and anti-glial fibrillary acidic protein (GFAP) antibodies using a transfected cell-based assay. She was diagnosed with overlapping syndrome of MOG­IgG­associated disease and GFAP astrocytopathy. She received steroid pulse therapy (methylprednisolone, 1 g for 5 days), followed by a gradual tapering of oral prednisolone and the addition of an immunosuppressant (tacrolimus, 3 mg per day). Six months after the initial presentation, she had no symptoms. An MRI showed that the lesions had diminished, and no enhancement was found. CONCLUSIONS: We report a case that was positive for double antibodies, which was initially misdiagnosed as infectious meningoencephalitis. This case broadens the clinical and phenotypic presentation of the overlapping syndrome spectrum.

Upregulation of circ-FBL promotes myogenic proliferation in myasthenia gravis by regulation of miR-133/PAX7.

Myasthenia gravis (MG) is a disease involving neuromuscular transmission that causes fatigue of skeletal muscles and fluctuating weakness. It has been shown that impairment of myogenic differentiation and myofiber maturation may be the underlying cause of MG. In this study, we detected the abnormal expression of circular RNA (circRNA) using next-generation sequencing in patients with MG. We then investigated the regulatory mechanism and the relationship among circRNA, microRNA, and messenger RNA using quantitative reverse-transcription polymerase chain reaction, bioinformatics analysis, and luciferase report analysis. The expression of inflammatory cytokines and regulatory T lymphocytes was shown to be increased. Circ-FBL was significantly increased in MG patients. Bioinformatics and luciferase report analyses confirmed that miR-133 and PAX7 were the downstream targets of circ-FBL. Overexpression of circ-FBL promoted myoblast proliferation by regulation of miR-133/PAX7. Taken together, our study showed that upregulation of circ-FBL promoted myogenic proliferation in patients with MG by regulating miR-133/PAX7.

Tacrolimus as a therapeutic option in patients with acquired neuromyotonia.

OBJECTIVE: To analyze the clinical characteristics and outcomes of patients diagnosed with acquired neuromyotonia and who were treated with tacrolimus. METHODS: A single center, retrospective study was performed on patients with acquired meuromyotonia whose treatment included tacrolimus. The clinical information, antibody tests, and electromyography results were reviewed. The Numeric Rating Scale for pain and modified Rankin scale were used to quantify outcomes. RESULTS: This study included four patients who presented with fasciculation or myokymia in their limbs. Electromyography suggested peripheral nerve hyperexcitability. Autoantibodies including contactin-associated protein 2 (CASPR2), leucine-rich glioma inactivated protein 1 (LGl1) or IgLON5 antibody were detected in three patients, and another patient had Sjogren's syndrome. Initial treatment included membrane-stabilizing drugs and/or corticosteroids. Tacrolimus was administered at a dose of 3 mg once daily to all patients. All patients showed clinical improvement after the treatment. No recurrence was observed after gradual tapering or discontinuation of therapy during follow-up. CONCLUSIONS: Tacrolimus may be a therapeutic option for acquired neuromyotonia. Further studies on tacrolimus in larger patient cohort should be performed.

Correlation between anemia and clinical severity in subacute combined degeneration patients.

OBJECTIVES: Subacute combined degeneration (SCD) is a demyelinating disease commonly caused by vitamin B12 deficiency. Several studies have been reported SCD could be accompanied by anemia. However, the correlation between anemia and clinical severity of SCD patients is unclear. In this study, we aim to analyze the clinical characteristics of SCD concomitant with anemia, and investigate the effect of anemia in predicting the severity of SCD. METHODS: A total 42 patients were included in the study. Clinical, laboratory, radiological findings, and outcomes from the patients were analyzed. All patients were treated with vitamin B12 for no less than 6 months and a functional disability rating scale was used to evaluate severity of neurological impairment at the time of admission and 3 and 6 months after admission in our study. RESULTS: 85.7% patients had macrocytosis. Decreased serum vitamin B12 levels were found in 27 patients (64.3%). MRI showed long-segment abnormality on the spinal cord in 22 patients. No differences in rating score were found in patients grouped by sex, age, clinical course, serum vitamin B12, or MRI manifestations at the time of admission or at the follow-up visits. Negative correlation was seen between hemoglobin levels and the clinical severity scores on admission. CONCLUSION: Not all patients with SCD concomitant with anemia had decreased serum vitamin B12 level. The inverse correlation between hemoglobin level and clinical severity suggests the degree of anemia can help in evaluating the extent of neurologic impairment.

Hypertrophic Pachymeningitis in Chinese Patients: Presentation, Radiological Findings, and Clinical Course.

BACKGROUND: Hypertrophic pachymeningitis (HP) is generally regarded as a rare inflammatory disease, which results in a diffuse thickening of the dura mater. We retrospectively collected data from patients with HP. METHODS: A total of 16 patients with HP were included in our study. The clinical features, laboratory evaluation, imaging findings, treatment, and outcome were reviewed. RESULTS: Of the 16 cases, half were male, with a mean age of 52.6 ± 13.2 years. The mean duration from onset to diagnosis was 8.6 months. The most frequent presenting symptoms in HP cases were a recurrently chronic headache (81.3%) and multiple cranial nerve injury (50%). Antineutrophil cytoplasmic antibody- (ANCA-) related HP was found in 5 cases and IgG4-related HP in 1 case. The intracranial pressure was elevated in 4 cases. The cerebrospinal fluid (CSF) had lymphocytosis in 5 cases and increased protein in 12 cases. Immunoglobulins (IgG, IgA, and IgM) and protein showed linear relationships in the CSF. On magnetic resonance imaging (MRI), localized or diffuse dura maters were thickened in all cases. HP combined with subacute subdural hemorrhage or hypertrophic spinal pachymeningitis was also observed in individual cases. Biopsy of the dura mater in one case showed amounts of inflammatory cells infiltrating, with an increased percentage of IgG4-positive plasma cells. Of all cases referring to glucocorticoid treatment, the symptoms have improved significantly in 10 cases. In other 6 cases, mycophenolate mofetil or azathioprine was added. All patients showed clinical improvement at the follow-up visits. CONCLUSION: The clinical characters of HP are chronic onset, recurrently chronic headache, and multiple cranial nerves paralysis. Inflammatory changes in CSF caused by intrathecal synthesis of immunoglobulin, characteristic dural enhancement on MRI, and pathologic biopsy are all helpful for diagnosis. The addition of immunosuppressant, especially mycophenolate mofetil, is a good choice for steroid-resistance HP.