This editorial describes new MDS criteria for multiple system atrophy (MSA). The criteria aim to improve the accuracy of the diagnosis of MSA and to increase diagnostic accuracy in the early stages of the disease leading to increased patient enrollment in clinical trials. The criteria provide detailed definitions of diagnostic findings in a lexicon, which should be reviewed during the interview and diagnosis. The criteria define four levels of diagnostic certainty. The newly created “possible prodromal MSA” is a research category with low specificity, but it is expected to be used to establish future diagnostic biomarkers to catch patients in the earliest stages of the disease.

Remudy (REgistry of MUscular DYstrophy) is a patient registry started in 2009 in collaboration with TREAT–NMD, an international clinical research network, to promote clinical development of hereditary neuromuscular diseases. In close collaboration with the Japan Muscular Dystrophy Association, a patient organization, the registry office was established at the National Center of Neurology and Psychiatry, and the registry started with dystrophinopathies, and is now operating registries for GNE myopathy, myotonic dystrophy, Facioscapulohumeral muscular dystrophy, and congenital muscular disorders. It has conducted various epidemiological studies, contributed to clinical trial feasibility studies and patient recruitment, and disseminated information to patients. In recent years, the use of real–world data in therapeutic development has been attracting attention, and among these, the utilization of the registry under the pharmaceutical system is being promoted under the Clinical Innovation Network. It is hoped that the registry will be widely utilized in areas ranging from therapeutic development to safety monitoring activities.

The patient registry of amyotrophic lateral sclerosis (ALS) can play many roles in providing appropriate care to patients and promoting therapeutic development for ALS. In Japan, a multicenter registration and follow–up system called Japanese Consortium for Amyotrophic Lateral Sclerosis research (JaCALS) was built in 2006. Genomic DNA samples and B–cell lines of ALS patients were stored and linked to the clinical information. JaCALS showed natural histories and genetic backgrounds of Japanese ALS patients and clinical and genetic factors associated with progression and prognosis of ALS. Technology has been developed to create iPS cells from B–cell lines and perform phenotypic analysis, indicating that the combination of clinical and genomic information with iPS cells may play an important role in pathophysiological analysis and therapeutic drug screening. Efforts are also being made to create real–world evidence by utilizing large–scale longitudinal clinical information. The role of the patient registry in therapeutic development and validation is expected to increase in the future.

Clinical research based on patient registries has recently been a global trend. J–CAT (Japan Consortium of Ataxias) is the only registry in Japan characterized by Web–based patient–driven registration with informed consent. Detailed clinical information and clinical resources including genomic DNA, plasma and B–lymphoblast cell line have been accumulated in J–CAT. Mutational screening for major disease types has been conducted in all the registrants. On September 2022, 2365 registrants, 1949 genomic DNA, 515 plasma samples, and 334 B–lymphoblast cell lines have been obtained. Ongoing projects based on J–CAT include elucidation of molecular epidemiology, establishment of disease–specific prospective natural history, delineation of idiopathic cerebellar ataxia (IDCA) and support for differential diagnosis of autoimmune cerebellar ataxia. J–CAT plays an indispensable role in clinical researhes for the development of cures for ataxias.

Multiple system atrophy (MSA) is a neurodegenerative disease characterized by autonomic failure with various combination of cerebellar ataxia, Parkinsonism and pyramidal signs with the average age at onset in late 50s. The prevalence of MSA in Japan has been estimated to be 12,000. The detailed natural history and molecular basis of MSA, however, still remain to be elucidated. To facilitate the research on MSA, we established the MSA registry in 2016. In this registry, detailed clinical information including Unified Multiple System Atrophy Rating Scale parts 1 and 2 has been collected in a prospective manner. The bioresource including genomic DNA, plasma and lymphoblastoid cell lines has been collected, and deposited to the Rare Disease Bank at The National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN). To date, 530 patients with MSA have been registered in this registry. The detailed natural history of MSA established based on the MSA registry is expected to contribute to design future clinical trials.

Human T–cell leukemia virus type 1 (HTLV–1)–associated myelopathy (HAM) is a severe refractory disease, with only few effective treatments, characterized by progressive paraparesis due to chronic inflammation of the spinal cord. Due to its low prevalence in other developed countries outside Japan, only limited data on biomarkers or treatment strategies for HAM are available. As a result, there is no internationally recognized treatment for HAM and the quality of clinical care is low. In rare diseases such as HAM, large scale studies to collect continuous clinical data have been difficult. Since a patient registry could be useful to prospectively collect information from many patients. We established the nationwide registration system “HAM–net” in 2012. The HAM–net has been an effective tool for promoting epidemiological studies.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease characterized by recurrent stroke and progressive cognitive impairment, which is caused by the NOTCH3 mutation. Although CADASIL was previously considered a rare disease, recent genomic studies have recognized pathogenic NOTCH3 mutations in approximately 1% of the general population in East Asia. The clinical course is not uniform in CADASIL patients. The genotype–phenotype correlations remain elusive.

We are currently conducting an AMCAD trial to evaluate the safety and efficacy of adrenomedullin, a vasoactive peptide with strong angiogenic, anti–inflammatory, and oligodendrogenetic effects, in CADASIL patients. However, since CADASIL appears to be underdiagnosed, it would be difficult to conduct a larger confirmatory trial in Japan ; international collaborative research is important to promote drug development for CADASIL. We therefore plan to establish an East Asian CADASIL registry in collaboration with Taiwan and South Korea. Researchers in each country will enter clinical data of CADASIL patients, which will be stored in an electronic data capture system. MRI data will be evaluated by an independent review board. More than 1000 CADASIL patients will be enrolled in the registry.

Intractable/Rare Diseases Act (effective in 2015) covers more than 20 syndromes/diseases in which epileptic seizure is a main symptom or one of the main symptoms. To unveil the present situations of intractable/rare epilepsy syndromes/diseases, the “Rare Epilepsy Syndrome Registry (RES–R)” was initiated in 2014 in Japan. RES–R covers a wide variety of items about epilepsy, from seizure type to psychosocial status. With the collaboration of physicians engaged in epilepsy practice from all over Japan, RES–R accumulates and in part follows epilepsy cases to gain epidemiological evidence on intractable/rare epilepsy syndromes/diseases. There are 3454 cases registered as of Nov 2021. Interim analysis showed that 63% of patients with epilepsy other than idiopathic or self–limited syndrome suffered from monthly seizures, 71% comorbidities, and 87% fulfilled the severity criteria of the Act. However, the number of cases registered might represent only about 4% of the cases of rare epilepsy syndrome/disease in Japan estimated from the literature. A follow–up study of 27 new–onset West syndrome patients revealed improved seizure status after 2 years in 66.7%, but worsened intellectual developmental status in 55.6%, with overall improvement in 51.9%. We also conducted a prospective cohort study in which 60 patients with focal cortical dysplasia type II registered in RES–R were included as an external control of investigator–initiated sirolimus trial. In parallel with RES–R, we started a Cause of Death in Epilepsy registry since 2018, where sudden unexpected death consists of one fourth of the causes of death in epilepsy so far. Epilepsy syndrome registry should help facilitate proper application of the Intractable/Rare Diseases Act as well as collaborative clinical studies on epilepsy.

Patient registry is useful and essential for understanding of disease pathology and natural history in real world. Lysosomal Storage Diseases are ultra–rear diseases and most of them are progressive course. Recently many therapeutic interventions are developed and the prognosis is getting better. However it gets more important to elucidate the pathophysiology of the disease using patient registry to find the best way of treatment for each of the patient. Now it is a big issue how to create the patient registry which is effective for establishing natural history. I describe the situation and the hurdle for the establishing the patient registry in this section.

Objective : To clarify the effectiveness of combination therapy of prednisolone (PSL) and immunosuppressive drugs in the acute phase of peripheral neuropathy associated with eosinophilic granulomatosis with polyangiitis (EGPA).

Methods : Twenty–four patients with EGPA and peripheral neuropathy who were diagnosed between April 1999 and March 2019 were enrolled in the study. We retrospectively analyzed the changes in muscle strength and electrophysiological parameters between the time before and one year after the treatment. The changes after the treatment were compared between patients with only corticosteroid hormone and patients with intensified treatment of corticosteroid hormone and immunosuppressive drugs.

Results : In both patient groups, we found significant improvements in the compound muscle action potential amplitude of the tibial nerve and strength of the tibialis anterior and gastrocnemius muscles, whereas the sensory nerve action potentials of the sural nerve showed significant decreases in amplitude. There were no significant differences in the effect of treatment between the patient groups with only corticosteroid hormone therapy and intensified therapy with immunosuppressive drugs.

Conclusion : The initial intensified therapy with immunosuppressive drugs might not have additional effects on corticosteroid hormone one year after the acute phase of EGPA with peripheral neuropathy. Sural nerve SNAP decreased over time, contrary to the recovery of muscle strength, and may reflect residual sensory symptoms that persist after treatment.

Objective: This study aimed to investigate the current status and efficacy of plasma pheresis (PP) therapy for the acute phase of neuromyelitis optica spectrum disorder (NMOSD)

Methods: We retrospectively evaluated the clinical profiles of seven patients with anti–AQP4 antibody–positive NMOSD who underwent either plasma exchange or immunoadsorption plasmapheresis (PP) therapies between 2008 and 2020. Expanded disability status scale (EDSS) was evaluated at the nadir of the attacks and at 1 month after the first treatment.

Results: One patient aged 52 years in whom PP was initiated at 5 days after the onset achieved a 2.0–point reduction in EDSS despite manifesting severe condition (EDSS 8.5). Two patients achieved a 1.0–point reduction in EDSS and were characterized by a relatively young–onset (an average of 48 years of age) and mild conditions (an average EDSS of 2.5), despite the delayed initiation of PP at an average of 20 days after the onset. Four patients refractory to PP therapy had an elderly–onset (an average of 75.3 years of age), severe conditions (an average EDSS of 9.0), and delayed initiation of PP at an average of 24 days after the onset.

Conclusion: PP seemed to have a potential role as a rescue therapy in not only severe cases but also mild cases of subacute phase of NMOSD.

Positioning amyotrophic lateral sclerosis (ALS) patients is difficult because patients would like specific positions but have difficulty expressing themselves. However, because certain positions were commonly seen in clinical practice, research was conducted to identify common positions and their rationales, hoping to achieve comfortable positioning and patient comfort. The subjects were 29 ALS patients requiring fully assisted positioning, and their preferences and rationales for angles of head elevation and lateral position, upper and lower limb support methods, and the use of pillows and blankets were investigated. The results showed that 72% of subjects preferred head elevation, 64% upper limb elevation, 88% lower limb elevation, and 62% a low lateral position angle of ≤20 degrees. There were also commonalities in choices of pillows and blankets among patients. The common positioning conditions served as measures to alleviate pain, since maintenance of sensory function is a characteristic of ALS. We believe that comfortable positioning is possible by applying the identified position preferences. In addition, the results suggest that achieving a comfortable position is possible even at the stage where communication becomes difficult.

OriHime^®, an example of a telepresence robot, was used as part of occupational therapy for inpatients with intractable neurological diseases. The Schedule for the Evaluation of Individual Quality of Life – Direct Weighting (SEIQoL–DW) was used to evaluate changes in quality of life (QOL) as a result of robot use. The subjects were four long–term care inpatients, one with progressive muscular dystrophy and three with amyotrophic lateral sclerosis. The patients experienced pseudo–outings by remote manipulation of telepresence robots installed in their homes while staying in bed and were able to communicate with their families. QOL was evaluated by the SEIQoL–DW before and after the use of robots. SEIQoL index score, a QOL index, increased in all patients after using the robots. They all listed the “family” domain (cue) as one they considered to be important in their own lives, and the levels of importance and satisfaction of the “family” cue also increased. For inpatients with intractable neurological diseases with limited ability for communication and movement, we believe that support using telepresence robots serves to confirm and strengthen the connection between the patients and their families, resulting in improved QOL.