桑原 聡

We describe a 48-year-old man, suffering from difficulties in closing his eyes. He subsequently experienced progressive weakness in the facial and bulbar regions and upper limbs. His father and paternal grandmother had limb weakness as initial manifestations and were diagnosed with amyotrophic lateral sclerosis (ALS). In the present case, neuroimaging and laboratory studies were unremarkable, and neurophysiological studies disclosed diffuse denervation. Genetic testing identified a heterozygous c.10A>G, p.K4E (K3E) variant in superoxide dismutase 1 (SOD1) gene, and he was diagnosed with familial ALS. In ALS, facial muscles are rarely involved as an initial symptom. The present patient is a first case of facial onset ALS with K3E variant in SOD1 gene. Two case reports identified facial palsy as an initial manifestation in familial ALS with C6G variant in SOD1 gene. Several ALS patients with variants in SOD1 gene may have facial onset history.

BACKGROUND: Peripheral nerve imaging is increasingly recognized as a powerful tool to evaluate nerve hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and Charcot-Marie-Tooth diseases (CMT), whereas data in pediatric patients are limited. CASE DESCRIPTION: We describe the case of a 15-year-old Japanese girl with asymmetric demyelinating polyneuropathy, who, at the age of 10 years, was initially diagnosed with a demyelinating form of CMT. Fluorescence in situ hybridization for peripheral myelin 22 was negative, and already-known pathogenic variants were not detected by whole-genome sequencing, and nerve conduction studies revealed multifocal conduction blocks. Over the next 5 years, the patient showed gradual improvement in muscle weakness and sensory disturbance without immunological treatment and was referred to our hospital. RESULTS: At the age of 15 years, magnetic resonance (MR) neurography showed asymmetric multifocal fusiform enlargement of nerve roots, brachial and lumbosacral plexuses, and intermediated nerve trunks, as well as cranial nerves. Based on the MR neurography findings and multifocal nerve conduction blocks, she was diagnosed as having multifocal CIDP (multifocal demyelinating sensory and motor neuropathy [MADSAM]) according to the European Federation of Neurological Societies/Peripheral Nerve Society diagnostic criteria. DISCUSSION: Clinical diagnosis of childhood CIDP is challenging because its neurological manifestations and nerve conduction study findings occasionally resemble those of inherited demyelinating neuropathies. MR neurography is helpful for the assessment of patterns of nerve hypertrophy; MADSAM-CIDP is characterized by multiple fusiform nerve enlargement, whereas CMT shows symmetric and diffuse nerve hypertrophy. CONCLUSION: The MR neurography patterns would help in diagnosing pediatric demyelinating neuropathies.

BACKGROUND: In individuals with Parkinson's disease (PD), visually guided saccades (VGSs) reportedly reflect general motor dysfunction and cognitive impairments. However, it has not been fully elucidated whether the VGS abnormalities result from nigrostriatal degeneration or other PD-related neural changes. METHODS: We measured VGS latency and gain in 50 PD participants and 56 age-matched normal controls (NCs), and PD participants underwent dopamine transporter (DAT) single-photon emission computed tomography (SPECT) within 2 months of the measurement. VGSs were evoked by a white dot on a monitor, which was presented at the center and pseudo-randomly jumped off horizontally (10° or 20° eccentricity) or vertically (10° or 15°). First, we compared the parameters between PD participants and NCs for each target location. Second, in the participants who exhibited striatal DAT asymmetry on SPECT, VGSs contralaterally directed to the more severely affected striatum were compared with those ipsilaterally directed. Third, effects of the DAT-SPECT specific binding ratio (SBR) on VGSs were analyzed. RESULTS: PD participants demonstrated prolonged latencies when the target was presented at the upward 15° eccentricity and decreased gains at all target locations. Contralateral VGSs relative to the side of the more severely affected striatum were more delayed and hypometric than ipsilateral. The SBR had a significant positive effect on VGS gain. CONCLUSIONS: In participants with PD, saccadic abnormalities were emphasized when VGSs were directed contralaterally to the more severely affected striatum. Moreover, the dopaminergic nigrostriatal degeneration on DAT-SPECT was mainly associated with VGS gain.

INTRODUCTION: Early-onset dementia (EOD), defined as dementia onset before the age of 65 years, is relatively rare, but its social impacts are significant. This study aimed to characterize the diagnosis and clinical and social status of EOD subjects in the 11 dementia centers in Chiba Prefecture, Japan. METHODS: A retrospective 1-year survey was conducted. Collected data included clinical diagnosis, age at onset, age at survey, neuropsychological test, family history, employment, and living status. RESULTS: We identified 208 EOD subjects, including 123 (59.4%), 24 (11.6%), 21 (10.1%), 17 (8.2%), and 10 (4.8%) with Alzheimer's disease (AD), vascular dementia, frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies/Parkinson's disease dementia, and alcohol-related dementia, respectively. The Mini-Mental State Examination (MMSE) score <24 was observed in 50-75% of patients and was not correlated with disease duration. Twenty-four (16.4%) subjects had positive family history of EOD. EOD subjects were at risk of early retirement, and 133 subjects lived with their family, in whom 64 (30.8%) lived with their child. CONCLUSION: In dementia centers, AD, FTLD, and Lewy body dementia had relatively large proportion. Employment, economy, and social supports are urgently needed for EOD subjects and their family.

Pareidolia is a visual illusion of meaningful objects that arise from ambiguous forms embedded in visual scenes. Previous studies showed that pareidolias are frequently observed in patients with Parkinson's disease (PD) as well as dementia with Lewy bodies. However, whether pareidolias are useful for differentiating PD from other neurodegenerative parkinsonism disorders including multiple system atrophy (MSA) is unclear. The noise pareidolia test (NPT) was performed in 40 and 48 patients with PD and MSA, respectively. A receiver operating characteristic (ROC) curve analysis was used to evaluate sensitivity and specificity. Results of neuropsychological tests were also compared between patients with PD with and without pareidolias. Visual hallucinations were present in none of the subjects. Pareidolic response in the NPT was observed in 47.5% and 18.8% of patients with PD and MSA, respectively. The number of pareidolic responses in patients with PD was significantly larger compared with patients with MSA (P=0.001). ROC curve analyses showed the sensitivity and specificity at 33% and 98%, respectively. Among patients with PD, those with pareidolias demonstrated higher State-Trait Anxiety Inventory-state (P=0.044) and State-Trait Anxiety Inventory-trait (P=0.044) than those without pareidolias. Pareidolias can be found in patients with PD without visual hallucinations, and the pareidolia test may be a highly specific test for differentiating PD from MSA. Thus, anxiety may be associated with pareidolias in patients with PD.

INTRODUCTION: This study aimed to use a novel MRI contrast, the standardized T1-weighted/T2-weighted (sT1w/T2w) ratio, to assess damage of the white matter and gray matter in multiple system atrophy (MSA). Furthermore, this study investigated whether the sT1w/T2w ratio was associated with cognitive impairment in MSA. METHODS: The white matter and gray matter sT1w/T2w ratio of 37 MSA patients and 19 healthy controls were measured. Correlation analyses were used to evaluate the relationship between sT1w/T2w ratio values and clinical variables, and a multivariate analysis was used to identify independent factors associated with cognitive impairment in MSA. RESULTS: MSA patients showed a higher white matter sT1w/T2w ratio value than controls (p < 0.001), and the white matter sT1w/T2w ratio value was significantly correlated with the International Cooperative Ataxia Rating Scale score (r = 0.377, p = 0.021) and the Addenbrooke's cognitive examination III score (r = -0.438, p = 0.007). Cognitively impaired MSA patients had a significantly higher white matter sT1w/T2w ratio value than cognitively preserved MSA patients (p = 0.010), and the multiple logistic regression analysis revealed that the median white matter sT1w/T2w ratio value was independently associated with cognitive impairment in MSA. CONCLUSION: The sT1w/T2w ratio is sensitive to degenerative changes in the white matter that is associated with cognitive ability in MSA patients.

Objective: To investigate changes in serum complements and their regulators in the pathogenesis of myasthenia gravis (MG). Methods: Forty-four patients with acetylcholine receptor antibody-positive MG, as well as 20 patients with non-inflammatory neurological disorders were enrolled. Serum complements (C3, C4 and soluble C5b-9) and complement regulators (vitronectin, clusterin and properdin) were extensively analysed by enzyme-linked immunosorbent assay and their associations with clinical profiles of MG were examined. Results: Serum C3, C4 and clusterin levels were not significantly different between patients with MG and controls. The patients with MG had higher soluble C5b-9 (P = 0.09) and vitronectin (P = 0.001) levels than the controls; moreover, vitronectin levels decreased after treatment (P = 0.09). Serum properdin (P = 0.03) levels were lower in the patients with MG than in the controls, and negatively correlated with the MG Activities of Daily Living score (rs = −0.26, P = 0.09) and with the presence of bulbar palsy (P = 0.04). Conclusion: Our results show that activation of complements and an altered complement network could contribute to the inflammatory pathogenesis of MG.

Background: Indications for subthalamic nucleus deep brain stimulation (STN-DBS) surgery are determined basically by preoperative motor function; however, postoperative quality of life (QOL) is not necessarily associated with improvements in motor symptoms, suggesting that neuropsychiatric symptoms might be related to QOL after surgery in patients with Parkinson's disease. Objectives: We aimed to examine temporal changes in neuropsychiatric symptoms and their associations with QOL after STN-DBS. Materials and Methods: We prospectively enrolled a total of 61 patients with Parkinson's disease (mean age = 65.3 ± 0.9 years, mean disease duration = 11.9 ± 0.4 years). Motor function, cognitive function, and neuropsychiatric symptoms were evaluated before and after DBS surgery. Postoperative evaluation was performed at 3 months, 1 year, and 3 years after surgery. Results: Of the 61 participants, 54 completed postoperative clinical evaluation after 3 months, 47 after 1 year, and 23 after 3 years. Frontal lobe functions, depression, and verbal fluency significantly worsened 3 years after STN-DBS. Non-motor symptoms such as impulsivity and the Unified PD Rating Scale (UPDRS) part I score were associated with QOL after STN-DBS. Conclusions: Frontal lobe functions, depression, and verbal fluency significantly worsened 3 years after STN-DBS. The UPDRS part I score and higher impulsivity might be associated with QOL after STN-DBS.

Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction. The neuromuscular junction damage associated with MG is caused by anti-acetylcholine receptor (AChR) antibody and complements. Recently, eculizumab (an anti-C5 monoclonal antibody) was approved for patients with anti-AChR antibody-positive generalized refractory MG. Here, we report a Japanese man with MG who well responded to eculizumab, but experienced acute severe worsening of myasthenic symptoms 2 months after its discontinuation. Plasmapheresis did not improve his symptoms; hence, eculizumab was re-administered, resulting in a dramatic response within a week. This is an informative case because eculizumab discontinuation in patients with MG has been very rarely reported. If eculizumab treatment is clinically well effective and AChR antibody titer does not decrease, clinicians should be aware that acute and critical deterioration of MG may occur after the eculizumab discontinuation.

OBJECTIVE: The interpretation of electrophysiological findings may lead to misdiagnosis in polyneuropathies. We investigated the electrodiagnostic accuracy of three supervised learning algorithms (SLAs): shrinkage discriminant analysis, multinomial logistic regression, and support vector machine (SVM), and three expert and three trainee neurophysiologists. METHODS: We enrolled 434 subjects with the following diagnoses: chronic inflammatory demyelinating polyneuropathy (99), Charcot-Marie-Tooth disease type 1A (124), hereditary neuropathy with liability to pressure palsy (46), diabetic polyneuropathy (67), and controls (98). In each diagnostic class, 90% of subjects were used as training set for SLAs to establish the best performing SLA by tenfold cross validation procedure and 10% of subjects were employed as test set. Performance indicators were accuracy, precision, sensitivity, and specificity. RESULTS: SVM showed the highest overall diagnostic accuracy both in training and test sets (90.5 and 93.2%) and ranked first in a multidimensional comparison analysis. Overall accuracy of neurophysiologists ranged from 54.5 to 81.8%. CONCLUSIONS: This proof of principle study shows that SVM provides a high electrodiagnostic accuracy in polyneuropathies. We suggest that the use of SLAs in electrodiagnosis should be exploited to possibly provide a diagnostic support system especially helpful for the less experienced practitioners.

BACKGROUND: Individuals with early-onset Alzheimer disease (EOAD) differ from those with late-onset Alzheimer disease (LOAD) not only in genetics and age at onset but also in their clinical symptoms. OBJECTIVE: To differentiate the neuropathological and neurocognitive features of EOAD and LOAD by comparing the pattern of regional gray matter volume (GMV) reduction and its symptomatic correlates. METHOD: Three-dimensional T1-weighted MRIs and Mini-Mental State Examination (MMSE) scores were obtained from 12 individuals with EOAD, 65 with LOAD, and 49 healthy controls (HC). Regional GMV reduction between the three groups was assessed using voxel-based morphometry. Multiple regression analyses were conducted with MMSE total score as an independent variable. RESULTS: Compared to the HC, both AD groups showed a significant GMV reduction in the bilateral hippocampus and the left temporoparietal junction; in addition, the LOAD group showed one in the bilateral anterior temporal lobes. Multiple regression analyses revealed a positive correlation between MMSE total score and GMV in the left anterior temporal lobe in both AD groups; that is, lower scores were associated with reduced GMV. Interestingly, a positive correlation in hippocampal GMV was revealed only in the LOAD group. CONCLUSION: MMSE total score is associated with the anterior temporal lobe volume in individuals with AD. Hippocampal volume and its relationship with MMSE total score are associated with LOAD pathophysiology but not EOAD pathophysiology. The hippocampal volume reduction and low MMSE scores are hallmarks of LOAD but are less specific to EOAD, which may cause a delay in diagnosis.

Summary Myasthenia gravis (MG) is an autoantibody-mediated inflammatory disease of the neuromuscular junction. Biomarkers indicating disease activity in MG are warranted. Recently, the soluble urokinase plasminogen activator receptor (suPAR) has been reported to be associated with inflammation, tissue damage, disease activity and prognosis in various diseases, including autoimmune diseases. In this study, serum suPAR levels were measured in 40 patients with anti-acetylcholine receptor antibody-positive MG and 30 controls, and their correlations with clinical variables and severity scale scores were investigated. We identified that serum suPAR levels significantly correlated with MG activities of daily living scale (Spearman's ρ = 0·45; P = 0·004) and MG Foundation of America classification (Spearman's ρ = 0·37; P = 0·02) at serum sampling, but not with anti-acetylcholine receptor antibody titers. In conclusion, serum suPAR levels can be a candidate for a novel biomarker of disease activity in anti-acetylcholine receptor antibody-positive MG.

Some cancers are related to atherosclerotic diseases; therefore, these two types of disease may share some antibody biomarkers in common. To investigate this, a first screening of sera was performed from patients with esophageal squamous cell carcinoma (ESCC) or acute ischemic stroke (AIS) for serological identification of antigens using recombinant cDNA expression cloning (SEREX). The amplified luminescent proximity homogeneous assay-linked immunosorbent assay (AlphaLISA) method, which incorporates glutathione donor beads and anti-human IgG acceptor beads, was used to evaluate serum antibody levels. SEREX screening identified low-density lipoprotein receptor-related protein-associated protein 1 (LRPAP1) as a target antigen of serum IgG antibodies in the sera of patients with ESCC or AIS. Antigens, including recombinant glutathione S-transferase-fused LRPAP1 protein, were prepared to examine serum antibody levels. AlphaLISA revealed significantly higher antibody levels against the LRPAP1 protein in patients with solid cancers such as ESCC and colorectal carcinoma and some atherosclerosis-related diseases such as AIS and diabetes mellitus compared with healthy donors. Correlation analysis revealed that the elevated serum antibody levels against LRPAP1 were associated with smoking, a well-known risk factor for both cancer and atherosclerosis. Serum LRPAP1 antibody is therefore a common marker for the early diagnosis of some cancers and atherosclerotic diseases and may reflect diseases caused by habitual smoking.

OBJECTIVE: Approximately 15%-20% of patients with Guillain-Barré syndrome (GBS) are unable to walk independently at 6 months from the onset of neurological symptom. The modified Erasmus GBS outcome score (mEGOS) has been reported as a prognostic tool.Herein we investigated the association between a poor outcome, inability to walk independently at 6 months and presence of antiganglioside antibodies. METHODS: The clinical and serological data of 177 patients with GBS were retrospectively collected in Japan to assess the associations between a poor outcome and serum IgG antibodies against each ganglioside (GM1, GD1a, GalNAc-GD1a, GQ1b and GT1a). In addition, we investigated whether the combination of mEGOS and serum IgG antibodies against gangliosides is useful in predicting a poor outcome. RESULTS: The patients with IgG anti-GD1a antibodies more frequently showed poor outcomes than those without these antibodies (9 (36%) of 25 vs 8 (6%) of 127 patients, p<0.001). Particularly, 80% showed a poor outcome when they had both serum IgG anti-GD1a antibody and a high mEGOS of ≥10 on day 7 of admission. CONCLUSIONS: The combination of serum IgG anti-GD1a antibodies and a high mEGOS could help in making a more accurate prognosis of patients than mEGOS alone, especially for predicting poor outcomes.

BACKGROUND: Neurological disorders with IgG antibodies against myelin-oligodendrocyte glycoprotein (MOG-IgG) have been increasingly recognised as a new type of neuroinflammatory disorder. OBJECTIVE: The study aimed to identify regional and ethnic differences in clinical profiles of MOG-IgG-associated disorders between East Asian (Japanese) and Caucasian (German) patients. METHODS: Demographic, clinical and therapeutic data from 68 MOG-IgG-positive adults were collected (Japanese, n=44; German, n=24). RESULTS: Age and sex were similar between cohorts, with optic neuritis occurring most frequently at onset (Japanese: 61%; German: 58%). However, Japanese patients had a lower annualised relapse rate (0.4 vs 0.8, p=0.019; no relapse, 64% vs 25%, p=0.002) and lower Expanded Disability Status Scale score at the last visit (1.0 vs 2.0; p=0.008), despite similar follow-up periods (mean, 73.9 months vs 73.4 months), than those of German patients, respectively. Cerebral syndromes were more common (27% vs 4%; p=0.021) and myelitis less common (21% vs 50%; p=0.012) in Japanese than in German patients, respectively. Japanese patients were more commonly treated with long-term corticosteroids (73%), whereas German patients were more commonly treated with rituximab or other immunosuppressants (63%). CONCLUSIONS: Among patients with MOG-IgG, Japanese tended to have a monophasic milder disease, whereas the majority of German patients had a relapsing course and more frequent myelitis, findings compatible with neuromyelitis optica spectrum disorder. Although the attack-prevention treatment regimens were considerably different, genetic and environmental factors may be important to determine clinical phenotypes and disease activity.

Peroxiredoxins (PRXs) are intracellular anti-oxidative enzymes but work as inflammatory amplifiers under the extracellular condition. To date, the function of PRXs in the pathogenesis of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is not fully understood. The aim of this study was to investigate whether PRXs play a role in the pathogenesis of MS and NMOSD. We analyzed levels of PRXs (PRX1, PRX5 and PRX6) in the cerebrospinal fluid (CSF) and serum of 16 patients with MS, 16 patients with NMOSD and 15 patients with other neurological disorders (ONDs). We identified potential correlations between significantly elevated PRXs levels and the clinical variables in patients with MS and NMOSD. Additionally, pathological analyses of PRXs (PRX1-6) in the central nervous system (CNS) were performed using the experimental autoimmune encephalomyelitis (EAE), animal model of MS. We found that serum levels of PRX5 and PRX6 in patients with MS and NMOSD were higher compared with those in patients with ONDs (P &lt  0·05). Furthermore, high levels of PRX5 and PRX6 were partly associated with blood–brain barrier dysfunction and disease duration in NMOSD patients. No significant elevation was found in CSF PRXs levels of MS and NMOSD. Spinal cords from EAE mice showed remarkable PRX5 staining, especially in CD45+ infiltrating cells. In conclusion, PRX5 and PRX6 may play a role in the pathogeneses of MS and NMOSD.

OBJECTIVE: The 'split hand' sign refers to preferential wasting of the thenar and first dorsal interosseous muscles with relatively sparing of the hypothenar muscles in amyotrophic lateral sclerosis (ALS) and both cortical and spinal/peripheral excitotoxic mechanisms have been proposed. We aimed to study split hand and axonal excitability in spinal and bulbar muscular atrophy (SBMA) in which cortical motor neurons are intact. METHODS: In 35 patients with genetically confirmed SBMA, 55 with ALS, 158 with other neuromuscular diseases and 90 normal controls; split hand was strictly determined by amplitudes of compound muscle action potentials. Nerve excitability testing of median motor axons was performed in 35 SBMA and 55 patients with ALS and 45 normal controls. RESULTS: Split hand was as frequently found for patients with SBMA (57%) and ALS (62%), compared with disease (20%) and normal (0%) controls. Excitability testing showed that in both SBMA and ALS, strength-duration time constant was longer, and threshold changes in depolarising threshold electrotonus and superexcitability in the recovery cycle were greater than in normal controls (p<0.01). CONCLUSIONS: Split hand is not specific to ALS and can be caused by the peripheral mechanism alone in SBMA, whereas the effect of upper motor neuron lesion cannot be excluded in ALS. Our results also suggest that SBMA and ALS share common axonal excitability changes; increased nodal persistent sodium and reduced potassium currents that may accelerate motor neuronal death and differently affect axons-innervating different muscles. Ion channel modulators could be a therapeutic option for both SBMA and ALS.

Background and purpose: The silent progression of patients with multiple sclerosis (MS) has been reported. The aim of this study was to investigate the association between brain atrophy rates and disease-modifying drugs (DMDs) in patients with MS during their relapse-free period. Methods: Patients with relapsing-remitting MS were classified into two groups on the basis of clinical records, i.e. a first-generation DMD group treated with interferon-beta-1a, interferon-beta-1b or glatiramer acetate and a second-generation DMD group treated with dimethyl fumarate, fingolimod or natalizumab. Brain volume was calculated with SPM12. Results: A total of 45 patients with relapsing-remitting MS were enrolled in the first-generation (n = 22) or second-generation (n = 23) DMD group. The annualized relapse rate was lower in the first-generation than in the second-generation DMD group (median 0.26 vs. 0.59 P &lt  0.001). The annualized atrophy rate of the normalized brain volume was not different between the first- and second-generation DMD groups after analysis of covariance (median 0.13% vs. 0.59% P = 0.17). Conclusions: The median annualized atrophy rate of normalized brain volume in the first-generation DMD group was similar to the previously reported annual brain atrophy rate of healthy controls, which may suggest that treatment with a first-generation DMD need not be changed when patients with MS are clinically inactive.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

Background: Mepolizumab is an option for add-on therapy in cases of refractory or relapsing eosinophilic granulomatous polyangiitis (EGPA). However, it has not been fully investigated if add-on mepolizumab is effective for active refractory or active relapsing EGPA patients with life- and/or organ-threatening manifestations, especially with severe neuropathy. Case presentation: We herein report on a 63-year-old man with severe progressive neuropathy secondary to active relapsing EGPA. In this case, the optimal dose of glucocorticoids and cyclophosphamide could not be used because of glaucoma and signet ring cell carcinoma. Add-on therapy of mepolizumab showed prompt immunological remission and marked improvement in neurological manifestations. Conclusions: Mepolizumab can be considered as an important induction therapy option for active relapsing or refractory EGPA. It has the potential to effectively improve neurological disturbances associated with severe neuropathy in EGPA.

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG nucleotide repeat expansion in atrophin 1. A previous report described cerebellar white matter lesions on magnetic resonance imaging (MRI) in elderly-onset DRPLA patients, but this finding has not been fully investigated in a total population of DRPLA patients, including juvenile or early-adult onset patients. Herein, we attempted to determine the frequency, distribution pattern, and features of the cerebellar white matter lesions in 30 consecutive DRPLA patients. We also assessed the relationships between the cerebellar white matter lesions and clinical parameters and other MRI findings. The cerebellar white matter lesions were found in 43% of the 30 DRPLA patients, and in 70% of the late adult-onset DRPLA patients. In approx. Two-thirds of the patients with cerebellar white matter lesions, the lesions were localized in the paravermal area (paravermal lesions). Multiple logistic regression analyses revealed that the Fazekas grade of 'cerebral' white matter lesions was independently associated with 'cerebellar' white matter lesions. In conclusion, cerebellar white matter lesions are one of the distinctive MRI features in DRPLA patients, especially in patients with older age at onset. Cerebellar white matter lesions, as well as cerebral white matter lesions, might originate from the disease process of DRPLA itself, and they often have a characteristic distribution of paravermal lesions.

OBJECTIVE: Facioscapulohumeral muscular dystrophy (FSHD) is a heterogenetic disorder predominantly characterized by progressive facial and scapular muscle weakness. Patients with FSHD either have a contraction of the D4Z4 repeat on chromosome 4q35 or mutations in D4Z4 chromatin modifiers SMCHD1 and DNMT3B, both causing D4Z4 chromatin relaxation and inappropriate expression of the D4Z4-encoded DUX4 gene in skeletal muscle. In this study, we tested the hypothesis whether LRIF1, a known SMCHD1 protein interactor, is a disease gene for idiopathic FSHD2. METHODS: Clinical examination of a patient with idiopathic FSHD2 was combined with pathologic muscle biopsy examination and with genetic, epigenetic, and molecular studies. RESULTS: A homozygous LRIF1 mutation was identified in a patient with a clinical phenotype consistent with FSHD. This mutation resulted in the absence of the long isoform of LRIF1 protein, D4Z4 chromatin relaxation, and DUX4 and DUX4 target gene expression in myonuclei, all molecular and epigenetic hallmarks of FSHD. In concordance, LRIF1 was shown to bind to the D4Z4 repeat, and knockdown of the LRIF1 long isoform in muscle cells results in DUX4 and DUX4 target gene expression. CONCLUSION: LRIF1 is a bona fide disease gene for FSHD2. This study further reinforces the unifying genetic mechanism, which postulates that FSHD is caused by D4Z4 chromatin relaxation, resulting in inappropriate DUX4 expression in skeletal muscle.

OBJECTIVE: To establish a clinician-led guideline for the diagnosis and treatment of Hirayama disease (HD) using a modified Delphi technique. METHODS: Based on a combination of a systematic review and opinion of ten experts, a protocol for the consensus of the diagnosis, treatment and follow-up assessment of HD was established. A modified 3-round Delphi survey was then performed by more than 40 panelists from various countries of the world. Both levels of evidence and levels of agreement were derived in all statements of finial guideline. RESULTS: A total of 47 experts from 6 countries were enrolled in the expert panel in this study. Highly consistent results were achieved during the three Delphi rounds. An expert-led guideline finally constructed includes 24 statements related to diagnosis, treatment and follow-up assessment of HD. CONCLUSIONS: The modified Delphi technique used in this study resulted in an expert-led guideline concerning several clinical aspects of HD. SIGNIFICANCE: This clinician-led guideline may provide a helpful direction for clinical practice with regard to the diagnosis and treatment of HD.

Background: Dopamine replacement therapy is an established treatment for motor symptoms of Parkinson's disease, but its long-term use is often limited by the eventual development of motor complications, including levodopa-induced dyskinesia. Genetic background, particularly polymorphisms of dopamine metabolism genes, may affect the occurrence of dyskinesia in Parkinson's disease patients. Methods: We investigated polymorphisms of dopamine metabolism genes, including catechol-O-methyltransferase, monoamine oxidase B, dopamine beta-hydroxylasedopamine, dopamine receptors D1, D2, and D3, and dopamine transporter, in 110 patients with Parkinson's disease. Cox proportional hazards regression was used to detect associations between genotypes and levodopa-induced dyskinesia. Results: Monoamine oxidase B rs1799836 was the only polymorphism correlated with risk of dyskinesia. Patients with an AG or GG genotype were more likely to have dyskinesia than those with an AA genotype (adjusted hazard ratio, 3.41; 95% confidence interval, 1.28-9.10). Also, Kaplan-Meier curves demonstrated that patients with an AG or GG genotype developed dyskinesia earlier than those with an AA genotype (log-rank test, p = .004). Conclusions: In Parkinson's disease patients, the monoamine oxidase B rs1799836 G allele is associated with a greater likelihood of developing dyskinesia than the A allele, possibly due to its association with lower monoamine oxidase B activity in the brain. Thus, detection of monoamine oxidase B polymorphisms may be useful for determining the optimal dosing of antiparkinson medications.

Objective: Lambert–Eaton myasthenic syndrome (LEMS) is a paraneoplastic neurological syndrome, most frequently associated with small-cell lung carcinoma (SCLC). The survival of LEMS patients depends on the presence of SCLC, whereas the functional outcome in patients without SCLC has not been fully clarified. The aim of this study was to elucidate the long-term prognosis of LEMS patients with or without SCLC. Methods: We collected data from seven consecutive Japanese patients with LEMS without SCLC (n = 4) or LEMS with SCLC (n = 3) consulting Chiba university hospital, Chiba, Japan from 2003 to 2019. The functional disability was assessed with the modified Rankin Scale. Results: The median observation period was 52 months (range 18–168 months); one LEMS with SCLC patient died as a result of SCLC 18 months after diagnosis, whereas the remaining two LEMS with SCLC patients with complete remission of their tumor still showed improvement in neurological symptoms 52 and 168 months after treatment, respectively. All LEMS patients without SCLC showed a favorable response to treatment and good functional prognosis (modified Rankin Scale 1 or 2) during the follow-up period (48–120 months). Conclusions: In Japanese LEMS patients, the long-term neurological outcome is generally favorable. Our results also suggest that even in LEMS with SCLC patients, successful treatment for their cancer could result in sustained improvement in neurological symptoms.

INTRODUCTION: Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is a rare symptom. Several studies have reported that a small brainstem lesion could cause WEBINO. CASE REPORT: The authors present the case of an 88-year-old female individual who developed sudden-onset diplopia and gait disturbance. Neurological examination revealed WEBINO with convergence impairment, gaze-evoked upward nystagmus on upward gaze, and bilateral limb ataxia. Brain magnetic resonance imaging revealed a small paramedian pontine tegmentum infarction, responsible for the symptoms. A literature review of WEBINO in ischemic stroke revealed that most patients exhibited impaired convergence and other neurological symptoms. CONCLUSION: Gaze-evoked upward nystagmus on upward gaze and bilateral limb ataxia accompanied by WEBINO due to a small brainstem lesion were the characteristic findings of our case.

BACKGROUND: The "hot cross bun" (HCB) sign, a cruciform hyperintensity in the pons on magnetic resonance imaging (MRI), has gradually been identified as a typical finding in multiple system atrophy, cerebellar-type (MSA-C). Few reports have evaluated the sensitivity of an HCB, including a cruciform hyperintensity and vertical line in the pons, which precedes a cruciform hyperintensity, in the early stages of MSA-C. Moreover, the difference in frequency and timing of appearance of an HCB between MSA-C and spinocerebellar ataxia type 3 (SCA3) has not been fully investigated. METHODS: This study investigated the time at which an HCB and orthostatic hypotension (OH) appeared in 41 patients with MSA-C, based on brain MRI and head-up tilt test. The MRI findings were compared with those of 26 patients with SCA3. The pontine signal findings on T2-weighted MRI were graded as 0 (no change), 1 (a vertical T2 high-intensity line), or 2 (a cruciform T2 high-intensity line), with grades 1 or 2 considered as an HCB. OH 30/15 was defined as a decrease in systolic blood pressure of > 30 mmHg or diastolic blood pressure of > 15 mmHg. RESULTS: Among the 24 patients with MSA-C within 2 years from the onset of motor symptoms, an HCB was detected in 91.7%, whereas OH 30/15 was present in 60.0%. Among the 36 patients with MSA-C within 3 years from the onset of motor symptoms, a grade 2 HCB was detected in 66.7% of those with MSA-C but in none of those with SCA-3. CONCLUSIONS: HCB is a highly sensitive finding for MSA-C, even in the early stages of the disease. A grade 2 HCB in the early stage is an extremely specific finding for differentiating MSA-C from SCA-3.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated peripheral neuropathy that is currently classified into several clinical subtypes, which are presumed to have different pathogenic mechanisms. Recently, studies identified a subgroup of patients with CIDP who were positive for IgG4 autoantibodies against paranodal proteins, such as neurofascin-155 and contactin-1, who respond poorly to first-line therapies for typical CIDP, including intravenous immunoglobulin therapy. OBJECTIVE: This study aims to evaluate the efficacy and safety of intravenous rituximab according to IgG4 autoantibody status in patients with refractory CIDP. METHODS: The Evaluation of the Efficacy and Safety of Rituximab in Refractory CIDP Patients with IgG4 Autoantibodies in the Exploratory Clinical (RECIPE) trial consists of 2 cohorts: a multicenter, placebo-controlled, randomized study cohort of 15 patients with IgG4 autoantibody-positive CIDP (rituximab:placebo = 2:1) and an open-label trial cohort of 10 patients with antibody-negative CIDP. The primary endpoint is improvement in functional outcome assessed using the adjusted Inflammatory Neuropathy Cause and Treatment Disability Scale score at 26, 38, or 52 weeks after the start of treatment with rituximab in patients with CIDP and anti-paranodal protein antibodies. Secondary outcome measures include grip strength, manual muscle testing sum scores, results of nerve conduction studies, and other functional scales. RESULTS: We plan to enroll 25 cases for the full analysis set. Recruitment is ongoing, with 14 patients enrolled as of January 2020. Enrollment will close in September 2020, and the study is planned to end in December 2021. CONCLUSIONS: This randomized controlled trial will determine if rituximab is safe and effective in patients with anti-paranodal antibodies. An open-label study will provide additional data on the effects of rituximab in patients with antibody-negative CIDP. The results of the RECIPE trial are expected to provide evidence for the positioning of rituximab as a pathogenesis-based therapeutic for refractory CIDP. TRIAL REGISTRATION: ClinicalTrials.gov NCT03864185, https://clinicaltrials.gov/ct2/show/NCT03864185 ; The Japan Registry of Clinical Trials jRCT2041180037, https://jrct.niph.go.jp/en-latest-detail/jRCT2041180037. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17117.

POEMS (polyneuropathy, organomegaly, endocrinopathy monoclonal gammopathy, and skin changes) syndrome is occasionally associated with Castleman disease (CD) and their prognosis is considered as poorer than that in POEMS alone patients. To elucidate recent prognosis of POEMS syndrome coexisting with CD, we reviewed clinical data of 102 patients with POEMS syndrome treated at our institution between 2000 and 2018 and compared clinical characteristics, response to treatment, and prognosis between POEMS patients with biopsy-proven CD (POEMS-CD) and those without it. Fourteen POEMS-CD patients and 56 POEMS alone patients were identified, and the remaining 32 patients with unbiopsied lymphadenopathy were excluded. POEMS-CD patients significantly showed earlier onset and less severe neuropathic symptoms. Most of the POEMS-CD patients were treated with thalidomide and dexamethasone (n = 10, 71%), and subsequently received autologous stem cell transplantation (n = 6, 43%). Response to thalidomide was better in patients with POEMS-CD than those with POEMS alone (90% vs 43% clinical response, [p = .012]; 80% vs 45% normalization of serum VEGF levels, [p = .079]). The 10-year overall survival (95% confidence interval) was 89% (50-98%) in POEMS-CD patients and 61% (42-77%) in those with POEMS alone. POEMS syndrome associated with CD constitutes a subgroup of POEMS syndromes characterized by earlier onset, mild polyneuropathy, and favorable response to treatment. Recognition of this subgroup is significant for determination of therapeutic strategy.

Excitability properties at the motor point of the abductor digiti minimi (ADM) muscle were measured using an accelerometer placed on the little finger tip in 31 healthy subjects, and the results were compared with those at the wrist level of the ulnar nerve. ADM motor point stimulation allowed us to demonstrate a significantly shorter strength-duration time constant and smaller threshold changes in deporalizing and hyperpolarizing threshold electrotonus than those at wrist stimulation. At the wrist, hyperpolarizing threshold electrotonus correlated with age (smaller threshold changes), while other excitability indices did not show age-dependent changes at both sites. There were no significant gender differences at these sites. The differences between the wrist and ADM motor point suggest that there are smaller persistent sodium currents and greater inward and outward rectification at the ADM point compared with the wrist. Motor point excitability testing can provide new insights into the pathophysiology of distal motor axons in various peripheral neuropathies and motor disorders.

Areflexia or hyporeflexia is a mandatory clinical criterion for the diagnosis of Guillain-Barré syndrome (GBS). A systematic review of the literature from 1 January 1993 to 30 August 2019 revealed 44 sufficiently detailed patients with GBS and hyper-reflexia, along with one we describe. 73.3% of patients were from Japan, 6.7% from the USA, 6.7% from India, 4.4% from Italy, 4.4% from Turkey, 2.2% from Switzerland and 2.2% from Slovenia, suggesting a considerable geographical variation. Hyper-reflexia was more frequently associated with antecedent diarrhoea (56%) than upper respiratory tract infection (22.2%) and the electrodiagnosis of acute motor axonal neuropathy (56%) than acute inflammatory demyelinating polyneuropathy (4.4%). Antiganglioside antibodies were positive in 89.7% of patients. Hyper-reflexia was generalised in 90.7% of patients and associated with reflex spread in half; it was present from the early progressive phase in 86.7% and disappeared in a few weeks or persisted until 18 months. Ankle clonus or Babinski signs were rarely reported (6.7%); spasticity never developed. 53.3% of patients could walk unaided at nadir, none needed mechanical ventilation or died. 92.9% of patients with limb weakness were able to walk unaided within 6 months. Electrophysiological studies showed high soleus maximal H-reflex amplitude to maximal compound muscle action potential amplitude ratio, suggestive of spinal motoneuron hyperexcitability, and increased central conduction time, suggestive of corticospinal tract involvement, although a structural damage was never demonstrated by MRI. Hyper-reflexia is not inconsistent with the GBS diagnosis and should not delay treatment. All GBS variants and subtypes can present with hyper-reflexia, and this eventuality should be mentioned in future diagnostic criteria for GBS.

OBJECTIVE: The aim of this study is to describe and clarify the factors affecting the prognosis of Japanese patients with amyotrophic lateral sclerosis (ALS) undergoing tracheostomy invasive ventilation (TIV) therapy. METHODS: We conducted a prospective longitudinal observational case-control study using a multicentre registry. ALS patients who started TIV therapy after registration (TIV group) and those who did not receive TIV (non-TIV group) were included. We compared the survival time between the TIV group and the non-TIV group using a propensity score matching analysis and evaluated the prognostic factors in the TIV group. RESULTS: From February 2006 to January 2018, 190 patients in the TIV group and 1093 patients in the non-TIV group were included in this study. The mean age of disease onset and usage rate of gastrostomy and non-invasive ventilation therapy differed between the groups. In the propensity score matching analysis using known prognostic factors, the median overall survival time of the TIV group was significantly greater than that of the non-TIV group (11.33 years vs 4.61 years; p<0.001). Analysis using the Cox proportional hazard model suggested that older age of onset and respiratory onset was an independent factor for poor prognosis after starting TIV therapy. CONCLUSION: We showed that there was a significant difference of approximately 7 years in life expectancy between Japanese ALS patients who did and did not receive TIV therapy.

OBJECTIVE: To establish whether amyotrophic lateral sclerosis (ALS) is a multistep process in South Korean and Japanese populations when compared to Australian cohorts. METHODS: We generated incident data by age and sex for Japanese (collected between April 2009 and March 2010) and South Korean patients with ALS (collected between January 2011 and December 2015). Mortality rates were provided for Australian patients with ALS (collected between 2007 and 2016). We regressed the log of age-specific incidence against the log of age with least squares regression for each ALS population. RESULTS: We identified 11,834 cases of ALS from the 3 populations, including 6,524 Australian, 2,264 Japanese, and 3,049 South Korean ALS cases. We established a linear relation between the log incidence and log age in the 3 populations: Australia r 2 = 0.99, Japan r 2 = 0.99, South Korea r 2 = 0.99. The estimate slopes were similar across the 3 populations, being 5.4 (95% confidence interval [CI], 4.8-5.5) in Japanese, 5.4 (95% CI, 5.2-5.7) in Australian, and 4.4 (95% CI, 4.2-4.8) in South Korean patients. CONCLUSIONS: The linear relationship between log age and log incidence is consistent with a multistage model of disease, with slope estimated suggesting that 6 steps were required in Japanese and Australian patients with ALS while 5 steps were needed in South Korean patients. Identification of these steps could identify novel therapeutic strategies.

Complement-dependent disruption of motor endplate is detected in anti-acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG). We measured serum AChR α1 subunit protein levels, which may be associated with neuromuscular damage, in 55 patients with MG (47 were seropositive and 8 were negative) and in 20 controls. Serum AChR α1 subunit protein concentrations were higher in patients with anti-AChR antibody-positive MG than those in controls (P = .04), were negatively correlated with MG activities of daily living score (P = .01), and tended to be higher in ocular MG than in generalized MG. AChR α1 subunit protein elevation may be related to seropositive MG pathogenesis, especially in the ocular type.

OBJECTIVE: To investigate the immunological characteristics and their clinical relevance in anti-myelin oligodendrocyte glycoprotein (MOG)-IgG-associated and anti-aquaporin-4 (AQP4)-IgG-associated disorders (MOGAD and AQPAD) and multiple sclerosis (MS). METHODS: We measured peripheral blood helper T cell subsets (Th1, Th2, Th17 and regulatory T cell (Treg)) in patients with MOGAD (n=26), AQPAD (n=32) and MS (n=28) in the attack and remission phases by flow cytometry with intracellular cytokine staining. We also studied their correlation with clinical parameters. Ten normal subjects served as healthy controls. RESULTS: In all the three disorders, Th17 significantly increased at attack, and downregulated in the remission phases, although still elevated compare with healthy controls. MOGAD and AQPAD patients shared the common T cell profiles, while the extent of Th17 shift was more prominent in AQPAD. Patients with MS showed decreased Th2 than ones with MOGAD and AQPAD at attack. In terms of clinical correlation, MS patients showed that higher Th1 and Th17 proportion was associated with more frequent relapse and more severe clinical disability, whereas in MOGAD, higher Treg was associated with milder clinical severity. In AQPAD, no obvious correlation of Th profiles with clinical manifestation was found. CONCLUSIONS: The present study first investigated intracellular cytokine levels among MOGAD, AQPAD and MS. The different patterns and extent of helper T cell profiles could reflect the pathogenesis of each disorders, and may affect disease severity and activity.

Objective A randomized controlled trial has shown the efficacy of thalidomide against Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome; however, there are still refractory patients. We studied the effects of lenalidomide, a derivative of thalidomide, on patients refractory to thalidomide. Methods This prospective single-arm trial evaluated the safety and efficacy of lenalidomide plus dexamethasone in refractory or recurrent patients with POEMS syndrome. The regimen was administered as six 28-day cycles with lenalidomide on days 1-21 (15 mg in cycle 1, and 25 mg in cycle 2-6) plus dexamethasone once a week (20 mg). The primary endpoints were the rate of reduction in the serum vascular endothelial growth factor (VEGF) level at 24 weeks and the incidence of adverse events. This trial was registered with ClinicalTrial.gov, NCT02193698. Results Between July 2014 and December 2015, five men were enrolled. All patients had been refractory to thalidomide plus dexamethasone for more than 24 weeks. The mean rate of reduction in the serum VEGF level at 24 weeks was 59.6%±8.3% (p=0.0003). The mean serum VEGF level decreased from 2,466±771 pg/mL to 974±340 pg/mL. No serious adverse events were observed, and all patients completed six cycles treatment. Discussion Lenalidomide is a therapeutic option for thalidomide-refractory patients with POEMS syndrome.

In demyelinating polyneuropathies, distribution patterns of demyelination reflect underlying pathogenesis. Median and ulnar nerve conduction studies were reviewed in 85 typical chronic inflammatory demyelinating polyneuropathy (CIDP) patients and 29 multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). Distal latencies were prolonged in typical CIDP and near normal in MADSAM. Abnormal amplitude reductions in the nerve trunks were more frequent in MADSAM than typical CIDP. Presumably because the blood-nerve barrier is anatomically deficient at the distal nerve terminals, antibody-mediated demyelination is a major pathophysiology in typical CIDP. In contrast, blood-nerve barrier breakdown is likely to be predominant in MADSAM.

© Author(s) (or their employer(s)) 2020. Aim: To determine whether changes in the serum levels of vascular endothelial growth factor (VEGF) after thalidomide therapy will affect the peripapillary retinal thickness (pRT) associated with optic disc oedema (ODE) in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome. Methods: This was a retrospective, observational case series of 23 right eyes of 23 treatment-naïve patients with POEMS syndrome and ODE whose intracranial pressure was within the normal range. The pRT was determined by spectral-domain optical coherence tomography, and the serum level of VEGF was determined by ELISA at baseline and 6 months after the thalidomide therapy. We determined whether a change in the pRT from baseline was significantly correlated with the serum level of VEGF from that at 6 months after the thalidomide treatment. Results: Six months after treatment, the mean serum level of VEGF was significantly reduced from 7153±4214 pg/mL to 1067±769 pg/mL (p<0.001), and the pRT was significantly decreased from 471.2±203 μm to 318.1±53.9 μm (p<0.001). The change in the pRT from baseline was significantly and linearly correlated with the change in the serum level of VEGF from that at 6 months after treatment (r=0.67, p=0.00039). Conclusions: The close relationship between the pRT and the serum level of VEGF may offer clues on the pathogenesis of POEMS syndrome and potentially add a new candidate cause for the pathogenesis of ODE.