Reliability of the unified multiple system atrophy rating scale using the telephone.

OBJECTIVE: The unified multiple system atrophy rating scale (UMSARS) was used to evaluate various symptoms of multiple system atrophy (MSA). And UMSARS part 1 was originally developed for use in interviews, but the need for telemedicine is increasing in COVID-19 pandemic. The purpose of this study is to evaluate the reliability of the UMSARS part 1 telephone survey. METHODS: Thirty-two MSA patients took the UMSARS part 1 face-to-face, followed by two more telephone evaluations. Intraclass correlation coefficients (ICC) and Cronbach's alpha (α) coefficients were calculated, and the inter-rater reliability was determined. At the same time, we asked about the problems in COVID-19 pandemic. RESULTS: The study participants included 15 men and 17 women with mean age of 67.1 years (SD, 8.3). For the total UMSARS part 1 score, the inter-rater ICC and Cronbach's α coefficient were 0.89 to 0.92, and 0.84 to 0.87, respectively. More than half of the items had a relatively high ICC. Cronbach's α coefficients were more than 0.7 for all items. Changes that occurred in COVID-19 pandemic included reduced outings and lack of rehabilitation in about half of the cases. CONCLUSION: The UMSARS part 1 has high inter-rater reliability and internal consistency. Evaluation of subjective symptoms showed that some variability could occur. In addition, there was concern about the influence of lack of rehabilitation due to COVID-19 pandemic.

The prevalence and incidence of multiple sclerosis over the past 20 years in northern Japan.

OBJECTIVES: The prevalence of multiple sclerosis (MS) in East Asia is thought to be lower than in Western countries. Globally, there is a trend of increasing MS prevalence. We investigated the changes in the prevalence and clinical phenotype of MS in the Tokachi province of Hokkaido in northern Japan, from 2001 to 2021. METHODS: Data processing sheets were sent to all related institutions inside and outside the Tokachi area of Hokkaido island in Japan and were collected from April to May 2021. The prevalence according to the Poser's diagnostic criteria for MS was determined on March 31, 2021. RESULTS: In 2021, the crude MS prevalence in northern Japan was 22.4/100,000 (95% confidence interval, 17.6-28.0). The prevalences of MS standardized by the Japanese national population in 2001, 2006, 2011, 2016, and 2021 were 6.9, 11.5, 15.3, 18.5, and 23.3, respectively. The female/male ratio was 4.0 in 2021, increased from 2.6 in 2001. We checked the prevalence using the 2017 revised McDonald criteria, and found only additional male patient who had not fulfilled Poser's criteria. The age- and sex-adjusted incidence of MS per 100,000 individuals increased from 0.09 in 1980-1984 to 0.99 in 2005-2009; since then, it has remained stable. The proportions of primary-progressive, relapsing-remitting, and secondary-progressive MS types in 2021 were 3%, 82%, and 15%, respectively. CONCLUSION: Our results demonstrated a consistent increase in the prevalence of MS among the northern Japanese over 20 years, particularly in females, and consistently lower rates of progressive MS in northern Japan than elsewhere in the world.

IgG4-Related Peripheral Neuropathy with Unilateral Cervical Nerve Root and Brachial Plexus Swelling: A Case Report.

A 64-year-old man presented with left upper limb weakness and dysesthesia for 4 months. Magnetic resonance imaging demonstrated swelling from the 6th-8th left cervical nerve roots to the left brachial plexus. The serum IgG4 level was elevated (762.7 mg/dL). 18F-FDG-PET showed high uptake in the mediastinal lymph nodes, and biopsy revealed infiltration of IgG4-positive plasma cells. We diagnosed IgG4-related neuropathy, and steroid therapy administration improved the symptoms. IgG4-related disease should be considered in the differential diagnosis of peripheral nerve swellings. If biopsy of the disordered nerves is difficult, lymph nodes or other organs should be considered.

Improved Long-Term Survival with Edaravone Therapy in Patients with Amyotrophic Lateral Sclerosis: A Retrospective Single-Center Study in Japan.

Reports on the long-term survival effect of edaravone, which was approved for the treatment of amyotrophic lateral sclerosis (ALS) in 2015 in Japan, are rare. Herein, we report our retrospective analysis of 45 consecutive patients with ALS who initially visited our hospital between 2013 and 2018. Of these, 22 patients were treated with edaravone for an average duration of 26.6 (range, 2-64) months, whereas the remaining patients were not treated with edaravone and comprised the control group. There were no differences in baseline demographics between the two groups. The primary endpoint was tracheostomy positive-pressure ventilation (TPPV) or death, and the follow-up period ended in December 2020. The survival rate was significantly better in the edaravone group than in the control group based on the Kaplan-Meier analysis, which revealed that the median survival durations were 49 (9-88) and 25 (8-41) months in the edaravone and control groups, respectively (p = 0.001, log-rank test). There were no serious edaravone-associated adverse effects during the study period. Overall, the findings of this single-center retrospective study suggest that edaravone might prolong survival in patients with ALS.

Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia.

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4+ T-cells, CD8+ T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor ß-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.

Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease.

INTRODUCTION: Perry disease (Perry syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease. METHODS: We evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy. RESULTS: We identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension. CONCLUSIONS: MIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease.

Myasthenic Crisis Complicated with Myxedema, Positive for Both Anti-acetylcholine Receptor and Anti-muscle-specific Tyrosine Kinase Antibodies.

We herein report the case of myasthenic crisis occurring in a 51-year-old man. He had experienced ptosis, increased body weight with edema, and fatigue with dyspnea. He presented at our emergency department with disturbed consciousness. He was originally diagnosed with myxedema coma, and he required artificial respiration. Because his weakness persisted and he was positive for anti-acetylcholine receptor antibodies and anti-muscle-specific tyrosine kinase antibodies, we diagnosed myasthenic crisis after various examinations. His clinical response to treatment was good and he was discharged in an ambulatory status 3 months after admission. This case demonstrates that myasthenic crisis may occur in association with myxedema.

Prevalence and clinical features of neuromyelitis optica spectrum disorders in northern Japan.

OBJECTIVE: To clarify the prevalence and clinical characteristics of neuromyelitis optica spectrum disorders (NMOSD) in Japan and compare them with those in other ethnic populations. METHODS: Data processing sheets were sent to all related institutions in northern Japan and were collected from April to May 2016. Prevalence was determined on March 31, 2016, using the 2015 International Panel for NMO Diagnosis criteria. RESULTS: The crude prevalence was 4.1/100,000 (95% confidence interval 2.2-6.9) for NMOSD in northern Japan, with a significantly higher number of female than male patients (female: male 12:2). The positivity for anti-aquaporin-4 antibody was 78.6%, and the mean age at onset was 45.2 years. All patients were subjected to preventive therapy in the form of treatment with steroids or immunosuppressive agents. CONCLUSIONS: Our results showed that the prevalence of NMOSD in the Japanese population is similar to that in Caucasians.

Once-daily glatiramer acetate decreases magnetic resonance imaging disease activity in Japanese patients with relapsing-remitting multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) prevalence, clinical patterns, and treatment responses vary between races and geographical latitudes. Glatiramer acetate (GA; Copaxone) has provided a safe, effective treatment option for relapsing-remitting MS patients in the USA, European nations, and other countries for decades. The objective of the present study was to assess the safety and efficacy of GA in reducing magnetic resonance imaging disease activity in Japanese patients with active relapsing-remitting MS. METHODS: This phase 2, multicenter, open-label, single-arm, 52-week study measured the effect of GA 20 mg once-daily on magnetic resonance imaging disease activity. GA efficacy was evaluated through week 36, and safety through week 52. The primary end-point was change in the mean number of T1-weighted gadolinium-enhancing (GdE) lesions from pretreatment (weeks -8, -4 and baseline) to weeks 28, 32 and 36. Secondary end-points included a change in mean number of new T2-weighted lesions, GdE lesion and T2 lesion volumes, annualized relapse rate, and Expanded Disability Status Scale scores. RESULTS: GA therapy reduced the number of new GdE lesions by 65.66% (95% CI 33.19-82.35%). The number of new T2 lesions and GdE lesion volume were also reduced from pretreatment. The annualized relapse rate was reduced by 42% compared with the 1 year before treatment. Changes in T2 lesion volume and Expanded Disability Status Scale scores were favorable, but less pronounced. Most common adverse events were injection-site reactions. CONCLUSIONS: The present study confirmed the well-established safety, tolerability and efficacy profile of GA in Japanese MS patients.

Validity and reliability of a pilot scale for assessment of multiple system atrophy symptoms.

BACKGROUND: Multiple system atrophy (MSA) is a rare progressive neurodegenerative disorder for which brief yet sensitive scale is required in order for use in clinical trials and general screening. We previously compared several scales for the assessment of MSA symptoms and devised an eight-item pilot scale with large standardized response mean [handwriting, finger taps, transfers, standing with feet together, turning trunk, turning 360°, gait, body sway]. The aim of the present study is to investigate the validity and reliability of a simple pilot scale for assessment of multiple system atrophy symptoms. METHODS: Thirty-two patients with MSA (15 male/17 female; 20 cerebellar subtype [MSA-C]/12 parkinsonian subtype [MSA-P]) were prospectively registered between January 1, 2014 and February 28, 2015. Patients were evaluated by two independent raters using the Unified MSA Rating Scale (UMSARS), Scale for Assessment and Rating of Ataxia (SARA), and the pilot scale. Correlations between UMSARS, SARA, pilot scale scores, intraclass correlation coefficients (ICCs), and Cronbach's alpha coefficients were calculated. RESULTS: Pilot scale scores significantly correlated with scores for UMSARS Parts I, II, and IV as well as with SARA scores. Intra-rater and inter-rater ICCs and Cronbach's alpha coefficients remained high (> 0.94) for all measures. CONCLUSION: The results of the present study indicate the validity and reliability of the eight-item pilot scale, particularly for the assessment of symptoms in patients with early state multiple system atrophy.

Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study.

BACKGROUND: Higher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS. METHODS: We enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42-45° north), and 187 MS patients and 235 HCs from the southern half (33-35° north) of the Japanese archipelago (33-45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke's Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity. RESULTS: The HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (p (corr) = 0.0004 and p (corr) = 0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p = 0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p = 0.0012 and p < 0.0001, respectively). DRB1*04:05-positive MS patients had lower MSSS scores and lower frequencies of Barkhof brain lesions and CSF IgG abnormalities than DRB1*04:05-negative MS patients (p = 0.0415, p = 0.0026, and p < 0.0001, respectively). Multivariate analyses revealed that latitude and DRB1*04:05 were independently associated with the lowest quartile of MSSS and that latitude was positively associated with Barkhof brain lesions and CSF IgG abnormalities. DRB1*04:05 was negatively associated with these parameters. MSSS was decreased by 0.57 per DRB1*04:05 allele (p = 0.0198). CONCLUSIONS: Living at a higher latitude and carrying the DRB1*04:05 allele independently lessens MS symptom severity as defined by MSSS. However, these factors influence the frequency of Barkhof brain lesions and CSF IgG abnormalities in opposite ways; higher latitude increases the frequency of Barkhof brain lesions and CSF IgG abnormalities, whereas DRB1*04:05 decreases them.

Comparison of Different Symptom Assessment Scales for Multiple System Atrophy.

To identify the most sensitive scale for use in clinical trials on multiple system atrophy (MSA), a short and sensitive scale is needed for MSA clinical trials. Potential candidates are the Unified MSA Rating Scale (UMSARS), Scale for the Assessment and Rating of Ataxia (SARA), Berg Balance Scale (BBS), MSA Health-Related Quality of Life scale (MSA-QoL), and Scales for Outcomes in Parkinson's Disease-Autonomic questionnaire (SCOPA-AUT). We enrolled patients with MSA from eight hospitals in Hokkaido, Japan. Board-certified neurologists assessed each patient at 6-month intervals and scored them on the UMSARS, SARA, BBS, MSA-QoL, and SCOPA-AUT. Score changes were evaluated using the standardized response mean (SRM). The correlation between disease duration and each score was examined. The first evaluation was conducted on 85 patients (60 patients with MSA cerebellar ataxia dominant subtype [MSA-C] and 25 patients with MSA Parkinsonism-dominant subtype [MSA-P]). Sixty-nine patients were examined after 6 months and 63 patients after 12 months. The UMSARS Part 4 had the largest SRM after 6 months and the SARA after 12 months. SRMs for MSA-P, the shorter duration group, and the early-onset group were larger than were those for MSA-C, the longer duration group, and the late-onset group. SRMs for items regarding skilled hand activities, walking, and standing were relatively large. Our study indicates that the UMSARS (parts 2 and 4), SARA, and BBS are sensitive scales for evaluating MSA progression over 12 months. Items with large SRMs effectively evaluated short-term changes.

Latitude and HLA-DRB1 alleles independently affect the emergence of cerebrospinal fluid IgG abnormality in multiple sclerosis.

BACKGROUND: It is unclear whether the prevalence of oligoclonal IgG bands (OCBs) in multiple sclerosis (MS) is different between northern and southern regions of Asia. OBJECTIVE: This study aimed to compare the prevalence of OCBs and positive cerebrospinal fluid (CSF) findings between northern and southern regions of Japan and to investigate the association of these CSF findings with HLA-DRB1 alleles. METHODS: The study included 180 MS patients from Hokkaido (northern Japan) and 184 patients from Kyushu (southern Japan). The IgG index was defined as increased if it was >0.658. Presence of CSF OCBs and/or increased IgG index was defined as positive CSF findings. RESULTS: Positive CSF findings and OCB positivity were significantly higher in MS patients from Hokkaido than in those from Kyushu (p < 0.0001 for both). Logistic regression analysis revealed that after adjusting for covariates that can be related to abnormal CSF IgG production, the geographic region (Hokkaido) showed odds ratios (ORs) of 4.08 and 2.57, whereas the HLA-DRB1*04:05 allele showed ORs of 0.36 and 0.30 for positive CSF findings and OCB positivity, respectively. CONCLUSIONS: The results indicate that latitude and HLA-DRB1 alleles independently affect the emergence of CSF IgG abnormalities in Japanese patients with MS.

Novel GNE compound heterozygous mutations in a GNE myopathy patient.

INTRODUCTION: Molecular studies have revealed that some patients with myopathies with rimmed vacuoles have pathogenic mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) and Z-band alternatively spliced PDZ motif-containing protein (ZASP) genes. METHODS: We investigated a patient with distal myopathy with rimmed vacuoles by muscle biopsy and sequenced 6 candidate genes. RESULTS: The patient carried GNE compound heterozygous missense mutations (p.V421A and p.N635K) and a ZASP variant (p.D673N). This patient also presented with distal weakness sparing the quadriceps muscles and had atypical results for Z-band-associated protein immunostaining. This finding indicates that the GNE mutations are pathogenic, and the diagnosis is compatible with GNE myopathy. CONCLUSIONS: By combining pathological studies and candidate gene screening, we identified a patient with GNE myopathy due to novel GNE compound heterozygous mutations.

DNAJB6 myopathy in an Asian cohort and cytoplasmic/nuclear inclusions.

DNAJB6, which encodes DnaJ homolog, subfamily B, member 6 (DNAJB6) was recently identified as a causative gene for limb-girdle muscular dystrophy type 1D (LGMD1D). DNAJB6 is a member of heat shock protein 40 and contains a J domain, G/F domain and C-terminal domain. Only three different mutations have been identified in 11 families. In this study, we identified seven Japanese individuals from four unrelated families who carried a DNAJB6 mutation. We found a novel p.Phe96Ile substitution and a previously reported p.Phe96Leu change in the G/F domain of DNAJB6. All affected individuals showed slowly progressive muscle weakness, mainly in their legs, and their muscle pathology showed cytoplasmic inclusions and rimmed vacuoles. Our immunohistochemical analysis detected cytoplasmic accumulations associated with chaperone-assisted selective autophagy together with intranuclear accumulations of DNAJB6 and heat shock 22-kD protein 8 (HSPB8). This is the first report of Asian patients with LGMD1D. Our new findings may contribute to understanding the pathological mechanisms of this myopathy.

Increased prevalence, incidence, and female predominance of multiple sclerosis in northern Japan.

OBJECTIVE: To carry out the third epidemiologic surveillance of multiple sclerosis (MS) in Tokachi province, on the northernmost island of Japan, and to compare the results of the present survey on the prevalence, incidence, and characteristics of MS and neuromyelitis optica (NMO) with those of previous surveys performed in 2001 and 2006. METHODS: A data processing sheet was sent to all MS-related institutions in Tokachi province, and all sheets were collected in March 2011. The criteria of Poser were used for diagnosing MS and the criteria proposed by Wingerchuk for diagnosing NMO. We then compared the results of the present survey with those of previous surveys performed in 2001 and 2006 in the same community. RESULTS: Fifty-seven patients diagnosed with MS according to the criteria of Poser were identified. The prevalence was 16.2/100,000 in 2011, which was higher than in the previous studies. The female/male ratio of MS was 2.63, 2.75, and 3.38 in 2001, 2006, and 2011, respectively. Three patients fulfilled the criteria for diagnosis of NMO in 2011; the prevalence of NMO was 0.9/100,000. CONCLUSIONS: The results of this study suggest that the prevalence and the female predominance of MS have been increasing, due to an increase in the incidence after 1990, and that the prevalence of NMO is relatively low in northern Japan.

[A case of posterior reversible encephalopathy syndrome occurring after anemia correction].

A 53-year-old woman was admitted to our hospital with headache and convulsion. Advanced anemia with a Hb level of 3.5 g/dl had been detected about a month earlier, and it had been treated by iron administration to achieve a Hb level of 8.9 g/dl. The patient developed status epilepticus on admission. The blood pressure was elevated, and brain diffusion weighted imaging and fluid attenuated inversion recovery imaging revealed high intensity areas in the bilateral posterior and parietal lobes, right frontal lobe, and right basal ganglia. The cerebrospinal fluid protein was elevated. The convulsions settled after continuous infusion of thiamylal under mechanical ventilation. Subsequently, the patient became conscious, and the brain MRI abnormalities gradually disappeared. While a number of factors such as hypertension, medication and others have been reported as causes of posterior reversible encephalopathy syndrome (PRES), comparatively rapid anemia correction could also possibly precipitate PRES as like as this case. Thus anemia correction needs to be undertaken carefully.

Clinical features of spinal cord sarcoidosis: analysis of 17 neurosarcoidosis patients.

The diagnosis of neurosarcoidosis is often difficult; the imaging signs of spinal cord sarcoidosis sometimes mimic those of cervical spondylotic myelopathy, which is common in elderly persons. We examined the characteristics of spinal cord sarcoidosis in Japanese patients with neurosarcoidosis. This case series identified patients with neurosarcoidosis at four general hospitals and one university hospital from April 1998 to September 2010. All diagnoses were based on the diagnostic criteria proposed by Zajicek et al. Seventeen patients (nine men and eight women) were involved: six patients with spinal cord lesions accompanied by cervical spondylosis, five with cerebral lesions, three with cranial nerve lesions, two with meningitis, and one with nerve root lesions. Patients with spinal cord sarcoidosis had a higher onset age, longer duration from onset to diagnosis, reduced leukocytosis in the cerebrospinal fluid (CSF), and lower angiotensin-converting enzyme (ACE) levels in the CSF. The results of this study indicate that diagnosis of spinal cord sarcoidosis requires careful evaluation.