Sousuke Takeuchi

JNK activation is associated with intracellular β-amyloid accumulation

Abstract c-Jun has been implicated in the pathogenesis of Alzheimer’s disease (AD), but the upstream cascade leading to c-Jun activation in AD is not known. Activation of c-Jun N-terminal kinase (JNK) is obviously a candidate for the upstream event. We tested this possibility focusing on PS1-linked AD. First, we observed that JNK is actually activated in cerebral neurons of PS1-linked AD patients, using immunohistochemistry and Western blot analyses with anti-activated JNK antibodies. We analyzed the relationship between β-amyloid (βA) and JNK activation by using aged transgenic mice overexpressing mutant (M146L) PS1 and human AD brains. The mice showed no neuronal loss but a very few diffuse βA deposits, corresponding to the early stage of PS1-linked AD brain. Some neurons were reactive for anti-βA antibodies in the cerebral cortex. Interestingly, JNK activation was observed in neurons showing intracellular βA immunoreactivity in transgenic mice. Association between intracellular βA and JNK activation was confirmed in cortical neurons of sporadic and PS1-linked AD patients. Furthermore, introduction of βA peptides into the primary culture cortical neurons induced JNK activation and cell death. Collectively, these results suggested that intracellular βA accumulation might trigger JNK activation leading to neuronal death.

Anti-TIF1-γ antibody and cancer-associated myositis A clinicohistopathologic study

Objective:We aimed to analyze the clinical and histopathologic features of cancer-associated myositis (CAM) in relation to anti–transcriptional intermediary factor 1 &ggr; antibody (anti-TIF1-&ggr;-Ab), a marker of cancer association. Methods:We retrospectively studied 349 patients with idiopathic inflammatory myopathies (IIMs), including 284 patients with pretreatment biopsy samples available. For the classification of IIMs, the European Neuromuscular Center criteria were applied. Patients with CAM with (anti-TIF1-&ggr;-Ab[+] CAM) and without anti-TIF1-&ggr;-Ab (anti-TIF1-&ggr;-Ab[−] CAM) were compared with patients with IIM without cancers within and beyond 3 years of myositis diagnosis. Results:Cancer was detected in 75 patients, of whom 36 (48%) were positive for anti-TIF1-&ggr;-Ab. In anti-TIF1-&ggr;-Ab(+) patients with CAM, cancers were detected within 1 year of myositis diagnosis in 35 (97%) and before 1 year of myositis diagnosis in 1. All the anti-TIF1-&ggr;-Ab(+) patients with CAM satisfied the dermatomyositis (DM) criteria, including 2 possible DM sine dermatitis cases, and were characterized histologically by the presence of perifascicular atrophy, vacuolated fibers (VFs), and dense C5b-9 deposits on capillaries (dC5b-9). In contrast, 39 anti-TIF1-&ggr;-Ab(−) patients with CAM were classified into various subgroups, and characterized by a higher frequency of necrotizing autoimmune myopathy (NAM). Notably, all 7 patients with CAM classified into the NAM subgroup were anti-TIF1-&ggr;-Ab(−) and exhibited no dC5b-9 or VFs. Conclusions:CAM includes clinicohistopathologically heterogeneous disease entities. Among CAM entities, anti-TIF1-&ggr;-Ab(+) CAM has characteristically shown a close temporal association with cancer detection and the histopathologic findings of dC5b-9 and VFs, and CAM with NAM is a subset of anti-TIF1-&ggr;-Ab(−) CAM.

AP-2β represses D1A dopamine receptor gene transcription in Neuro2a cells

Abstract Expression of the D 1A dopamine receptor in brain is restricted to specific neuronal populations. To investigate the mechanism of this selective expression, we localized a silencer upstream of the human D 1A gene and identified its binding transcription factor in the D 1A -negative neural cell line Neuro2a. Using deletion CAT analysis, we narrowed this silencer to the region between nucleotides −561 and −532 relative to the CAP site. This 30-bp region, designated D1AS1, contains a sequence homologous to the AP-2 binding site and binds to a factor that also interacts with the AP-2 consensus sequence. In gel supershift assays, this factor is recognized by anti-AP-2β antibody. Co-transfection of Neuro2a cells with an AP-2β expression vector repressed the basal CAT activity of D 1A promoter–reporter plasmids in a D1AS1-dependent manner. RT-PCR analysis indicated that, among AP-2 family members, Neuro2a cells express only AP-2β. Furthermore, co-transfection of these cells with decoy oligonucleotides corresponding to the D1AS1 sequence de-repressed the D 1A gene promoter. Unlike in Neuro2a cells, AP-2β could not repress the D 1A promoter in the D 1A -positive neural cell line, NS20Y. In addition, the expression of AP-2β in different brain regions does not inversely correlate with that of D 1A dopamine receptor. These observations taken together indicate that AP-2β is a repressive transcription factor that acts on the D1AS1 silencer of the D 1A dopamine receptor gene via some cell-specific mechanism(s) in Neuro2a.

Low-dose intravenous propofol as a possible therapeutic option for acute confusional migraine

Acute confusional migraine (ACM) is a rare form of migraine disorder in which patients present with confusional state along with a migraine headache and for which there is no established treatment. Here,we report a case of a youngmanwith ACM,who showed amarked response to low-dose intravenous propofol administration. He developed a confusional state during the course of his usual migraine headache with the typical visual aura. To achieve adequate sedation to perform the necessary examinations at the emergency department, he was administered intravenous propofol, which unexpectedly improved his confusional state. Although a few case reports on the efficacy of intravenous valproic acid or prochlorperazine exist, this is the first case that suggests a potential effect of low-dose propofol in terminating the acute confusional state of the ACM. The efficacy of propofol may be in part explained by its suppressing effect on widespread cortical spreading depression, which is considered one of the possible underlying mechanisms of ACM. Acute confusional migraine (ACM) is a rare form of migraine disorder in which patients present with a confusional state along with a migraine headache [1-4] and which is predominantly seen in pediatric patients [5-7]. Thus far, few case reports exist on the treatment of ACM except for intravenous valproic acid [1,8] or intravenous prochlorperazine [9]. Here, we report a case of a patient with strongly suspected ACM who received a propofol infusion, which unexpectedly and markedly alleviated his confusion. A 24-year-oldman had experiencedmigraine headaches with a typical aura (blinking and narrowed visual field) several times a year since hewas a young teenager. He had no family history of headaches andhad never takenprophylacticmedication formigraine. Since themorning on the day of the episode, he had a moderate headache and nausea along with usual intermittent aura. The symptoms gradually worsened, and approximately 3 hours later, mild consciousness disturbance emerged. His speech was inconsistent and mildly disoriented. He was soon transported to the emergency department (ED) of our hospital because he vomited and collapsed on the ground. On arrival at the hospital, he was in the confusional and mildly agitated state and did not follow our instructions, nor was he able to adequately explain his symptoms. ☆ Funding source: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. ☆☆ Conflict of interest: None. ★ Authorship: (1) conception and design of the report: KS, AH, NA, and ST; (2) drafting the article or critical revision for important intellectual content: KS and AH; (3) final approval of submitted version: ST. 0735-6757/© 2016 Elsevier Inc. All rights reserved. Downloaded for Anonymous User (n/a) at Maimonides Medical Cen For personal use only. No other uses without permission He appeared to have mild aphasia, but no convulsions or apparent motor deficits were observed. Brain computed tomographic scan and routine blood tests revealed no abnormal findings. As he could not remain calm, approximately 30 to 40 mg (b1 mg/kg) of intravenous propofol was infused to secure adequate sedation to perform a cerebrospinal fluid test and brain magnetic resonance imaging. Results of both tests were normal, except for a slightly narrowed main trunk of the left middle cerebral artery visible in the magnetic resonance imaging (Figure). Within 20 minutes of the propofol administration, the patients consciousness markedly recovered, but he could not remember most of the details of the confusional episode. He still complained of mild difficulty in word recall and a narrowed visual field, both of which gradually improved. No recurrence was observed until the next day, and he was diagnosed with ACM. To the best of our knowledge, this is the first report describing the possible efficacy of low-dose intravenous propofol in terminating the confusional state of ACM. Although we could not perform electroencephalogram during the confusional episode, we concluded that our case is compatible with the clinical picture of ACM [2,3]. There are a limited number of earlier reports on ACM treatment, except for a few cases in which intravenous valproic acid [1,8] or prochlorperazine [9] was reported to be effective. Although ACM has been reported as a self-limiting disease that typically resolves within 24hours or after deep sleep [2,3], leaving the patientswith alteredmental status until their confusional state resolves naturally can be sometimes challenging. The efficacy and safety of the use of low, nonanesthetic dose (1 mg/kg) of propofol for migraine headache has been reported in some earlier case studies of patients with refractory or intractable migraine headache [10-12]. Therefore, the use of intravenous propofol at the ED can be considered another therapeutic option, especially in some hospitals or countries where intravenous valproate is not available. The requirement to secure necessary sedation to perform examinations for sufficient exclusion of other differential diagnosis, [2,3] would also, in part, justify the use of propofol for ACMpatients. The reason for possible efficacy of propofol for the treatment of ACM is unclear. A complex aura, where cortical spreading depression (CSD) involves a broader range of brain areas, including the cerebral hemisphere and brainstem, is considered one of the possible underlying mechanisms of ACM [2]. Valproic acid is known to reduce cortical excitability [13] and suppress CSD [14] in migraine patients, explaining the pharmacological mechanism of valproic acid as a commonly used migraine prophylaxis. Although the ability of propofol to suppress CSD is controversial at the experimental level [14], the possible efficacy of intravenous propofol in the treatment of ACM may be the result of a CSD-suppressive effect, as in the case of valproic acid. ter JC from ClinicalKey.com by Elsevier on January 16, 2018. . Copyright ©2018. Elsevier Inc. All rights reserved. Figure. Brainmagnetic resonance angiography revealed a slightly narrowedmain trunk of the left middle cerebral artery (shown with white arrowheads). 195.e6 K. Sato et al. / American Journal of Emergency Medicine 35 (2017) 195.e5–195.e6 To conclude, we report a case of a patient with strongly suspected ACM, who showed amarked response to intravenous propofol infusion. The possible efficacy of propofol was indicated, and we would like to suggest propofol as another potential therapeutic option for ACM. Further investigation is required. Downloaded for Anonymous User (n/a) at Maimonides Medical Ce For personal use only. No other uses without permission Kenichiro Sato, MD Ayumi Hida, MD, PhD* Noritoshi Arai, MD, PhD Sousuke Takeuchi, MD, PhD Department of Neurology, Center Hospital of the National Center for Global Health and Medicine, Tokyo 162-8655, Japan *Corresponding author. Tel.: +81 3 3201 7181; fax: +81 3 3202 1012 E-mail address: ayumi-hida@umin.ac.jp http://dx.doi.org/10.1016/j.ajem.2016.06.104

Autoimmune cerebellar ataxia with initial seronegativity and low-titer anti-glutamic acid decarboxylase antibody in the cerebrospinal fluid

In cases with anti‐glutamic acid decarboxylase (GAD) antibody‐positive cerebellar ataxia, the titer of the antibody is usually very high. However, a few cases of low‐titer GAD antibody‐positive cerebellar ataxia patients have been described recently. In such patients, the antibody has been detected predominantly in serum, rather than in cerebrospinal fluid.

A favorable outcome of intensive immunotherapies for new-onset refractory status epilepticus (NORSE)

BackgroundNew-onset refractory status epilepticus (NORSE) is a newly defined critical disease entity characterized by prolonged periods of refractory epileptic seizure with no readily identifiable cause in otherwise healthy individuals. Its etiology is uncertain, but autoimmune encephalitis is a possible candidate for the underlying cause of this condition. Immunotherapies could be considered for this condition, but its efficacy is not established.Case presentationA 31-year-old man with no prior history presented with refractory status epilepticus. His seizure persisted even with multiple anti-epileptic drugs and required prolonged general anesthesia under mechanical ventilation. Magnetic resonance imaging and cerebrospinal fluid did not indicate the cause of seizure, and autoantibodies related to encephalitis were not detected. It was speculated that the patient had occult autoimmune encephalopathy because of its acute-onset clinical course preceded by fever, even without definite evidence of an autoimmune mechanism. The patient received intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulin in succession and manifested a favorable outcome after these treatments.ConclusionOur case supports the efficacy of immunotherapies for NORSE even though it does not manifest definite evidence for autoimmune background. Clinicians should consider these immunotherapies for NORSE as early as possible, because this condition is associated with high mortality and morbidity owing to prolonged seizure activity and long-term intensive care including general anesthesia and mechanical ventilation.

Old Stroke as an Independent Risk Etiology for Todd's Paralysis

BACKGROUND Todds paralysis (TP) is a well-known postictal paresis in which patients present with transient weakness in their limb(s) after seizures. Although recognized as a stroke mimic in clinical practice, the pathophysiological mechanism and clinical features of TP remain unknown. Furthermore, its diagnosis can be erroneous in neurological emergency practice. We aimed to illustrate the clinical features and identify factors associated with TP. METHODS This single-center, retrospective observational study included consecutive adult patients who presented with convulsive seizure and were referred to an urban tertiary care emergency department between August 2010 and April 2016. The diagnosis of TP was set as the primary outcome measure. Clinical and laboratory variables were evaluated. RESULTS Of 1381 eligible convulsive seizures in 1187 patients, TP was observed in 89 seizures (6.4%) in 75 patients. Patients with TP were significantly older, more likely to have convulsive status epilepticus, and had a longer duration of convulsion than patients without TP. TP was found in 19.7% (39 of 198) of convulsive seizures with remote etiologies including those due to old stroke. These etiologies were identified as independent significant risk factors for TP compared with seizures with cryptogenic etiology. The positive likelihood ratio of TP seizures was 11.2 for remote seizure etiologies. CONCLUSIONS Our results indicated that the diagnosis of TP highly suggests premorbid or comorbid structural lesions in the central nervous system, including old stroke. This consideration in seizure etiology may help in reducing the risk of misdiagnosis of acute stroke in emergency settings and further antiepileptic treatment.

The Prehospital Predictors of Tracheal Intubation for in Patients who Experience Convulsive Seizures in the Emergency Department

Objective To identify the prehospital factors predicting the performance of tracheal intubation (TI) at the emergency department (ED) in patients with convulsive seizure or epilepsy. Methods We performed a retrospective analysis of seizure patients who underwent TI at the ED soon after arrival. The clinical variables obtained in the prehospital setting were reviewed. Patients The study population included consecutive adult patients who were transported to an urban tertiary care ED due to convulsive seizure between August 2010 and September 2015. Results Among the 822 eligible patients, 59 patients (7.2%) underwent TI at the ED. Four independent prehospital predictors were identified using multivariate analysis: age ≥50 years (+1 point), meeting the definition of convulsive status epilepticus (+4 points), and an on-scene heart rate of ≥120 bpm (+1 point) led to a higher likelihood of TI, while a higher on-scene (alert or confused) level of consciousness (-3 points) led to a lower likelihood of TI. The derived prediction rule (the sum of all points) had good predictive performance with an area under the curve of 0.88 (95% confidence interval: 0.79-0.97), a sensitivity of 0.62, a specificity of 0.91, and a positive likelihood ratio of 10.6, when the cut-off value was set to 5 points. Conclusion We constructed a simple prehospital prediction rule to help predict the need for TI in seizure patients, even in the prehospital phase. This may possibly lead to the more effective management of seizure patients in the ED.

Improved 123I-Ioflupane Binding After Immunotherapy in Anti–NAE Antibody–Positive Hashimoto Encephalopathy That Clinically Mimicked Multiple System Atrophy

We describe an 84-year-old man with anti-NH2-terminal of α-enolase antibody-positive Hashimoto encephalopathy that clinically mimicked multiple system atrophy who underwent investigation by dopamine transporter SPECT before and after immunotherapy. Before treatment, dopamine transporter SPECT showed reduced striatal I-ioflupane binding, with a mean specific binding ratio of 2.42, even though he had no apparent parkinsonism. After immunotherapy, mean specific binding ratio was improved to 3.22. Dopamine transporter SPECT was useful in this case to detect subclinical striatal dysfunction, and evaluation both before and after immunotherapy helped to distinguish between neurodegenerative disease and neuroimmunological disorder.

Hearing loss in lateral medullary syndrome

We report a case of lateral medullary syndrome with hemiparesis and hearing loss. A 69‐year‐old man was diagnosed with right‐sided lateral medullary syndrome and cerebellar vermis infarction with ipsilateral hemiparesis as a result of an upper cervical lesion. On the seventh hospital day, ipsilateral hearing loss suddenly emerged. The results of auditory and vestibular tests, including auditory brainstem responses, suggested a possible lesion in the vestibulocochlear nerve. Hearing loss could be attributed to a non‐anterior inferior cerebellar artery, vertebral artery and/or posterior inferior cerebellar artery infarction. The possibility of comorbidity of hearing loss with lateral medullary syndrome in this case suggests the possible usefulness of further intensive antithrombotic therapy in cases of lateral medullary syndrome with uncommon presentations.