Impact of COVID-19 pandemic on epilepsy care in Japan: A national-level multicenter retrospective cohort study.

OBJECTIVE: The impact of the coronavirus disease 2019 (COVID-19) pandemic on epilepsy care across Japan was investigated by conducting a multicenter retrospective cohort study. METHODS: This study included monthly data on the frequency of (1) visits by outpatients with epilepsy, (2) outpatient electroencephalography (EEG) studies, (3) telemedicine for epilepsy, (4) admissions for epilepsy, (5) EEG monitoring, and (6) epilepsy surgery in epilepsy centers and clinics across Japan between January 2019 and December 2020. We defined the primary outcome as epilepsy-center-specific monthly data divided by the 12-month average in 2019 for each facility. We determined whether the COVID-19 pandemic-related factors (such as year [2019 or 2020], COVID-19 cases in each prefecture in the previous month, and the state of emergency) were independently associated with these outcomes. RESULTS: In 2020, the frequency of outpatient EEG studies (-10.7%, p<0.001) and cases with telemedicine (+2,608%, p=0.031) were affected. The number of COVID-19 cases was an independent associated factor for epilepsy admission (-3.75*10-3 % per case, p<0.001) and EEG monitoring (-3.81*10-3 % per case, p = 0.004). Further, the state of emergency was an independent factor associated with outpatient with epilepsy (-11.9%, p<0.001), outpatient EEG (-32.3%, p<0.001), telemedicine for epilepsy (+12,915%, p<0.001), epilepsy admissions (-35.3%; p<0.001), EEG monitoring (-24.7%: p<0.001), and epilepsy surgery (-50.3%, p<0.001). SIGNIFICANCE: We demonstrated the significant impact that the COVID-19 pandemic had on epilepsy care. These results support those of previous studies and clarify the effect size of each pandemic-related factor on epilepsy care.

Acute Hyponatremia Resulting from Duloxetine-induced Syndrome of Inappropriate Antidiuretic Hormone Secretion.

A 77-year-old woman who had taken a single oral dose of duloxetine subsequently developed a headache and nausea. On the first day, her serum sodium level was 135 mEq/L. She became confused on the third day. Her serum sodium level was 119 mEq/L and her antidiuretic hormone level was 1.9 IU. We diagnosed her with acute hyponatremia from duloxetine-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH). This case suggests that we must not rule out SIADH on the basis of normal serum sodium levels when a patient who has started serotonin-norepinephrine reuptake inhibitor (SNRI) treatment presents with symptoms similar to hyponatremia.

Autopsy-proven case of paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

We report a case of a male patient with a 19-year history of monoclonal and later polyclonal gammopathy who subsequently developed tetraparesis, bulbar palsy, and respiratory failure. Autopsy findings showed degeneration of the hypoglossal nuclei, prominent neuronal loss and atrophy in the anterior horn of the whole spinal cord despite the presence of mild astrocytosis, degeneration of the gracilis on one side, and infiltration of inflammatory cells, which included B cells and plasma cells in the anterior and posterior roots of the lumbar spinal cord, iliopsoas muscle, and perivascular area of the cervical cord. On immunostaining, cytoplasmic inclusions of phosphorylated transactivation response DNA-binding protein of 43 kDa were observed in the motor neurons and astrocytes of the hypoglossal nuclei and whole spinal cord. The final diagnosis was paraneoplastic lower motor neuron disease with sensorimotor neuropathy due to Waldenström's macroglobulinemia.

The Frequency and Risk Factors for Ischemic Stroke in Myotonic Dystrophy Type 1 Patients.

INTRODUCTION: Patients with myotonic dystrophy type 1 have several cardiac abnormalities, especially myocardial conduction disorders. Few studies have investigated cerebral infarction. We investigated the frequency of both symptomatic and asymptomatic ischemic strokes in patients with myotonic dystrophy type 1. METHODS: Patients who were diagnosed with myotonic dystrophy type 1 using genetic testing or clinical examinations at Asahikawa Medical Center were included. We retrospectively reviewed their medical history, neuroradiological imaging, electrocardiograms, and treatment. Their CHADS2 and CHA2DS2-VASc scores were calculated. RESULT: A total of 108 patients were diagnosed with myotonic dystrophy type 1. Magnetic resonance imaging was performed in 72 and 1 patient whose results were not available was excluded. Among these, 2 patients had atrial flutter and 3 had atrial fibrillation. Regarding the CHADS2 score, 11 patients scored more than 2. Regarding the CHA2DS2-VASc score, 22 patients scored more than 2. Ischemic strokes were found in 9 patients with 1 having an atrial flutter and 4 having atrial fibrillation. All patients with stroke had CHADS2 and CHA2DS2-VASc scores higher than 2. There were significant differences between the 2 groups in atrial fibrillation (P < .001), CHADS2 score (P < .001), and CHA2DS2-VASc score (P < .001). CONCLUSIONS: Ischemic stroke in patients with myotonic dystrophy type 1 is associated with atrial fibrillation. The CHADS2 score seems to be useful for the management of patients with myotonic dystrophy type 1. Repeated electrocardiograms are necessary for managing these patients.

Kallikrein 6 secreted by oligodendrocytes regulates the progression of experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of the disease. Here, we examined the pathophysiological role of Kallikrein 6 (Klk6), a serine protease produced by oligodendrocytes (OLs), in EAE using Klk6 knockout (Klk6-/-) mice. Compared with Klk6+/+ (wild-type) mice, Klk6-/- mice showed milder EAE symptoms, including delayed onset and milder paralysis. Loss of Klk6 suppressed matrix metalloprotease-9 expression and diminished the infiltration of peripheral inflammatory cells into the CNS by decreasing blood-brain barrier (BBB) permeability and reducing expression levels of inflammatory cytokines, chemokines and their receptors. Scanning electron microscopic analysis revealed demyelination characterized by myelin detachment from the axons in the early phase of EAE progression (days 3-7) in Klk6+/+ mice but not in Klk6-/- mice. Interestingly, anti-MOG (myelin oligodendrocyte glycoprotein) autoantibody was also detected in the cerebrospinal fluid (CSF) and spinal cord on day 3 after MOG immunization. Furthermore, treatment of primary cultured OLs with anti-MOG autoantibody induced oligodendroglial morphological changes and increases in myelin basic protein and Klk6 expression. We also developed a novel enzyme-linked immunoabsorbent assay method for detecting activated KLK6 in human CSF. In human autopsy brain samples, expression of active KLK6 was detected in OLs using an antibody that specifically recognizes the protein's activated form. Taken together, our findings demonstrate that Klk6 secreted by OLs plays a critical role in the pathogenesis of EAE/MS and that it might serve as a potential therapeutic target for MS.

Limbic Encephalitis Associated with Human Herpesvirus-7 (HHV-7) in an Immunocompetent Adult: The First Reported Case in Japan.

A 35-year-old male who had not previously suffered any major illnesses was admitted to our hospital because of general fatigue, fever, headache, vomiting, consciousness disturbance, and seizures. A neurological examination showed that he was in a semi-comatose state and exhibited neck stiffness. Brain magnetic resonance imaging detected high-intensity areas in the bilateral hippocampi and periventricular white matter. A cerebrospinal fluid examination revealed mononuclear pleocytosis, an elevated protein level, and positivity for human herpesvirus-7 (HHV-7) DNA. The patient's condition improved after the administration of methylprednisolone, intravenous immunoglobulins, and acyclovir. This is the first known case of limbic encephalitis associated with HHV-7 in an immunocompetent Japanese adult.

Recurrent ischemic stroke in a patient with the Trousseau syndrome treated with dabigatran.

A 70-year-old man with multiple ischemic strokes was diagnosed with cardiac embolism and treated with dabigatran. Three months later, he suddenly developed vertigo and vomiting. Magnetic resonance imaging, showed recurrent lesions and blood tests revealed hypercoagulability, hypoproteinemia, and elevated cytokeratin 19 fragments that serve as a tumor marker of lung cancer. Chest computed tomography showed there were small nodules in bilateral lungs and swollen mediastinal lymph nodes. A conclusive diagnosis was impossible because the patient declined invasive procedures. We suspected primary lung cancer and diagnosed concomitant arterial thrombosis. We initially administered low-molecular-weight heparin, which we later changed to vitamin K antagonist. Although stroke did not recur thereafter, liver metastasis resulted in death 6 months later. The effectiveness of novel oral anticoagulants for preventing the Trousseau syndrome remains unclear. Further study is needed to prevent venous and arterial thromboses arising from the Trousseau syndrome.

Effectiveness of oral iron chelator treatment with deferasirox in an aceruloplasminemia patient with a novel ceruloplasmin gene mutation.

A 59-year-old man presented with refractory anemia, choreoathetosis in the left upper extremity, an unsteady gait and cognitive dysfunction. The laboratory findings showed a marked decrease in ceruloplasmin. Magnetic resonance images revealed iron deposition in the brain and visceral organs. Iron accumulation was also observed in hepatocytes. Genetic analyses of the ceruloplasmin gene revealed a novel homozygous mutation of c.2185 delC in exon 12. The oral chelator deferasirox was effective in treating the left-side choreoathetosis and unsteady gait. Providing early treatment using deferasirox may be useful for preventing the progression of symptomatic neurological dysfunction.

Prostacyclin stimulated integrin-dependent angiogenic effects of endothelial progenitor cells and mediated potent circulation recovery in ischemic hind limb model.

BACKGROUND: Prostacyclin (PGI2) enhances angiogenesis, especially in cooperation with bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the mechanisms of PGI2 in EPC-mediated angiogenesis in vivo remain unclear. The purpose of this study was to clarify the role of PGI2 in EPC-mediated angiogenesis using BM-specific IP deletion mice. METHODS AND RESULTS: Hind limb ischemia (HLI) was induced in wild-type (WT) mice transplanted with IP-deleted BM (WT/BM(IP(-/-)). Recovery of blood flow (RBF) in WT/BM(IP(-/-)) was impaired for 28 days after HLI, whereas RBF in IP(-/-)/BM(WT) was attenuated for up to 7 days compared with WT/BM(WT). The impaired RBF in WT/BM(IP(-/-)) was completely recovered by intramuscular injection of WT EPCs but not IP(-/-) EPCs. The impaired effects of IP(-/-) EPCs were in accordance with reduced formation of capillary and arterioles in ischemic muscle. An ex vivo aortic ring assay revealed that microvessel formation was enhanced by accumulation/adhesion of EPCs to perivascular sites as pericytes. IP(-/-)EPCs, in which expression of integrins was decreased, had impaired production of angiogenic cytokines, adhesion to neovessels and their angiogenic effects. The small-interfering RNA (siRNA)-mediated knockdown of integrin ß1 in WT EPCs attenuated adhesion to microvessels and their in vivo and in vitro angiogenic effects. CONCLUSIONS: PGI2 may induce persistent angiogenic effects in HLI through adhesion of EPCs to perivascular sites of neovessels via integrins in addition to paracrine effects.

Effects of antidepressants on GluR2 Q/R site-RNA editing in modified HeLa cell line.

Marked reduction of RNA editing at the glutamine (Q)/arginine (R) site of the glutamate receptor subunit type 2 (GluR2) in motor neurons may be a contributory cause of neuronal death specifically in sporadic ALS. It has been shown that deregulation of RNA editing of several mRNAs plays a causative role in diseases of the central nervous system such as depression. We analyzed the effects of eight antidepressants on GluR2 Q/R site-RNA editing in a modified HeLa cell line that stably expresses half-edited GluR2 pre-mRNA. We also measured changes in RNA expression levels of adenosine deaminase acting on RNA type 2 (ADAR2), the specific RNA editing enzyme of the GluR2 Q/R site, and GluR2, in order to assess the molecular mechanism causing alteration of this site-editing. The editing efficiency at the GluR2 Q/R site was significantly increased after treatment with seven out of eight antidepressants at a concentration of no more than 10 microM for 24h. The relative abundance of ADAR2 mRNA to GluR2 pre-mRNA or to beta-actin mRNA was increased after treatment with six of the effective antidepressants, whereas it was unchanged after treatment with milnacipran. Our results suggest that antidepressants have the potency to enhance GluR2 Q/R site-editing by either upregulating the ADAR2 mRNA expression level or other unidentified mechanisms. It may be worth investigating the in vivo efficacy of antidepressants with a specific therapeutic strategy for sporadic ALS in view.

An adult case of relapsing human herpesvirus-6 encephalitis.

Human herpesvirus-6 (HHV-6) is the main etiologic agent of exanthema subitum in young children. Central nervous system (CNS) infections in children due to HHV-6 have been described on many occasions. HHV-6 is also a common cause of infections in immunocompromised individuals. However, little is known concerning the impact of HHV-6 on the CNS in immunocompetent adults. We report the first case of relapsing HHV-6 encephalitis in a healthy 73-year-old female.

Treatment of Japanese restless legs syndrome patients with cabergoline: an open clinical preliminary trial.

OBJECTIVE: To determine the effective dose of cabergoline in Japanese patients with restless legs syndrome (RLS). METHODS: Six cases of idiopathic RLS and three of RLS with Parkinson disease (PD) participated in an open clinical preliminary trial. All cases were diagnosed based on the clinical criteria of the International RLS Study Group. Three RLS cases (1.3%) were detected out of 229 consecutive cases with PD. RLS severity was evaluated with International RLS Study Group (IRLSSG) Rating Scale Version 2.2 before and one year after the treatment with cabergoline. RESULTS: For 6 idiopathic RLS patients, the IRLSSG questionnaire scores improved from 25.5+/-3.7 to 10.7+/-8.9 (p=0.028, Wilcoxon test) with 1 mg of daily cabergoline at the endpoint. For 3 RLS cases with PD, the score was 21.7+/-3.7 before the treatment, and RLS symptoms completely disappeared with 1 mg of cabergoline. One of RLS cases with PD required additional cabergoline later because of parkinsonism. No adverse event with cabergoline was reported in this study. CONCLUSION: One mg of daily cabergoline is effective in some Japanese patients of RLS.

Edaravone diminishes free radicals from circulating neutrophils in patients with ischemic brain attack.

OBJECTIVE: Treatment with a free radical scavenger could be a new option for ischemic brain attack, however, little is known about the alteration of oxidative stress markers induced by edaravone, a novel free radical scavenger, in human ischemic brain attack. METHODS: We investigated the effects of edaravone on the oxidative stress markers in patients with ischemic brain attack. Twenty-one patients with ischemic brain attack and 19 controls were enrolled in this study. Blood samples were obtained just before and soon after the first administration of edaravone (30 mg) or ozagrel (40 mg). Intracellular reactive oxygen species of neutrophils were measured using 6-carboxy-2', 7'-dichlorodihydrofluorescin diacetate and a fluorescence-activated cell sorter. Superoxide from neutrophils, induced by phorbol myristate acetate (PMA), was determined by luminol-amplified chemiluminescence assay. RESULTS: Treatment with 30 mg of edaravone significantly decreased the intracellular reactive oxygen species (ROS) of neutrophils (Wilcoxon test, p=0.0001) and PMA-induced superoxide produced by neutrophils (Wilcoxon test, p=0.001). Ozagrel did not alter the intracellular ROS or superoxide production of neutrophils. CONCLUSION: Reduction of intracellular ROS and suppression of superoxide production in neutrophils provide a potential explanation for the clinical efficacy of edaravone in patients with ischemic brain attack.