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Osamu Kano,1 Yoshihisa Urita,2 Hirono Ito,1 Takanori Takazawa,1 Yuji Kawase,1 Kiyoko Murata,1 Takehisa Hirayama,1 Ken Miura,1 Yuichi Ishikawa,1 Tetsuhito Kiyozuka,3 Jo Aoyagi,3 Yasuo Iwasaki11Department of Neurology, 2Department of General Medicine and Emergency Care, Toho University Omori Medical Center, Tokyo, Japan; 3Department of Neurology, Federation of National Public Service Personnel Mutual Aid Associations, Mishuku Hospital, Tokyo, JapanObjective: While acetylcholinesterase inhibitors, such as donepezil, galantamine, and rivastigmine, are beneficial in treating behavioral symptoms of patients with Alzheimer's disease (AD), their dose-limiting effects include gastrointestinal disturbances, such as nausea, vomiting, and diarrhea. We aimed to predict the occurrence of these gastrointestinal disturbances with rivastigmine therapy for optimal drug choice and improved compliance.Materials and methods: Thirty patients with mild-to-moderate AD (scores 10–22 on the Mini-Mental State Examination) were administered a rivastigmine 18 mg patch with domperidone 30 mg (RWD) and without domperidone (RWOD; n = 15 each) for 20 weeks. Gastrointestinal disturbances were evaluated using a frequency scale for symptoms of gastroesophageal reflux disease (FSSG), Bristol stool form scale, laboratory data (hemoglobin, albumin, total cholesterol), body weight, and amount of food intake.Results: After 12 weeks, FSSG scores were higher in the RWOD group compared to baseline scores; however, no significant differences were noted between the RWD and RWOD groups. We then subdivided each group based on high and low baseline scores; the RWOD high-score (≥4) subgroup showed increased FSSG after 12 weeks compared with the baseline score. In both RWD and RWOD groups, the low-score (≤3) subgroups showed no changes during the dose-escalation phase.Conclusion: For AD patients with higher FSSG scores at baseline, domperidone was effective in preventing rivastigmine-related gastrointestinal disturbances.Keywords: Alzheimer's disease, acetylcholinesterase inhibitors, domperidone, gastroesophageal reflux disease, gastrointestinal disturbance, rivastigmine

Osamu Kano,1 Hirono Ito,1 Takanori Takazawa,1 Yuji Kawase,1 Kiyoko Murata,1 Konosuke Iwamoto,1 Tetsuro Nagaoka,1 Takehisa Hirayama,1 Ken Miura,1 Riya Nagata,1 Tetsuhito Kiyozuka,2 Jo Aoyagi,2 Ryuta Sato,2 Teruo Eguchi,3 Ken Ikeda,1 Yasuo Iwasaki11Department of Neurology, Toho University Omori Medical Center, 2Department of Neurology, Federation of National Public Service Personnel Mutual Aid Associations Mishuku Hospital, 3Sakura-kai Medical Group, Tokyo, JapanAbstract: Clinical trials have shown the benefits of acetylcholinesterase inhibitors, such as donepezil and galantamine, and an N-methyl-d-aspartate receptor antagonist, memantine, in patients with Alzheimer’s disease (AD). However, little is known regarding the effects of switching from donepezil 5 mg/day to galantamine 16 or 24 mg/day, or regarding the effects of adding memantine to established therapy compared with increasing the dose of donepezil. This report discusses two studies conducted to evaluate treatment with galantamine and memantine with respect to cognitive benefits and caregiver evaluations in patients with AD receiving donepezil 5 mg/day for more than 6 months. Patients with mild or moderate AD (scores 10–22 on the Mini-Mental State Examination) were enrolled in the Galantamine Switch study and switched to galantamine (maximum doses 16 mg versus 24 mg). Patients with moderate to severe AD (Mini-Mental State Examination scores 3–14) were enrolled in the Donepezil Increase versus Additional Memantine study and either had their donepezil dose increased to 10 mg/day or memantine 20 mg/day added to their existing donepezil dose. Patients received the study treatment for 28 weeks and their Disability Assessment for Dementia, Mental Function Impairment Scale, Cohen-Mansfield Agitation Inventory, and Neuropsychiatric Inventory scores were assessed with assistance from their caregivers. For the Galantamine Switch study after 8 weeks, agitation evaluated by the Cohen-Mansfield Agitation Inventory improved in both the 16 mg and 24 mg groups compared with baseline. However, there were no significant differences between the two galantamine groups. Agitation was also less in patients in the additional memantine group than in the donepezil increase group. In summary, switching to galantamine from donepezil and addition of memantine in patients with AD receiving donepezil were both safe and meaningful treatment options, and particularly efficacious for suppression of agitation.Keywords: Alzheimer’s disease, galantamine, memantine, donepezil, agitation, acetylcholinesterase inhibitors

Presents a letter to the editor on kynurenic acid in lateral sclerosis patients.

The frequency and risk of embolism by Lambl's excrescences (LEs) remain unclear. We herein report an autopsy case of LEs that caused cardioembolic stroke. A 74-year-old man with colon cancer was hospitalized for ischemic stroke. His D-dimer levels were elevated. Thus, a diagnosis of ischemic stroke with Trousseau syndrome was made. At the autopsy, we found LEs in the aortic valves and thromboembolism of the brain blood vessels. This finding demonstrated that fibrin clots had adhered to the LEs because of coagulation abnormalities associated with Trousseau syndrome and became embolized. This case highlights the risk of LEs in patients with coagulation abnormalities.

The accurate regulation of phosphorylation at the kinetochore is essential for establishing chromosome bi-orientation. Phosphorylation of kinetochore proteins by the Aurora B kinase destabilizes improper kinetochore-microtubule attachments, whereas the phosphatase PP2A has a counteracting role. Imbalanced phosphoregulation leads to error-prone chromosome segregation and aneuploidy, a hallmark of cancer cells. However, little is known about the molecular events that control the balance of phosphorylation at the kinetochore. Here, we show that localization of SET/TAF1, an oncogene product, to centromeres maintains Aurora B kinase activity by inhibiting PP2A, thereby correcting erroneous kinetochore-microtubule attachment. SET localizes at the inner centromere by interacting directly with shugoshin 2, with SET levels declining at increased distances between kinetochore pairs, leading to establishment of chromosome bi-orientation. Moreover, SET overexpression induces chromosomal instability by disrupting kinetochore-microtubule attachment. Thus, our findings reveal the novel role of SET in fine-tuning the phosphorylation level at the kinetochore by balancing the activities of Aurora B and PP2A., (© 2019 Asai et al.)

A 68-year-old female with severe aplastic anemia (SAA) refractory to initial immunosuppressive therapy, including anti-thymocyte globulin (ATG) and cyclosporine, received a reduced-intensity cord blood transplant (CBT) in June 2015. Tacrolimus (TAC) and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis, and she received prolonged TAC and prednisolone to treat chronic GVHD. The patient presented with progressive ataxia 14 months after CBT. A brain magnetic resonance image (MRI, FLAIR) detected a high-intensity lesion in the left cerebellar hemisphere, which suggested infarction. Her consciousness level gradually continued to deteriorate and another brain MRI (T2) revealed that the size of the cerebellar lesion had increased and had involved the pons. A cerebrospinal fluid (CSF) examination showed normal cell count and protein levels; however, polymerase chain reaction (PCR) analysis of CSF was positive for JC virus (JCV). Therefore, she was eventually diagnosed with progressive multifocal leukoencephalopathy (PML) and treated with mefloquine. The symptoms were reduced after 3 months, and JCV in CSF disappeared without new lesions after 6 months. This is an unusual case of PML initially involving the cerebellum, and we report here PML after an immunosuppressive therapy and CBT in the patient with SAA.

Purpose: Early rehabilitation is widely recommended for acute-stroke patients. We tested the hypothesis that the functional prognosis of stroke patients receiving daily early rehabilitation in a clinical practice setting is generally better than that of patients receiving rehabilitation only on weekdays., Materials and Methods: We analyzed hospitalized patients who experienced either cerebral infarctions or cerebral hemorrhages and subsequently underwent rehabilitation at our hospital between October 2010 and September 2014. We examined the association between training frequency and activities of daily living improvements, as indicated by the Barthel Index (BI) effectiveness., Results: In total, 661 patients with cerebral infarctions and 245 with intracerebral hemorrhages (ICHs) were analyzed. The BI effectiveness was highest for patients receiving high-frequency therapy following cerebral infarction. In addition, multiple linear regression analysis indicated that BI effectiveness was significantly and positively correlated with high-frequency therapy (coefficient, 0.072; 95% confidence interval, 0.019-0.126; p < 0.01) in patients with cerebral infarctions. There was no significant difference in BI effectiveness between therapeutic protocols for patients with ICHs., Conclusion: This retrospective cohort study demonstrated that extensive therapy can result in functional recovery in patients with cerebral infarctions. Implications for Rehabilitation Early intervention with intensive rehabilitation therapy is important for improving the functional recovery of patients during acute-care hospitalization. Few acute hospitals provide more than 2 h of daily rehabilitation for patients with acute stroke. In a daily clinical practice setting, this clinical study demonstrates a direct relationship between early intervention with intensive rehabilitation therapy and good functional recovery of stroke patients in an acute ward.

Objective: Early rehabilitation for acute stroke patients is widely recommended. We tested the hypothesis that daily intervention by speech therapists promotes safe oral intake of patients with acute stroke., Methods: We analyzed hospitalized patients who experienced cerebral infarction and cerebral hemorrhage and who underwent rehabilitation between October 2010 and September 2014 at our hospital. In total, 936 patients were analyzed, and 452 patients underwent daily speech therapy. We examined the association of training frequency and eating status., Results: Multiple linear regression analysis indicated that daily speech therapy was correlated significantly and positively with a reduction in the number of days of hospitalization until oral intake commenced (coefficient, -.998; 95% confidence interval, -1.793 to -.202; P < .05), and was not correlated with the cessation of oral intake due to aspiration pneumonia after resuming oral intake., Conclusion: Our retrospective cohort study demonstrated that daily intervention by speech therapists in patients with acute stroke shortens the number of days until oral intake without increasing the incidence of aspiration pneumonia., (Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Oxidative stress plays a role in the pathogenesis of neuronal death. Serum levels of urate or lipid were associated with the incidence of Parkinson's disease (PD)., Objective: We compared urate, paraoxonase-1 (PON1), iron, ferritin and lipid in sera of 119 PD patients and 120 healthy controls matched by age, sex and body mass index. We aimed to elucidate whether those serological data are correlated with disease progression., Results: Mean age (SD) of PD patients was 73.4 (8.7) years. Mean Yahr stage (SD) was 3.2 (0.9). Mean disease duration (SD) was 6.9 (5.1) years. Mean dose of L-DOPA (SD) was 355 (157) mg/day. As compared to controls, serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), urate and PON1 activity were significantly reduced, and serum ferritin levels were significantly increased in male and female PD patients. Serum urate levels and PON1 activities were inversely related, and serum ferritin levels were correlated with Yahr stage and PD duration in men and women. Serum levels of TC and LDL-C were inversely related to Yahr stage or PD duration in female patients., Conclusions: Our studies indicated serological profiles of urate, PON1, ferritin, TC and LDL-C in PD patients. These serological changes were linked to PD progression. Metabolism of lipid, oxidant- and antioxidant-related substances may contribute to the pathogenesis and the progression of PD., (Copyright © 2011 S. Karger AG, Basel.)

Background: Clinicoradiological variability of vertebrobasilar dolichoectasia (VBD) is known. Little is known about cardiovascular disease (CVD) risk and neuroradiological profiles of asymptomatic VBD., Methods: A total of 7,345 adults (5,534 men and 1,811 women) underwent physical checkup (PC) and brain magnetic resonance (MR) studies between 2004 and 2007. Asymptomatic VBD was diagnosed by neurological examination and MR angiography. Neuroradiological features were analyzed in VBD subjects. CVD risk factors were compared between VBD subjects and 5,000 controls matched by sex and age., Results: Ninety-six subjects (85 men and 11 women) had asymptomatic VBD. The detection rate was 1.3% and the male/female ratio 2.5. The mean age +/- SD was 60.4 +/- 10.6 years (60.0 +/- 10.2 in men and 64.0 +/- 13.1 in women). As compared to controls, the frequency of hypertension, obesity, smoking, dyslipidemia, diabetes mellitus and a family history of stroke or CVD was increased significantly in VBD subjects. The mean diameter +/- SD of the basilar artery (BA) was 4.7 +/- 0.2 mm. Only 4 subjects (4%) had a severe degree of elongation and lateral displacement of the BA. Contact of the vertebral artery with the rostral ventrolateral medulla (AMC) was found in 81 subjects: right AMC in 22 subjects and left AMC in 59 subjects. Frequency of hypertension was significantly higher in the left-AMC subjects (57%) than in subjects with right AMC (9%) and no AMC (5%). Other neuroradiological findings revealed small infarcts in 42 subjects, brainstem compression in 4, hydrocephalus in 4 and brain saccular aneurysm in 3., Conclusions: Asymptomatic VBD was detected in 1.3% of the Japanese PC group. Our data indicated male predominance, multiple CVD risk factors, neurovascular hypertension and small infarcts in asymptomatic VBD., (Copyright 2010 S. Karger AG, Basel.)

Introduction: Homonymous hemianopia is not a rare symptom. Many causative lesions and pathologies are known, although a unilateral optic tract lesion caused by syphilis is rare., Case Report: A 56-year-old woman developed a congruous right homonymous hemianopia and bilateral tonic pupils with irregular shape. Brain T2-weighted and fluid attenuated inversion recovery magnetic resonance imaging (MRI) revealed a spindle-like high-intensity lesion in her left postchiasmal optic tract. The rim of this lesion enhanced with gadolinium without meningeal enhancement. Serum and cerebrospinal fluid venereal disease research laboratory tests were positive. Cerebrospinal fluid contained 71 white blood cells/microL (mononuclear cells = 97%) and 48 mg/dL of protein. The hemianopia disappeared after administration of benzylpenicillin., Conclusions: Neurosyphilis should be added to the list of differential diagnoses for an isolated optic tract lesion.

We examined whether pramipexole (PPX) can influence depressive scale in normal and mild depressive parkinsonian patients. In an open study of PPX as an add-on to L-dopa therapy or single administration, 36 nondemented outpatients with Parkinson's disease (PD) were entered first. All were in the stage II or III of Hoehn and Yahr scale (H&Y). PPX were started at 0.125 mg/day and daily doses were increased to 1.5 mg/day. At 3 months after PPX treatment, patients were re-evaluated. Hamilton Depression Rating Scale (HAM-D), Unified Parkinson's Disease Rating Scale III, H&Y stage, and freezing of gait questionnaire were compared in patients before and after PPX treatment. These scores were significantly improved after PPX administration. There were no correlations between HAM-D and those motor functions. We suggest that PPX treatment has antidepressant effects in depressive PD patients and also ameliorates HAM-D score in nondepressive PD patients in addition to motor function.

A 40-year-old man was admitted to our department, because of sudden onset of dysphagia, hoarseness, left neck pain and headache. There were no skin lesions. On neurological examination, there were paralysis of the left soft palate and constrictor muscles of the pharynx, weakness of the left sternocleidomastoid and left upper trapezius. In cerebrospinal fluid (CSF) examination, cell count and protein concentration were elevated. Antibody titer to varicella zoster virus (VZV) was elevated in both the serum and CSF. And VZV-DNA was detected by PCR from CSF. Gd enhanced MRI showed the nodular lesion at the left jugular foramen. The diagnosis of Vernet's syndrome (VS) associated with VZV infection was made. The patient's symptoms were immediately improved with 30 mg of prednisone and 3 g of varaciclovir daily for 14 days. Only a few cases of VS due to VZV have been reported previously. Our case is the first case that detected VZV-DNA in CSF by PCR.

Cheiro-oral-pedal syndrome is characterized by specific sensory disturbance around the corner of the mouth, in the hand and in the foot on the same side. Lesions responsible for causing this syndrome vary. We report two cases of cheiro-oral-pedal syndrome due to midbrain and pontine hemorrhage, respectively. Pontine hemorrhage producing cheiro-oral-pedal syndrome has been reported in three cases, but this is the first case that midbrain hematoma exhibits this syndrome. Damage in the sensory pathway can cause cheiro-oral-pedal syndrome. Difference in the threshold may explain the specific sensory pattern in this syndrome. Cheiro-oral-pedal syndrome is caused by lacunar infarction in majority of the cases. However, it should be kept in mind that hematomas can cause cheiro-oral-pedal syndrome.

We report a case of myasthenia gravis (MG) associated with autoimmune thrombocytopenic purpura (AITP) and autoimmune hemolytic anemia (AIHA), and after that gastric cancer appeared. A 51-year-old man began to suffer from fluctuated muscle weakness in 1985. Muscle weaknesses became exacerbated, and he was admitted to our hospital in 1989. He was diagnosed as MG associated with AITP. After a thymectomy (hyperplasia), prednisolone therapy was started, subsequently his condition was satisfactory. In March 1995, he developed severe anemia and icterus. He was diagnosed as Evans' syndrome (AIHA and AITP) with MG. High-doses of immunoglobulin administration improved the anemia, but thrombocytopenia continued. In November 2002, he suffered marked petechia; the platelet count decreased to 1000/microl. Methylprednisolone pulse therapy and platelet transfusion were started. Gastrofiberscopy was performed and biopsy specimens revealed signet cell-type adenocarcinoma. On December 19, 2002, subtotal gastrectomy and splenectomy were performed. After that, his condition has remained satisfactory, without MG symptoms or thrombocytopenia. This is the first such case report in the literature.

We report the case of a 64-year-old man with sudden onset of numbness in the right hand and foot. Neurological examinations were normal except for hypersthesia, and hyperalgesia of the right hand and foot. Brain MRI demonstrated a high signal intensity on T2-weighted image and a low signal intensity on T1-weighted image in the left tegmetum of the pons. He was diagnosed with pontine infarction presenting with cheiro-pedal syndrome (CPS). Damage in the sensory pathways can cause CPS. Difference in the threshold may explain the specific sensory pattern in this syndrome. Further examination of the relationship between sensory symptoms and localization on MRI is needed to clarify this syndrome.

Many patients with variant forms of Guillain-Barré syndrome (vGBS) associated with anti-ganglioside antibodies, including Miller Fisher syndrome (MFS), sometimes exhibit miniature endplate potential (MEPP) frequency increases (MFI, described as alpha-latrotoxin-like effects in a previous report) and the factor to produce this effect is present in their sera. MFI-positive sera increase the frequency of MEPPs, then block neuromuscular transmission at the mouse neuromuscular junction. A connection between this effect at the neuromuscular junction and some vGBS symptoms is suspected. We measured MFI directly at several points during the clinical course of 8 vGBS patients who had various symptoms and courses. Six patients had confirmed MFI and this activity decreased with convalescence. In 3 clinically mild cases, we were able to elicit MFI using normal serum to supply complement after exposure to the patient's serum. The anti-GQ1b/GT1a IgG titer, the extent of ophthalmoplegia and the extent of MFI were significantly correlated. They did not correlate with the severity of limb weakness or the occurrence of respiratory failure. These results support the hypothesis that MFI caused by anti-ganglioside antibodies is the pathogenic mechanism responsible for ophthalmoplegia in vGBS; different mechanisms or antibodies may explain limb weakness and respiratory failure. Furthermore, MFI may be an important indicator of how serum injures the nerve terminals. The symptoms of vGBS may result from multiple pathogenic factors.