Secondary cardiac involvement in anti-SRP-antibody-positive myopathy: an 87-year-old woman with heart failure symptoms as the first clinical presentation.

BACKGROUND: Necrotizing myopathy (NM) is defined by the dominant pathological feature of necrosis of muscle fibers without substantial lymphocytic inflammatory infiltration. Anti-signal recognition particle (SRP)-antibody-positive myopathy is related to NM. Anti-SRP-antibody-positive myopathy can comorbid with other disorders in some patients, however, comorbidity with malignant tumor and myopericarditis has still not been reported. CASE PRESENTATION: An 87-year-old woman with dyspnea on exertion and leg edema was referred to our hospital because of suspected heart failure and elevated serum creatine kinase level. Upon hospitalization, she developed muscle weakness predominantly in the proximal muscles. Muscle biopsy and immunological blood test led to the diagnosis of anti-SRP-antibody-positive myopathy. A colon carcinoma was also found and surgically removed. The muscle weakness remained despite the tumor resection and treatment with methylprednisolone. Cardiac screening revealed arrhythmia and diastolic dysfunction with pericardial effusion, which recovered with intravenous immunoglobulin (IVIg) treatment. CONCLUSIONS: We reported the first case of anti-SRP-positive myopathy comorbid with colon carcinoma and myopericarditis. This case is rare in the point that heart failure symptoms were the first clinical presentation. The underlying mechanism is still not clear, however, physicians should be carefully aware of the neoplasm and cardiac involvement in anti-SRP-antibody positive-myopathy patients and should consider farther evaluation and management.

Brain volume loss is present in Japanese multiple sclerosis patients with no evidence of disease activity.

No evidence of disease activity-3 (NEDA-3), defined as absence of clinical relapse, disability progression, and brain magnetic resonance imaging (MRI) activity, has emerged as the therapeutic target of disease-modifying therapy for multiple sclerosis (MS). However, recent studies have revealed that NEDA-3 might not be sufficient to prevent cognitive deterioration and predict long-term disability. In addition to NEDA-3, brain atrophy has recently been recognized as a pivotal biomarker that is closely associated to disability in patients with MS. This retrospective observational study included 22 Japanese MS patients with relatively mild disease (median expanded disability status scale = 1.75). Fifteen patients (68%) received disease-modifying therapy (DMT), including interferon (IFN)-ß (n = 6), IFN-ß, or azathioprine followed by fingolimod (n = 4), fingolimod (n = 4), and IFN-ß followed by natalizumab (n = 1). It revealed that 14 (64.6%) patients achieved NEDA-3 in the 2-year observational period. However, nine (64.3%) of the patients with NEDA-3 were revealed to have a significant BVL, defined as ≥ 0.4% per year. Importantly, these nine patients included all patients receiving IFN-ß therapy (n = 6), whereas patients without BVL included none of these patients. Conversely, patients treated with fingolimod following IFN-ß did not have significant BVL. These results indicate that evaluation of NEDA-4 is encouraged especially in patients with IFN-ß therapy in MS clinical practice in Japan although Japanese MS patients have generally been thought to possess a milder disease including brain atrophy compared to their Western counterparts.

Association between Delirium and Prehospitalization Medication in Poststroke Patients.

PURPOSE: Medication is an important risk factor for delirium; however, the association between delirium and prehospitalization medication is unclear. We investigated the association between prestroke medication and poststroke delirium. MATERIALS AND METHODS: All patients hospitalized in the stroke care unit from September 2011 to September 2012 were selected, and their delirium symptoms, patient information, and pre- and poststroke medications were analyzed. Delirium was defined as a score of 4 or higher on the Intensive Care Delirium Screening Checklist. Factors that were related to delirium were extracted using univariate analysis, and the independent risk factors were determined using multivariate analysis. RESULTS: Of the 269 patients analyzed, 97 (36%) experienced delirium. Univariate analysis revealed significant differences between the delirium and nondelirium groups in age, dementia, previous cerebrovascular disease, craniotomy, all insertion-tube types, and 6 categories of prestroke medication. Prestroke polypharmacy was associated with poststroke delirium (P = .002). Multivariate analysis showed that taking antianxiety agents or sleep aids was an independent risk factor for delirium (odds ratio: 3.17, 95% confidence interval: 1.16-8.82). CONCLUSIONS: The present study suggests that prestroke medication affects the onset of poststroke delirium. These findings can contribute to the prediction and prevention of this condition.

Continuous diffuse brain atrophy independent of relapse as a hallmark of multiple sclerosis beginning from relapsing-remitting stage.

BACKGROUND: Neurodegenerative changes are observed in relapsing-remitting multiple sclerosis (RRMS) and are prominent in secondary progressive MS (SPMS). However, whether neurodegenerative changes accelerate and are altered after the transition into SPMS or in the presence of relapses remains uncertain. METHODS: In this study, 73 patients with MS (seven with relapsing RRMS, 56 with relapse-free RRMS, and 10 with relapse-free SPMS) were evaluated for brain segmental volume changes over a 2-year follow-up period. Volume change was calculated using a within-subject unbiased longitudinal image analysis model. RESULTS: The rates of brain volume change in the 11 brain regions evaluated were relatively similar among different brain regions. Moreover, they were similar among the relapsing RRMS, relapse-free RRMS, and SPMS groups, even after adjusting for age. CONCLUSIONS: The relatively constant brain segmental atrophy rate throughout the disease course, regardless of relapse episodes, suggests that RRMS and SPMS are continuous, uniform, and silent progressing brain atrophy diseases on a spectrum.

Early-onset herpes simplex encephalitis type 1 triggered by COVID-19 disease: A case report.

Coronavirus disease 2019 (COVID-19) causes a systemic inflammatory response and a temporary immunosuppression of hosts. Several reports have showed that reactivation of herpes simplex virus type 1 (HSV-1) is strongly associated with COVID-19. We present a case of a 66-year-old female, who developed HSV-1 encephalitis, showing impaired consciousness and typical MRI findings such as hyperintense lesions in the temporal lobe, insular cortices, bilateral medial frontal lobe on diffusion-weighted imaging, 7 days after the onset of COVID-19 symptoms. The number of cases of encephalitis in patients with COVID-19 is increasing. However, there has been limited reports of HSV-1 encephalitis following COVID-19, especially for cases with an interval of 7 days or less from the onset of COVID-19 symptoms to the onset of HSV-1 encephalitis. Our case highlights the importance of considering HSV-1 encephalitis in the differential when managing a patient with COVID-19-associated neurologic complications, even if it is in the early stages of COVID-19.

Recurrent Lymphocytic Hypophysitis Presenting as Internal Carotid Artery Stenosis and Oculomotor Nerve Palsy.

A 75-year-old woman presented with nausea and vomiting. Magnetic resonance imaging (MRI) revealed that she had a pituitary mass. A biopsy revealed lymphocytic hypophysitis (LYH). Symptoms were improved by hormone replacement therapy. Although she was asymptomatic, follow-up MRI revealed an increase in the size of the mass. Intravenous methylprednisolone (IVMP) reduced the size of the mass; however, right ophthalmalgia and oculomotor nerve palsy developed. MRI showed that the pituitary mass had enlarged to the right oculomotor nerve in the cavernous sinus and to the right internal carotid artery (ICA), causing stenosis of the ICA. After IVMP administration, the symptoms dramatically improved, but ICA stenosis persisted.

Long-term safety and effectiveness of eculizumab in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: a 2-year interim analysis of post-marketing surveillance in Japan.

Background: The terminal complement C5 inhibitor eculizumab is approved in Japan for relapse prevention in aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and is undergoing mandatory post-marketing surveillance (PMS) of clinical use. Objectives: The objective of the study is to assess the real-world, long-term safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD. Design: Regulatory-mandated PMS analysis implemented as an all-case surveillance of all patients with AQP4+ NMOSD who have been treated with eculizumab in Japan since its approval in November 2019. Methods: This PMS interim analysis assessed the safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD from November 2019 to April 2022. Results: Of 147 patients treated with eculizumab who consented to publication, 71 had at least one case report form collected and locked at the interim analysis data cut-off, constituting the safety analysis set; three patients from PREVENT (NCT01892345) were excluded from the effectiveness analysis set. Twelve and 10 patients in the safety and effectiveness analysis sets discontinued, respectively. In the safety analysis set, 67/71 patients (94.4%) were female, mean illness duration was 6.8 [standard deviation (SD): 6.2] years, mean age at eculizumab initiation was 50.7 (SD: 13.3) years, and mean eculizumab treatment duration was 44.6 (SD: 23.7) weeks. At diagnosis of NMOSD, 34/71 patients (47.9%) and 35/71 patients (49.3%) in the safety analysis set had symptoms of optic neuritis and transverse myelitis, respectively. In the safety analysis set, 19/71 patients (26.8%) reported adverse events, 10/71 (14.1%) reported adverse drug reactions (ADRs), and 7/71 (9.9%) reported serious ADRs; no meningococcal infections were observed. In the effectiveness analysis set, 64/68 patients (94.1%) were female, mean disease duration was 6.9 (SD: 6.3) years, mean age at eculizumab initiation was 50.6 (SD: 13.2) years, and 27/68 (39.7%) were tested for C5 genetic polymorphism (all negative). In the 2 years before eculizumab, 51/68 patients (75.0%) experienced relapse. Relapse rate was 0.02/patient-year after eculizumab initiation versus 0.74/patient-year in the 2 years before eculizumab. Overall, 37/68 patients (54.4%) were prescribed immunosuppressants in the 6 months before and 19/40 (47.5%) in the 6-12 months after starting eculizumab treatment. The proportion of patients taking >10 mg/day of prednisolone decreased from 45.6% at 24-20 weeks before to 23.1% and 0% at 48-52 and 100-104 weeks after eculizumab, respectively. Conclusion: This article reports interim PMS data for Japanese patients and provides updated real-world evidence for the safety of eculizumab and its effectiveness at preventing relapses in patients with AQP4+ NMOSD. Safety and effectiveness results are consistent with those from PREVENT.

High-efficacy therapy reduces subcortical grey matter volume loss in Japanese patients with relapse-onset multiple sclerosis: A 2-year cohort study.

BACKGROUND: Different treatment strategies can have varying effects on disability and whole brain volume in patients with multiple sclerosis (MS). However, the association between regional brain volume and treatment efficacy is currently unclear. Our objective was to determine whether whole brain volume, as well as the regional volume of cortical and subcortical grey matter, differ with the administration of high-efficacy therapy (HET) versus low-efficacy therapy (LET). METHODS: We evaluated clinical data and change in regional brain volume in 44 patients with relapse-onset MS, who underwent HET (n = 19) or LET (n = 25). Regional brain volume was determined with three-dimensional T1-weighted magnetic resonance imaging using FreeSurfer. The association between volume change and treatment type was assessed via generalised linear mixed models (GLMMs). RESULTS: During the observation period (2.0 ± 0.16 years), the proportion of patients with a "no evidence of disease activity-3″ status was significantly greater in those who underwent HET versus LET (p = 0.012). HET was positively associated with volume changes in the cortex (ß = 0.64, p = 0.0499), left (ß = 0.98, p = 0.0033) and right (ß = 0.77, p = 0.019) caudate and right putamen (ß = 0.87, p = 0.0077), after adjusting for age, sex, and MS severity scores in the GLMMs. Further correction for multiple comparisons by false discovery rate revealed that HET was consistently associated with the volume changes of the left caudate (p = 0.049) and right putamen (p = 0.049). CONCLUSION: HET can improve the mid-term prognosis of Japanese patients with relapse-onset MS by reducing disease activity and regional brain volume loss.

Suppression of experimental autoimmune encephalomyelitis by ghrelin.

Ghrelin is a recently identified gastric hormone that displays strong growth hormone-releasing activity mediated by the growth hormone secretagogue receptor. While this unique endogenous peptide participates in the regulation of energy homeostasis, increases food intake, and decreases energy expenditure, its ability to inhibit the production of proinflammatory cytokines in vitro indicates its role in the regulation of inflammatory process in vivo. Here we examine the effect of exogenous ghrelin on the development of experimental autoimmune encephalomyelitis (EAE), a representative model of multiple sclerosis. In the C57BL/6 mouse model of EAE induced by sensitization to myelin oligodendrocyte glycoprotein 35-55 peptide, we found that alternate-day s.c. injections of ghrelin (5 mug/kg/day) from day 1 to 35 significantly reduced the clinical severity of EAE. The suppression of EAE was accompanied by reduced mRNA levels of proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6 in the spinal cord cellular infiltrates and microglia from ghrelin-treated mice at the peak of disease, suggesting the role of ghrelin as an antiinflammatory hormone. Consistently, ghrelin significantly suppressed the production of proinflammatory cytokines in LPS-stimulated microglia in vitro. These results shed light on the new role of ghrelin in the regulation of inflammation with possible implications for management of human diseases.

Theory of mind and its neuroanatomical correlates in people with multiple sclerosis.

Background Theory of mind (ToM) is one of the several different concepts in social cognition and is defined as the ability to access the mental states of others or to adopt the point of view of others. Although studies have shown that ToM is impaired in people with multiple sclerosis (MS), the results based on individual ToM tasks are conflicting; some studies have shown deficits only in the 'Reading the Mind in the Eyes' Test (RMET), while others have reported poor performance in the Faux Pas Test (FPT) as well as RMET. Furthermore, little is known about the relationship between ToM performance and neuroanatomical characteristics in MS. This study investigated ToM impairment and its relationship to regional brain volume or cortical thickness in people with MS. Methods This cross-sectional study included 20 participants with relapse-onset MS and 27 age- and sex-matched volunteers as healthy controls (HC). All the participants underwent neuropsychological (NP) tests as well as ToM tasks, including RMET and FPT. Participants with MS underwent brain MRI within 6 months before and after undergoing the NP and ToM tests. Regional volume of subcortical structures or cortical thickness were analysed based on 3D T1-weighted images using FreeSurfer software. Results Both RMET and FPT scores were significantly lower in participants with MS than in HC (p = 0.0049, p = 0.0071, respectively). Imaging analyses showed that FPT scores, but not RMET scores, were positively correlated with the right thalamus (R2 = 0.26, p = 0.012) and left pallidum (R2 = 0.39, p = 0.0021) volumes after adjusting for age. Furthermore, surface-based morphometry revealed significant correlation between age-adjusted cortical thickness of ten cortical areas, including the fusiform gyrus, orbitofrontal cortex, temporal-parietal junction, and superior temporal gyrus, and FPT scores. Conclusions These study findings showed that both RMET and FPT performances are impaired in participants with MS. Furthermore, FPT deficits, but not RMET deficits, were significantly associated with the volume of two subcortical structures as well as the thickness of ten cortical areas, suggesting that FPT is an appropriate task to access ToM performance in MS.

Serum amyloid A level correlates with T2 lesion volume and cortical volume in patients with multiple sclerosis.

It is unclear whether brain atrophy in multiple sclerosis (MS) is associated with not only neuroinflammation but also systemic inflammation. Here we found that systemic inflammatory marker serum amyloid A (SAA) was moderately correlated with cortical volume in the patients with clinically isolated syndrome (CIS) and MS (r = -0.41, p = 0.019). SAA was also significantly correlated with T2 lesion volume (T2LV) even after adjusting for age, disease duration, and disease modifying therapy (p = 0.0050). Thus, systemic inflammation may be associated with cortical atrophy, possibly via an increase in the T2LV in patients with CIS/MS.

The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.

A case of anti-AQP4 antibody-positive neuromyelitis optica spectrum disorder with MRI-proven lesions in lumbar nerve roots.

Neuromyelitis optica spectrum disorder (NMOSD) affects the central nervous system but is rarely reported to cause peripheral nervous system damage. We report a case of a 57-year-old woman with numbness and muscle weakness of the left lower limb during the course of 12 years of anti-AQP4 antibody-positive NMOSD. Lumbar magnetic resonance imaging (MRI) showed a contrast effect on the left L4, L5, and S1 nerve roots, which is a highly unusual presentation. Although radiculopathy without myelopathy is unusual in AQP4-positive NMOSD, the MRI-confirmed nerve root lesions in our case indicate that it can occur.

NKT cell-dependent amelioration of a mouse model of multiple sclerosis by altering gut flora.

Improved hygiene has been suggested to influence certain autoimmune disorders, such as multiple sclerosis. In this study, we addressed whether altering the composition of gut flora may affect susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We administered a mixture of non-absorbing antibiotics, kanamycin, colistin, and vancomycin (KCV), orally to mice induced to develop EAE. The antibiotic treatment, beginning 1 week prior to sensitization, altered the composition of gut flora and, intriguingly, also ameliorated the development of EAE. While this result was associated with a reduced production of pro-inflammatory cytokines from the draining lymph node cells, a reduction of mesenteric Th17 cells was found to correlate with disease suppression. In addition, we found that Valpha14 invariant NKT (iNKT) cells were necessary for maintaining the mesenteric Th17 cells. The homologous effects of KCV treatment and iNKT cell depletion led us to speculate that KCV treatment may suppress EAE by altering the function of iNKT cells. Consistent with this hypothesis, KCV treatment did not suppress EAE that was induced in iNKT cell-deficient mice, although it was efficacious in mice that lacked Valpha19 mucosal-associated invariant T cells. Thus, gut flora may influence the development of EAE in a way that is dependent on iNKT cells, which has significant implications for the prevention and treatment of autoimmune diseases.

[A case of antisynthetase syndrome with anti-EJ antibody complicated by pericarditis].

A 69-year-old man was admitted with neck muscle weakness, symmetric proximal muscle weakness, skin rash and elevated serum creatine kinase levels. Muscle biopsy showed perifascicular necrosis and perimysial alkaline phosphatase activity. Chest CT revealed interstitial lung disease and colorectal cancer was diagnosed on colonoscopy. He was serologically positive for anti-EJ antibody, leading to the diagnosis of antisynthetase syndrome (ASS). After laparoscopic low anterior resection of the rectum, he received intravenous methylprednisolone (1,000 mg/d for 3 days) followed by oral prednisolone (50 mg/d). Although his muscle weakness improved after corticosteroid therapy, he developed pericardial effusion with resultant asymptomatic hypotension and arrhythmia possibly due to pericarditis. Corticosteroid monotherapy was insufficient to control the disease, and, we decided to use oral cyclosporin concurrently. After this combined therapy started, pericardial effusion and arrhythmia were improved. We should keep in mind that pericarditis can occur in patients with anti-EJ antibody-positive ASS, and early combined therapy with corticosteroid and immunosuppressive drugs for ASS may improve the patient's prognosis.

[Bilateral medial medullary infarction presented with monoplegia of the lower limb, followed by paraplegia and finally by tetraplegia].

A 69-year-old Japanese man suddenly developed monoplegia of left lower extremity, followed by paraplegia and finally by tetraplegia. MRI revealed an infarction in bilateral medial medulla extending from the cervicomedullary junction up to the upper limit of the medulla. Both hypoglossal nerve palsy and sensory disturbance were absent. At the pyramidal decussation, fibers to the lower extremities cross caudal to the fibers going to the upper extremities, therefore right below the decussation, fibers to the lower extremities run medial side of the fibers to the upper extremities, but later the former run lateral side of the latter. In this patient, the authors considered that the lesion initially damaged the pyramidal decussation at a slightly lower level, involving the tract to left lower extremity, and then extended to right lower extremity, to the left upper extremity, finally to the right upper extremity. Bilateral medial medullary infarction must be considered in the clinical course seen as in this patient.