澁谷 和幹

Abstract Introduction/Aims Multifocal motor neuropathy (MMN) is a rare disease for which epidemiological and clinical data are limited. We conducted a nationwide survey to determine disease prevalence, incidence, clinical profile, and current treatment status in Japan. Methods A nationwide survey was conducted in 2021 using an established epidemiological method. Questionnaires were sent to all neurology and pediatric neurology departments in Japan. An initial questionnaire was administered to determine the number of patients with and incidence of MMN. A second questionnaire was administered to collect detailed clinical information. The European Federation of Neurological Societies/Peripheral Nerve Society 2010 guidelines were used as diagnostic criteria. Results The estimated number of patients with MMN was 507. The estimated prevalence was 0.40 per 100,000 individuals. Detailed clinical profiles were available for 120 patients. The male‐to‐female ratio was 2.3:1 and the median onset age was 42 years. The median disease duration at diagnosis was 25 months. Most patients presented with upper limb‐dominant muscle weakness. Motor nerve conduction blocks were found in 62% of patients and positive anti‐GM1 IgM antibody results in 54%. A total of 117 (98%) patients received immunoglobulin therapy, and 91% of them showed improvement. At the time of the last visit (median, 82 months from treatment initiation), 89 (74%) patients were receiving maintenance immunoglobulin therapy. A slight progression of neurological deficits was observed during follow‐up. Discussion Most patients with MMN in Japan received induction and maintenance immunoglobulin therapies, which appear to suppress long‐term disease progression.

Decreased cough strength in myasthenia gravis (MG) leads to aspiration and increases the risk of MG crisis. The aim of this study was to clarify the reliability and validity of cough peak flow (CPF) measurements in MG. A total of 26 patients with MG who underwent CPF measurements using the peak flow meter by themselves were included. MG symptoms were evaluated by pulmonary function tests and clinical MG assessment scales before and after immune-treatments. The relationship between CPF and pulmonary function tests and MG comprehensive were assessed. The cut-off value of CPF for aspiration risk was determined and the area under the curve (AUC) was calculated. The intraclass correlation coefficient was more than 0.95 for pre-and post-treatment. Positive correlations were found between CPF and almost all spirometric values as well as between the differences of pre-and post-treatment in CPF and quantitative myasthenia gravis score. The CPF for identifying the aspiration risk was used to calculate the CPF cut-off value of 205 L/min with a sensitivity of 0.77, specificity of 0.90, and AUC of 0.85. The CPF, a convenient measure by patients themselves, has a high reliability in patients with MG, and is a useful biomarker reflecting MG symptoms.

Abstract Background Multiple system atrophy (MSA) is a progressive, incurable, life-threatening neurodegenerative disease uniquely characterized by the risk of sudden death, which makes diagnosis delivery challenging for neurologists. Empirical studies on breaking a diagnosis of MSA are scarce, with no guidelines currently established. This study aimed to investigate neurologists’ current practices and experiences in delivering the diagnosis of MSA. Methods We conducted a multicenter online survey and employed a mixed-methods (quantitative and qualitative) study design in which responses to open-ended questions were analyzed qualitatively using critical incident technique. Results Among the 194 neurologists surveyed, 166 opened the survey (response rate = 85.6%), of whom 144 respondents across various Japanese regions completed the survey. Accordingly, 92.3% and 82.8% of the participating neurologists perceived delivering the diagnosis of MSA and explaining the risk of sudden death as difficult, respectively. Factors independently associated with difficulties in diagnosis delivery included explaining the importance of the family decision making process in life-prolonging treatment, perceived difficulties in delivering information regarding the risk of sudden death, and perceived difficulties in differential diagnosis of MSA. Conclusions Our findings showed that the majority of neurologists perceived delivering the diagnosis of MSA and explaining the risk of sudden death as difficult, which could have been associated with the difficulty of breaking the diagnosis of MSA. Difficulty in conveying bad news in MSA are caused by various factors, such as empathic burden on neurologists caused by the progressive and incurable nature of MSA, the need to explain complex and important details, including the importance of the family decision-making process in life-prolonging treatment, difficulty of MSA diagnosis, and communication barriers posed by mental status and cognitive impairment in patients or their family members. Neurologists consider various factors in explaining the risk of sudden death (e.g., patient’s personality, mental state, and degree of acceptance and understanding) and adjust their manner of communication, such as limiting their communication on such matters or avoiding the use of the term “sudden death” in the early stages of the disease. Although neurologists endeavor to meet the basic standards of good practice, there is room for the multiple aspects for improvement.

Objective: This study aimed to reveal the diagnostic utility of Gold Coast (GC) criteria in Japanese patients with amyotrophic lateral sclerosis (ALS) by comparing the sensitivity/specificity with revised El Escorial (R-EE) and Awaji criteria, because its utility has not been studied in Asian ALS. Methods: Consecutive 639 patients (529 with ALS and 110 with ALS mimics), who were suspected of ALS and referred to three Japanese ALS centers, were enrolled. Diagnostic accuracy and characteristics of false positive and negative in GC criteria were compared with those of the Awaji and R-EE criteria. Patients were categorized as definite, probable or possible ALS according to each criterion. Results: The sensitivity of GC criteria (96.8%, 95% confidence interval [CI]: 95.3-98.3%) was higher than that of Awaji (89.6%, 95% CI: 87.0-92.2%) and R-EEC (89.2, 95% CI: 86.6-91.8%) criteria (both, p < 0.001). The specificity was also higher with GC criteria (77.3%, 95% CI: 69.5-85.1%) than Awaji (65.5%, 95% CI: 56.6-74.4%) and R-EEC (66.4, 95% CI: 57.6-75.2%) criteria (both, p < 0.01). Using GC criteria, patients with cervical spondylosis and Parkinson's syndrome tended to be diagnosed with ALS (i.e. "false positive"). Additionally, ALS patients diagnosed only by GC criteria less frequently had upper motor neuron (UMN) signs, compared with the other two criteria. Conclusion: Gold Coast criteria improve diagnostic accuracy for ALS in an Asian population, especially in patients with subtle UMN signs.

Abstract Background and purpose The aim of this study was to determine the prevalence of anti‐myelin‐associated glycoprotein (MAG) neuropathy and the current status of such patients in Japan. Methods We conducted a nationwide survey in 2021 using established epidemiological methods. Questionnaires were sent to all neurology and pediatric neurology departments throughout Japan to identify patients with anti‐MAG neuropathy. An initial questionnaire was used to determine the number of patients, with a second one used to collect detailed clinical information. Results The estimated number of patients with anti‐MAG neuropathy was 353, with a prevalence of 0.28 per 100,000 and an incidence of 0.05 per 100,000. The detailed clinical profiles of 133 patients were available. The median (range) age of onset was 67 (30–87) years, with a prominent peak in the age range 66–70 years, and the male‐to‐female ratio was 3.6. Most patients had distal sensory‐predominant polyneuropathy, and neuropathic pain (50%), or sensory ataxia (42%), while 18% had Waldenström's macroglobulinemia or multiple myeloma. Intravenous immunoglobulin was the most frequently used treatment (65%), but the response rate was &lt;50%, whereas rituximab was given in 32% of patients, and 64% of these showed improvement. At the last visit, 27% of patients could not walk independently. Conclusions This study on anti‐MAG neuropathy provides updated insights into the epidemiology of this disease, clinical profiles, and treatment approaches in Japan. Rituximab therapy, used for only one‐third of the patients, demonstrated efficacy. During the final visit, a quarter of the patients were unable to walk independently. Further studies are warranted to determine the optimal management of this rare and intractable disorder.

Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.

BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

Mechanical insufflation-exsufflation (MI-E) is an effective airway clearance device for impaired cough associated with respiratory muscle weakness caused by neuromuscular disease. Its complications on the respiratory system, such as pneumothorax, are well-recognized, but the association of the autonomic nervous system dysfunction with MI-E has never been reported. We herein describe two cases of Guillain-Barré syndrome with cardiovascular autonomic dysfunction during MI-E: a 22-year-old man who developed transient asystole and an 83-year-old man who presented with prominent fluctuation of blood pressure. These episodes occurred during the use of MI-E with abnormal cardiac autonomic testing, such as heart rate variability in both patients. While Guillain-Barré syndrome itself may cause cardiac autonomic dysfunction, MI-E possibly caused or enhanced the autonomic dysfunction by an alternation of thoracic cavity pressure. The possibility of MI-E-related cardiovascular complications should be recognized, and its appropriate monitoring and management are necessary, particularly when used for Guillain-Barré syndrome patients.

<目的>慢性炎症性脱髄性多発ニューロパチー患者を対象に,経静脈的免疫グロブリン(intravenous immunoglobulin:IVIg)維持療法の点滴時間,患者満足度に関する前向き観察研究を行った.<方法>20歳以上の患者23例において5%IVIg(n=10)又は10%IVIg製剤(n=13)の維持療法を定期的に受けていた2群において前向き調査を行った.両製剤の点滴準備時間と投与時間を測定し,患者のquality of life(QOL),治療満足度,労働生産性障害スコアを調査した.<結果>総点滴時間は10%IVIgが5%IVIgの約半分であった(204分 vs. 437分;p=0.0026).QOL指標のEuroQol 5 dimensions 5-levelの平均QOL値は10%IVIgが5%IVIgより高く(0.74 vs. 0.57),5つのドメインのいずれのスコアも10%IVIgが良好であった.治療満足度,労働生産性の障害に関するスコアは両群で同程度であった.<結論>患者が自覚する両製剤の治療効果に差はみられないが,10%製剤による点滴時間短縮の利便性は患者QOLを向上させるものと考えられた.(著者抄録)

BACKGROUND: In typical patients with multiple system atrophy with predominant parkinsonism (MSA-P) levodopa is ineffective. However, there are some of these patients who respond well to levodopa treatment. Levodopa efficacy in MSA-P patients is thought to be related to the degree of putaminal damage, but the pathological causation between the putaminal involvement and levodopa efficacy has not been established in detail. OBJECTIVE: This study aimed to evaluate the neuropathological features of the nigrostriatal dopaminergic system in a "levodopa-responsive" MSA-P patient in comparison with "levodopa-unresponsive" conventional MSA-P patients. MATERIALS AND METHODS: Clinicopathological findings were assessed in a 53-year-old Japanese man with MSA who presented with asymmetric parkinsonism, levodopa response, and later wearing-off phenomenon. During autopsy, the nigrostriatal pathology of presynaptic and postsynaptic dopaminergic receptor density and α-synuclein status were investigated. The other two patients with MSA-P were examined using the same pathological protocol. RESULTS: Four years after the onset, the patient died of sudden cardiopulmonary arrest. On autopsy, numerous α-synuclein-positive glial cytoplasmic inclusions in the basal ganglia, pons, and cerebellum were identified. The number of neurons in the putamen and immunoreactivity for dopamine receptors were well-preserved. In contrast, significant neuronal loss and decreased dopamine receptor immunoreactivity in the putamen were observed in the "levodopa-unresponsive" MSA-P control patients. These putaminal pathology results were consistent with the findings of premortem magnetic resonance imaging (MRI). All three patients similarly exhibited severe neuronal loss in the substantia nigra and decreased immunoreactivity for dopamine transporter. CONCLUSION: Levodopa responsiveness in patients with MSA-P may be corroborated by the normal putamen on MRI and the preserved postsynaptic nigrostriatal dopaminergic system on pathological examination. The results presented in this study may provide a rationale for continuation of levodopa treatment in patients diagnosed with MSA-P.

BACKGROUND: Previous studies have shown that patients with amyotrophic lateral sclerosis (ALS) have hyperexcitability in both the motor cortex and peripheral motor axons, but the relationship between central and peripheral excitability has not been fully disclosed. METHODS: Threshold tracking transcranial magnetic stimulation (TMS) and motor nerve excitability testing were prospectively performed in 53 patients with ALS and 50 healthy subjects, and their relations to compound muscle action potential (CMAP) amplitude and revised ALS Functional Rating Scale were cross-sectionally analysed. RESULTS: Compared with controls, patients with ALS showed both cortical and peripheral hyperexcitability; TMS showed reduced short-interval intracortical inhibition (interstimulus interval 1-7 ms) (p<0.001) and shortened silent period (p<0.05), and median nerve excitability testing revealed greater changes in depolarising threshold electrotonus (TEd) and greater superexcitability (p<0.0001, both), suggesting reduced axonal potassium currents. Significant correlations between cortical and peripheral excitability indices were not found. Greater changes in TEd (90-100 ms) (R=-0.33, p=0.03) and superexcitability (R=0.36, p=0.01) were associated with smaller amplitude of CMAP, whereas cortical excitability indices had no correlation with CMAP amplitude. More rapid motor functional decline was associated with only greater TEd (90-100 ms) (β=0.46, p=0.001). CONCLUSIONS: Our results suggest that in ALS, cortical excitability is continuously high regardless of the extent of the peripheral burden, but peripheral hyperexcitability is associated with the extent of the peripheral burden and disease evolution speed. Alterations of ion channel function may play an important role in ALS pathophysiology.

Objective: We aimed to investigate the hypothesis that amplitudes of compound muscle action potential (CMAP) elicited by single stimulation decrease by baseline neuromuscular blocking in myasthenia gravis (MG), and to examine correlation of CMAP amplitudes with baseline muscle weakness.Methods: One hundred ninety-four consecutive patients who underwent repetitive 3 Hz nerve stimulation tests (RNST) at our laboratory were included in the study. Of these, 109 patients were diagnosed as suffering from MG, and the remaining 85 with other disease served as the non--MG controls. RNST was performed on the nasalis, trapezius, and abductor digiti minimi (ADM) muscles. CMAP amplitudes elicited by the first stimulation were compared between the two groups. In MG patients, we studied the correlation of CMAP amplitudes with MG Foundation of America (MGFA) class, total scores of manual muscle testing (MMT), and 4th decrement (%) of RNST.Results: Compound muscle action potential amplitudes in MG were significantly lower than in controls ( p < 0.05 in all muscles tested). Decreases in CMAP amplitudes were more prominent in generalized than in ocular MG (p < 0.05), and in patients with MGFA III-V classes than in those with 0-II (p < 0.01 in the trapezius and ADM). CMAP amplitudes partially correlated with total MMT scores and MG-ADL scale scores. Additionally, CMAP amplitudes elicited by the first stimulation correlated with the 4th decrement of RNST (p < 0.01 in all muscles tested). Conclusion: Compound muscle action potential amplitudes are reduced in MG, presumably by baseline neuromuscular transmission block, and could reflect persistent muscle weakness, rather than fatigue, in MG patients.

Importance: The effectiveness of currently approved drugs for amyotrophic lateral sclerosis (ALS) is restricted; there is a need to develop further treatments. Initial studies have shown ultrahigh-dose methylcobalamin to be a promising agent. Objective: To validate the efficacy and safety of ultrahigh-dose methylcobalamin for patients with ALS enrolled within 1 year of onset. Design, Setting, and Participants: This was a multicenter, placebo-controlled, double-blind, randomized phase 3 clinical trial with a 12-week observation and 16-week randomized period, conducted from October 17, 2017, to September 30, 2019. Patients were recruited from 25 neurology centers in Japan; those with ALS diagnosed within 1 year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after 12-week observation were eligible for randomization: 1- or 2-point decrease in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) total score, a percent forced vital capacity greater than 60%, no history of noninvasive respiratory support and tracheostomy, and being ambulatory. The target participant number was 64 in both the methylcobalamin and placebo groups. Patients were randomly assigned through an electronic web-response system to methylcobalamin or placebo. Interventions: Intramuscular injection of methylcobalamin (50-mg dose) or placebo twice weekly for 16 weeks. Main Outcomes and Measures: The primary end point was change in ALSFRS-R total score from baseline to week 16 in the full analysis set. Results: A total of 130 patients (mean [SD] age, 61.0 [11.7] years; 74 men [56.9%]) were randomly assigned to methylcobalamin or placebo (65 each). A total of 129 patients were eligible for the full analysis set, and 126 completed the double-blind stage. Of these, 124 patients proceeded to the open-label extended period. The least square means difference in ALSFRS-R total score at week 16 of the randomized period was 1.97 points greater with methylcobalamin than placebo (-2.66 vs -4.63; 95% CI, 0.44-3.50; P = .01). The incidence of adverse events was similar between the 2 groups. Conclusions and Relevance: Results of this randomized clinical trial showed that ultrahigh-dose methylcobalamin was efficacious in slowing functional decline in patients with early-stage ALS and with moderate progression rate and was safe to use during the 16-week treatment period. Trial Registration: ClinicalTrials.gov Identifier: NCT03548311.

Amyotrophic lateral sclerosis (ALS) is a devastating disease with evidence of degeneration involving upper and lower motor neuron compartments of the nervous system. Presently, two drugs, riluzole and edaravone, have been established as being useful in slowing disease progression in ALS. Riluzole possesses anti-glutamatergic properties, while edaravone eliminates free radicals (FRs). Glutamate is the excitatory neurotransmitter in the brain and spinal cord and binds to several inotropic receptors. Excessive activation of these receptors generates FRs, inducing neurodegeneration via damage to intracellular organelles and upregulation of proinflammatory mediators. FRs bind to intracellular structures, leading to cellular impairment that contributes to neurodegeneration. As such, excitotoxicity and FR toxicities have been considered as key pathophysiological mechanisms that contribute to the cascade of degeneration that envelopes neurons in ALS. Recent advanced technologies, including neurophysiological, imaging, pathological and biochemical techniques, have concurrently identified evidence of increased excitability in ALS. This review focuses on the relationship between FRs and excitotoxicity in motor neuronal degeneration in ALS and introduces concepts linked to increased excitability across both compartments of the human nervous system. Within this cellular framework, future strategies to promote therapeutic development in ALS, from the perspective of neuronal excitability and function, will be critically appraised.

Background: Decremental responses in repetitive nerve stimulation studies have been reported in the limb muscles of patients with amyotrophic lateral sclerosis (ALS).Aim: To reveal the function of neuromuscular junction (NMJ) in the frontalis muscle, which is less affected in ALS.Methods: We performed axonal-stimulated single-fiber EMG studies in the frontalis muscles in 27 patients with ALS, 32 with myasthenia gravis (MG), and 12 healthy controls were performed.Results: The mean value of mean consecutive difference (MCD) in ALS was greater than controls (P < .05), but smaller than MG (P < .01) [ALS; 26.5, MG;47.7, control;16.4 (mu s)]. The percentage of endplates with increased jitter (MCD >51 mu s) in ALS was also greater than controls (P < .001) but smaller than MG (P < .001) [ALS; 7.7, MG; 29.4, control; 0.8 (%)]. In ALS, the mean MCD was negatively correlated with the bulbar subset of ALS functional rating scale revised (ALSFRS-R) (r = -0.67, P < .01). No axonal blocking was observed in all cohorts. In the facial muscles that are relatively preserved in ALS, jitter in single-fiber EMG was significantly increased, possibly caused by dysfunction of the presynaptic NMJ and motor nerve terminals.Conclusions: Assessment of neuromuscular transmission could provide a new insight into the pathophysiology of motor nerve terminal dysfunction in ALS.

Objective Immunomodulatory drugs and proteasome inhibitors are therapeutic options for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. This study aimed to evaluate the efficacy and safety of the combination of ixazomib, lenalidomide, and dexamethasone (IRd) for POEMS syndrome. Methods Six consecutive patients with POEMS syndrome who were treated with the IRd regimen at Chiba University Hospital between April 2018 and August 2021 were included. Serum M-protein and serum vascular endothelial growth factor (sVEGF) levels, overall neuropathy limitation scales (ONLS), clinical symptoms, and adverse events were assessed. Results Of the six patients, five had received prior treatments. Patients received a median of 5 cycles (range, 3-28 cycles) of IRd. Following treatment, serum M-protein disappeared in two patients, sVEGF levels returned to normal in two patients, two patients showed a reduction in the ONLS of 1, and clinical symptoms improved in four patients. The median level of sVEGF decreased from 2,395 pg/mL (range, 802-6,120 pg/mL) to 1,428 pg/mL (range, 183-3,680 pg/mL) in three months. Adverse events, including rash, neutropenia, sensory peripheral neuropathy, and nausea, were observed in three patients, which necessitated dose reduction or discontinuation of treatment. Conclusion IRd can be a therapeutic option for POEMS syndrome, albeit with careful monitoring of adverse events.

A previous study using traditional paired-pulse TMS methods (amplitude-tracking) has reported differences in resting motor threshold (RMT) and short-interval intracortical inhibition (SICI) between healthy subjects of Caucasian and Han Chinese backgrounds, probably due to differences in the skull shape. The amplitude-tracking method delivers stimuli with constant intensity, and causes substantial variabilities in MEP amplitudes. To overcome this variability, threshold tracking transcranial magnetic stimulation (TT-TMS) has been developed. The present study aimed to investigate whether racial differences in motor cortical function exist, using TT-TMS. A total of 83 healthy volunteers (30 Caucasians, 25 Han Chinese and 28 Japanese) were included in the present series. In TT-TMS and nerve conduction studies, electrodes were placed on the dominant limb, with measures recorded from the abductor pollicis brevis muscle. Stimulations were delivered with a circular coil, directly above primary motor cortex. There were no significant differences at all the SICI intervals between races. Similarly, there were no significant differences in other measures of excitability including mean RMT, intracortical facilitation, and cortical silent period. Contrary to traditional amplitude-tracking TMS, motor cortical excitability and thereby motor cortical function is minimally influenced by racial differences when measured by TT-TMS. Recent studies have disclosed that SICI measured by TT-TMS differentiates amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. CASE PRESENTATION: A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. CONCLUSIONS: We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.

INTRODUCTION: In this study we aimed to investigate the dispersion of mean consecutive difference (MCD) of concentric needle jitter studies of patients with myasthenia gravis (MG) and its effect on diagnostic sensitivity for MG. METHODS: One hundred fifty-three patients, including 76 patients with MG and 77 controls with possible MG who later received another diagnosis, underwent stimulated concentric needle jitter studies of the frontalis muscle. MCD mean, standard deviation (SD), and coefficient of variation (CV) were calculated. Diagnostic sensitivity and specificity were determined using receiver operating characteristic (ROC) analyses. RESULTS: MG patients showed a significantly greater MCD mean (MG: control, 26.3 μs; 13.5 μs [median]; P < .0001), MCD SD (MG: control, 12.8 μs; 5.1 μs [median]; P < .0001), and MCD CV (MG: control, 46.1; 37.5 [median]; P < .001) than those without MG. An ROC curve of SD showed a large area under the curve (0.88), and a cut-off value of 7.2 μs, which was calculated by maximum Youden index, exhibited high diagnostic sensitivity (86%) for MG. Combined MCD mean, outliers, and SD criteria showed higher sensitivity (88%) than conventional criteria alone (82%), at the expense of lower specificity. Five MG patients with normal MCD mean and abnormal MCD SD had only ocular symptoms. DISCUSSION: The dispersion of MCD as measured by MCD SD greater than 7.2 μs is significantly increased in patients with MG and may be a useful measure of abnormal jitter in the diagnosis of MG, especially for identifying patients with mild disease.

Background: Language dysfunction is a feature of cognitive impairment in amyotrophic lateral sclerosis (ALS) that may compromise communication. Objective: To elucidate language dysfunction in patients with ALS and its relationship with other neuropsychological tests and to identify the brain regions associated with this dysfunction using perfusion image. Methods: Overall, 37 patients with ALS were included in this study. Their neuropsychological function was investigated using the Western Aphasia Battery (WAB), Frontal Assessment Battery and Behavioral Assessment of the Dysexecutive Syndrome. N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography was used to examine regional cerebral blood flow and its relationship with WAB scores was investigated using multiple regression analyses, controlled for age, sex and years of education. Results: Frequency of language abnormality in ALS was 8.5% for spontaneous speech, 25.7% for auditory verbal comprehension, 8.8% for repetition, 14.7% for naming, 17.6% for reading and 51.4% for writing. The writing error was mainly omission and substitution of kana letters. Executive tests were correlated with naming (r > 0.5, p < 0.001) and reading (r > 0.4, p < 0.01) scores. With respect to the writing sub-test, positive perfusional relationship was only detected in the left angular gyrus. Conclusions: The left angular gyrus is the region associated with the writing errors observed in ALS.

We herein report a case of seronegative immune-mediated necrotizing myopathy (IMNM) concurrent with anti-Kv1.4 and anti-titin antibodies. A 72-year-old Japanese woman presented with a 29-year history of fluctuating high serum creatine kinase (CK) levels followed by intermittent ptosis and respiratory muscle weakness. This case highlights the fact that marked respiratory muscle weakness requiring intubation can be seen in an ambulant patient with IMNM. Marked respiratory muscle weakness, rhabdomyolysis-like acute elevation of CK levels, and anti-striational muscle antibodies may be a characteristic constellation of findings in a distinct subgroup of patients with inflammatory myopathy with myasthenia gravis or similar symptoms.