High-dose steroid-responsive COVID-19-related encephalopathy with a sudden onset of dysarthria mimicking stroke: a case report.

There has been limited research on encephalitis/encephalopathy, which is a less common coronavirus disease 2019 (COVID-19) neurological complication. The differentiation between stroke and encephalopathy with stroke mimickers is challenging in patients with COVID-19. Here, we describe a case of COVID-19-related encephalopathy mimicking stroke that was successfully treated with high-dose steroid pulse therapy. The patient suddenly experienced language disturbance with a left facial droop and symmetric numbness in his upper limbs. Magnetic resonance imaging (MRI) scans revealed hyperintensities in both the white matter and splenium. No pneumonia was observed. MRI abnormalities and neurological symptoms resolved after steroid pulse therapy and administration of remdesivir. High-dose steroid pulse treatment (for 3 days) might alleviate COVID-19-related encephalopathy.

[A case of Guillain-Barré syndrome with unilateral diaphragmatic nerve palsy that was longitudinally evaluated using multiple examinations].

The patient, a 50-year-old woman, presented with fever and diarrhea in early July, X. One week later, she noticed muscle weakness in both lower extremities, which upon examination was found to be dominant in the distal muscles, with associated loss of tendon reflexes. We diagnosed the case as Guillain-Barré syndrome. After admission, the patient experienced decreased oxygenation, and a chest X-ray indicated elevation of the left hemidiaphragm. The phrenic nerve conduction studies revealed laterality of the amplitude of compound muscle action potential, and diaphragmatic ultrasonographic examination revealed decreased left diaphragmatic wall motion. We diagnosed the patient with unilateral diaphragmatic nerve palsy and initiated intravenous immunoglobulin and methylprednisolone treatment. After 2 weeks, the patient demonstrated good clinical recovery, increased diaphragmatic nerve amplitude, and improved diaphragmatic movement. We evaluated the longitudinal clinical course of unilateral diaphragmatic nerve palsy in the patient using nerve conduction tests and diaphragmatic echocardiography. The longitudinal evaluation allowed us to assess the pathological condition more sensitively so that the prognosis could be predicted accurately.

Prognostic Factor for Subacute Encephalitis with First-Episode Psychosis.

INTRODUCTION: Although symptomatic manifestations in encephalitis vary, they typically include seizures, memory deficit(s), and altered consciousness. Psychosis also occurs as an initial manifestation. In clinical practice, clinicians often encounter the question of whether first-episode psychosis (FEP) originates from encephalitis itself or if encephalitis presenting with FEP develops concurrently. The prognosis of FEP among patients with overall encephalitis, including autoimmune encephalitis, remains uncertain. METHODS: We examined a prognostic factor in patients with encephalitis who had both FEP and CSF pleocytosis. A total of 36 patients who presented with FEP were enrolled. A score of ≥3 and ≤2 on the modified Rankin scale were defined as poor and good outcomes, respectively. A total of 13 independent variables were analyzed by the multivariate logistic regression analysis. RESULTS: Significant variables on univariate logistic regression analysis included female sex (OR 5.571, 95% CI: 1.297-23.934; p = 0.021) and the use of mechanical ventilation during the acute stage (OR 7.286, 95% CI: 1.508-35.211; p = 0.013). On multivariate logistic regression analysis, the use of mechanical ventilation during the acute stage (OR 5.446, 95% CI: 1.044-28.615; p = 0.044) was significantly associated with poor outcomes. CONCLUSIONS: The use of mechanical ventilation is a poor prognostic factor of subacute encephalitis with FEP, and female sex may be a risk factor for unfavorable development of the disease.

Effects of a False Window on the Change of Cognitive Function in Patients Admitted to a Neurological Ward.

False windows can display a variety of outdoor scenery in rooms without real windows. We aimed to assess the effects of three different hospital beds on the change in the frontal assessment battery scores in patients aged ≥ 20-year-old admitted in our neurological ward. We included 24 patients on the window side, 12 patients on the aisle side with a false window, and 12 patients on the aisle side without a false window. There were no statistical differences in the change of cognitive function among the three hospital beds. Only the length of hospital stay was a significant associated factor.

Pathological features of inflammatory myopathy as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation.

Chronic graft-versus-host disease (cGVHD) is the most important complication resulting in the death of bone marrow transplantation (BMT) survivors. It is also a relatively rare cause of inflammatory myopathy (IM). We report the case of a 46-year-old woman who developed severe cGVHD-related IM after BMT for myelodysplastic syndrome. She presented with severe muscle pain and weakness with cGVHD-related symptoms in other organs. Myopathological analysis showed moderate cell infiltration with remarkable necrotic and regenerative fibers. Sarcoplasm and capillaries expressed C5b9 and myxovirus resistance protein 1. Non-necrotic fibers in perifascicular regions expressed MHC-II. Steroid therapy did not sufficiently control cGVHD-related IM, and the patient was concurrently treated with an immunosuppressant. Our findings show that IM is a key manifestation of cGVHD and that the expression of interferon-inducible proteins in muscle pathology is useful for identifying cGVHD-related IM.

C9orf72-Derived Proline:Arginine Poly-Dipeptides Modulate Cytoskeleton and Mechanical Stress Response.

Proline:arginine (PR) poly-dipeptides from the GGGGCC repeat expansion in C9orf72 have cytotoxicity and bind intermediate filaments (IFs). However, it remains unknown how PR poly-dipeptides affect cytoskeletal organization and focal adhesion (FA) formation. Here, we show that changes to the cytoskeleton and FA by PR poly-dipeptides result in the alteration of cell stiffness and mechanical stress response. PR poly-dipeptides increased the junctions and branches of the IF network and increased cell stiffness. They also changed the distribution of actin filaments and increased the size of FA and intracellular calcium concentration. PR poly-dipeptides or an inhibitor of IF organization prevented cell detachment. Furthermore, PR poly-dipeptides induced upregulation of mechanical stress response factors and led to a maladaptive response to cyclic stretch. These results suggest that the effects of PR poly-dipeptides on mechanical properties and mechanical stress response may serve as a pathogenesis of C9orf72-related neurodegeneration.

Effect of galvanic vestibular stimulation on axial symptoms in Parkinson's disease.

Postural imbalance, abnormal axial posture, and axial rigidity are the characteristic features of Parkinson's disease (PD), and they are referred to as axial symptoms. The symptoms are difficult to manage since they are often resistant to both L-DOPA and deep brain stimulation. Hence, other treatments that can improve Parkinsonian axial symptoms without adverse effects are required. Vestibular dysfunction occurs in PD since neuropathological changes and reflex abnormalities are involved in the vestibular nucleus complex. Galvanic vestibular stimulation (GVS), which activates the vestibular system, is a noninvasive method. This review aimed to assess the clinical effect of GVS on axial symptoms in PD. To date, studies on the effects of GVS on postural instability, anterior bending posture, lateral bending posture, and trunk rigidity and akinesia in PD had yielded interesting data, and none of the patients presented with severe adverse events, and the others had mild reactions. GVS indicated a possible novel therapy. However, most included a small number of patients, and the sample sizes were not similar in some studies that included controls. In addition, there was only one randomized controlled clinical trial, and it did not perform an objective evaluation of axial symptoms. In this type of research, vestibular contributions to balance should be distinguished from others such as proprioceptive inputs or nonmotor symptoms of PD.

Zonisamide for the Efficacy of Sleep Abnormality in Parkinson's Disease (ZEAL Study): A Protocol for Randomized Controlled Trials.

Background: Sleep disorders are one of the most frequent non-motor symptoms of Parkinson's disease (PD), and the efficacy of dopaminergic agents remains controversial. Clinical randomized control trials for the treatment of sleep disorders in PD are limited. Zonisamide (1,2-benzisoxazole-3-methanesulfonamide) improved motor symptoms and wearing-off in patients with PD. Patients with PD were reported to have dream-enacting behavior that was resolved after treatment with zonisamide. This study aimed to verify the safety and efficacy of zonisamide for sleep disorders and rapid eye movement (REM) sleep behavioral disorders using a mobile two-channel electroencephalography (EEG)/electrooculography (EOG) recording system. Methods and Analysis: The present study is a randomized placebo-controlled trial to determine the efficacy of zonisamide for sleep disorders in patients with PD. This study was designed to be single-blind, but the subject allocation is randomized by an independent allocation manager via computer-generated block randomization. The subjects in the treatment group took zonisamide (25 mg per day) before bedtime for 28 days. The sleep index is analyzed using a portable EEG/EOG recording system collected on two consecutive nights within 7 days prior to the intervention and reobtained on one night within 2 days after the 28-day administration of zonisamide. The amount of change in sleep efficiency before and after the 28-day administration will be compared between the zonisamide treatment group and placebo group concerning the primary endpoint. As for the secondary endpoint, the change in the ratio of other sleep parameters, including REM sleep without atonia, or sleep architecture will be evaluated. Ethics and Dissemination: The protocol was approved by the Nara Medical University Certified Review Board (CRB5200002). The trial was notified and registered with the Japan Registry of Clinical Trials (jRCTs051200160). Written informed consent will be obtained from every participant using informed consent approved by the CRB. The results of this trial will be disseminated through peer-reviewed scientific journals.

C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers.

Nuclear import receptors (NIRs) not only transport RNA-binding proteins (RBPs) but also modify phase transitions of RBPs by recognizing nuclear localization signals (NLSs). Toxic arginine-rich poly-dipeptides from C9orf72 interact with NIRs and cause nucleocytoplasmic transport deficit. However, the molecular basis for the toxicity of arginine-rich poly-dipeptides toward NIRs function as phase modifiers of RBPs remains unidentified. Here we show that arginine-rich poly-dipeptides impede the ability of NIRs to modify phase transitions of RBPs. Isothermal titration calorimetry and size-exclusion chromatography revealed that proline:arginine (PR) poly-dipeptides tightly bind karyopherin-ß2 (Kapß2) at 1:1 ratio. The nuclear magnetic resonances of Kapß2 perturbed by PR poly-dipeptides partially overlapped with those perturbed by the designed NLS peptide, suggesting that PR poly-dipeptides target the NLS binding site of Kapß2. The findings offer mechanistic insights into how phase transitions of RBPs are disabled in C9orf72-related neurodegeneration.

Gene Expression Profiles of Human Cerebral Organoids Identify PPAR Pathway and PKM2 as Key Markers for Oxygen-Glucose Deprivation and Reoxygenation.

Ischemic stroke is one of the most common neurological diseases. However, the impact of ischemic stroke on human cerebral tissue remains largely unknown due to a lack of ischemic human brain samples. In this study, we applied cerebral organoids derived from human induced pluripotent stem cells to evaluate the effect of oxygen-glucose deprivation/reoxygenation (OGD/R). Pathway analysis showed the relationships between vitamin digestion and absorption, fat digestion and absorption, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and complement and coagulation cascades. Combinational verification with transcriptome and gene expression analysis of different cell types revealed fatty acids-related PPAR signaling pathway and pyruvate kinase isoform M2 (PKM2) as key markers of neuronal cells in response to OGD/R. These findings suggest that, although there remain some limitations to be improved, our ischemic stroke model using human cerebral organoids would be a potentially useful tool when combined with other conventional two-dimensional (2D) mono-culture systems.

[Elevation of cerebrospinal fluid anti-cyclic citrullinated peptides antibody index is useful for rheumatoid meningitis preceding neurological symptoms without arthritis: a case report].

We report a 62-year-old female with rheumatoid meningitis. She presented with mental disorder, loss of consciousness, generalized seizures, and cognitive impairment. Brain MRI demonstrated high intensity lesions and abnormal enhancement along the left frontal and parietal sulci. Her serum and cerebrospinal fluid were positive for anti-cyclic citrullinated peptides (CCP) antibody, and the antibody index of cerebrospinal fluid anti-CCP antibody increased, which led us to suspect rheumatoid meningitis. Her symptoms improved immediately by methylpredonisolone pulse therapy and anti-CCP antibody turned negative in cerebrospinal fluid. However, she revealed arthritis with the reduction of betamethasone and was diagnosed as rheumatoid arthritis. We suggest that the elevation of antibody index of cerebrospinal fluid anti-CCP antibody is useful in the diagnosis of rheumatoid meningitis preceding neurological symptoms without arthritis, and anti-CCP antibody in cerebrospinal fluid may be helpful as the evaluation of the treatment.

Brainstem Organoids From Human Pluripotent Stem Cells.

The brainstem is a posterior region of the brain, composed of three parts, midbrain, pons, and medulla oblongata. It is critical in controlling heartbeat, blood pressure, and respiration, all of which are life-sustaining functions, and therefore, damages to or disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells (hPSCs) recapitulate the course of human brain development and are expected to be useful for medical research on central nervous system disorders. However, existing organoid models are limited in the extent hPSCs recapitulate human brain development and hence are not able to fully elucidate the diseases affecting various components of the brain such as brainstem. Here, we developed a method to generate human brainstem organoids (hBSOs), containing midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, dopaminergic neurons, and neural crest lineage cells. Single-cell RNA sequence (scRNA-seq) analysis, together with evidence from proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem, which raises the possibility of making use of hBSOs in investigating central nervous system disorders affecting brainstem and in efficient drug screenings.

Safety and efficacy of rituximab in neuromyelitis optica spectrum disorders (RIN-1 study): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Pharmacological prevention against relapses in patients with neuromyelitis optica spectrum disorder (NMOSD) is developing rapidly. We aimed to investigate the safety and efficacy of rituximab, an anti-CD20 monoclonal antibody, against relapses in patients with NMOSD. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled clinical trial at eight hospitals in Japan. Patients aged 16-80 years with NMOSD who were seropositive for aquaporin 4 (AQP4) antibody, were taking 5-30 mg/day oral steroids, and had an Expanded Disability Status Scale (EDSS) score of 7·0 or less were eligible for the study. Individuals taking any other immunosuppressants were excluded. Participants were randomly allocated (1:1) either rituximab or placebo by a computer-aided dynamic random allocation system. The doses of concomitant steroid (converted to equivalent doses of prednisolone) and relapses in previous 2 years were set as stratification factors. Participants and those assessing outcomes were unaware of group assignments. Rituximab (375 mg/m2) was administered intravenously every week for 4 weeks, then 6-month interval dosing was done (1000 mg every 2 weeks, at 24 weeks and 48 weeks after randomisation). A matching placebo was administered intravenously. Concomitant oral prednisolone was gradually reduced to 2-5 mg/day, according to the protocol. The primary outcome was time to first relapse within 72 weeks. Relapses were defined as patient-reported symptoms or any new signs consistent with CNS lesions and attributable objective changes in MRI or visual evoked potential. The primary analysis was done in the full analysis set (all randomly assigned patients) and safety analyses were done in the safety analysis set (all patients who received at least one infusion of assigned treatment). The primary analysis was by intention-to-treat principles. This trial is registered with the UMIN clinical trial registry, UMIN000013453. FINDINGS: Between May 10, 2014, and Aug 15, 2017, 38 participants were recruited and randomly allocated either rituximab (n=19) or placebo (n=19). Three (16%) patients assigned rituximab discontinued the study and were analysed as censored cases. Seven (37%) relapses occurred in patients allocated placebo and none were recorded in patients assigned rituximab (group difference 36·8%, 95% CI 12·3-65·5; log-rank p=0·0058). Eight serious adverse events were recorded, four events in three (16%) patients assigned rituximab (lumbar compression fracture and infection around nail of right foot [n=1], diplopia [n=1], and uterine cancer [n=1]) and four events in two (11%) people allocated to placebo (exacerbation of glaucoma and bleeding in the right eye chamber after surgery [n=1], and visual impairment and asymptomatic white matter brain lesion on MRI [n=1]); all patients recovered. No deaths were reported. INTERPRETATION: Rituximab prevented relapses for 72 weeks in patients with NMOSD who were AQP4 antibody-positive. This study is limited by its small sample size and inclusion of participants with mild disease activity. However, our results suggest that rituximab could be useful maintenance therapy for individuals with NMOSD who are AQP4 antibody-positive. FUNDING: Japanese Ministry of Health, Labour and Welfare, Japan Agency for Medical Research and Development, and Zenyaku Kogyo.

Increased Signal in the Superior Cerebellar Peduncle of Patients with Progressive Supranuclear Palsy.

OBJECTIVE: The provisional diagnosis of progressive supranuclear palsy (PSP) depends on a combination of typical clinical features and specific MRI findings, such as atrophy of the tegmentum in the midbrain. Atrophy of the superior cerebellar peduncle (SCP) distinguishes PSP from other types of parkinsonism. Histological factors affect the conventional fluid-attenuated inversion recovery (FLAIR) signals, such as the extent of neuronal loss and gliosis. METHODS: We investigated patients with PSP to verify the percentage of patients with various PSP phenotypes presenting a high signal intensity in the SCP. Three interviewers, who were not informed about the clinical data, visually inspected the presence or absence of a high signal intensity in the SCP on the FLAIR images. We measured the pixel value in the SCP of each patient. Clinical characteristics were evaluated using the Mann-Whitney test, followed by the χ2 test. RESULTS: Ten of the 51 patients with PSP showed a high signal intensity in the SCP on FLAIR MRI. Higher pixel values were observed within the SCP of patients with a high signal intensity in the SCP than in patients without a high signal intensity (p < 0.001). The sensitivity and specificity of the high signal intensity in the SCP of patients with PSP was 19.6% and 100%, respectively. This finding was more frequently observed in patients with PSP with Richardson's syndrome (PSP-RS) (25.7%) than other phenotypes (6.2%). CONCLUSION: The high signal intensity in the SCP on FLAIR MRI might be an effective diagnostic tool for PSP-RS.

A Nationwide Survey on Danon Disease in Japan.

Danon disease, an X-linked dominant cardioskeletal myopathy, is caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). To clarify the clinicopathological features and management, we performed the first nationwide, questionnaire-based survey on Danon disease in Japan. A total of 39 patients (17 males, 22 females) from 20 families were identified in the analysis. All patients had cardiomyopathy. Of the 21 patients who died, 20 (95%) died of cardiac failure or sudden cardiac arrest. Most patients had hypertrophic cardiomyopathy. Wolf⁻Parkinson⁻White syndrome was present at a comparatively high incidence (54% in males, 22% in females). Only one female patient received a heart transplant, which is the most effective therapy. Histopathologically, all male patients showed autophagic vacuoles with sarcolemmal features in muscle. Half of the probands showed de novo mutations. Male patients showed completely absent LAMP-2 expression in muscle. In contrast, female patients showed decreased LAMP-2 expression, which is suggested to reflect LAMP-2 haploinsufficiency due to a heterozygous null mutation. In conclusion, Danon disease is an extremely rare muscular disorder in Japan. Cardiomyopathy is the most significant prognostic factor and the main cause of death. Our findings suggest that the present survey can extend our understanding of the clinical features of this rare disease.

Accidental hypothermia in Parkinson's disease.

We describe two patients with Parkinson's disease who presented with accidental hypothermia and review seven patients to delineate the characteristics of hypothermia. All cases of hypothermia occurred in the winter. As clinical symptoms preceding the onset of hypothermia, deterioration of bradykinesia or limb coldness was evident. Most cases of hypothermia were accompanied by impaired consciousness and deterioration of parkinsonian features. After warming the body, the hypothermia improved in a relatively short period. Levodopa, dopamine agonists or anticholinergic agents were given to five patients, three patients and three patients, respectively. Bradykinesia developed in most patients a short time before the onset of hypothermia. In various neurological diseases, deterioration of the disease can occur on the background of metabolic/electrolyte disturbance. However, the fact that the bradykinesia developed a short time prior to the onset of hypothermia warrants close observation for signs of temperature dysregulation in patients with substantial neurologic deterioration, especially in the winter.

Step Numbers and Hoehn-Yahr Stage after Six Years.

BACKGROUND: Freezing of gait (FOG) has been linked to increased numbers of steps taken while walking. We tested the hypothesis that an increased number of steps associated with FOG might predict the exacerbation of the severity of Parkinson's disease (PD). METHODS: We prospectively studied 26 patients. Clinical assessments were performed and balance was evaluated in 30 patients with Hoehn-Yahr stage III PD 6 years previously. Gait parameters were analyzed with the use of an originally designed, suddenly narrowed path. PD-related independent variables, balance investigation-related variables, and gait-independent-related variables were analyzed by multiple logistic regression analysis. RESULTS: The Hoehn-Yahr stage increased in 14 patients and was unchanged in 12 patients. The 36-item Short-Form Health Survey score (OR 1.079, p = 0.041, 95% CI 1.003-1.161) and the number of steps on the suddenly narrow path (OR 1.605, p = 0.047, 95% CI 1.006-2.56) were related to an increase in the Hoehn-Yahr stage. The number of steps was significantly higher on the suddenly narrowed path (11.3 ± 3.6) than on a straightly narrowed path (10.1 ± 3.2) at the time of final follow-up in the 26 patients (p < 0.001). CONCLUSIONS: An increased number of steps associated with FOG, which was elicited by the suddenly narrowed path, might be one predictor of an upgrade of stage in patients with Hoehn-Yahr stage III PD.

Can Postural Instability Respond to Galvanic Vestibular Stimulation in Patients with Parkinson's Disease?

OBJECTIVE: Galvanic vestibular stimulation (GVS) activates the vestibular afferents, and these changes in vestibular input exert a strong influence on the subject's posture or standing balance. In patients with Parkinson's disease (PD), vestibular dysfunction might contribute to postural instability and gait disorders. METHODS: Current intensity was increased to 0.7 mA, and the current was applied to the patients for 20 minutes. To perform a sham stimulation, the current intensity was increased as described and then decreased to 0 mA over the course of 10 seconds. The patient's status was recorded continuously for 20 minutes with the patient in the supine position. RESULTS: Three out of 5 patients diagnosed with PD with postural instability and/or abnormal axial posture showed a reduction in postural instability after GVS. The score for item 12 of the revised Unified Parkinson's Disease Rating Scale part 3 was decreased in these patients. CONCLUSIONS: The mechanism of postural instability is complex and not completely understood. In 2 out of the 5 patients, postural instability was not changed in response to GVS. Nonetheless, the GVS-induced change in postural instability for 3 patients in our study suggests that GVS might be a therapeutic option for postural instability.