Clinical uses of a robot (hybrid-assisted limb or HALTM)in patients with post-stroke spasticity after botulinum toxin injections

Spasticity is the major cause of disabilities in stroke-survivors. Botulinum neurotoxin (BoNT) injections have been used to reduce the muscle tone in those patients, but its efficacy in functional outcome is not well delineated. We have studied the effect of a robot (Hybrid-Assisted Limb or HAL™) designed for assisting the elbow flexion and extension in those who underwent BoNT injections with reduced muscle tone. We enrolled 15 post stroke patients who had BoNT injections for more than 12 months. They were measured for active ROM (range of motion) with video recordings before and after the use of HAL for 40 minutes. Active ROM was measured by a rater who were blinded as to the use of the robot. Significant increase of active ROM was observed immediately after the use of HAL, and the effect was maintained for another 12 months by repeating the sessions. It is suggested from present study that the combined use of BoNT and robotics is effective efficacious for regaining the active function of the upper limb in stroke survivors. J. Med. Invest. 68 : 297-301, August, 2021.


筋萎縮性側索硬化症(ALS)を疑う神経症候とその特徴 筋力低下，体のぴくつき

筋萎縮性側索硬化症(ALS)を疑う神経症候とその特徴 筋力低下，体のぴくつき


言語聴覚士 脳神経内科を標榜する療養型病床における言語聴覚士の役割

言語聴覚士 脳神経内科を標榜する療養型病床における言語聴覚士の役割

Home Health Care for the People with Intractable Diseases


Factors associated with DWI-ASPECTS score in patients with acute ischemic stroke due to cerebral large vessel occlusion

The Alberta Stroke Program Early CT score (ASPECTS) of patients with acute ischemic stroke at the time of admission varies. It is crucial to select appropriate methods of treatment, such as recombinant tissue-plasminogen activator, and/or endovascular thrombectomy. According to the recent guidelines, endovascular thrombectomy for patients with large vessel occlusion (LVO) and lesion of ischemic tissue that was not yet infarcted is effective. This result demonstrates the importance of patient selection based on neuroradiological imaging. However, there are many patients who are judged as ineligibility for recanalization therapy because of presence of large ischemic core, indicating unfavorable ASPECTS, at the time of admission. We investigated the factors associated with favorable diffusion-weighted image (DWI)-ASPECTS score at the time of admission. We studies patients with LVO within 24 h from onset who were admitted into our hospital. We divided them into two groups, with favorable DWI-ASPECTS (≥6), and unfavorable DWI-ASPECTS (<6) at the time of admission. We investigated factors associated with favorable DWI-ASPECTS by evaluation of our patients' severity of clinical symptom, etiology, and radiological findings. This study showed that mild white matter lesion (Fazekas scale ≤1), absence of internal carotid artery (ICA) occlusion and cardioembolic stroke were independent factor of favorable DWI-ASPECTS at the time of admission. (odds ratio 12.92, p < 0.001, odds ratio 0.31, p = 0.001, odds ratio 0.16, p = 0.001, respectively) CONCLUSIONS: Absence of severe white matter lesion, cardioembolic stroke, and ICA occlusion might be associated with favorable DWI-ASPECTS at the time of admission.


Neuropsychiatric systemic lupus erythematosus with cerebellar vasculitis and obstructive hydrocephalus requiring decompressive craniectomy.

A 36-year-old woman who had been diagnosed with systemic lupus erythematosus (SLE) was admitted to our hospital due to increasing disease SLE activity. Despite the intensification of immunosuppressive treatment, headache newly developed and worsened. Magnetic resonance imaging (MRI) revealed spreading of a high-intensity area along the sulci of the bilateral cerebellar hemispheres. She was diagnosed with neuropsychiatric SLE and methylprednisolone (mPSL) pulse therapy was started. However, consciousness disorder due to cerebellar oedema with obstructive hydrocephalus appeared and required decompressive craniectomy. The histological findings of the biopsy specimens from cerebellar vermis were compatible with features of vasculitis. She was successfully treated adding intravenous cyclophosphamide therapy.


Prediction of improvement after extended thymectomy in non-thymomatous myasthenia gravis patients

It is popularly believed that myasthenia gravis (MG) patients show acetylcholine receptor antibody (AChRAb) production associated with the thymus (germinal centers, approximately 80%). It has been suggested that thymectomy can remove the area of autoantibody production. This study aimed to determine whether the solid volume of the thymus calculated using three-dimensional (3D) imaging could be used to predict the efficacy of thymectomy. Additionally, the study assessed the relationships of the solid volume with germinal centers, change in the serum AChRAb level, postoperative MG improvement, and prednisolone (PSL) dose reduction extent. This retrospective study included 12 consecutive non-thymomatous MG patients (9 female and 3 male patients), who underwent extended thymectomy at our institution over the last 10 years. The mean patient age was 43.3 ± 14.2 years (range, 12-59 years). The study assessed the number of germinal centers per unit area, change in the serum AChRAb level, postoperative MG improvement, PSL dose reduction extent, and solid volume of the thymus. The number of germinal centers per unit area was significantly correlated with the solid volume of the thymus. The PSL dose reduction extent tended to be correlated with the solid volume. Our findings suggest that the solid volume of the thymus can possibly predict steroid dose reduction. Additionally, the solid volume of the thymus in 3D images is the most important indicator for predicting the efficacy of extended thymectomy.


A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

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). 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). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10). 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.


Efficacy of Istradefylline for the Treatment of ADCY5-Related Disease

View Supplementary Video 1 View Supplementary Video 2.


A case of led to diagnosis of malignancy by brachial plexus ultrasonography

腕神経叢エコー検査が契機となって悪性腫瘍が診断できた1例

A 72-year-old man admitted to our hospital due to severe pain and drop hand in the left arm. MRI and CT of the head and neck at an outside hospital showed no abnormality. Neurological findings revealed distal weakness in the left upper extremity, vague pain between the radial aspect of the left hand and the middle of the digits 1-3, as well as brisk reflexes in the left extremities. Small masses were palpable in the posterior neck, the lower jaw, and the left neck. Clinically, left radial neuropathy and cervical radiculopathy were suspected. We performed ultrasound of the nerve roots, brachial plexus, and the radial nerve. There was a mass compressing the left brachial plexus from the caudolateral direction. Additionally, nerve swelling in the left arm was identified. Skin biopsy over the mass suggested metastatic adenocarcinoma. Chest CT scan showed a mass in the upper right lobe suggestive of a lung cancer. We concluded that the pain was due to radial neuropathy and upper and middle trunk disturbance of the left brachial plexopathy, of which neuromuscular ultrasound was useful in diagnosis.


Cerebral Venous Thrombosis: An Unexpected Complication with Cerebrospinal Fluid Leaks after a Fall in a Patient with Spinocerebellar Ataxia Type 6.


Cognitive and Behavioral Status in Japanese ALS Patients: A Multicenter Study

Amyotrophic lateral sclerosis (ALS) patients may present with cognitive and behavioral abnormalities similar to frontotemporal dementia (FTD). In this multicenter study we examined Japanese ALS patients with and without FTD in order to characterize the full extent of cognitive and behavioral abnormalities, including associations with functional motor status, anxiety and depression. Patients were evaluated using the Montreal Cognitive Assessment (MoCA), Frontal Assessment Battery (FAB), Hospital Anxiety and Depression Scale, ALS Functional Rating Scale-Revised, spirometry, and verbal fluency tests. Caregivers were asked to complete the ALS-FTD-Questionnaire (ALS-FTD-Q), a behavioral screen. We defined severe cognitive impairment (MoCA < 21 or FAB < 11), mild impairment (11 ≤ MoCA ≤ 25 or 11 ≤ FAB ≤ 15), and normal cognition (MoCA > 25 or FAB > 15). Severe and mild behavioral impairments and normal behavior were defined by the ALS-FTD-Q scores. In 145 ALS patients, better cognitive scores were correlated with earlier age at onset, whereas a worse behavioral score was associated with a longer disease duration and higher level of anxiety and depression. Around seventy percent of all ALS patients showed mild (40-45%) or severe cognitive impairment with cognitive impairment outnumbering behavioral impairment fivefold. Cognitive functions were more impaired in patients with age of onset over 65 years, while behavioral scores were not related to age. Considering the high prevalence of in particular cognitive impairment, and the diversity of impairments, the cognitive and behavioral aspects of Japanese ALS patients should be given more attention clinically.


Prognosis of Amyotrophic Lateral Sclerosis Patients Undergoing Tracheostomy Invasive Ventilation Therapy in Japan

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. 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. 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. 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.

Journal of Neurology, Neurosurgery, and Psychiatry


Differences in Cerebellar Perfusion Between Parkinson's Disease and Multiple System Atrophy

Objective biomarkers are required for differential diagnosis of Parkinson's disease (PD), multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). We aimed to determine if cerebellar blood flow, measured using N-isopropyl-[I] p-iodoamphetamine single photon emission computed tomography (I -IMP-SPECT), was useful for differentiating between PD, MSA and PSP. Twenty-four patients with PD, seventeen patients with MSA with predominant parkinsonian features (MSA-P), sixteenth patients with MSA with predominant cerebellar ataxia (MSA-C) and eight patients with PSP were enrolled. Twenty-seven normal controls' data were used for the calculation of z score. All patients underwent I -IMP-SPECT, and data were analyzed using a three-dimensional-stereotactic surface projection program. Cerebellar perfusion in MSA-P (MSA-P vs PD, P = .002; MSA-P vs PSP, P < .001) and MSA-C (MSA-C vs PD, P < .001; MSA-C vs PSP, P < .001) were significantly decreased compared with PD or PSP. There was no significant difference in perfusion between PD and PSP groups (P = .061). The area under the receiver operating characteristic curve for cerebellar perfusion between MSA-P and PD was 0.858. Our findings revealed that cerebellar perfusion by I-IMP-SPECT was useful for differentiating between PD and MSA-P.


Successful treatment of progressive multifocal leukoencephalopathy with mirtazapine and mefloquine in refractory myeloma


Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients

Amyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosutinib for the treatment of patients with ALS and to explore the efficacy of bosutinib on ALS. This study is the first clinical trial of administered bosutinib for patients with ALS. An open-label, multicentre phase I dose escalation study has been designed. The study consists of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALS Functional Rating Scale-Revised (ALSFRS-R) score decreased by 1-3 points during the 12-week observation period receive bosutinib for 12 weeks. Three to six patients with ALS are enrolled in each of the four bosutinib dose levels (100, 200, 300 or 400 mg/day) to evaluate the safety and tolerability under a 3+3 dose escalation study design. Dose escalation and maximum tolerated dose are determined by the safety assessment committee comprising oncologists/haematologists and neurologists based on the incidence of dose-limiting toxicity in the first 4 weeks of the treatment at each dose level. A recommended phase II dose is determined by the safety assessment committee on completion of the 12-week study treatment in all subjects at all dose levels. The efficacy of bosutinib is also evaluated exploratorily using ALS clinical scores and biomarkers. This study received full ethical approval from the institutional review board of each participating site. The findings of the study will be disseminated in peer-reviewed journals and at scientific conferences. UMIN000036295; Pre-results, JMA-IIA00419; Pre-results.


Cone beam-computed tomography angiography by intravenous contrast injection is reliable to evaluate patients with large vessel occlusion

Mechanical thrombectomy (MT) for acute ischemic stroke (AIS) patients due to emergent large vessel occlusion (ELVO) is standard treatment, the benefits, however, are highly time-sensitive. After patient eligibility for reperfusion therapy is determined by conventional radiological examinations, the time to be transferred from the department of radiological examination to angiography-suites is critical. We speculated that the time required for the diagnosis of AIS might be reduced if we could determine MT eligibility in patients with ELVO at angiography-suites. Modern angiography-suites with flat panel detectors can perform cone beam (CB)-CT. We performed CB-CTA using intravenous injection of contrast agent to evaluate occlusion sites, collateral score, and construction of vessels distal to occlusion sites and determined if CB-CTA could be useful to evaluate patients with ELVO. We included 15 patients with ELVO diagnosed by conventional MRI or CT/CTA, and investigated whether CB-CTA was reliable to diagnose occlusion sites. We also studied if collateral score on CB-CTA was associated with prognosis after successful reperfusion by MT by comparison between favorable (modified Rankin scale (mRS) 0-2), and unfavorable outcome group (mRS 3-6). There was strong agreement of occlusion sites between CB-CTA and conventional radiological examination (κ = 0.80). Collateral score determined by CB-CTA was significantly different between favorable outcome and unfavorable outcome group (median collateral score 2.3 v.s. 1.3, p = 0.040). Although prospective study of AIS patients at a radiography department is indispensable, CB-CTA performed in an angiography-suite might be useful to evaluate patients with ELVO.


JETALS: The Japanese Early-stage Trial of high dose methylcobalamin for ALS

High-dose methylcobalamin was found to be a therapeutic candidate for amyotrophic lateral sclerosis (ALS) through clinical experience. Our previous study (E0302-J081-761) has suggested that high-dose methylcobalamin (E0302) prolonged the overall survival and suppressed progression in ALS patients with a disease duration less than 12 months in, exploratory analyses. Therefore, we plan to conduct an investigator-initiated trial "The Japan Early-stage Trial of high dose methylcobalamin for ALS (JETALS)" to evaluate the efficacy and safety of E0302 for ALS patients within 12 months from onset. JETALS is a prospective, multicenter, placebo-controlled, double-blind, randomized Phase III study, conducted at 25 tertiary neurology centers, and is funded by the Japan Agency for Medical Research and Development. A total of 128 patients were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo, twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale (ALSFRS-R) total score at 16 weeks. The patient enrollment period is from November 2017 to September 2019, and the follow-up is scheduled to end in March 2020. If the results are positive, we intend to apply for E0302 approval for methylcobalamin as a new drug for treating ALS.

高用量メコバラミンは臨床経験をとおして筋萎縮性側索硬化症(ALS)に対する有効性が示唆され，第Ⅱ/Ⅲ相試験(E0302-J081-761)において部分解析ではあるが発症1年以内のALS患者に対して生存期間延長とALS機能評価スケール(ALSFRS-R)合計点数の低下の抑制効果が認められた．今回われわれは発症1年以内のALS患者に対する高用量メコバラミン(E0302)の有効性・安全性の検証を目的として「高用量E0302の筋萎縮性側索硬化症に対する第Ⅲ相試験—医師主導治験—」(JETALS)を開始した．本治験は前向き，多施設共同，プラセボ対象，二重盲検，ランダム化比較第Ⅲ相試験であり，国内25施設が参加する．128例の被験者に対して16週にわたりE0302 50mgもしくはプラセボの週2回筋肉注射を行う．主要評価項目は割付日から16週目までのALSFRS-R合計点数の変化量である．症例登録期間は2017年11月∼2019年9月であり，2020年3月に治験終了予定である．有効性が確認され早期に承認されることが期待される．

Brain and Nerve = Shinkei kenkyū no shinpo

脳と神経 - 神経研究の進歩


Co-morbidity of progressive supranuclear palsy and amyotrophic lateral sclerosis: a clinical-pathological case report.

Our case demonstrates the clinicopathological comorbidity of PSP and ALS in a sporadic patient. The possibility of multiple proteinopathies should be considered when distinct symptoms develop during the disease course.

A 77-year-old man presented with gait disturbance for 2 years, consistent with PSP with progressive gait freezing. At 79 years old, he developed muscle weakness compatible with ALS. The disease duration was 5 years after the onset of PSP and 5 months after the onset of ALS. Neuropathological findings demonstrated the coexistence of PSP and ALS. Immunohistochemical examination confirmed 4-repeat tauopathy, including globose-type neurofibrillary tangles, tufted astrocytes, and oligodendroglial coiled bodies as well as TAR DNA-binding protein 43 kDa pathology in association with upper and lower motor neuron degeneration. Immunoblotting showed hyperphosphorylated full-length 4-repeat tau bands (64 and 68 kDa) and C-terminal fragments (33 kDa), supporting the diagnosis of PSP and excluding other parkinsonian disorders, such as corticobasal degeneration. Genetic studies showed no abnormalities in genes currently known to be related to ALS or PSP.


A method for differential diagnosis of parkinsonian syndromes

Neurological findings are important for the differential diagnosis of Parkinson's disease (PD), multiple system atrophy with predominant parkinsonian features (MSA-P), and progressive supranuclear palsy (PSP). There is currently no fast and reliable method to distinguish these patients. To address this, we propose a novel approach to measure midbrain and pons size using a longitudinal "one line" method from the mid-sagittal view. Structural images were acquired from 101 subjects who underwent 3.0 T MRI (20 controls, 44 PD, 20 MSA, 12 PSP, and 5 corticobasal syndrome). We measured the middle cerebellar peduncle (MCP), superior cerebellar peduncle (SCP), midbrain, and pons. Brainstem size was measured by area or length of the longitudinal axis, which we named the "one line" method. We conducted intraclass correlation coefficients to assess the extent of agreement and consistency among raters, and receiver operating characteristic curves were used to determine diagnostic accuracy. Intraclass correlation coefficients (ICC) of MCP width were excellent in sagittal and axial sections while those of SCP width were moderate. There were also excellent ICCs between raters for "one line" method of the midbrain and pons, while areas showed good ICCs. "One line" method and area of the midbrain were better than SCP width for the differential diagnosis of PSP from MSA-P and PD. In contrast, there was no clearly superior measurement for differentially diagnosing MSA-P. The "one line" method was comparable with area for inter-rater agreement and diagnostic accuracy even though this was a simple and fast way.


Deterministic-tractography-based approach for diagnosis and disease monitoring of amyotrophic lateral sclerosis

Upper and lower motor neuron signs are required for the diagnosis of amyotrophic lateral sclerosis. The detection of upper motor neuron signs is key for the diagnosis, as quite a few patients with amyotrophic lateral sclerosis lack upper motor neuron signs during the course of disease. This study sought to investigate whether deterministic tractography of the corticospinal tract, reflecting upper motor neuron signs, could be a surrogate biomarker for amyotrophic lateral sclerosis. Fifteen patients with amyotrophic lateral sclerosis and ten controls underwent imaging on a 3.0 T MRI. The corticospinal tract was reconstructed using deterministic tractography, and the track number was calculated. We analyzed the differences between the groups and the relationship between the track number and disease severity, disease duration, progression rate or upper motor neuron signs. A reduction in the track number of the corticospinal tract was found in amyotrophic lateral sclerosis compared with controls (Student's t test, P = 0.008). The sensitivity and specificity were 0.67 and 0.9, respectively. The track number correlated with disease severity alone (r = 0.71, P = 0.003), and significantly associated with upper motor neuron signs (P = 0.004). These findings suggest that the deterministic-tractography-based approach is a potential biomarker for the diagnosis and disease monitoring of amyotrophic lateral sclerosis.


Potential Utility of 123I-MIBG Scintigraphy as a Predictor of Falls in Parkinson's Disease

Falls are associated with poor prognosis in patients with Parkinson's disease (PD). Although several factors related to falls were reported in patients with PD, objective predictors of falls are not identified. We aimed to determine whether I-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy could be a useful biomarker to predict falls. Forty-five patients with PD were enrolled in this study. These subjects were followed up more than 5 years after MIBG scintigraphy and were divided into two groups: one with decreased uptake of MIBG and the other without decreased uptake of MIBG. The cut-off value for the delayed heart-to-mediastinum ratio was 1.8. Kaplan-Meier analysis and a log-rank test were performed to test the predictive power of MIBG cardiac scintigraphy for falls. Univariate analysis was selected because we did not have appropriate data for adjustment, such as motor and cognitive assessment. The group with decreased uptake of MIBG had a significantly higher incidence of falls than that without decreased uptake of MIBG ( = 0.022, log-rank test). Although the limitations of this study were lack of several key factors including motor and cognitive assessment, MIBG cardiac scintigraphy may be used to predict falls in patients with PD.


The Claw Sign: An angiographic Predictor of Recanalization After Mechanical Thrombectomy for Cerebral Large Vessel Occlusion.

Mechanical thrombectomy undoubtedly improves functional outcomes for patients with acute ischemic stroke. Although we have observed occlusion sites that protrude proximally into the vessel on angiography, termed the "claw sign," we have been unable to state its clinical significance. In this study, we aimed to determine whether the presence of a claw sign was related to recanalization success after mechanical thrombectomy. We retrospectively included 73 consecutive patients treated for acute cerebral large vessel occlusion by mechanical thrombectomy between January 2014 and December 2017. The angiographic claw sign was defined as a thrombus that protruded proximally by more than half the diameter of the parent artery. Claw sign positivity, clinical and etiological features, and outcomes were compared between groups with and without recanalization. The claw sign was observed in 29 of 73 (40%) patients and was positive significantly more frequently in those with recanalization (50.0%) than in those without recanalization (5.9%) (P < .01). By multivariate analysis, the claw sign was the only pretreatment parameter to predict successful recanalization (odds ratio, 12.50; 95% confidence interval, 1.50-103.00; P = .019). The presence of the claw sign might predict successful recanalization in patients undergoing mechanical thrombectomy for large vessel occlusion.

Journal of Stroke & Cerebrovascular Diseases


Differences in the intra-cerebellar connections and graph theoretical measures between Parkinson's disease and multiple system atrophy

Parkinson's disease (PD) does not present with motor symptoms until dopaminergic neuronal loss exceeds 50%. This might indicate that a network-level compensatory mechanism involving surviving regions in PD acts to reduce brain abnormalities. In contrast, there is no evidence of a compensatory mechanism in multiple system atrophy (MSA). We hypothesized that a comparison of these two diseases would help to identify compensatory effects in PD. We recruited 23 patients with PD, 11 patients with MSA, and 11 controls that showed an aging brain but no neurological deficits. All subjects underwent resting state functional magnetic resonance imaging (fMRI). Regions of interest were defined according to the motor network related to the basal ganglia and cerebellum. Network-level analyses were performed. Network-based statistical analyses revealed that functional connectivity in PD brains was reduced between cerebellar lobules IX on both sides and vermis X, as compared with MSA brains. Transitivity was reduced in MSA as compared with controls. We demonstrated that a part of the intra-cerebellar connectivity was reduced in PD, and that network segregation was reduced in MSA. However, there was no evidence of compensatory effects in PD.


Deep learning for waveform identification of resting needle electromyography signals

Given the recent advent in machine learning and artificial intelligence on medical data analysis, we hypothesized that the deep learning algorithm can classify resting needle electromyography (n-EMG) discharges. Six clinically observed resting n-EMG signals were used as a dataset. The data were converted to Mel-spectrogram. Data augmentation was then applied to the training data. Deep learning algorithms were applied to assess the accuracies of correct classification, with or without the use of pre-trained weights for deep-learning networks. While the original data yielded the accuracy up to 0.86 on the test dataset, data-augmentation up to 200,000 training images showed significant increase in the accuracy to 1.0. The use of pre-trained weights (fine tuning) showed greater accuracy than "training from scratch". Resting n-EMG signals were successfully classified by deep-learning algorithm, especially with the use of data augmentation and transfer learning techniques. Computer-aided signal identification of clinical n-EMG testing might be possible by deep-learning algorithms.


MiR-33a is a therapeutic target in SPG4-related hereditary spastic paraplegia human neurons

Recent reports, including ours, have indicated that microRNA (miR)-33 located within the intron of sterol regulatory element binding protein (SREBP) 2 controls cholesterol homeostasis and can be a potential therapeutic target for the treatment of atherosclerosis. Here, we show that , which encodes a microtubule-severing protein called SPASTIN, was a novel target gene of in human. Actually, the miR-33 binding site in the 3'-UTR is conserved not in mice but in mid to large mammals, and it is impossible to clarify the role of on in mice. We demonstrated that inhibition of , a major form of in human neurons, via locked nucleic acid (LNA)-anti-miR ameliorated the pathological phenotype in hereditary spastic paraplegia (HSP)-SPG4 patient induced pluripotent stem cell (iPSC)-derived cortical neurons. Thus, miR-33a can be a potential therapeutic target for the treatment of HSP-SPG4.


Simultaneous approach to tandem occlusion in acute ischemic stroke patients: Percutaneous Transluminal Angioplasty (PTA) using push wire of stent retriever


Amyotrophic lateral sclerosis of long clinical course clinically presenting with progressive muscular atrophy

Amyotrophic lateral sclerosis (ALS) primarily affects upper and lower motor neurons. Phosphorylated trans-activation response DNA-binding protein of 43 kDa (TDP-43) inclusion bodies are reportedly a pathological hallmark of sporadic ALS. Here, we present an atypical case of sporadic ALS that progressed very slowly, persisted for 19 years, and clinically appeared to only affect the lower motor neurons; however, upper motor neuron degeneration was detected at autopsy. Furthermore, no inclusion bodies positive for phosphorylated TDP-43, ubiquitin, fused in sarcoma, or superoxide dismutase-1 were detected in the central nervous system. We performed exome-sequencing data analysis but found no genetic disorders. This was therefore an unusual case of lower motor neuron-predominant ALS without TDP-43 pathology or known gene-disease associations. We also reviewed autopsied ALS cases that progressed slowly and had no phosphorylated TDP-43 or ubiquitin-positive inclusions and present the clinicopathological features of such cases. Based on these results, there may be a sporadic ALS subgroup that progresses slowly and shows no accumulation of phosphorylated TDP-43.


Texture analysis of sonographic muscle images can distinguish myopathic conditions.

Given the recent technological advent of muscle ultrasound (US), classification of various myopathic conditions could be possible, especially by mathematical analysis of muscular fine structure called texture analysis. We prospectively enrolled patients with three neuromuscular conditions and their lower leg US images were quantitatively analyzed by texture analysis and machine learning methodology in the following subjects : Inclusion body myositis (IBM) [N=11] ; myotonic dystrophy type 1 (DM1) [N=19] ; polymyositis/dermatomyositis (PM-DM) [N=21]. Although three-group analysis achieved up to 58.8% accuracy, two-group analysis of IBM plus PM-DM versus DM1 showed 78.4% accuracy. Despite the small number of subjects, texture analysis of muscle US followed by machine learning might be expected to be useful in identifying myopathic conditions. J. Med. Invest. 66 : 237-240, August, 2019.

The Journal of Medical Investigation : JMI


Classification of needle-EMG resting potentials by machine learning

The diagnostic importance of audio signal characteristics in needle electromyography (EMG) is well established. Given the recent advent of audio-sound identification by artificial intelligence, we hypothesized that the extraction of characteristic resting EMG signals and application of machine learning algorithms could help classify various EMG discharges. Data files of 6 classes of resting EMG signals were divided into 2-s segments. Extraction of characteristic features (384 and 4,367 features each) was used to classify the 6 types of discharges using machine learning algorithms. Across 841 audio files, the best overall accuracy of 90.4% was observed for the smaller feature set. Among the feature classes, mel-frequency cepstral coefficients (MFCC)-related features were useful in correct classification. We showed that needle EMG resting signals were satisfactorily classifiable by the combination of feature extraction and machine learning, and this can be applied to clinical settings. Muscle Nerve 59:224-228, 2019.


Distinct Incidence of Takotsubo Syndrome Between Amyotrophic Lateral Sclerosis and Synucleinopathies: A Cohort Study.

Takotsubo syndrome (TTS) is an acute cardiac syndrome characterized by regional left ventricular dysfunction with a peculiar circumferential pattern, which typically results in apical ballooning. Evidence indicates a pivotal role of catecholamines in TTS, and researchers have discussed multiple hypotheses on the etiology, including multivessel coronary spasm, myocardial stunning, excessive transient ventricular afterload, and cardiac sympathetic overactivity with local noradrenaline spillover. Although central nervous system disorders, such as stroke and epilepsy, are known to trigger TTS, the incidence and clinical features of TTS in neurodegenerative disorders are poorly understood. Here, we retrospectively examined TTS cases in a single-center cohort composed of 250 patients with amyotrophic lateral sclerosis (ALS) and 870 patients with synucleinopathies [582 patients with Parkinson's disease (PD), 125 patients with dementia with Lewy bodies (DLB), and 163 patients with multiple system atrophy (MSA)] and identified 4 (1.6%, including 2 women) cases with ALS and no cases with synucleinopathies. Two ALS patients underwent autopsy and the pathological findings were compatible with the chronological changes identified in catecholamine-induced cardiomyopathy. A literature review identified 16 TTS cases with ALS, 1 case each with PD and DLB, and no cases with MSA. When current and previous TTS cases with ALS were concatenated: 55% (11/20) were female; 35% (7/20) had a bulbar-onset and 45% (9/20) had a limb-onset; the mean age of TTS onset was 63.3 ± 9.0 years and the mean interval time from ALS onset to TTS development was 4.9 ± 3.0 years; no (0/16) patients developed TTS within 12 months after ALS onset; 50% (10/20) underwent artificial ventilations; the mortality was 17% (3/18); and most cases had precipitating factors, and TTS development was associated with gastrostomy, tracheostomy, or infections in 45% (9/20) of the patients. This study demonstrated that ALS is a considerable predisposing factor of TTS and that synucleinopathies rarely cause TTS. The distinct TTS incidence between ALS and synucleinopathies may be due to cardiac sympathetic overactivity in ALS and may also be affected by cardiac sympathetic denervation in synucleinopathies. Moreover, the etiology of TTS in ALS may be reasonably explained by the two-hit theory.


123I-MIBG心筋シンチグラフィーとパーキンソン病患者における転倒リスクの評価


Compound heterozygote mutations in the SIGMAR1 gene in an oldest-old patient with amyotrophic lateral sclerosis.


CSF cystatin C and diffusion tensor imaging parameters as biomarkers of upper motor neuron degeneration in amyotrophic lateral sclerosis.

Reduced cystatin C in CSF can reflect UMN involvement as shown in high-field MR of ALS, potentially providing a new biomarker for UMN degeneration in ALS.

MR findings indicated that decreased anisotropy, increased diffusion, and increased myo-inositol/creatine ratio were also significantly correlated with UMN involvement in patients with ALS. The CSF cystatin C levels were significantly lower in patients with ALS than in the other three groups. The reduction of CSF cystatin C levels was significantly correlated with clinical UMN involvement (r = -0.505, p = 0.023).


Guillan-Barre syndrome in local area in Japan, 2006-2015: an epidemiological and clinical study of 108 patients

Many epidemiological studies of Guillain-Barré syndrome (GBS) and Fisher syndrome (FS) have been conducted in Europe and America. In contrast, epidemiological studies are rare in Asia where the GBS subtypes differ from those in Western countries. This study was undertaken to clarify the incidence of GBS and FS in a local area in Japan as well as their seasonal trends. Seventy-one GBS and 37 FS patients were recorded from 2006 to 2015 in an area of approximately 1.5 million inhabitants in Japan. The incidence, seasonal trends and clinical features of GBS and FS were examined. The incidence rate of GBS was 0.42 cases per 100 000 person-years and that of FS was 0.22 cases per 100 000 person-years. The incidence of GBS increased with age and FS affected predominantly patients aged from 45 to 64 years old. There was some seasonal clustering of acute motor axonal neuropathy (AMAN) and FS in spring and summer, but it was not significant. AMAN and FS patients had a high frequency of preceding infection (AMAN, 68% gastrointestinal infection; FS, 65% upper respiratory infection). Antecedent respiratory infection was significantly associated with FS as an outcome. Serum antibodies to ganglioside GM1 were detected in 71% of AMAN patients and antibodies to GQ1b were detected in 81% of FS patients. Our study offers evidence of a lower incidence of GBS and a higher incidence of FS in a local area in Japan than in Western countries.


未治療のサルコイドーシスに合併した進行性多巣性白質脳症

未治療のサルコイドーシスに合併した進行性多巣性白質脳症


Phenotype variability and allelic heterogeneity in KMT2B-Associated disease.

We further demonstrate the allelic heterogeneity and phenotypic variations of KMT2B-associated disease. Haploinsufficiency is one of molecular pathomechanisms underlying the disease. Cardinal clinical features include combined dystonia accompanying mild psychomotor disability. Cerebellum would be affected in KMT2B-associated disease.


Risk Factors of Neurological Deterioration in Patients with Cerebral Infarction due to Large Artery Atherosclerosis

In some patients with acute ischemic stroke, neurological deterioration (ND) is observed, and it is difficult to predict at the time of admission. Especially in some patients with large-artery atherosclerosis (LAA), aggressive medical treatments and surgical interventions might be helpful to prevent ND. Therefore, we investigated factors associated with ND in patients with LAA. We studied patients with LAA who were admitted to our hospital. We divided them into 2 groups with (group 1) and without deterioration (group 2), and evaluated their medical records, risk factors, and radiological findings, such as number of diffusion-positive lesion and degree of stenosis. Our study population consisted of 171 patients; 71 (41.5%) did and 100 (58.5%) did not suffer deterioration. By univariate analysis, blood pressure (BP), heart rate, National Institutes of Health Stroke Scale (NIHSS) score, number of diffusion-positive lesion, count of red blood cell, high-density lipoprotein, and degree of stenosis differed significantly between the 2 groups. By multivariate analysis, systolic BP (170 mm Hg, odds ratio: 7.20, P <.001) was associated with ND. Furthermore, number of diffusion-weighted image (DWI)-positive lesion (8), degree of stenosis (>80.0%), and NIHSS score (4) were also independent factors associated with ND. High BP, severity of neurological deficit at the time of admission, and radiological findings, such as degree of stenosis and number of DWI-positive lesion, are independently associated with ND in patients with LAA.

Journal of Stroke & Cerebrovascular Diseases


Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability.

Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation. This study is to explore the novel SPAST splice site donor variant, c.1004+3A>C, in seven patients from two families, one from Italy and the other from Japan. Exon 6 is skipped out by the variant, leading to a premature termination of translation, p.Gly290Trpfs*5. Measurement of SPAST transcripts in lymphocytes demonstrated a reduction through nonsense-mediated mRNA decay (NMD). Intra- and inter-familial phenotypic variations were observed, including age-at-onset, severity of spasticity, and scoliosis. Our study demonstrated further evidence of allelic heterogeneity in SPG4, dosage effects through NMD, and broad clinical features of the SPAST mutation.


Usefulness of the superior cerebellar peduncle for differential diagnosis of progressive supranuclear palsy: A meta-analysis.

Previous studies have reported the usefulness of superior cerebellar peduncle (SCP) abnormalities in diagnosing progressive supranuclear palsy. However, the results of these studies were heterogeneous. In the present meta-analysis, we aimed to establish more robust evidence of SCP abnormalities in progressive supranuclear palsy, and to determine the cause of the previously reported heterogeneity. We identified six studies on SCP size and three studies on apparent diffusion coefficient. Key features of each study were extracted and standardized differences in size and apparent diffusion coefficient values were calculated. There was some heterogeneity in terms of the reduction in SCP size in patients with progressive supranuclear palsy compared to those with Parkinson's disease. Moreover, age and Hoehn-Yahr stage negatively correlated with standardized mean difference in SCP size between patients with progressive supranuclear palsy and Parkinson's disease. There was homogenous agreement that the SCP was smaller in patients with progressive supranuclear palsy compared to those with multiple system atrophy. Finally, in terms of apparent diffusion coefficient, there was no significant difference between patients with progressive supranuclear palsy, Parkinson's disease, or multiple system atrophy. Together, these findings suggest that SCP size, when corrected for age and disease severity, could be a diagnostic tool for progressive supranuclear palsy.


Proteasome impairment in neural cells derived from HMSN-P patient iPSCs.

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is caused by a heterozygous mutation (P285L) in Tropomyosin-receptor kinase Fused Gene (TFG), histopathologically characterized by progressive spinal motor neuron loss with TFG cytosolic aggregates. Although the TFG protein, found as a type of fusion oncoprotein, is known to facilitate vesicle transport from endoplasmic reticulum (ER) to Golgi apparatus at ER exit site, it is unclear how mutant TFG causes motor neuron degeneration. Here we generated induced pluripotent stem cells (iPSCs) from HMSN-P patients, and differentiated the iPSCs into neural cells with spinal motor neurons (iPS-MNs). We found that HMSN-P patient iPS-MNs exhibited ubiquitin proteasome system (UPS) impairment, and HMSN-P patient iPS-MNs were vulnerable to UPS inhibitory stress. Gene correction of the mutation in TFG using the CRISPR-Cas9 system reverted the cellular phenotypes of HMSN-P patient iPS-MNs. Collectively, these results suggest that our cellular model with defects in cellular integrity including UPS impairments may lead to identification of pathomechanisms and a therapeutic target for HMSN-P.


Spontaneous brain activity in the sensorimotor cortex in amyotrophic lateral sclerosis can be negatively regulated by corticospinal fiber integrity.

Previous studies failed to detect reduced value of the amplitude of low frequency fluctuation (ALFF) derived from resting state functional magnetic resonance imaging in the primary motor cortex in amyotrophic lateral sclerosis (ALS) though primary motor cortex was mainly affected with ALS. We aimed to investigate the cause of masking the abnormality in the primary motor cortex in ALS and usefulness of ALFF for differential diagnosis among diseases showing muscle weakness. We enrolled ten patients with ALS and eleven disease controls showing muscle weakness. Voxel-wise analysis revealed that significant reduction of ALFF value was present in the right sensorimotor cortex in ALS. There was a significant negative correlation between ALFF value in the right sensorimotor cortex and fractional anisotropy (FA) value in the posterior limbs of the internal capsule (PLIC). For a diagnostic tool, the area under receiver operating characteristic curve improved if the ALS patients with disease duration >1 year were excluded. The present findings raised the possibility of usefulness of ALFF value in the sensorimotor cortex for differential diagnosis of ALS, and supported the notion that adjustment for FA value in the PLIC could improve accuracy.


Mitochondrial trifunctional protein deficiency: an adult patient with similar progress to Charcot-Marie-Tooth disease.

シャルコー・マリー・トウース病に類似した三頭酵素欠損症の成人例

A 45-year-old man presented to us due to slowly progressive muscle weakness and sensory disturbances in his lower limbs since his 40's. He reported multiple episodes of exercise-induced severe muscle fatigue and brown urine in his childhood, which disappeared by age 20. A nerve conduction study showed peripheral axonal neuropathy and then Charcot-Marie-Tooth disease (CMT) was considered as the most likely diagnosis; however, exome sequencing failed to identify a mutation in the known genes of CMTs. Since age 55, he recurrently developed severe rhabdomyolysis that required hospitalization. On suspicion of lipid metabolism disorders, we performed serum acylcarnitine analysis, and which revealed mildly elevated long-chain fatty acids. We re-examined variants obtained via exome sequencing and found a mutation in HADHB. Mitochondrial trifunctional protein (MTP) deficiency is a rare autosomal recessive disorder of mitochondrial fatty acid beta-oxidation caused by HADHA or HADHB mutation. It can be a life-threatening multiorgan disorder with early infantile onset, but it can also present in childhood or adolescence with peripheral neuropathy and recurrent rhabdomyolysis. This case of adult-diagnosed MTP deficiency was characterized by slowly progressive peripheral neuropathy masquerading CMT in addition to muscular symptoms. MTP deficiency should be considered in patients with the combination of peripheral neuropathy and recurrent rhabdomyolysis.


A case of neuromyelitis optica spectrum disorder (NMOSD) with Sjögren's syndrome manifested only brain involvement by preceding parotitis.

耳下腺炎を契機に発症し，脳病変のみを反復したシェーグレン症候群合併視神経脊髄炎関連疾患の一例

A 33 year-old woman presented with intentional incontinence, motor aphasia, supranuclear gaze palsy, and spasticity after parotitis. Brain magnetic resonance images (MRI) showed abnormal signaling in long corticospinal tract involving internal capsules and cerebral peduncles, middle cerebellar peduncle, and frontal subcortical white matter lesions. She had a long history of dry eye and mouth. Immunoserological study showed that she was positive for anti-SS-A, aquaporin 4 (AQP4), and AQP5 antibodies. She clinically showed not only Sjögren's syndrome but also neuromyelitis optica spectrum disorder (NMOSD) without optic neuritis or myelitis. She responded to steroid followed by plasma exchange dramatically. Thereafter, the relapse of brain lesion was once detected while tapering of steroid, but her symptoms have been stable for several years after administration of immunosuppressant. This case suggested that salivary gland inflammation might be associated with the pathogenesis of NMOSD.


Optimal Timing of Diffusion-Weighted Imaging to Avoid False-Negative Findings in Patients With Transient Ischemic Attack

We aimed to investigate the optimal timing of diffusion-weighted imaging (DWI) in patients with transient ischemic attack (TIA). Seventy-three consecutive patients with TIA underwent DWI on admission (initial DWI) and at 24 hours after admission (second DWI). Patients were divided into 2 groups based on initial DWI findings in relation to the second examination: false negative (group 1) and other (group 2). The probability of initial false-negative findings was determined for each hour from TIA onset to initial DWI. Multivariate analysis was used to evaluate the independent risk factors associated with false-negative findings on initial DWI. Of the 73 patients examined (56 men; mean age, 68 years), 9 (12%) were categorized into group 1. The latency from TIA onset to initial DWI was 1.7±0.6 hours for group 1 (range, 1-2.8 hours) and 3.3±2.6 hours for group 2 (range, 35 minutes to 12 hours). The probability of false-negative findings on initial DWI decreased in a time-dependent manner (25%, 21%, and 7% for 1, 2, and 3 hours, respectively), and no false-negative findings were observed on initial DWI performed at >3 hours from symptom onset. Short latency (2 hours) from TIA onset to initial DWI was an independent risk factor related to false-negative findings (odds ratio, 13.11; 95% confidence interval, 1.07-161.38; P=0.045). If the duration between TIA symptom onset and initial DWI is <2 hours, a repeat examination should be performed to minimize the risk of false-positive findings.


A Case of Anti-SRP Positive Immune-mediated Necrotizing Myopathy Treated Effectively with Combined Immunotherapy

複合的免疫治療が奏功した抗SRP抗体陽性壊死性ミオパチーの1例

症例は60歳代，男性．全身倦怠感，四肢脱力を主訴に受診．筋炎としステロイド単独で治療を開始したが，反応性は乏しく，筋病理・抗体検査にて抗SRP抗体陽性壊死性ミオパチー(anti-signal recognition particle immune-mediated necrotizing myopathy:anti-SRP iNM)と診断し，免疫グロブリン大量静注療法，免疫抑制薬を併用したところ，症状の改善を得た．積極的に自己抗体の測定を行うことが壊死性ミオパチー(immune-mediated necrotizing myopathy:iNM)の早期診断・治療に重要である．

The Journal of the Japanese Society of Internal Medicine


Imaging-based differential diagnosis between multiple system atrophy and Parkinson's disease.

There are many tools for differentiating between multiple system atrophy with predominant parkinsonian features (MSA-P) and Parkinson's disease (PD). These include middle cerebellar peduncle (MCP) width, apparent diffusion coefficient (ADC) value of the putamen and cerebellum, and (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy images. We aimed to directly compare the above-mentioned methods, and to determine the optimal tool for differential diagnosis. Eleven patients with MSA-P and 36 patients with PD were enrolled. Of these, 7 patients with MSA-P and 14 patients with PD were chosen as background-matched subjects. We measured MCP width, ADC value of the putamen and cerebellum, and MIBG myocardial scintigraphy images. Area under curve (AUC) of receiver operating characteristic (ROC) was assessed to compare the above-mentioned methods. MCP width and ADC value of the putamen may be helpful for differentiating between MSA-P and PD relative to other methods in background-matched patients (MCP, AUC=0.95; putamen ADC, AUC=0.88; cerebellar ADC, AUC=0.70; MIBG, AUC=0.78). Similar AUCs were seen in all patients with different backgrounds. Our findings suggested that MCP width and ADC value of the putamen could be superior to ADC value of the cerebellum and MIBG uptake for differentiating between MSA-P and PD.


Mystery Case: Parkinsonism in a diabetic uremic patient.


MFN2 transcripts escaping from nonsense-mediated mRNA decay pathway cause Charcot-Marie-Tooth disease type 2A2

Journal of Neurology, Neurosurgery, and Psychiatry


Late-onset spastic paraplegia type 10 (SPG10) family presenting with bulbar symptoms and fasciculations mimicking amyotrophic lateral sclerosis

Pathogenic mutations in the KIF5A-SPG10 gene, encoding the kinesin HC5A, can be associated with autosomal dominant hereditary spastic paraplegia (ADHSP). It accounts for about 10% of the complicated forms of ADHSP. Peripheral neuropathy, distal upper limb amyotrophy, and cognitive decline are the most common additional clinical features. We examined a 66-year-old Japanese woman manifesting gait disturbance and spastic dysarthria for 6years with positive family history. She showed evidence of upper and lower motor neuron involvement and fasciculations, thus mimicking amyotrophic lateral sclerosis (ALS). Genetic analysis revealed a heterozygous variant in KIF5A (c.484C>T, p.Arg162Trp) in 2 symptomatic members. The mutation was also identified in 4 asymptomatic members, including 2 elderly members aged over 78years. Electromyography in the 2 symptomatic members revealed evidence of lower motor neuron involvement and fasciculation potentials in distal muscles. This report describes the first known Asian family with a KIF5A mutation and broadens the clinical and electrophysiological spectrum associated with KIF5A-SPG10 mutations. Given that our cases showed pseudobulbar palsy, fasciculation and altered penetrance, KIF5A-SPG10 might well be considered as a differential diagnosis of sporadic ALS.


The difference of apparent diffusion coefficient in the middle cerebellar peduncle among parkinsonian syndromes: Evidence from a meta-analysis.

The measurement of middle cerebellar peduncle (MCP) width allows for differential diagnosis between Parkinson's disease (PD) and multiple system atrophy with predominant parkinsonian features (MSA-P). However, it remains controversial whether apparent diffusion coefficient (ADC) value in the MCP of MSA-P is elevated or not. In the present study, we aimed to assess the usefulness of ADC value in the MCP for differential diagnosis between PD and MSA-P. An on-line literature search yielded 5 eligible studies. We expressed between-group difference of ADC value as the standardized mean difference (SMD). The proportion of variation due to heterogeneity was computed and expressed as I(2). ADC in the MCP of MSA-P was significantly increased compared with PD with heterogeneous studies (P=0.0007, I(2)=81%). A meta-regression analysis of MSA-P was conducted for "UPDRS III", and revealed a significant correlation between UPDRS III and SMD (P=0.01). Our meta-regression analysis has clarified the contribution of severity of MSA-P to heterogeneity of the included studies for ADC in the MCP. This finding raised the possibility that ADC in the MCP depended on severity of MSA-P, and less severe patients with MSA-P should be mainly enrolled in future study to assess the ability for differential diagnostic tool.


Late-onset myasthenia gravis is predisposed to become generalized in the elderly


Fractional anisotropy in the supplementary motor area correlates with disease duration and severity of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is progressive and fatal neurodegenerative disorder with upper and lower motor neuron signs. There are no biomarkers to track disease progression. To address this issue, we investigated regions in which fractional anisotropy (FA) values derived from diffusion weighted images correlated with both disease severity and duration in ALS patients. Fourteen patients with ALS were enrolled in this study. Voxel-based analysis revealed volume of interests (VOIs) showing significant correlation. Finally, Spearman rank correlation coefficient was assessed between FA value in each VOI and disease severity or duration. In the VOI of left supplementary motor area (SMA), FA value significantly correlated with disease severity and duration both (disease severity, rho = 0.59, p = 0.025; disease duration, rho = -0.69, p = 0.006). The present finding suggested the possibility that the abnormality in motor-related region including SMA could be a candidate for a biomarker to track disease progression.


Extranodal NK/T-cell lymphoma, nasal type, manifesting as rapidly progressive dementia without any mass or enhancing brain lesion.

Among the many potential etiologies for rapidly progressive dementia (RPD), primary central nervous system extranodal NK/T-cell lymphoma, nasal-type (ENKL) is a rare entity. We present the first reported case of autopsy-proven RPD due to ENKL without any mass or enhancing lesion of the brain. A 54-year-old immunocompetent man presented with RPD, myoclonus and ataxia. The mini-mental state examination (MMSE) score was 22/30. His brain MRI revealed progressive brain atrophy without gadolinium enhancement or mass lesion. Five months after the initial evaluation, cognitive impairment further worsened with an MMSE score of 3/30. At the advanced stage, lumbar MRI showed swollen cauda equina with gadolinium enhancement. The number of Epstein-Barr virus (EBV) DNA in cerebrospinal fluid had gradually increased. Twelve months after onset, the patient died of respiratory failure. Pathological findings revealed that lymphoma cells had diffusely invaded the meninges, parenchyma of the brain, spinal cord and cauda equina. Cells were positive for CD3, CD56 and EBV-encoded small RNAs and negative for CD20. No evidence of malignancy was identified in the visceral organs. This report indicates that ENKL should be recognized as one of the rare causes of RPD. Early testing for EBV-DNA in cerebrospinal fluid and imaging of cauda equina would be useful diagnostic tools.


The ratio of N-acetyl aspartate to glutamate correlates with disease duration of amyotrophic lateral sclerosis

Glutamate (Glu)-induced excitotoxicity has been implicated in the neuronal loss of amyotrophic lateral sclerosis. To test the hypothesis that Glu in the primary motor cortex contributes to disease severity and/or duration, the Glu level was investigated using MR spectroscopy. Seventeen patients with amyotrophic lateral sclerosis were diagnosed according to the El Escorial criteria for suspected, possible, probable or definite amyotrophic lateral sclerosis, and enrolled in this cross-sectional study. We measured metabolite concentrations, including N-acetyl aspartate (NAA), creatine, choline, inositol, Glu and glutamine, and performed partial correlation between each metabolite concentration or NAA/Glu ratio and disease severity or duration using age as a covariate. Considering our hypothesis that Glu is associated with neuronal cell death in amyotrophic lateral sclerosis, we investigated the ratio of NAA to Glu, and found a significant correlation between NAA/Glu and disease duration (r=-0.574, p=0.02). The "suspected" amyotrophic lateral sclerosis patients showed the same tendency as possible, probable and definite amyotrophic lateral sclerosis patients in regard to correlation of NAA/Glu ratio with disease duration. The other metabolites showed no significant correlation. Our findings suggested that glutamatergic neurons are less vulnerable compared to other neurons and this may be because inhibitory receptors are mainly located presynaptically, which supports the notion of Glu-induced excitotoxicity.


Multimodal analysis based on high-field magnetic resonance and motor evoked potentials: A case report of multiple sclerosis


Ocular myasthenia gravis with anti-muscle-specific tyrosine kinase antibodies: Two new cases and a systematic literature review


An autopsy case of progressive generalized muscle atrophy over 14 years due to post-polio syndrome

約14年の経過でポストポリオ症候群が広範に進行した1剖検例

We report the case of a 72-year-old man who had contracted acute paralytic poliomyelitis in his childhood. Thereafter, he had suffered from paresis involving the left lower limb, with no relapse or progression of the disease. He began noticing slowly progressive muscle weakness and atrophy in the upper and lower extremities in his 60s. At the age of 72, muscle weakness developed rapidly, and he demonstrated dyspnea on exertion and dysphagia. He died after about 14 years from the onset of muscle weakness symptoms. Autopsy findings demonstrated motoneuron loss and glial scars not only in the plaque-like lesions in the anterior horns, which were sequelae of old poliomyelitis, but also throughout the spine. No Bunina bodies, TDP-43, and ubiquitin inclusions were found. Post-polio syndrome is rarely fatal due to rapid progressive dyspnea and dysphagia. Thus, the pathological findings in the patient are considered to be related to the development of muscle weakness.

症例は死亡時74歳の男性である．小児期の急性灰白髄炎罹患後に左下肢麻痺が残存した．60歳頃より四肢筋力低下，72歳頃より呼吸機能障害・嚥下障害が進行し，発症約14年後に死亡した．神経病理学的には脊髄にポリオ後遺症と思われるplaque-like lesionのほか，脊髄全長にわたりグリオーシスを伴う前角細胞脱落を認めたが，Bunina小体やユビキチン・TDP43陽性封入体などamyotrophic lateral sclerosis(ALS)に特徴的とされる構造物は認めなかった．ポストポリオ症候群は稀に呼吸機能障害や嚥下障害が急速に進行して致死的となる場合があり，これらの病理所見はポストポリオ症候群による運動麻痺の進行と関連していると考えられた．


Intramuscular dissociation of echogenicity in the triceps surae characterizes sporadic inclusion body myositis

Differential diagnosis of sporadic inclusion body myositis (s-IBM) and polymyositis (PM)/dermatomyositis (DM) is difficult and can affect proper disease management. Detection of heterogeneous muscular involvement in s-IBM by muscle sonography could be a unique diagnostic feature. Sonography of the lower leg and forearm was performed in patients with s-IBM, PM/DM and control subjects (n = 11 each). Echo intensities (EIs) of the adjacent muscles [medial head of the gastrocnemius versus soleus and the flexor digitorum profundus (FDP) versus flexor carpi ulnaris (FCU)] were scored by three blinded raters. The mean EIs of these muscles were compared using computer-assisted histogram analysis. Both evaluation methods showed high echoic signals in the gastrocnemius of patients with s-IBM. EIs were significantly different between the gastrocnemius and soleus in patients with s-IBM, but not in those with DM/PM and the controls. In the forearm, although the EI of the FDP was higher in the s-IBM group than in the other groups, the EI differences between the FDP and FCU did not differ significantly between disease groups. The difference in area under the curves to differentiate between s-IBM and DM/PM was greatest between the gastrocnemius-soleus EIs (0.843; P = 0.006). High echoic signals in the medial gastrocnemius compared with those of the soleus are suggestive of s-IBM over PM/DM.


Predictors of a favorable outcome after recanalization in patients with cerebral major vessel occlusion

Although tissue plasminogen activator and endovascular treatment were reported to be useful for recanalization in patients with major vessel occlusion (MVO), the outcome in some patients with recanalization was unfavorable. We could detect prolongation of the ipsilateral posterior cerebral artery (PCA) to the ischemic side on magnetic resonance angiography in some patients (ipsilateral-PCA sign). We investigated the predictors including radiological findings for a favorable outcome after successful recanalization. We included 76 patients with MVO of the anterior circulation and documented recanalization by treatment. We divided our patients into 2 groups: group F (modified Rankin scale [mRS] score = 0-2) and group UF (mRS score = 3-6). We compared biomarkers between the groups. National Institutes of Health Stroke Scale (NIHSS) score before treatment in group F (8.5) was lower than that in group UF (16.0; P <.001). Sensitivity of the ipsilateral-PCA sign was commonly associated with group F (67.5% versus 19.4%, P <.001), and specificity of the sign was 80.6%. Absence of infarcts in the anterior cerebral artery (ACA) territory and ACA occlusion were also associated with a favorable outcome. In multivariate analysis, the ipsilateral-PCA sign and NIHSS score (≤ 10) were independent predictors of favorable outcome (odds ratio = 9.92, 95% confidence interval [CI] 2.71-36.23, P = .001; and odds ratio = 9.15, 95% CI 2.44-34.36, P = .001, respectively) The ipsilateral-PCA sign and low NIHSS score (≤ 10) were predictors of a favorable outcome in patients with MVO and documented recanalization by treatments.

Journal of Stroke & Cerebrovascular Diseases


Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation.

We identified a novel homozygous mutation in the splice site donor (SSD) of intron 30 (c.5866+1G>A) in consanguineous Japanese SPG11 siblings showing late-onset spastic paraplegia using the whole-exome sequencing. Phenotypic variability was observed, including age-at-onset, dysarthria and pes cavus. Coding DNA sequencing revealed that the mutation affected the recognition of the constitutive SSD of intron 30, splicing upstream onto a nearby cryptic SSD in exon 30. The use of constitutive splice sites of intron 29 was confirmed by sequencing. The mutant transcripts are mostly subject to degradation by the nonsense-mediated mRNA decay system. SPG11 transcripts, escaping from the nonsense-mediated mRNA decay pathway, would generate a truncated protein (p.Tyr1900Phefs5X) containing the first 1899 amino acids and followed by 4 aberrant amino acids. This study showed a successful clinical application of whole-exome sequencing in spastic paraplegia and demonstrated a further evidence of allelic heterogeneity in SPG11. The confirmation of aberrant transcript by splice site mutation is a prerequisite for a more precise molecular diagnosis.


The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments.

These observations suggest that clusters of raft-derived vesicles that resemble GVD bodies are substructures of pretangles other than PHFs. These tau kinase-bearing vesicles are likely involved in the modification of tau protein and in NFT formation. This article is protected by copyright. All rights reserved.


Autopsy case of severe generalized dystonia and static ataxia with marked cerebellar atrophy.


The effect of tremor onset on middle cerebellar peduncle of Parkinson's disease.

The majority of studies of Parkinson's disease (PD) focused on basal ganglia initially; however, accumulating evidence suggests cerebellar involvement in pathophysiology. We aimed to investigate the effects of tremor onset on middle cerebellar peduncle (MCP) width of PD patients and of disease duration on differential diagnosis. We measured MCP width of 81 PD, 34 multiple system atrophy (MSA) and 16 normal controls, using MRI. A meta-analysis was performed including two previous and the present studies. We carried out correlation analysis between disease duration and MCP width separately in subgroup of PD with or without tremor onset. Receiver operating characteristic curves were analyzed. Our meta-analysis indicated that MCP width was significantly smaller in MSA relative to PD with homogeneous studies. There was significant correlation between disease duration and MCP width in PD without tremor onset. In contrast, there was no correlation observed in PD with tremor onset. Subclassification according to disease duration showed improved area under curve of PD vs. MSA with predominant parkinsonian features. MCP width could be a valuable tool for differential diagnosis. Our finding suggested that MCP was impaired in advanced stage of PD without tremor onset as part of the abnormality of the cerebellar system.


CSF cytokine profile distinguishes multifocal motor neuropathy from progressive muscular atrophy.

The CSF cytokine profile of patients with MMN is distinct from that of patients with PMA and ALS. The similarity of the cytokine profiles between patients with PMA and ALS suggests that PMA shares common immunologic features with ALS in the CNS, even without clinical evidence of upper motor neuron involvement.

Neurology® Neuroimmunology & Neuroinflammation


A homozygous mutation of VWA3B causes cerebellar ataxia with intellectual disability.

Mutated VWA3B was found to be likely associated with cerebellar degeneration with intellectual disability. Although a rare cause of cerebellar degeneration, these findings indicate a critical role for VWA3B in the apoptosis pathway in neuronal tissues.

Journal of Neurology, Neurosurgery, and Psychiatry


Neurofilament light chain level in cerebrospinal fluid can differentiate Parkinson's disease from atypical parkinsonism: Evidence from a meta-analysis.

A reliable test that facilitates the accurate diagnosis of Parkinson's and disorders will help with both, clinical management and therapeutic research. In this context, neurofilament light chain (NFL) is candidate for a biomarker in cerebrospinal fluid (CSF). A comprehensive literature search yielded 4 eligible studies. We expressed between-group difference of NFL concentration in CSF as the standardized mean difference. Four studies involved 166 Parkinson's disease (PD), 116 multiple system atrophy (MSA) and 73 progressive supranuclear palsy (PSP) patients. Patients with MSA showed higher concentration of NFL concentration in CSF than those with PD (standardized mean difference=1.60, P<0.0001). These studies were homogeneous (P=0.17). NFL in CSF in PSP was significantly elevated relative to PD with homogeneous studies (standardized mean difference=2.04, P<0.0001; P=0.99). The present meta-analysis suggested that NFL concentration in CSF in MSA and PSP was significantly increased relative to PD, and that this could help us to separate PD from atypical parkinsonian syndromes.


Is the Susceptibility Vessel Sign on 3-Tesla Magnetic Resonance T2*-Weighted Imaging a Useful Tool to Predict Recanalization in Intravenous Tissue Plasminogen Activator?

The aim of this study was to investigate the independent factors associated with the absence of recanalization approximately 24 h after intravenous administration of tissue-type plasminogen activator (IV TPA). The previous studies have been conducted using 1.5-Tesla (T) magnetic resonance imaging (MRI). We studied whether the characteristics of 3-T MRI findings were useful to predict outcome and recanalization after IV tPA. Patients with internal carotid artery (ICA) or middle cerebral artery (MCA) (horizontal portion, M1; Sylvian portion, M2) occlusion and treated by IV tPA were enrolled. We studied whether the presence of susceptibility vessel sign (SVS) at M1 and low clot burden score on T2*-weighted imaging (T2*-CBS) on 3-T MRI were associated with the absence of recanalization. A total of 49 patients were enrolled (27 men; mean age, 73.9 years). MR angiography obtained approximately 24 h after IV tPA revealed recanalization in 21 (42.9 %) patients. Independent factors associated with the absence of recanalization included ICA or proximal M1 occlusion (odds ratio, 69.6; 95 % confidence interval, 5.05-958.8, p = 0.002). In this study, an independent factor associated with the absence of recanalization may be proximal occlusion of the cerebral arteries rather than SVS in the MCA or low T2*-CBS on 3-T MRI.


Val66Met polymorphism of brain-derived neurotrophic factor is associated with idiopathic dystonia.

The Val66Met (G196A; rs6265) single nucleotide polymorphism of brain-derived neurotrophic factor (BDNF) affects morphology and neuronal activity, and is expected to be associated with central nervous system disorders. However, it remains controversial whether Val66Met polymorphism is a risk factor for idiopathic dystonia. We aimed to clarify the impact of BDNF polymorphism on idiopathic dystonia. A literature search of PubMed was carried out. A random-effects model was employed for the meta-analysis. A pooled odds ratio (OR) was calculated along with 95% confidence intervals (CI) to reflect the risk of idiopathic dystonia in each genotype (GG, AG, AA) or minor allele. The proportion of variation due to heterogeneity was computed and expressed as I(2). Five case-control studies, comprising a total sample size of 1804 subjects (784 idiopathic dystonia patients, 1020 normal controls), were included in this meta-analysis. AA genotype was significantly more frequent in patients with idiopathic dystonia (OR=1.47, 95% CI 1.09-1.99, p=0.01, four studies, n=1716). This finding was derived from homogeneous studies (p=0.97, I(2)=0%). Our meta-analysis has revealed a significant overall effect of the AA genotype on the development of idiopathic dystonia.


The two-1 layered susceptibility vessel sign on 3-tesla T2*-weighted imaging is a predictive biomarker of stroke subtype

A susceptibility vessel sign (SVS) on 1.5-tesla (T)-T2*-weighted images may predict cardioembolism. It has also been detected in patients with large artery atherosclerosis. In patients with major vessel occlusion, the SVS was comprised 2 layers on 3T-T2*-weighted images. We assessed the efficacy of 2-layered SVS on 3T-T2*-weighted imaging scans for predicting cardioembolism. Our study included 132 patients who had ischemic stroke within the preceding 24 hours and presented with internal carotid artery or middle cerebral artery occlusion because of cardioembolism or large artery atherosclerosis. We compared 2-layered SVS and SVS on 3T-T2*-weighted imaging scans for their sensitivity, specificity, and diagnostic odds ratio for predicting cardioembolism. We enrolled 132 patients (72 men; mean age, 74.5 years); of these, 63 (47.7%) were presented with cardioembolism. Although the sensitivity of SVS and 2-layered SVS for cardioembolism and large artery atherosclerosis was not statistically different (74.6% and 58.0%, respectively), the sensitivity of 2-layered SVS was significantly higher in patients with cardioembolism (42.9%) than those with large artery atherosclerosis (2.9%; P<0.001). The specificity and diagnostic odds ratio for 2-layered SVS for cardioembolism were 97.1% and 25.1; for SVS they were 42.0% and 2.1, respectively. The specificity of 2-layered SVS for cardioembolism was high. It may be useful for predicting cardioembolism and for the management of patients with acute ischemic stroke.


脳梗塞発症後早期からの抗血小板薬使用が予後に及ぼす影響の検討

脳梗塞発症後早期からの抗血小板薬使用が予後に及ぼす影響の検討


Predictors of neurologic deterioration in patients with small-vessel occlusion and infarcts in the territory of perforating arteries

It is difficult to predict neurologic deterioration in patients with small-vessel occlusion (SVO), that is, small infarcts in the territory of cerebral perforating arteries. We reviewed 110 patients with SVO who were admitted to our hospital. We divided them into groups with (n = 32, group 1) and without deterioration (n = 78, group 2) and evaluated their medical records, risk factors, magnetic resonance imaging findings, grade of periventricular hyperintensity (PVH), maximum diameter of the infarct area, and the number of slices showing infarcts on diffusion-weighted images (DWI). Our study population consisted of 110 patients (71 males and 39 females; mean age 69.2 years): 32 (29%) did and 78 (71%) did not suffer deterioration. By univariate analysis, the age, current smoking, history of stroke, maximum diameter of the infarcted area, number of DWI slices with infarcts, frequency of PVH, and PVH grade based on Fazekas classification differed significantly between the 2 groups. By multivariate analysis, conventional risk factors other than PVH and history of stroke were not associated with neurologic deterioration (PVH grade ≥ 2 versus PVH grade ≤ 1, odds ratio 6.72, P = .006; with stroke versus without stroke, odds ratio .21, P = .049). We also found that higher the PVH grade, the worse the National Institutes of Health Stroke Scale score at the time of discharge. PVH and without history of stroke are independently associated with neurologic deterioration in patients with SVO.

Journal of Stroke & Cerebrovascular Diseases


Increased proinflammatory cytokines in sera of patients with multifocal motor neuropathy.

Proinflammatory cytokines may contribute to peripheral nerve demyelination in MMN.


Case of neuromyelitis optica spectrum disorder associated with central pontine and extrapontine myelinolysis preceded by syndrome of inappropriate antidiuretic hormone secretion

抗利尿ホルモン分泌異常症候群で発症し，橋中心・橋外髄鞘崩壊症を合併した視神経脊髄炎関連疾患の1例

A 36-year-old woman complained of general malaise. She presented with hyponatremia and plasma osmotic pressure was lower than urinary osmotic pressure. In addition, serum antidiuretic hormone level was higher than the measurement sensitivity. She was diagnosed with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). She fell into a coma despite correction of serum sodium level. Brain magnetic resonance imaging (MRI) revealed high signal intensities in the cerebral cortex, striatum, thalamus, hypothalamus, midbrain, and pons in fluid-attenuated inversion recovery images. Spinal MRI revealed a longitudinally extending lesion in the cervical cord. Serum sample was positive for anti-aquaporin-4 antibody, supporting the diagnosis of neuromyelitis optica spectrum disorder (NMOSD) combined with central pontine and extrapontine myelinolysis. In patients with NMOSD, the immune reaction can gradually cause destructive changes of the hypothalamus and lead to unstable ADH secretion in the absence of immunomodulatory treatment.


The difference in putamen volume between MSA and PD: Evidence from a meta-analysis.

Our findings based on group-level analysis suggested that volumetry of the putamen could be useful for differential diagnosis between MSA and PD at the early stage of disease, and also help to enroll more accurate disease group for disease modifying study in future.

Six studies, comprising a sample size of 84 MSA and 180 PD, were included in this meta-analysis. The overall effect indicated that putamen volume in MSA was significantly more reduced than that in PD with heterogeneous studies (P = 0.0004, 6 studies, n = 264, I(2) = 87%). A subgroup analysis revealed that the category of "Hoehn-Yahr stage of PD" showed a significant subgroup difference with a significant subgroup summary effect (subgroup difference: P = 0.003).


MIBG Myocardial Scintigraphy can Predict the Occurrence of Wearing-off Phenomenon in Early-stage Parkinsons Disease


Are multifocal motor neuropathy patients underdiagnosed? An epidemiological survey in Japan

Our objective was to do an epidemiologic survey of patients with multifocal motor neuropathy (MMN) in comparison with those with amyotrophic lateral sclerosis (ALS) in Japan. In this retrospective study, we examined 46 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. Diagnosis was based on the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) and the revised El Escorial criteria. The efficacy of intravenous immunoglobulin (IVIg) was also taken into consideration in the diagnosis of MMN. The ratio of MMN to ALS patients (0-0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.29 MMN patients and 6.63 ALS patients per 100,000 population. The frequency of MMN patients was around 1 out of 20 ALS patients, and MMN was possibly underdiagnosed in some centers.


MRI Can Detect Nigral Volume Loss in Patients with Parkinson's Disease: Evidence from a Meta-Analysis.

Background: Parkinson's disease (PD) involves the degeneration of dopaminergic neurons in substantia nigra compacta. However, it is still a contentious issue whether magnetic resonance imaging (MRI) can detect the nigral volume loss in PD patients. Objective: We synthesized the results of published research on SN volumetry using a meta-analysis method in order to clarify this issue. Methods: A comprehensive literature search yielded 8 eligible studies. Nigral size was expressed as the standardized mean difference (SMD) between normal controls and PD patients. In addition, subgroup analysis was performed in order to identify the best condition for nigral volumetry. The proportion of variation due to heterogeneity was computed and expressed as I2. Results: Eight studies involved 172 normal control and 193 PD patients. The overall effect indicated that nigral volume in PD was significantly smaller than normal controls with homogeneous studies (SMD = -0.65, P < 0.0001; I2 = 47%). Maximum of subgroup effect was observed in 'volumetry' among three approaches ('thickness': SMD = -0.35, P = 0.18, I2 = not available; 'area': SMD = -0.39, P = 0.14, I2 = 0%; 'volumetry': SMD = -0.82, P = 0.0006, I2 = 56%). The approach including T1-weighted images (T1WI) showed larger effect ('with T1WI': SMD = -1.11, P < 0.00001, I2 = 36%; 'without T1WI': SMD = -0.32, P = 0.04, I2 = 0%). Conclusions: These findings suggest that volumetry based on T1WI could be the most sensitive option to identify nigral volume loss in PD patients.


Thinning of cervical nerve roots and peripheral nerves in ALS as measured by sonography.

Sonographic evaluation of nerve roots and peripheral nerves may be a useful disease marker in ALS to confirm the diagnosis and to potentially monitor the disease progression.


Comparison between botulinum neurotoxin type A2 and type A1 by electrophysiological study in healthy individuals.

Botulinum neurotoxin type A1 (BoNTs/A1) and type B (BoNT/B) have been used for treating hyperactive muscle contractions. In the present study, we compared the effect of botulinum neurotoxin subtype A2 (6.5 mouse LD50 units A2 neurotoxin, A2NTX) and onabotulinumtoxinA (10 mouse LD50 units BoNT/A1 product) by measuring the compound muscle action potentials (CMAPs) before and after administration. In total, 8 healthy subjects were examined in the present study. A2NTX was injected into the extensor digitorum brevis (EDB) muscle, followed by onabotulinumtoxinA injection into the contralateral EDB muscle after 16 weeks. The CMAP amplitudes from the EDB, abductor hallucis (AH), and abductor digiti minimi pedis (ADM) muscles were measured after each BoNT injection on days 1, 3, 7, 14, 28, 56, 84, and 112 to assess the effect of the toxin. On day 14, both A2NTX and onabotulinumtoxinA produced an approximately 70% decline in EDB CMAP amplitude compared to the baseline values; significant reduction of the CMAP continued through day 112. The CMAP amplitudes from neighboring muscles (AH and ADM) remained intact throughout the study period, except for a slight but significant drop at day 28 after onabotulinumtoxinA injection compared to A2NTX. The current findings indicate that small doses (6.5 units and 10 units) of A2NTX and onabotulinumtoxinA have at least comparable onset and duration of action, although similar clinical effects were obtained with lower dose using A2NTX.


Reversibility of ischemic findings on 3-tesla magnetic resonance T2(*)-weighted image after recanalization

Ischemic vessel signs (IVS) can be detected on 3-tesla T2(*)-weighted magnetic resonance images as a vessel enlargement at the territory of acute ischemia caused by major vessel occlusion or stenosis. Here, we studied changes in IVS before and after recanalization by the administration of intravenous recombinant tissue plasminogen activator (IV rtPA), carotid artery stenting or percutaneous transluminal angioplasty in patients with major vessel occlusion or stenosis. We performed magnetic resonance imaging for all patients treated by IV rtPA at the time of admission, shortly after and 24-72 hours after treatment with IV rtPA. We reviewed the IVS to assess its natural course of IVS by assessing patients who did not recanalize. IVS tended to disappear after recanalization. Conversely, in patients without recanalization, IVS did not disappear shortly after IV rtPA; rather, it disappeared 24-72 hours after IV rtPA, especially in the presence of complete infarction. Recanalization by IV rtPA or endovascular treatment contributed to improved clinical deficits or the prevention from further progression. IVS can be a parameter of misery perfusion and an important factor to detect the patients who have an indication of treatment for recanalization.

The Journal of Medical Investigation : JMI


Clinicopathologic features of autosomal recessive amyotrophic lateral sclerosis associated with optineurin mutation

We performed clinicopathological analyses of two amyotrophic lateral sclerosis (ALS) patients with homozygous Q398X optineurin (OPTN) mutation. Clinically, both patients presented signs of upper and lower motor neuron degeneration, but only Patient 1 showed gradual frontal dysfunction and extrapyramidal signs, and temporal lobe and motor cortex atrophy. Neuropathological examination of Patient 1 revealed extensive cortical and spinal motor neuron degeneration and widespread degeneration of the basal ganglia. Bilateral corticospinal tracts exhibited degeneration. Loss of spinal anterior horn cells (AHCs) and gliosis were observed, whereas posterior columns, Clarke's columns, intermediate lateral columns, and the Onuf's nucleus were spared. In the brainstem, moderate neuronal loss and gliosis were noted in the hypoglossal and facial motor nuclei. No Bunina bodies were found in the surviving spinal and brainstem motor neurons. Transactivation response (TAR) DNA-binding protein 43 (TDP-43)-positive neuronal and glial cytoplasmic inclusions were observed throughout the central nervous system. The Golgi apparatus in motor neurons of the brainstem and spinal cord was often fragmented. Immunoreactivity for OPTN was not observed in the brain and spinal cord, consistent with nonsense-mediated mRNA decay of OPTN. The TDP-43 pathology of Q398X was similar to that of an autosomal dominant E478G mutation. This result suggests that the loss-of-function, but not the proteinopathy itself, of OPTN results in TDP-43 deposits in neuronal and glial cytoplasm and Golgi apparatus fragmentation, leading to multisystem neurodegeneration.


Which target is best for patients with Parkinson's disease? A meta-analysis of pallidal and subthalamic stimulation.

The effect of GPi DBS was similar to STN DBS except for depression, however, only three studies described depression as adverse events. We need additional randomised trials with direct comparison between targets based on unified scoring of adverse events.

Journal of Neurology, Neurosurgery, and Psychiatry


Brush sign on 3-T t2*-weighted MRI as a potential predictor of hemorrhagic transformation after tissue plasminogen activator therapy

The brush sign (BS) is the enlargement of medullary veins on 3-T T2*-weighted MRI seen in patients with ischemic stroke because of major cerebral artery occlusion. However, the clinical relevance of BS in patients with acute stroke remains unclear. We assessed the correlation between detecting BS with the development of hemorrhagic transformation after intravenous thrombolysis. We enrolled consecutive patients with M1 or M2 occlusion treated with intravenous tissue plasminogen activator. We classified the patients into 2 groups: the group positive for BS (P-BS) and the group negative for BS (N-BS). We investigated the differences in MRI findings and the clinical outcome between the 2 groups. The subjects consisted of 36 patients (19 men; mean age, 74.7 years). Twenty-one patients (58%) had M1 occlusion, and 15 (42%) had M2 occlusion. Twenty-five patients (69%) were classified into the P-BS group and 11 (31%) into the N-BS group. Recanalization was observed in 15 (60%) and 10 (90%) patients in the P-BS and N-BS groups, respectively (P=0.116). Hemorrhagic transformation on MRI was observed more frequently in the P-BS group than in the N-BS group (64% versus 18%; P=0.027). A good outcome (mRS, 0-1) at discharge was found in 24% of patients in the P-BS group and in 45% of patients in the N-BS group (P=0.152). A multivariate logistic regression analysis revealed that the presence of BS (odds ratio, 9.08; 95% confidence interval, 1.4-59.8; P=0.022) was independently associated with hemorrhagic transformation. BS may predict the development of hemorrhagic transformation in patients with acute stroke treated with intravenous tissue plasminogen activator.


Exome sequencing reveals a novel MRE11 mutation in a patient with progressive myoclonic ataxia.

Progressive myoclonic ataxia (PMA) is a clinical syndrome defined as progressive ataxia and myoclonus and infrequent seizures in the absence of progressive dementia. Due to the extremely heterogeneous nature of PMA, a large proportion of PMA cases remain molecularly undiagnosed. The aim of this study was to clarify the molecular etiology of PMA. The patient was a 52-year-old female from consanguineous parents. She developed a jerking neck movement at age 9, which gradually expanded to her entire body. On physical examination at age 47, she exhibited generalized, spontaneous myoclonus that occurred continuously. She also presented with mild limb and truncal ataxia. An electroencephalogram revealed no abnormalities. A brain MRI displayed no atrophy of the cerebellum. Electrophysiological studies suggested myoclonus of a subcortical origin. For further evaluation, we performed exome sequencing, and we identified a novel homozygous missense mutation in the MRE11 gene (NM_005590:c.140C>T:p.A47V). Subsequently, we analyzed the expression of MRE11 and related proteins (RAD50 and NBS1) via Western blot, and they were markedly decreased compared to a healthy control. Mutations in the MRE11 gene have been known to cause an ataxia-telangiectasia-like (ATLD) disorder. Accumulating evidence has indicated that its wide phenotypic variations in ATLD correspond to genotypic differences. Interestingly, our case exhibited a relatively mild decrease in NBS1 compared to previously reported cases of a homozygous missense mutation, which may account for the milder phenotype in this patient. Moreover, together with a recently reported case of an MRE11 mutation, it is suggested that MRE11 mutations can present as PMA.


Increased interleukin-17 in the cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease: a case-control study of rapidly progressive dementia

Inflammatory responses in the cerebrospinal fluid (CSF) of patients with sporadic Creutzfeldt-Jakob disease (sCJD) remain elusive. We conducted a case-control study, in which 14 patients with sCJD, 14 with noninflammatory neurological disorders, and 14 with autoimmune encephalitis were enrolled. We used the suspension array system to measure the concentrations of 27 cytokines in CSF. The cytokine titers of the three groups were compared, and the correlation between the relevant cytokine titers and clinical parameters was investigated in the patients with sCJD. Levels of the two cytokines interleukin (IL)-1 receptor antagonist and IL-17 were significantly elevated in the patients with sCJD compared with those in the patients with noninflammatory neurological disorders: IL-17 levels in sCJD were approximately ten times higher than in the noninflammatory neurological disorders (mean, 35.46 vs. 3.45 pg/ml; P < 0.001) but comparable to that in encephalitis (mean, 32.16 pg/ml). In contrast, levels of classical proinflammatory cytokines such as IL-12(p70) and tumor necrosis factor-α were increased only in encephalitis. Although not significant, IL-17 titers tended to be higher in the patients with shorter disease duration before CSF sampling (r = -0.452; P = 0.104) and in those with lower CSF total protein concentrations (r = -0.473; P = 0.086). IL-17 is significantly increased in CSF in sCJD, which can be an early event in the pathogenesis of sCJD.


Increasing and persistent DWI changes in a patient with Hereditary Diffuse Leukoencephalopathy with Spheroids.

We report a case with genetically confirmed hereditary diffuse leukoencephalopathy with spheroids with distinctive MRI features. A 52-year-old woman with a family history of juvenile dementia presented with an 18-month history of progressive cognitive decline. Longitudinal magnetic resonance imaging studies of the brain revealed increasing and persistent white matter hyperintensities on diffusion-weighted images. Linear high intensity signal along axonal fibers arisen from the cerebral cortex was also shown. Finding of subcortical calcifications was noted on brain CT scan. Sequence analysis of CSF1R showed a novel missense mutation c.2467C>T (p.Ala823Val). Persistent and increasing diffusion on magnetic resonance image, presumably reflecting intramyelinic oedema in regions of neurodegeneration, is a distinctive feature observed in this case. The presence of this unique finding can be a diagnostic clue in the early stage of the disease.


Successful treatment of stiff person syndrome with sequential use of tacrolimus


Oromandibular dystonia associated with SCA36


Application of long-range polymerase chain reaction in the diagnosis of X-linked dystonia-parkinsonism


Basal ganglia hyperintensity on T1-weighted imaging of a patient with central nervous system metastasis producing carcinoembryonic antigens

We herein report unusual basal ganglia hyperintense lesions on noncontrast T1-weighted magnetic resonance imaging in a patient with central nervous system metastasis from lung adenocarcinoma that was treated with gefitinib. T2*-weighted magnetic resonance imaging showed no hypointense lesions, thereby excluding the possibility of calcification or haemorrhage. A stereotactic brain biopsy of the left basal ganglia lesions revealed atypical cells, some of which formed a glandular lumen with a micropapillary pattern. These cells were immunopositive for markers of lung adenocarcinoma, thereby confirming the diagnosis of metastasis. We speculate that proteins, including carcinoembryonic antigens from the adenocarcinoma cells in the basal ganglia, may have contributed to the hyperintensity observed on noncontrast T1-weighted magnetic resonance imaging.


Diagnostic spectrum of multifocal motor neuropathy


The TRK-fused gene is mutated in hereditary motor and sensory neuropathy with proximal dominant involvement.

Hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) is an autosomal-dominant neurodegenerative disorder characterized by widespread fasciculations, proximal-predominant muscle weakness, and atrophy followed by distal sensory involvement. To date, large families affected by HMSN-P have been reported from two different regions in Japan. Linkage and haplotype analyses of two previously reported families and two new families with the use of high-density SNP arrays further defined the minimum candidate region of 3.3 Mb in chromosomal region 3q12. Exome sequencing showed an identical c.854C>T (p.Pro285Leu) mutation in the TRK-fused gene (TFG) in the four families. Detailed haplotype analysis suggested two independent origins of the mutation. Pathological studies of an autopsied patient revealed TFG- and ubiquitin-immunopositive cytoplasmic inclusions in the spinal and cortical motor neurons. Fragmentation of the Golgi apparatus, a frequent finding in amyotrophic lateral sclerosis, was also observed in the motor neurons with inclusion bodies. Moreover, TAR DNA-binding protein 43 kDa (TDP-43)-positive cytoplasmic inclusions were also demonstrated. In cultured cells expressing mutant TFG, cytoplasmic aggregation of TDP-43 was demonstrated. These findings indicate that formation of TFG-containing cytoplasmic inclusions and concomitant mislocalization of TDP-43 underlie motor neuron degeneration in HMSN-P. Pathological overlap of proteinopathies involving TFG and TDP-43 highlights a new pathway leading to motor neuron degeneration.


Broad spectrum of dystonia associated with a novel thanatosis-associated protein domain-containing apoptosis-associated protein 1 mutation in a Japanese family with dystonia 6, torsion.


Antibodies to N-methyl-D-aspartate glutamate receptors in Creutzfeldt-Jakob disease patients.

Psychiatric symptom can be a prominent feature early in Creutzfeldt-Jakob disease (CJD), which is also common in autoantibody-mediated limbic encephalitis. We hypothesized that anti-neuronal autoantibodies, especially those against N-methyl-D-aspartate glutamate receptors (NMDAR), can also be associated with CJD. Thirteen patients with CJD and 13 patients with limbic encephalitis were enrolled. Immunohistochemistry demonstrated that serum of CJD patients reacted with neuronal components of the rat hippocampus, indicating that those samples contained anti-neuronal antibodies. Enzyme-linked immunosorbent assay revealed that titers of antibodies against peptides of GluN2B subunit of NMDAR were significantly elevated in the serum and cerebrospinal fluid of CJD patients.


Analysis of C9orf72 repeat expansion in 563 Japanese patients with amyotrophic lateral sclerosis.

Recently, a hexanucleotide repeat expansion in C9orf72 was identified as the most common cause of both sporadic and familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia in Western populations. We analyzed 563 Japanese patients with ALS (552 sporadic and 11 familial) using fluorescent fragment-length analysis of C9orf72 and repeat-primed polymerase chain reaction analysis. Haplotype analysis was performed for 42 single nucleotide polymorphisms in patients with C9orf72 repeat expansion. C9orf72 repeat expansion was found in 2 patients with sporadic ALS (2/552 = 0.4%) and no patients with familial ALS (0/11 = 0%). In the probands' families, 1 primary progressive aphasia patient and 1 asymptomatic 76-year-old individual exhibited C9orf72 repeat expansion. All of the patients with the C9orf72 repeat expansion carried the 20-single nucleotide polymorphism consensus risk haplotype. The frequency of the C9orf72 repeat expansion among Japanese patients is much lower than in Western populations. The existence of a 76-year-old asymptomatic carrier supported the notion of incomplete penetrance. The C9orf72 mutation should be analyzed in sporadic ALS patients after determining their family histories not only of frontotemporal dementia but also of primary progressive aphasia.


Generalized dystonia in a patient with a novel mutation in the GLUD1 gene