Ten-year fracture risk in Japanese patients with myasthenia gravis: A comprehensive assessment using the fracture risk assessment tool.

BACKGROUND: Myasthenia gravis (MG) is an immune disorder that causes muscle weakness with an increasing prevalence, particularly among the elderly in Japan. Glucocorticoid treatment for MG is problematic for bone health because of reduced bone density and increased fracture risk. The fracture risk assessment tool (FRAX®) can estimate fracture risk, but its applicability in patients with MG remains uncertain. METHODS: A prospective cohort study was conducted on 54 patients with MG between April and July 2012. Bone mineral density (BMD) was measured, and FRAX® scores were calculated with and without BMD. We also adjusted FRAX® scores based on glucocorticoid dosage. Patients were monitored for major osteoporotic fractures (MOF) until June 2022. Statistical analyses included Kaplan-Meier curves and Cox proportional hazards models. RESULTS: The study group included 12 men and 42 women with a mean age of 62 years. Higher FRAX® scores correlated with increased fracture risk, particularly in the hip and lumbar regions. The 10-year fracture-free rate was significantly lower in the high-FRAX® score group. The FRAX® score using BMD is a significant predictor of MOF risk. The hazard ratio for FRAX® scores was 1.17 (95% CI 1.10-1.26). CONCLUSION: We demonstrated the effectiveness of the FRAX® tool in assessing fracture risk among patients with MG. High FRAX® scores correlated with increased fracture risk, emphasizing its importance. These findings support the incorporation of FRAX® assessment into clinical management to enhance patient care and outcomes. However, the small sample size and observational nature suggest a need for further research.

Real-world experience with eculizumab and switching to ravulizumab for generalized myasthenia gravis.

OBJECTIVE: Eculizumab and ravulizumab are complement protein C5 inhibitors, showing efficacy and tolerability for patients with anti-acetylcholine receptor-positive (AChR+) generalized myasthenia gravis (gMG) in phase 3 clinical trials and subsequent analyses. The purpose of the present study was to evaluate the clinical significance of eculizumab and switching to ravulizumab for refractory AChR+ gMG patients in the real-world experience. METHODS: Among the database of Japan MG registry survey 2021, we studied AChR+ gMG patients who received eculizumab. We also evaluated these patients who switched from eculizumab to ravulizumab. Responder was defined as an improvement of at least 3 points in MG-ADL. We performed a questionnaire of preference between eculizumab and ravulizumab. RESULTS: Among 1,106 patients with AChR+ gMG, 36 patients (3%) received eculizumab (female 78%, mean age 56.0 years). Eculizumab was preferentially used in severe and refractory MG patients. The duration of eculizumab treatment was 35 months on average. MG-ADL improved from 9.4 ± 4.9 to 5.9 ± 5.1, and 25 (70%) of the 36 gMG patients were responders. Postintervention status was markedly improved after the eculizumab treatment. Of 13 patients who did not continue eculizumab, 6 showed insufficiencies. Early onset MG was most effective. However, 15 patients switching from eculizumab to ravulizumab kept favorable response and tolerability. Questionnaire surveys showed preference for ravulizumab over eculizumab. INTERPRETATION: Eculizumab and switching to ravulizumab showed to be effective for refractory AChR+ gMG patients in clinical settings.

Taste disorders and alopecia in myasthenia gravis.

BACKGROUND: Non-motor symptoms in myasthenia gravis (MG) are rarely confirmed. Although there are some small cohort studies, a large-systemic survey has not yet been performed. METHODS: We investigated the incidence and clinical characteristics of patients with MG who had taste disorders and alopecia using data of 1710 patients with MG enrolled in the Japan MG Registry 2021. RESULTS: Among them, 104 (6.1%) out of 1692 patients and 138 (8.2%) out of 1688 patients had histories of taste disorders and alopecia, respectively. Among the patients with MG, taste disorders were significantly more common in women, those with severe symptoms, refractory MG, or thymoma-associated MG, and were less common in those with ocular MG. The taste disorders often occurred after the onset of MG and often responded to MG treatments. Alopecia was more common in MG patients with a history of bulbar palsy and thymoma, and it often occurred before the onset of MG and sometimes responded to MG treatments. Multivariate logistic regression analysis revealed taste disturbance was associated with worst quantitative MG score and thymoma-associated MG; and alopecia was associated with thymoma-associated MG. CONCLUSION: Clinicians should be aware of the non-motor symptoms in MG, especially in patients with severe myasthenic symptoms and thymoma-associated MG.

Therapeutic Responses to Efgartigimod for Generalized Myasthenia Gravis in Japan.

Background and Objectives: Efgartigimod, which has been well tolerated and efficacious in individuals with generalized myasthenia gravis (MG), is available in Japan not only for the treatment of anti-acetylcholine receptor-positive (AChR+) but also anti-muscle-specific receptor tyrosine kinase (MuSK+) and seronegative generalized MG. We report details of the use of efgartigimod for generalized MG in clinical practice in Japan. Methods: We included patients with generalized MG in the 2021 survey of Japan Myasthenia Gravis Registry (JAMG-R) study group who received an initial cycle of efgartigimod between May and September 2022. We defined "responders" as patients who achieved a score ≥2 points for MG activities of daily living (MG-ADL) in the first treatment cycle. The MG composite and the Revised scale of the 15-item Myasthenia Gravis-Quality of Life scale (MG-QOL15-r) were also evaluated. Results: Of 1,343 JAMG-R patients, 36 (2.7%) started efgartigimod (female 68%, age 53 years). Their serologic profiles were as follows: AChR+, n = 19 (53%); MuSK+, n = 6 (17%); and seronegative, n = 11 (31%). Twenty-six patients (72%) had refractory MG. There were 81 cycles of efgartigimod during the 26-week observation in 34 patients (average, 2.4 cycles). The mean interval between cycles was 5.9 weeks. A continuous 4-weekly infusion of efgartigimod was performed in 65 (80%) of 81 cycles. In the first cycle, the MG-ADL score of the 34 patients decreased significantly from 10.5 ± 4.3 to 6.9 ± 5.1 (p = 0.003). Similarly, the mean MG composite and MG-QOL15-r decreased from 18.4 ± 13.6 to 11.8 ± 9.6 (p = 0.004) and from 19.2 ± 6.3 to 14.2 ± 8.3 (p = 0.007), respectively. Twenty-one (62%) patients were responders. Therapeutic responses were observed in the subsequent cycles. The duration of effectiveness of efgartigimod was varied among the responders; 4 responders had only a single effective cycle. Significant improvement was observed in the MuSK+ patients. Prednisolone dose of 7 patients was reduced. Our examination of the patients' postintervention status revealed that 6 patients achieved minimal manifestations. COVID-19 occurred in 5 patients. We failed to detect clinical or laboratory findings associated with responders. Discussion: Efgartigimod can be considered for the treatment of patients with generalized MG who do not achieve minimal manifestations, with a broad flexibility of patient selection and treatment schedules.

A Multifaceted Approach to Seizure Management in a Patient With Down Syndrome, Obstructive Sleep Apnea, and Hypothyroidism: A Case Report.

In this case study, a 16-year-old male with Down syndrome (DS) faced persistent nocturnal seizures despite anti-seizure medications and treatment for concurrent hypothyroidism. Obstructive sleep apnea (OSA), a common issue in patients with Down syndrome, was revealed as a trigger of the seizures. The implementation of continuous positive airway pressure (CPAP) therapy along with medication adjustments led to a significant decrease in seizure frequency, highlighting the importance of a comprehensive approach to seizure management in patients with complex medical conditions.

Anti-leucine-rich Glioma-inactivated 1 Protein-antibody Positive Encephalitis with Extensive Unilateral Cerebral Cortex and White Matter Lesions.

Encephalitis caused by antibodies targeting the leucine-rich glioma-inactivated 1 protein receptor, which belongs to the anti-voltage-gated potassium channel receptor complex, is characterized by hyponatremia, progressive cognitive impairment, seizures, and psychiatric disorders. The patient initially presented with faciobrachial dystonic seizures and subsequently developed encephalopathy. Brain magnetic resonance imaging revealed atypical unilateral hyperintense signals in the cerebral cortex and white matter. Intravenous corticosteroid pulse therapy effectively improved faciobrachial dystonic seizures and brain lesions.

Serum immunoglobulin G level reduction is a predictor of short-term improvement in patients with myasthenia gravis undergoing plasmapheresis.

OBJECTIVES: The aim of the study was to investigate the serological factors in predicting symptom improvement in myasthenia gravis (MG) patients who underwent plasmapheresis (PP). METHODS: The relationship between symptom improvement and change in immunoglobin G (IgG) and acetylcholine receptor antibody (AchR-Ab) levels in 21 MG patients after PP was analyzed. RESULTS: Patients were divided into two groups: the favorable (n = 11) or unfavorable (n = 10) response groups around the median MG composite improvement rate (50 [29, 56]%) 2 weeks after a PP course. In all patients, the IgG reduction rate before and after PP was higher in the favorable than the unfavorable response group. In AChR-Ab-positive patients, IgG and AChR-Ab reduction rates were higher in the favorable than the unfavorable response group. CONCLUSION: IgG reduction rate is a predictor of symptom improvement in MG patients who underwent PP.

Clinical features and outcomes of patients with muscle-specific kinase antibody-positive myasthenia gravis in Japan.

This study included 51 patients with muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG) from a Japanese multicenter survey to examine clinical features and outcomes. Median onset age was 37 years and female predominance was observed. All patients developed generalized symptoms and almost all (50/51) patients had bulbar symptoms. About half of the patients met the criteria for refractory MG. The refractory group had a lower age of onset, higher severity scores, and higher maximum daily doses of oral prednisolone compared to the nonrefractory group. The outcomes for MuSK-MG patients in Japan are not favorable, indicating the need for more aggressive treatment.

Comprehensive Management of Takayasu Arteritis Using Immunologic and Antithrombotic Interventions With Cerebral Circulation Support: A Case Report.

A 20-year-old woman with bilateral common carotid artery stenosis was diagnosed with Takayasu arteritis (TA). She suffered from a recurrent stroke, and repeated transient ischemic attacks (TIAs) occurred due to middle cerebral artery (MCA) stenosis. The clinical course indicated that TA contributed to MCA stenosis despite the negative results for serological inflammation markers. Immunotherapy with tocilizumab and methotrexate effectively reduced disease activity and improved symptoms. Bed rest and hydration prevented further TIAs and ischemic stroke progression. Long-term monitoring of neurological symptoms and angiography findings is essential to evaluate disease severity and treatment efficacy in TA patients with negative inflammatory markers.

Thiamine deficiency unrelated to alcohol consumption presented with urinary retention and Wernicke's encephalopathy: A case report.

Thiamine deficiency can present with rare neurological symptoms such as urinary retention, along with common symptoms like ataxia and decreased limb muscle strength. Early recognition and treatment are crucial to improve symptoms and prevent complications.

Siponimod ameliorates experimental autoimmune neuritis.

BACKGROUND: Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are human autoimmune peripheral neuropathy. Besides humoral immunity, cellular immunity is also believed to contribute to these pathologies, especially CIDP. Sphingosine-1-phosphate receptor 1 (S1PR1) regulates the maturation, migration, and trafficking of lymphocytes. As of date, the therapeutic effect of sphingosine-1-phosphate receptor (S1PR) agonists on patients with GBS or CIDP remains unclear. METHODS: To evaluate the effect of siponimod, an agonist of S1PR1 and S1PR5, on experimental autoimmune neuritis (EAN), an animal model of autoimmune peripheral neuropathy, was used. Lewis rats were immunized with 125 µg of synthetic peptide from bovine P2 protein. Rats in the siponimod group were orally administered 1.0 mg/kg siponimod and those in the EAN group were administrated the vehicle on days 5-27 post-immunization (p.i.) daily. The symptom severity was recorded daily. The changes in the expression of cytokines and transcription factors in the lymph nodes and cauda equina (CE) which correlate with the pathogenesis of EAN and recovery of injured nerve were measured using reverse transcription quantitative PCR. Histological study of CE was also performed. RESULTS: Flaccid paralysis developed on day 11 p.i. in both groups. Siponimod relieved the symptom severity and decreased the expression of interferon-gamma and IL-10 mRNAs in lymph nodes and CE compared with that in the EAN group. The expression of Jun proto-oncogene (c-Jun) mRNA increased from the peak to the recovery phase and that of Sonic hedgehog signaling molecule (Shh) and Glial cell line-derived neurotrophic factor (Gdnf) increased prior to increase in c-Jun with no difference observed between the two groups. Histologically, siponimod also reduced demyelinating lesions and inflammatory cell invasion in CE. CONCLUSIONS: Siponimod has a potential to ameliorate EAN. Shh and Gdnf, as well as C-Jun played a significant role during the recovery of injured nerves.

Impact of Early Treatment with Intravenous High-Dose Methylprednisolone for Ocular Myasthenia Gravis.

The efficacy of intravenous high-dose methylprednisolone (IVMP) in ocular myasthenia gravis (MG) has not been fully established. This study aimed to elucidate the effects of early intervention with IVMP for achieving the therapeutic targets (minimal manifestations [MM] or MM or better status with prednisolone ≤ 5 mg/day [MM5mg]) in ocular MG. In this observational study, we included a total of 1710 consecutive patients with MG enrolled in the Japan MG Registry in 2021. Of these, 204 patients with ocular MG who received immunotherapy were analyzed. The clinical course and time to first achieve MM or MM5mg after starting immunotherapy were compared between the early IVMP group (treated with IVMP within 3 months of treatment initiation) and the non-early IVMP group. Despite having greater clinical severity before immunotherapy and lower oral prednisolone doses throughout the course, the early IVMP group (n = 55) showed a higher rate of achievement of MM (P = 0.0040, log-rank test; hazard ratio 1.58, 95% confidence interval [CI] 1.13-2.20, P < 0.0001) and MM5mg (P = 0.0005, log-rank test; hazard ratio 1.78, 95% CI 1.27-2.51, P < 0.0001) compared with the non-early IVMP group (n = 149). In conclusion, an early intervention with IVMP is likely to increase the probability of achieving a better long-term outcome and reducing the total dose of corticosteroids in ocular MG.

Effectiveness of early cycles of fast-acting treatment in generalised myasthenia gravis.

BACKGROUND: Early fast-acting treatment (EFT) is the aggressive use of fast-acting therapies such as plasmapheresis, intravenous immunoglobulin and/or intravenous high-dose methylprednisolone (IVMP) from the early phases of treatment. EFT is reportedly beneficial for early achievement of minimal manifestations (MM) or better status with ≤5 mg/day prednisolone (MM5mg), a practical therapeutic target for myasthenia gravis (MG). OBJECTIVE: The current study aimed to clarify which specific EFT regimen is efficacious and the patient characteristics that confer sensitivity to EFT. METHODS: We recruited a total of 1710 consecutive patients with MG who enrolled in the Japan MG Registry for this large-cohort study. Among them, 1066 with generalised MG who had received immunotherapy were analysed. Prognostic background factors were matched in a 1:1 ratio using propensity score matching analysis between patients treated with EFT (n=350) and those treated without EFT (n=350). The clinical course and time to first achieve MM5mg after starting immunotherapy was analysed in relation to treatment combinations and patient characteristics. RESULTS: Kaplan-Meier analyses showed that EFT had a significant effect on the achievement of MM5mg (p<0.0001, log-rank test; HR 1.82, p<0.0001). Notably, EFT was efficacious for any type of MG, and the inclusion of IVMP resulted in earlier and more frequent achievement of MM5mg (p=0.0352, log-rank test; HR 1.46, p=0.0380). In addition, early administration of calcineurin inhibitors also promoted MM5mg achievement. CONCLUSION: Early cycles of intervention with EFT and early use of calcineurin inhibitors provides long-term benefits in terms of achieving therapeutic targets for generalised MG, regardless of clinical subtype.

Myasthenia Gravis Complicated by Eosinophilic Granulomatosis with Polyangiitis: A Case Report.

A 55-year-old woman with a history of allergic sinusitis was being administered cyclosporine for ptosis and diplopia due to myasthenia gravis since age 46 years. She developed painful dysesthesia that began in her feet and later spread to her palms, leading to difficulty in walking. Eosinophils were markedly increased in the peripheral blood. Nerve conduction studies revealed mononeuritis multiplex. Nerve biopsy showed the infiltration of eosinophils in the superior neurovasculature. Based on these findings, eosinophilic granulomatous polyangiitis was diagnosed. Methylprednisolone pulse therapy was followed by oral prednisolone. Two weeks after treatment, the patient could do normal daily activities without assistance. In patients with myasthenia gravis having a history of allergic diseases, considering EGPA as a complication and monitoring prior changes in blood data are necessary for early detection before apparent tissue damage.

Prehospital extracorporeal cardiopulmonary resuscitation for cardiac arrest patients in rural areas: a case report of two patients.

BACKGROUND: The prognosis of out-of-hospital cardiac arrest remains poor, especially for cardiopulmonary arrest patients in rural areas with longer transport duration to hospitals. CASE PRESENTATION: In June 2016, we began providing prehospital extracorporeal life support using a mobile operating room for emergency surgery. We report two patients who survived after receiving prehospital extracorporeal cardiopulmonary resuscitation and were discharged. A patient with cardiopulmonary arrest from accidental hypothermia due to drowning survived with good neurological outcomes after on-site extracorporeal cardiopulmonary resuscitation immediately after rescue. The other patient who survived experienced cardiopulmonary arrest at his workplace, which was approximately 90 min from the center. Prehospital extracorporeal cardiopulmonary resuscitation shortened the cardiopulmonary arrest time by an estimated 30 min, and the patient survived until the hospital. CONCLUSION: Prehospital extracorporeal cardiopulmonary resuscitation has the potential to save lives in rural areas by reducing low-flow time.

IL-9 Controls Central Nervous System Autoimmunity by Suppressing GM-CSF Production.

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are inflammatory diseases of the CNS in which Th17 cells play a major role in the disease pathogenesis. Th17 cells that secrete GM-CSF are pathogenic and drive inflammation of the CNS. IL-9 is a cytokine with pleiotropic functions, and it has been suggested that it controls the pathogenic inflammation mediated by Th17 cells, and IL-9R-/- mice develop more severe EAE compared with wild-type counterparts. However, the underlying mechanism by which IL-9 suppresses EAE has not been clearly defined. In this study, we investigated how IL-9 modulates EAE development. By using mice knockout for IL-9R, we show that more severe EAE in IL-9R-/- mice correlates with increased numbers of GM-CSF+ CD4+ T cells and inflammatory dendritic cells (DCs) in the CNS. Furthermore, DCs from IL-9R-/- mice induced more GM-CSF production by T cells and exacerbated EAE upon adoptive transfer than did wild-type DCs. Our results suggest that IL-9 reduces autoimmune neuroinflammation by suppressing GM-CSF production by CD4+ T cells through the modulation of DCs.

Oral corticosteroid dosing regimen and long-term prognosis in generalised myasthenia gravis: a multicentre cross-sectional study in Japan.

OBJECTIVE: We examined the correlation between the dosing regimen of oral prednisolone (PSL) and the achievement of minimal manifestation status or better on PSL ≤5 mg/day lasting >6 months (the treatment target) in patients with generalised myasthenia gravis (MG). METHODS: We classified 590 patients with generalised MG into high-dose (n=237), intermediate-dose (n=187) and low-dose (n=166) groups based on the oral PSL dosing regimen, and compared the clinical characteristics, previous treatments other than PSL and prognosis between three groups. The effect of oral PSL dosing regimen on the achievement of the treatment target was followed for 3 years of treatment. RESULTS: To achieve the treatment target, ORs for low-dose versus high-dose regimen were 10.4 (P<0.0001) after 1 year of treatment, 2.75 (P=0.007) after 2 years and 1.86 (P=0.15) after 3 years; and those for low-dose versus intermediate-dose regimen were 13.4 (P<0.0001) after 1 year, 3.99 (P=0.0003) after 2 years and 4.92 (P=0.0004) after 3 years. Early combined use of fast-acting treatment (OR: 2.19 after 2 years, P=0.02; OR: 2.11 after 3 years, P=0.04) or calcineurin inhibitors (OR: 2.09 after 2 years, P=0.03; OR: 2.36 after 3 years, P=0.02) was associated positively with achievement of treatment target. CONCLUSION: A low-dose PSL regimen with early combination of other treatment options may ensure earlier achievement of the treatment target in generalised MG.

Severe ileus and urinary retention in a patient with tuberculous meningitis.

An acute ileus and/or urinary retention are recognized as emergent complications requiring appropriate depressurizing treatments. Meningitis should be suspected as a cause of these autonomic disturbances.

Social disadvantages associated with myasthenia gravis and its treatment: a multicentre cross-sectional study.

OBJECTIVES: To clarify the social disadvantages associated with myasthenia gravis (MG) and examine associations with its disease and treatment. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: We evaluated 917 consecutive cases of established MG seen at 13 neurological centres in Japan over a short duration. OUTCOME MEASURES: All patients completed a questionnaire on social disadvantages resulting from MG and its treatment and a 15-item MG-specific quality of life scale at study entry. Clinical severity at the worst condition was graded according to the MG Foundation of America classification, and that at the current condition was determined according to the quantitative MG score and MG composite. Maximum dose and duration of dose ≥20 mg/day of oral prednisolone during the disease course were obtained from the patients' medical records. Achievement of the treatment target (minimal manifestation status with prednisolone at ≤5 mg/day) was determined at 1, 2 and 4 years after starting treatment and at study entry. RESULTS: We found that 27.2% of the patients had experienced unemployment, 4.1% had been unwillingly transferred and 35.9% had experienced a decrease in income, 47.1% of whom reported that the decrease was ≥50% of their previous total income. In addition, 49.0% of the patients reported feeling reduced social positivity. Factors promoting social disadvantages were severity of illness, dose and duration of prednisolone, long-term treatment, and a depressive state and change in appearance after treatment with oral steroids. Early achievement of the treatment target was a major inhibiting factor. CONCLUSIONS: Patients with MG often experience unemployment, unwilling job transfers and a decrease in income. In addition, many patients report feeling reduced social positivity. To inhibit the social disadvantages associated with MG and its treatment, greater focus needs to be placed on helping patients with MG resume a normal lifestyle as soon as possible by achieving the treatment target.

Early fast-acting treatment strategy against generalized myasthenia gravis.

INTRODUCTION: In this study we sought to clarify the effects of early fast-acting treatment (EFT) strategies on the time course for achieving the treatment target in generalized myasthenia gravis (MG). METHODS: This retrospective study of 923 consecutive MG patients analyzed 688 generalized MG patients who had received immunotherapy during the disease course. The time to first achieve minimal manifestations (MM) or better while receiving prednisolone at ≤5 mg/day for ≥6 months (MM-or-better-5mg) up to 120 months after starting immunotherapy was compared between EFT and non-EFT patients. RESULTS: Achievement of MM-or-better-5mg was more frequent and earlier in the EFT group (P = 0.0004, Wilcoxon test; P = 0.0001, log-rank test). Multivariate Cox regression analysis calculated a hazard ratio of 1.98 (P < 0.0001) for utilization of EFT. Dosing regimens of oral steroids in EFT produced no differences in the time course. CONCLUSIONS: EFT strategies are advantageous for early achievement of MM-or-better-5mg. Muscle Nerve 55: 794-801, 2017.