Noise Pareidolia Test in Parkinson's Disease and Atypical Parkinsonian Syndromes: A Retrospective Study.

INTRODUCTION: Pareidolias, or visual misperceptions, are a non-motor symptom of Parkinson's disease (PD) with unclear pathophysiology. The noise pareidolia test (NPT) is a tool for screening pareidolias. The usefulness of the NPT in differentiating PD from atypical parkinsonian syndromes (APS) is also unknown. METHODS: We retrospectively investigated 74 patients with PD and 18 patients with APS who took the NPT. Correlations between the number of pareidolic responses, gray matter volume, and cerebral blood flow were also examined in the patients with PD. RESULTS: The median number of pareidolic responses in patients with PD and patients with APS was 0 (interquartile range (IQR): 0-3) and 0 (IQR: 0-1), respectively, and tended to be higher in patients with PD than in those with APS (p = 0.077). It was significantly higher in patients with PD who had hallucinations (2; IQR: 0-9) (p = 0.016). The area under the receiver operating characteristic curve for the number of pareidolic responses in the NPT was 0.62 when used to differentiate PD and APS, and the optimal cutoff number of pareidolic responses was 2/3. Sensitivity and specificity were 25.7% and 100%, respectively. In the PD group, the number of pareidolic responses was correlated with age (r = 0.27; p = 0.021) and the Frontal Assessment Battery (FAB) score (r = -0.34; p = 0.0099). Magnetic resonance imaging showed no significant correlation between the number of pareidolic responses and the volume of focal gray matter. On cerebral hypoperfusion mapping, the left parietal lobe had a significant correlation with the number of pareidolic responses (r = 0.35; p = 0.027). CONCLUSION: The number of pareidolic responses in NPT was suggested to be useful as a red flag to rule out APS in differentiating PD from APS. In PD without dementia, the number of pareidolic responses was associated with reduced blood flow in the left parietal lobe.

Three-year follow-up of rheumatoid meningitis with matrix metalloprotease-9 levels in the serum and cerebrospinal fluid as indicators of disease activity: A case report.

Rheumatoid meningitis (RM) is an extra-articular complication of rheumatoid arthritis (RA). Although reports of RM sine arthritis exist, most patients with this presentation were diagnosed with RA within one year of RM onset. There are no established biomarkers reflecting the disease activity of RM. This case report highlights the elevation of matrix metalloprotease (MMP)-9 levels during the acute phase of RM and decline during remission. Additionally, this is the first case report of RA diagnosed three years after the onset of RM. It is important to further validate the utility of MMP-9 and conduct long-term follow-up of RM sine arthritis.

Japanese Mucuna pruriens (Hasshou beans) Showed Fast-acting and Long-lasting Effects in Parkinson's Disease.

Objective Mucuna pruriens (MP) is a legume whose seeds contain levodopa (LD), which has potential therapeutic effects against Parkinson's disease (PD). However, further research is needed to thoroughly evaluate its efficacy and safety for treating this condition. In this study, we analyzed the pharmacokinetics of MP grown in Japan and investigated its mechanism of action in PD. Methods MP seeds ground after roasting (containing 4.02% LD per MP powder) were used as the reagent and compared with an equivalent LD/carbidopa (CD) preparation. This clinical trial was conducted using a crossover design among PD patients attending our institution. Each patient received a single dose of 100/10 mg LD/CD tablets and 11 g of MP reagent. Results Among the seven patients with PD, MP prolonged the ON time 2-fold compared to LD/CD. The LD concentrations after MP intake were higher than those after LD/CD intake, whereas dyskinesia did not increase. An analysis of the LD metabolites showed that the 3-O-methyl-dopa/LD metabolic ratio was significantly lower after MP ingestion than after LD/CD ingestion, indicating that MP has a catechol-O-methyl transferase inhibitory effect. Conclusions This is the first report of a pharmacokinetic analysis conducted on actual patients with PD showing that MP significantly prolongs the ON time. The advantages of MP as a treatment for PD have been confirmed: it is inexpensive, as effective as LD, works faster and longer than LD, and does not increase dyskinesia.

Predictive value of the neutrophil-to-lymphocyte ratio for treatment response in patients diagnosed with definite or probable autoimmune encephalitis/encephalopathy.

Introduction: Autoimmune encephalitis/encephalopathy (AE) is a complex and heterogeneous disease, making it difficult to predict the prognosis. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a potential prognostic tool, but its usefulness remains a matter of debate. This study aimed to explore prognostic factors in cases of clinically definite or probable AE, including those with autoantibody-negative, or unknown status. Methods: Data on patients diagnosed with definite or probable AE, including those with autoantibody-negative, or unknown status, were retrospectively collected from the admission records of our department between January 2013 and December 2022. These patients were then categorized into either a good- or poor-response group, based on their short-term treatment response. Clinical characteristics, auxiliary examinations, and treatments were compared between the two groups. A multivariable logistic regression model was constructed to identify independent predictors of poor short-term treatment response by Akaike information criterion backward stepwise method. Results: A total of 31 patients were included in the final analysis, with 18 of them included in the poor-response group. In the univariable analysis, the poor-response group had a higher proportion of patients with a modified Rankin Scale (mRS) high score upon admission, female, epileptic seizures, or NLRs of 3.93 or higher than the good-response group (all p < 0.10). Furthermore, the multivariable logistic regression analysis revealed that the mRS score upon admission [OR: 5.51, 95% confidence intervals (CI): 1.29-23.50, p = 0.02], epileptic seizures (OR: 10.01, 95% CI: 1.16-86.66, p = 0.04), and NLRs of 3.93 or higher (OR: 11.37, 95% CI: 1.12-114.68, p = 0.04) were significantly associated with poor short-term treatment response. Conclusion: The NLR may play a supplementary role in predicting the short-term treatment response in patients diagnosed with definite or probable AE, including those with autoantibody-negative, or unknown status.

[Guillain-Barré syndrome associated with Epstein-Barr virus and cytomegalovirus reactivation during treatment for chronic graft-versus-host disease after allogeneic bone marrow transplantation].

Guillain-Barré syndrome (GBS) is a rare neurological complication of allogeneic hematopoietic stem cell transplantation (HSCT). The pathogenesis of post-HSCT GBS is unclear. Here, we report a case of GBS coincident with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation that occurred after HSCT in a patient with myelodysplastic syndrome. A 61-year-old man was admitted to our hospital because of gait disturbance due to lower limb muscle weakness, which arose during treatment for chronic graft-versus-host disease (GVHD) five months after allogeneic HSCT. He was diagnosed with GBS based on his clinical course, cerebrospinal fluid analysis, and a nerve conduction study. At that time, he exhibited EBV and CMV reactivation. GBS improved after intravenous injection of immunoglobulins. Our case suggests that reactivation of EBV and CMV during treatment for chronic GVHD may induce GBS, and that rapidly progressive muscular weakness coincident with EBV or CMV reactivation can be a diagnostic sign of GBS after allogeneic HSCT.

[Drugs Used to Treat Essential Tremors].

Based on the evidence level, the first-line agents for managing essential tremors include sympathomimetic agents and primidone; however, from a tolerability standpoint, sympathomimetic agents are the first choice. Arotinolol is the first treatment of choice because it is the only drug developed in Japan approved for treating essential tremors. If sympathomimetic agents are unavailable or ineffective, a change to primidone, or a combination of both, should be considered. Benzodiazepines and other anti-epileptic drugs should also be administered.

Complement biomarkers reflect the pathological status of neuromyelitis optica spectrum disorders.

Complement is involved in the pathogenesis of neuroimmune disease, but the detailed pathological roles of the complement pathway remain incompletely understood. Recently, eculizumab, a humanized anti-C5 monoclonal antibody, has been clinically applied against neuroimmune diseases such as myasthenia gravis and neuromyelitis optica spectrum disorders (NMOSD). Clinical application of eculizumab is also being investigated for another neuroimmune disease, Guillain-Barré syndrome (GBS). However, while the effectiveness of eculizumab for NMOSD is extremely high in many cases, there are some cases of myasthenia gravis and GBS in which eculizumab has little or no efficacy. Development of effective biomarkers that reflect complement activation in these diseases is therefore important. To identify biomarkers that could predict disease status, we retrospectively analyzed serum levels of complement factors in 21 patients with NMOSD and 25 patients with GBS. Ba, an activation marker of the alternative complement pathway, was elevated in the acute phases of both NMOSD and GBS. Meanwhile, sC5b-9, an activation marker generated by the terminal complement pathway, was elevated in NMOSD but not in GBS. Complement factor H (CFH), a complement regulatory factor, was decreased in the acute phase as well as in the remission phase of NMOSD, but not in any phases of GBS. Together, these findings suggest that complement biomarkers, such as Ba, sC5b-9 and CFH in peripheral blood, have potential utility in understanding the pathological status of NMOSD.

Characteristics of Guillain-Barré syndrome in super-elderly individuals.

BACKGROUND: Japan has the world's largest super-aging population, and the number of elderly patients with various diseases is increasing. Herein, we reported the characteristics of super-elderly patients, aged over 80 years, with Guillain-Barré syndrome (GBS), a typical neuroimmune disease. METHODS: During the period 2019-2021, 74 patients over the age of 80 years diagnosed with GBS at Kindai university were analyzed as the super-elderly group patients. The control group comprised 74 consecutive patients aged < 79 years, under the same conditions. GBS was diagnosed using Brighton diagnostic criteria. Electrophysiology was assessed using the Ho criteria. RESULTS: The mean age was 83.5 years in the super-elderly group and 51.7 years in the control group. Prior infection was recognized in 50% of cases in the super-elderly group and 77% of cases in the control group with fewer cases in the super-elderly group. The mean number of days until peak symptom presentation was longer in the super-elderly group. The percentage who required a ventilator was significantly higher among the super-elderly group than among the control group. Hughes functional grading scale was more severe in the super-elderly group. Electrophysiological examination revealed the demyelinating form was particularly common in the super-elderly group. Intravenous immunoglobulin was the most common treatment in both the groups, with no difference in efficacy. CONCLUSIONS: Super-elderly onset GBS tends to be severe, therefore it is important to diagnose and treat appropriately, even in the absence of prior episodes of infection.

Real-world application of plasmapheresis for neurological disease: Results from the Japan-Plasmapheresis Outcome and Practice Patterns Study.

INTRODUCTION: Plasmapheresis is a well-recognized treatment for autoimmune neurological diseases in Japan. However, the practice varies depending on the facility, and the actual treatment conditions are unclear. METHODS: To clarify real-world conditions, a prospective observational study was conducted on patients with neurological diseases who were scheduled to receive plasmapheresis. A dataset was analyzed that included 887 treatments from 210 patients with myasthenia gravis (MG), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and other diseases for 82, 30, 24, and 74 patients, respectively. RESULTS: The types of plasmapheresis performed included immunoadsorption plasmapheresis, plasma exchange, and double filtration plasmapheresis with 620, 213, and 54 treatments, respectively. Approximately, 60% of the treatments were performed using peripheral blood access alone. Non-serious adverse events were observed in 10 patients. CONCLUSIONS: A statistically significant improvement was observed after plasmapheresis in patients with MG, MS, and NMOSD. These were evaluated using the modified Rankin Scale.

Identification of double-stranded DNA in the cerebrospinal fluid of patients with acute neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system (CNS) characterized by severe myelitis and optic neuritis. Double-stranded DNA (dsDNA) is involved in the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus. However, its role in NMOSD remains unclear. In this study, the concentration of dsDNA in the cerebrospinal fluid (CSF) was quantified in 23 patients with NMOSD and 16 patients with other neurological diseases (ONDs). CSF dsDNA levels in patients with NMOSD (median: 0.03 ng/µL) were significantly higher than those in patients with ONDs (median: 0.01 ng/µl). CSF dsDNA levels showed no significant difference before and after treatment. Elevation of CSF dsDNA levels may suggest its essential role in the augmentation of CNS inflammation in patients with NMOSD.

Exploring steroid tapering in patients with neuromyelitis optica spectrum disorder treated with satralizumab in SAkuraSky: A case series.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare, chronic, autoimmune disease, characterized by astrocytopathic lesions in the central nervous system (Beekman et al., 2019; Fujihara et al., 2020). The main aim of NMOSD maintenance therapy is to reduce the frequency and severity of relapses and minimize future disability (Fujihara et al., 2020). Oral corticosteroids are used long-term to prevent relapses, but are associated with serious complications (Kessler et al., 2016; Kimbrough et al., 2012). In the SAkuraSky study, satralizumab reduced the risk of relapse in patients with NMOSD compared with placebo, with comparable rates of serious adverse events and infections between treatment arms (Yamamura et al., 2019). Here, we report on 16 patients who tapered their steroid dose during the openlabel extension (OLE) period of SAkuraSky. METHODS: SAkuraSky was a phase 3, multicenter, randomized, double-blind (DB), placebo-controlled study of satralizumab in combination with immunosuppressive therapies (ISTs) in patients with NMOSD. Patients were randomized 1:1 to receive 120 mg subcutaneous satralizumab or placebo in addition to a stable dose of their baseline IST. After completing the DB period or experiencing relapse, patients could enter the OLE period. In the OLE, all patients received satralizumab, and IST doses could be tapered at the investigator's discretion. We assessed the different steroid tapering patterns and their impact on relapse and safety. Patients were considered to have tapered their steroids if their steroid dose at the clinical cut-off date (CCOD: February 18, 2020) was lower than on the first day of the OLE. Annualized relapse rate (ARR) was calculated as the number of relapses divided by the total number of patientyears at risk. RESULTS: Overall, 36 patients receiving oral corticosteroids entered the OLE, of whom 16 tapered their steroid dose. The mean age (range) at baseline was 44.9 (16-73) years, all 16 were female, 14 (88%) were Japanese, and 15 (94%) were AQP4-IgG seropositive. None were receiving any additional ISTs. Patients tapered their steroids from a median of 10 (range: 5-25) mg/day at OLE baseline to 2.75 (0-15) mg/day at the CCOD. Three patients discontinued steroids entirely, and all three remained relapse free. One patient who remained relapse free had temporary increases in steroid dose. Three relapses were observed in two patients who tapered steroids during the OLE; all three relapses required treatment. One of the relapses occurred shortly after a drop in steroid dose from 25 to 10 mg/day. The ARR for steroid-tapered patients was numerically lower in the OLE period than the satralizumab group in the DB period. The safety profile of satralizumab was in line with the overall SAkuraSky population. Two serious infections were observed in steroid-tapered patients in the OLE, both in the same patient: one event (hepatitis E) occurred before the patient began tapering their steroid dose; and one event (influenza) occurred while the patient was tapering. CONCLUSION: During the OLE of SAkuraSky, 16 patients tapered steroids and the ARR did not increase from the DB period. Patient numbers limit interpretation.

Acute eye movement-retained internal ophthalmoplegia in atypical Miller Fisher syndrome variants are associated with IgG anti-GQ1b antibodies.

Ophthalmoplegia is a common neurological finding in Miller Fisher syndrome (MFS), but acute eye movement-retained internal ophthalmoplegia is a rare variant of MFS. In this report, we present three cases of acute eye movement-retained internal ophthalmoplegia; IgG anti-GQ1b antibodies were detected in all patients. We reviewed a total of 13 cases, including 10 previously reported cases, and revealed that IgG anti-GQ1b antibodies were identified in all but one patient. In addition, we investigated the correlation between acute eye movement-retained internal ophthalmoplegia and antibodies against ganglioside complexes. We found that anti-GQ1b antibodies in our patients reacted with GQ1b or GT1a but not GQ1b/GM1 or GQ1b/GD1a complexes, indicating that antibodies against disialosyl residues have a pathogenetic role in acute eye movement-retained internal ophthalmoplegia. This is the first study describing that acute eye movement-retained internal ophthalmoplegia is associated with IgG antibodies specific to GQ1b or GT1a.

The Japanese Society for Apheresis clinical practice guideline for therapeutic apheresis.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

Anti-AQP4 autoantibodies promote ATP release from astrocytes and induce mechanical pain in rats.

BACKGROUND: Intractable neuropathic pain is a common symptom of neuromyelitis optica spectrum disorder (NMOSD). However, the underlying mechanism of NMOSD pain remains to be elucidated. In this study, we focused on ATP, which is one of the damage-associated molecular patterns, and also a well-recognized molecule involved in peripheral neuropathic pain. METHODS: We assessed the development of pain symptoms by injecting anti-AQP4 recombinant autoantibodies (rAQP4 IgG) into rat spinal cords. We incubated HEK293 cells expressing AQP4 (HEK-AQP4) and rat astrocytes with rAQP4 IgG and assessed the level of ATP in the supernatant. We performed transcriptome analysis of the spinal cords injected with rAQP4 IgG. Pharmacological inhibition was also applied to investigate the involvement of ATP in the development of neuropathic pain in our rat model. The ATP concentration within the cerebrospinal fluid was examined in patients with NMOSD and other neurological diseases. RESULTS: Development of mechanical allodynia was confirmed in rAQP4 IgG-treated rats. AQP4-Ab-mediated extracellular ATP release from astrocytes was observed in vitro, and pharmacological inhibition of ATP receptor reversed mechanical allodynia in the rAQP4 IgG-treated rats. Furthermore, transcriptome analysis revealed elevation of gene expressions related to several ATP receptors including P2rx4 and IL1B in the spinal cord of rAQP4 IgG-treated rats. In patients, CSF ATP concentration was significantly higher in the acute and remission phase of NMOSD than in multiple sclerosis or other neurological disorders. CONCLUSION: Anti-AQP4 antibody was shown to induce the release of extracellular ATP from astrocytes. The ATP-mediated development of mechanical allodynia was also suggested in rats treated with anti-AQP4 antibody. Our study indicates the pivotal role of ATP in the pain mechanism of NMOSD.

Change in light-dark cycle affects experimental autoimmune encephalomyelitis.

The prevalence of multiple sclerosis is associated with geographic latitude. Low sun exposure or reduced daylight hours are considered possible causes. We examined whether a change in the number of daylight hours affects the course of experimental autoimmune encephalomyelitis (EAE) disease. Housing mice in a 24-h dark or light cycle upregulated internal corticosterone secretion and ameliorated the EAE disease course relative to that in mice housed in a conventional 12/12-h cycle environment. After EAE induction, the rhythmic pattern of corticosterone secretion was disrupted. Upregulation of internal steroid secretion might act as an immunosuppressive and ameliorate EAE.

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.

Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review.

OBJECTIVE: Since the last epidemiologic review of neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD), 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence, and basic demographic characteristics of NMOSD and provide a critical overview of studies. METHODS: PubMed, Ovid MEDLINE, and Embase using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); and age-, sex-, and ethnic group-specific incidence or prevalence. RESULTS: We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region (0.73/100 000 person-years [95% CI: 0.45-1.01] and 10/100 000 persons [95% CI: 6.8-13.2]). The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand (0.037/100 000 person-years [95% CI: 0.036-0.038] and 0.7/100,000 persons [95% CI: 0.66-0.74]). There was prominent female predominance in adults and the AQP4-Ab-seropositive subpopulation. The incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas White ethnicity had the lowest. No remarkable trend of incidence was described over time. CONCLUSION: NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiologic studies to identify genetic effects and etiologic factors.