Effects of Intensive Exercise on Cognitive Dysfunction in Patients With Pure Cerebellar Degeneration: A Single-Arm Pilot Study.

OBJECTIVE: To clarify the profile of cognitive dysfunction and the effects of intensive exercise in spinocerebellar degeneration (SCD). METHODS: We enrolled 60 healthy controls and 16 patients with purely cerebellar type SCD without gait disturbance or organic changes other than cerebellar changes. To assess cognitive function, we evaluated the participants using the Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), and Montreal Cognitive Assessment-Japanese (MoCA-J) at admission and after intensive exercise. RESULTS: Compared to the controls, SCD patients showed significant cognitive decline. As a result of intensive exercise, significant improvements in motor and cognitive functions were observed: the MMSE score improved from 27.7±1.9 to 29.0±1.3 points (p<0.001); the FAB score improved from 14.8±2.2 to 15.8±2.0 points (p=0.002); and the MoCA-J score improved from 24.6±2.2 to 26.7±1.9 points (p<0.001). For sub-scores, significant improvements were noted in serial 7, lexical fluency, motor series, and delayed recall. CONCLUSION: Our study indicates that intensive exercise can be effective not only for motor dysfunction but also for cognitive dysfunction (Clinical Trial Registration No. UMIN-CTR: UMIN000040079).

New diagnostic criteria for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy in Japan.

PURPOSE: Definite diagnosis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukocencephalopathy (CADASIL) is mostly done by identification of NOTCH3 mutations. We aimed to develop criteria for selecting patients suspected for CADASIL to undergo genetic testing. SUBJECTS AND METHODS: All subjects were Japanese. We recruited CADASIL patients genetically diagnosed up until 2011 (n=37, Group 1) or after 2011 (n=65, Group 2), 67 young stroke patients (≤55 years old), and 53 NOTCH3-negative CADASIL-like patients. The members of Japanese research committee for hereditary cerebral small vessel disease discussed and generated the new criteria to maximize positive rate in Group 1 CADASIL patients, followed by validation of sensitivity and specificity. RESULTS: In Group 1 CADASIL patients, the ages at onset excluding migraine were distributed widely (37-74 years old) and bimodal (<55 and >55 years old). Frequencies of an autosomal dominant family history and vascular risk factor(s) were 73 and 65%, respectively. From these findings, the panel considered appropriate cut-off values and weighting for each item. In CADASIL Group 1 versus young stroke controls, the sensitivity and specificity of the new criteria were 97.3% and 80.6%, respectively. However, in CADASIL Group 2 versus NOTCH3-negative controls, the sensitivity and specificity were 96.9% and 7.5%, respectively. Forty mutations of NOTCH3 distributed in exons 2-8, 11, 14, 18, 19, and 21 were identified in this study. Ten mutations were unreported ones. CONCLUSION: We propose the new criteria of high sensitivity, which will help physicians to assess the need for genetic testing.

Life-threatening Arrhythmias in a Becker Muscular Dystrophy Family due to the Duplication of Exons 3-4 of the Dystrophin Gene.

We herein present a report of three patients with Becker muscular dystrophy in the same family who developed complete atrioventricular block or ventricular tachycardia with severe cardiomyopathy. Our cases became unable to walk in their teens, and were introduced to mechanical ventilation due to respiratory muscle weakness in their twenties and thirties. In all three cases, a medical device such as a permanent cardiac pacemaker or an implantable cardiac defibrillator was considered to be necessary. The duplication of exons 3-4 in the dystrophin gene was detected in two of the patients. In patients with Becker muscular dystrophy, complete atrioventricular block or ventricular tachycardia within a family has rarely been reported. Thus attention should be paid to the possibility of severe arrhythmias in the severe phenotype of Becker muscular dystrophy.

Usefulness of intraventricular infusion of antifungal drugs through Ommaya reservoirs for cryptococcal meningitis treatment.

INTRODUCTION: Cryptococcal meningitis is a severe infection among immunosuppressed individuals, with a high mortality rate. Although amphotericin B is the first-choice drug for treatment, its use is restricted when adverse effects are clinically problematic. The usefulness of intraventricular infusion of antifungal drugs through Ommaya reservoirs for cryptococcal meningitis treatment has been unconfirmed. We evaluated the efficacy of intraventricular infusion of amphotericin B through Ommaya reservoirs. MATERIALS AND METHODS: We retrospectively analyzed 10 consecutive patients with cryptococcal meningitis who were refractory to systemic administration of antifungal drugs. RESULTS: Fever or nausea occurred in most patients. However, no patient complained of serious complications such as renal toxicity. Seven patients recovered completely or partially, whereas three patients died. CONCLUSIONS: To establish the efficacy of the intraventricular infusion of antifungal drugs through Ommaya reservoirs for cryptococcal meningitis, a prospective investigation should be designed to compare those treated according to the updated guidelines and those treated with antifungal drugs through the Ommaya reservoirs.

Suppression of Th1-mediated autoimmunity by embryonic stem cell-derived dendritic cells.

We herein demonstrate the immune-regulatory effect of embryonic stem cell-derived dendritic cells (ES-DCs) using two models of autoimmune disease, namely non-obese diabetic (NOD) mice and experimental autoimmune encephalomyelitis (EAE). Treatment of pre-diabetic NOD mice with ES-DCs exerted almost complete suppression of diabetes development during the observation period for more than 40 weeks. The prevention of diabetes by ES-DCs was accompanied with significant reduction of insulitis and decreased number of Th1 and Th17 cells in the spleen. Development of EAE was also inhibited by the treatment with ES-DCs, and the therapeutic effect was obtained even if ES-DCs were administrated after the onset of clinical symptoms. Treatment of EAE-induced mice with ES-DCs reduced the infiltration of inflammatory cells into the spinal cord and suppressed the T cell response to the myelin antigen. Importantly, the ES-DC treatment did not affect T cell response to an exogenous antigen. As the mechanisms underlying the reduction of the number of infiltrating Th1 cells, we observed the inhibition of differentiation and proliferation of Th1 cells by ES-DCs. Furthermore, the expression of VLA-4α on Th1 cells was significantly inhibited by ES-DCs. Considering the recent advances in human induced pluripotent stem cell-related technologies, these results suggest a clinical application for pluripotent stem cell-derived dendritic cells as a therapy for T cell-mediated autoimmune diseases.

Degradation of amyloid beta by human induced pluripotent stem cell-derived macrophages expressing Neprilysin-2.

The purpose of this study was to evaluate the therapeutic potential of human induced pluripotent stem (iPS) cell-derived macrophage-like cells for Alzheimer's disease (AD). In previous studies, we established the technology to generate macrophage-like myeloid lineage cells with proliferating capacity from human iPS cells, and we designated the cells iPS-ML. iPS-ML reduced the level of Aß added into the culture medium, and the culture supernatant of iPS-ML alleviated the neurotoxicity of Aß. We generated iPS-ML expressing the Fc-receptor-fused form of a single chain antibody specific to Aß. In addition, we made iPS-ML expressing Neprilysin-2 (NEP2), which is a protease with Aß-degrading activity. In vitro, expression of NEP2 but not anti-Aß scFv enhanced the effect to reduce the level of soluble Aß oligomer in the culture medium and to alleviate the neurotoxicity of Aß. To analyze the effect of iPS-ML expressing NEP2 (iPS-ML/NEP2) in vivo, we intracerebrally administered the iPS-ML/NEP2 to 5XFAD mice, which is a mouse model of AD. We observed significant reduction in the level of Aß in the brain interstitial fluid following administration of iPS-ML/NEP2. These results suggested that iPS-ML/NEP2 may be a potential therapeutic agent in the treatment of AD.

Decision making of amyotrophic lateral sclerosis patients on noninvasive ventilation to receive tracheostomy positive pressure ventilation.

OBJECTIVES: We retrospectively evaluated the decision-making process of amyotrophic lateral sclerosis (ALS) patients on noninvasive positive pressure ventilation (NPPV) concerning respiratory management with tracheostomy positive pressure ventilation (TPPV) in the future. PATIENTS AND METHODS: We investigated the clinical characteristics of 29 consecutive ALS patients who had been introduced to NPPV during a 7-year period from September 2001 to August 2008 at our institution. We evaluated whether they had decided or not to undergo respiratory management with TPPV when NPPV was introduced and compared the clinical characteristics of the patients in these 2 groups. RESULTS: At the point of introduction of NPPV, 16 patients had made a definite decision on whether to receive TPPV for life, whereas 13 patients made their decision after its introduction. Finally, 12 patients (75.0%) of the former group and only 3 patients (23.1%) of the latter group refused to live with TPPV. Thus, among the patients who hesitated to decide whether to receive TPPV after the initiation of NPPV, a significantly higher number (P=0.002) ultimately transferred to TPPV. CONCLUSION: In Japan, NPPV is an important factor promoting the decision to receive TPPV for patients who worried about the transition to TPPV. Further study is needed to realize what kind of an education actually influences on decision-making for TPPV and results in the happiness of ALS patients.

Discrimination of acute ischemic stroke from nonischemic vertigo in patients presenting with only imbalance.

Some patients who present with an acute feeling of imbalance are experiencing an ischemic stroke that is not evident on computed tomography (CT) scans. The aim of this study was to compare ischemic stroke and nonischemic vertigo patient groups and to investigate independent factors associated with ischemic stroke. We examined 332 consecutive patients with an acute feeling of imbalance who showed no neurologic findings or responsible lesions on CT scan at the hyperacute phase. We examined their clinical backgrounds, physical findings, and laboratory examinations, with ischemic stroke diagnosed by later CT and/or magnetic resonance imaging (MRI). We identified 41 (12.3%) ischemic stroke patients. Atrial fibrillation (odds ratio 4.1; 95% confidence interval 1.4-11.5), white blood cell count (10(3)/µL, 1.4; 1.2-1.6), head and/or neck pain (4.6; 2.1-10.3), first attack of imbalance feeling (3.3; 1.1-12.2), and dizziness (3.7; 1.7-8.3) were significant and independent factors associated with ischemic stroke among patients with an acute feeling of imbalance. We used these factors to calculate an "imbalance score"; 1 point was given for the presence of each factor and a score of 3-5 points was independently associated with ischemic stroke. An awareness of these factors may indicate that further examinations including MRI are necessary to rule out ischemic stroke.

Coexistence of Amyotrophic Lateral Sclerosis and Myasthenia Gravis.

The mechanisms by which amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration remain unknown. We present the case of a 77-year-old Japanese female with clinically probable ALS, who developed ALS symptoms 41 years after onset of myasthenia gravis (MG). We concluded that neither the relapse of MG nor the adverse effects of anti-cholinesterase medication aggravated her symptoms. Although MG and ALS are extremely rare, we reviewed several case reports describing their coexistence. We suggest that clinicians should consider the possibility of ALS occurring with MG. Further investigations will improve our understanding of the pathogenic relationship between ALS and MG.

[Intravenous recombinant tissue plasminogen activator therapy in a 14-week pregnant woman with embolic stroke due to protein S deficiency].

When cerebral infarction develops during pregnancy, treatment without adverse effects must be considered not only for the mother but also for the fetus. Because pregnant women were excluded from many clinical trials, clear treatment guidance for them is not shown in the package inserts or guidelines of many drugs. We report the case of a 35-year-old woman (gravida 3, para 2) who developed sudden onset of left visual field defect, left hemiparesis, and dysesthesia over the left forearm during her fourth month of pregnancy. Brain diffusion-weighted MRI showed high intensity areas in the right occipital lobe, and magnetic resonance angiography revealed an occlusion of the right posterior cerebral artery. She was treated with an intravenous injection of recombinant tissue plasminogen activator 2 h 55 min after symptom onset, and the visual field and sensorimotor deficits improved. MRA obtained 3 days after the onset showed recanalization of the right posterior cerebral artery. We also conducted electrocardiography, neck vascular ultrasound, cardiovascular ultrasound, transcranial Doppler recordings from the temple area, and laboratory examinations for complete blood count, biochemistry, coagulation factors, endocrine secretion, and autoantibodies. Reduced protein S activity (35%) along with high intensity transient signals on transcranial Doppler indicated microemboli to be the embolic source. All other tests were negative. Anticoagulation therapy was initiated to prevent recurrence. She was initially given intravenous heparin, and then switched to warfarin therapy at 15 weeks of gestation. The patient delivered a healthy infant via caesarean section. Although reports and experiences of thrombolytic therapy with injection of recombinant tissue plasminogen activator during pregnancy remain scant, this therapy might be carefully used, especially after due consideration and understanding of the risks and benefits for both mother and fetus.

Muscle biopsy findings predictive of malignancy in rare infiltrative dermatomyositis.

OBJECTIVE: The characteristic pathological muscular findings of polymyositis (PM) and dermatomyositis (DM) have been shown to reflect their different pathogeneses. Here, we characterized the muscle biopsy findings of PM and DM patients with or without malignancy. METHODS: We evaluated the muscle biopsy findings of 215 consecutive PM and DM patients admitted to our hospital between 1970 and 2009. Pathology of the lesion biopsy sections was classified into 3 types: endomysial infiltration-type, perivascular infiltration-type, and rare-infiltrative-type. RESULTS: There was no difference between the muscle pathology of PM patients with and without malignancy. However, the incidence of rare-infiltrative type muscle pathology in DM patients with malignancy was significantly higher than in those without such tumors (p=0.0345). CONCLUSION: The incidence of rare-infiltrative type muscle pathology may be a predictive marker of DM with malignancy.

Hyperacute-phase computed tomography-diffusion-weighted imaging discrepancy and response to thrombolysis.

This study investigated the incidence and clinical features of reversed discrepancy (RD) in patients with hyperacute ischemic stroke. Sixty-two patients with anterior circulation ischemic stroke were enrolled. All patients underwent computed tomography (CT) and magnetic resonance imaging within 3 hours and received therapy with intravenous tissue plasminogen activator. The relationships between the Alberta Stroke Programme Early CT Score on CT and diffusion-weighted imaging (DWI); deep white matter lesion on DWI (DWI-W), CT, or magnetic resonance imaging after 24 hours; dramatic improvement (defined as a change in National Institutes of Health Stroke Scale score of ≥ 10 points or a total National Institutes of Health Stroke Scale score of 0 or 1 after 24 hours); and thrombolysis-related hemorrhage were assessed. Two investigators identified RD when the early ischemic change was detected on CT but no obvious hyperintensity was noted on DWI. RD was found in 10 patients (16.1%), located in the basal ganglia in 5 patients (50%), in the basal ganglia plus the cortical area in 3 patients (30%), and in the cortical area in 2 patients (20%). Four of these 10 patients had an infarction of the basal ganglia and a DWI-W lesion. All 4 patients with both RD in the basal ganglia (bRD) and DWI-W (the bRD+W+ group) had an infarction of the basal ganglia within 24 hours. In contrast, all 4 patients with bRD but without DWI-W (the bRD+W- group) had no basal ganglia infarction. Dramatic improvement after intravenous tissue plasminogen activator therapy was significantly less common in the bRD+W+ group (0 of 4 patients) than in the bRD+W- group (3 of 4 patients; P = .0285). Our findings suggest that the presence of both bRD and a DWI-W lesion can be used to predict whether dramatic improvement will occur and whether the basal ganglia will progress to infarction.

Myasthenic crisis patients who require intensive care unit management.

The purpose of this report was to investigate predictive factors that necessitate intensive care in myasthenic crisis (MC). We retrospectively reviewed MC patients at our institution and compared ICU and ward management groups. Higher MG-ADL scale scores, non-ocular initial symptoms, infection-triggered findings, and higher MGFA classification were observed more frequently in the ICU group. In patients with these prognostic factors, better outcomes may be obtained with early institution of intensive care.

Long-term outcome of polymyositis treated with high single-dose alternate-day prednisolone therapy.

BACKGROUND: We previously reported no difference in the efficacies of high-dose alternate-day (ADT) and daily-dose (DDT) prednisolone therapies in myositis patients, but that the incidence of side effects was lower in the former. The aim of the present study was to compare the long-term outcomes of both treatments in polymyositis patients. METHODS: We compared clinical courses, efficacies, adverse reactions, and outcomes of 115 consecutive, biopsy-proven polymyositis patients treated between 1970 and 2008 with ADT (32 patients) or DDT (83 patients). RESULTS: Mean onset ages, disease severity, incidences of malignancy, and response rates did not differ between the ADT and DDT groups. Adverse reactions (incidence of diabetes) were significantly higher in the DDT group. In this group, the incidences of hyperlipidemia, infection, hypertension, and psychiatric symptoms were also slightly higher, but not significantly so. The 20-year survival rate of the ADT group (68%) was significantly higher (p = 0.0112) than that of the DDT group (37%). CONCLUSION: ADT might be useful as an initial treatment option for polymyositis.

An inhibitor of transforming growth factor beta type I receptor ameliorates muscle atrophy in a mouse model of caveolin 3-deficient muscular dystrophy.

Skeletal muscle expressing Pro104Leu mutant caveolin 3 (CAV3(P104L)) in mouse becomes atrophied and serves as a model of autosomal dominant limb-girdle muscular dystrophy 1C. We previously found that caveolin 3-deficient muscles showed activated intramuscular transforming growth factor beta (TGF-ß) signals. However, the cellular mechanism by which loss of caveolin 3 leads to muscle atrophy is unknown. Recently, several small-molecule inhibitors of TGF-ß type I receptor (TßRI) kinase have been developed as molecular-targeting drugs for cancer therapy by suppressing intracellular TGF-ß1, -ß2, and -ß3 signaling. Here, we show that a TßRI kinase inhibitor, Ki26894, restores impaired myoblast differentiation in vitro caused by activin, myostatin, and TGF-ß1, as well as CAV3(P104L). Oral administration of Ki26894 increased muscle mass and strength in vivo in wild-type mice, and improved muscle atrophy and weakness in the CAV3(P104L) mice. The inhibitor restored the number of satellite cells, the resident stem cells of adult skeletal muscle, with suppression of the increased phosphorylation of Smad2, an effector, and the upregulation of p21 (also known as Cdkn1a), a target gene of the TGF-ß family members in muscle. These data indicate that both TGF-ß-dependent reduction in satellite cells and impairment of myoblast differentiation contribute to the cellular mechanism underlying caveolin 3-deficient muscle atrophy. TßRI kinase inhibitors could antagonize the activation of intramuscular anti-myogenic TGF-ß signals, thereby providing a novel therapeutic rationale for the alternative use of this type of anticancer drug in reversing muscle atrophy in various clinical settings.

Modified ASPECTS for DWI including deep white matter lesions predicts subsequent intracranial hemorrhage.

We hypothesized that extensive early ischemic changes increase subsequent intracranial hemorrhage (ICH) in patients within 3 h of onset regardless of intravenous tPA (IV-tPA). We have established a modified scoring method, ASPECTS+W, including deep white matter lesions on DWI (DWI-W) in addition to the original ASPECTS regions. We aimed to elucidate whether CT-ASPECTS, DWI-ASPECTS, and ASPECTS+W could be useful tools in helping to predict subsequent ICH in acute ischemic stroke. One-hundred sixty-four consecutive patients with anterior circulation ischemic stroke were enrolled. All patients underwent both MRI and CT within 3 h of onset. ASPECTS+W was defined as an 11-point method combining the ten ASPECTS regions and DWI-W. The relationships of CT-ASPECTS, DWI-ASPECTS, and ASPECTS+W with ICH within the initial 36 h were assessed. Thirty-six patients (22%) were treated with IV-tPA. Follow-up CT was obtained in 159 patients, and 19 (12%) developed ICH. Patients with ICH had higher baseline NIHSS scores (median, 25 vs. 13, p = 0.010), a higher rate of IV-tPA (42 vs. 20%, p = 0.041), lower CT-ASPECTS (median, 7 vs. 10, p = 0.008), lower DWI-ASPECTS (6 vs. 9, p = 0.001), lower ASPECTS+W (6 vs. 9, p = 0.001), and higher DWI-W lesions (74 vs. 47%, p = 0.048) than those without ICH. ICA or M1 proximal occlusion was more frequently seen in patients with ICH (68 vs. 32%, p = 0.004) than in those without ICH. On multivariate regression analysis, lower ASPECTS+W (OR 0.75, 95% CI 0.58-0.96, p = 0.027) and administration of IV-tPA (OR 9.13, 95% CI 2.15-46.21, p = 0.004) independently predicted ICH development. In conclusion, ASPECTS+W is a useful tool for predicting ICH development independent of IV-tPA.

Significant CMAP decrement by repetitive nerve stimulation is more frequent in median than ulnar nerves of patients with amyotrophic lateral sclerosis.

INTRODUCTION: Several studies have shown a significant amplitude decrement in compound muscle action potentials (CMAPs) on repetitive nerve stimulation (RNS) of muscles involved in amyotrophic lateral sclerosis (ALS). In ALS, muscle wasting preferentially affects the thenar muscles (APB) rather than the hypothenar muscles (ADM). METHODS: We performed RNS studies in the APB and ADM muscles of 32 ALS patients to determine whether the effect of RNS differs between the median and ulnar nerves. RESULTS: The decremental responses to RNS were greater in the APB than in the ADM. Reduced CMAP amplitude was negatively correlated with CMAP decrement in median but not in ulnar nerves. CONCLUSIONS: The greater CMAP decrement in median nerve is attributable to preferential involvement of the APB in the pathophysiology of ALS or some underlying difference in the biology of the two muscles/nerves. Further investigations will better our understanding of the pathophysiology of ALS.

[Bow hunter's syndrome with spontaneous improvement].

A 74-year-old man complained of near loss of consciousness when he rotated his head to the left side. The symptom was reversed by returning his head to a neutral position. Transcranial Doppler studies with the patient's neck rotated into the left side revealed reduction of flow in his left vertebral artery. Vertebral angiography revealed a hypoplastic right vertebral artery and occlusion of the left vertebral artery at the C6 level on head rotation. We diagnosed him bow hunter's syndrome and treated him conservatively. Six months later, he was symptom-free on head rotation. Transcranial Doppler and vertebral angiography demonstrated the disappearance of the vertebral artery occlusion at the neck rotation. Some patient without any definite cause can be treated conservatively, and surgical interventions for bow hunter's syndrome should be carefully decided.