Publications by authors named "Michi Kawamoto"

45 Publications

[Bacterial Meningitis and Suppurative Thrombophlebitis after Trigger Point Injections: A Case Report].

Brain Nerve 2021 Jun;73(6):737-740

Department of Neurology, Kobe City Medical Center General Hospital.

A 73-year-old woman with untreated diabetes mellitus visited our emergency department with a 4-day history of progressive headache, fever, and chills. She received trigger point injections (TPI) into the right sternocleidomastoid for exercise-induced ipsilateral shoulder pain, 13 days before admission and into the right trapezius, 6 days before admission. Cerebrospinal fluid (CSF) evaluation revealed pleocytosis with a predominance of neutrophils, as well as elevated protein and reduced glucose levels. Magnetic resonance imaging of the cervical spine revealed inflammatory changes of the right-sided posterior cervical muscles and the right vertebral arch of the C5-C6 vertebrae without contrast enhancement of the right posterior cervical veins. She was diagnosed with bacterial meningitis and suppurative thrombophlebitis, and empiric broad-spectrum antibiotic therapy was administered intravenously. The initial blood culture yielded Streptococcus intermedius; however, CSF culture showed no growth. She recovered completely after a 4-week course of intravenously administered ampicillin and was discharged with oral clindamycin to complete a total 6-week antibiotic course. TPI are widely used as a safe therapeutic strategy associated with few complications, and serious infections are rare. However, clinicians must remain mindful of the possibility of these complications in immunocompromised patients, such as those with diabetes mellitus who undergo TPI. (Received September 18, 2020; Accepted December 21, 2020; Published June 1, 2021).
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http://dx.doi.org/10.11477/mf.1416201824DOI Listing
June 2021

Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes.

JAMA Neurol 2021 Jul;78(7):853-863

Department of Neurology, Nara Medical University, Nara, Japan.

Importance: Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown.

Objective: To identify and characterize the clinicopathologic features of patients with OPDM_LRP12.

Design, Setting, And Participants: This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot.

Main Outcomes And Measures: Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics.

Results: Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients.

Conclusions And Relevance: This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.
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http://dx.doi.org/10.1001/jamaneurol.2021.1509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164150PMC
July 2021

Isolated anhidrosis of an upper limb in a patient with lung cancer: "One-sleeve shirt sign".

QJM 2021 Mar 22. Epub 2021 Mar 22.

Department of Neurology, Kobe City Medical Center General Hospital, Kobe, Japan.

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http://dx.doi.org/10.1093/qjmed/hcab062DOI Listing
March 2021

Eribulin Mesylate-related Multifocal Demyelinating Neuropathy with Myokymia in a Breast Cancer Patient.

Intern Med 2021 Mar 8. Epub 2021 Mar 8.

Department of Neurology, Kobe City Medical Center General Hospital, Japan.

We herein report a 48-year-old woman receiving eribulin mesylate for breast cancer who presented with gait disorder, distal limb paresthesia, and weakness progressing monthly. A nerve conduction study indicated demyelination with multifocal conduction block. Considering the immune-mediated pathology of her condition, she was administered intravenous immunoglobulin. Her neurological symptoms improved promptly after intravenous immunoglobulin therapy and eribulin withdrawal. Furthermore, the limb myokymia seen at the time of admission disappeared. Her symptoms continued to improve without additional treatment. We conclude that eribulin was a rare cause of demyelinating neuropathy with multifocal conduction block derived from immune-mediated pathology.
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http://dx.doi.org/10.2169/internalmedicine.6780-20DOI Listing
March 2021

[Effects of the prehospital care with and without suspecting acute stroke: a single stroke center study].

Rinsho Shinkeigaku 2021 Feb 26;61(2):103-108. Epub 2021 Jan 26.

Department of Neurology, Kobe City Medical Center General Hospital.

We retrospectively examined the differences between paramedic triage and final diagnosis in the cases that were transported to our hospital between May 2016 and March 2019. About 30% of the patients with suspected stroke were diagnosed other than stroke. Some of the patients without suspected stroke were diagnosed with large vessel occlusion and were treated with mechanical thrombectomy. The time from arrival at the hospital to treatment was significantly longer in the patients without suspected stroke than with suspected stroke. To achieve a better prehospital care, we need to accept a wide range of stroke mimics, and to continuously feedback the paramedics about the importance of paralysis, cortical symptoms in stroke.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001487DOI Listing
February 2021

Electroencephalographic findings in Bickerstaff's brainstem encephalitis: A possible reflection of the dysfunction of the ascending reticular activating system.

Clin Neurophysiol Pract 2021 26;6:29-35. Epub 2020 Dec 26.

Department of Neurology, Kobe City Medical Center General Hospital, Japan.

Objectives: Bickerstaff's brainstem encephalitis (BBE) is a rare post-infectious inflammatory disease, which causes impaired consciousness by the dysfunction of the ascending reticular activating system (ARAS). We aimed to clarify EEG changes possibly caused by the dysfunction of the ARAS in BBE.

Methods: We retrospectively investigated 15 EEGs from 5 patients with definite BBE (i.e., the positivity for serum IgG anti-GQ1b antibodies was mandatory for the diagnosis) admitted to our hospital from January 2014 through December 2019, particularly focusing on whether N1 and N2 sleep patterns were maintained.

Results: All of the 10 EEGs recorded when patients had consciousness disturbance were abnormal. Stereotypical EEG changes correlating with their level of consciousness were identified: poorly organized posterior dominant rhythms with maintenance of sleep patterns in patients with mild consciousness disturbance (n = 5); predominant N1 and/or N2 sleep patterns even with external stimuli, including spindle coma pattern, in patients with moderate consciousness disturbance ("unarousable sleep-like" EEG) (n = 4); and generalized slow waves without N1 and N2 sleep patterns in patients with severe consciousness disturbance (n = 1). Among 5 patients, 3 (60%) had "unarousable sleep-like" EEG in their clinical course.

Conclusions: Patients with BBE showed stereotypical EEG changes correlating with their level of consciousness, mostly with maintenance of N1 and N2 sleep patterns, and often exhibited characteristic "unarousable sleep-like" EEG.

Significance: This study revealed characteristic EEG changes possibly caused by the dysfunction of the ARAS, which can be a diagnostic clue for BBE.
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http://dx.doi.org/10.1016/j.cnp.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809243PMC
December 2020

Extensive leukoencephalopathy associated with idiopathic capillary leak syndrome: report of a case with neuropathology.

Neurol Sci 2021 May 7;42(5):2095-2098. Epub 2021 Jan 7.

Department of Neurology, Kobe City Medical Center General Hospital, 650-0047, 2-1-1 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo, Japan.

Introduction: Idiopathic systemic capillary leak syndrome (ISCLS) is a rare cryptogenic disorder characterized by recurrent hemoconcentration, hypoalbuminemia, edema, and hypotension due to extravascular fluid leakage. This is the first report that details uncommon extensive leukoencephalopathy caused by ISCLS upon a neuropathological investigation.

Case Report: A 68-year-old female had recurrent episodes of hemoconcentration, hypoalbuminemia, and generalized edema and was diagnosed with ISCLS. After 9 years, brain magnetic resonance imaging (MRI) incidentally revealed extensive leukoencephalopathy without neurological deficits. Thorough examinations ruled out other disorders, and the cerebral involvement due to ISCLS was finally diagnosed. Three years later, she developed an acute-onset coma and status epilepticus together with hypotension and hemoconcentration, which were compatible with ISCLS recurrence. Electroencephalogram and MRI were correlated with a seizure arising from the left hemisphere. Extensive leukoencephalopathy did not show notable changes for 3 years. Although treatment for ISCLS recurrence temporally improved hemoconcentration and consciousness, consciousness worsened again by marked edema of the left hemisphere, and she died of cerebral herniation. A brain autopsy revealed straggly perivascular plasma leakage around the small vessels of the deep white matter, which supported that the leukoencephalopathy was caused by ISCLS. Widespread myelin pallor and decreased axonal density with sparse astrogliosis and microgliosis were observed in the cerebral white matter and corresponded with a chronic change in the MRI.

Conclusion: Current radiological and pathological observations revealed that frequent perivascular leakages could cause chronic leukoencephalopathy, were linked with the development of systemic capillary leakage in ISCLS, and provided insights into the mysterious pathophysiology.
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http://dx.doi.org/10.1007/s10072-020-05000-5DOI Listing
May 2021

[COVID-19 and the Hospital Neurologist: How should we confront the COVID pandemic?]

Brain Nerve 2020 Oct;72(10):1049-1056

Department of Neurology, Kobe City Medical Center General Hospital.

Ninety-six patients were admitted to our hospital during the first wave of the 2020 COVID pandemic. Our hospital, a core hospital in Kobe, was in confusion at the beginning of the pandemic. The following three factors were considered important for preventing the collapse of hospitals during the pandemic based on our experiences: avoidance of contact, prompt and accurate communication, and role-sharing among community medical institutions. Of the 96 patients, 36 had severe cases with several neurological problems: 18 had consciousness disorders, 19 had generalized weakness, 7 had polyneuropathy, and 2 had severe limb weakness. There are several unsolved pathological problems, and neurologists should play important roles in the treatment of patients with COVID.
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http://dx.doi.org/10.11477/mf.1416201647DOI Listing
October 2020

Stroke Systems of Care During the COVID-19 Epidemic in Kobe City.

J Stroke Cerebrovasc Dis 2020 Dec 30;29(12):105343. Epub 2020 Sep 30.

Department of Neurosurgery, Kobe City Medical Center General Hospital, Kobe, Japan. Electronic address:

Background: The novel coronavirus disease 2019 (COVID-19) outbreak raised concerns over healthcare systems' ability to provide suitable care to stroke patients. In the present study, we examined the provision of stroke care in Kobe City during the COVID-19 epidemic, where some major stroke centers ceased to provide emergency care.

Methods: This was a cross-sectional study. The Kobe Stroke Network surveyed the number of stroke patients admitted to all primary stroke centers (PSCs) in the city between March 1 and May 23, 2020, and between March 3 and May 25, 2019. In addition, online meetings between all PSC directors were held regularly to share information. The survey items included emergency response system characteristics, number of patients with stroke hospitalized within 7 days of onset, administered treatment types (IV rt-PA, mechanical thrombectomy, surgery, and endovascular therapy), and stroke patients with confirmed COVID-19.

Results: During the period of interest in 2020, the number of stroke patients hospitalized across 13 PSCs was 813, which was 15.5% lower than that during the same period of 2019 (p = 0.285). The number of patients admitted with cerebral infarction, intracerebral hemorrhage, and subarachnoid hemorrhage decreased by 15.4% (p = 0.245), 16.1% (p = 0.659), and 14.0% (p = 0.715), respectively. However, the rates of mechanical thrombectomy and surgery for intracerebral hemorrhage were slightly increased by 12.1% (p = 0.754) and 5.0% (p = 0.538), respectively. PSCs that ceased to provide emergency care reported a decrease in the number of stroke cases of 65.7% compared with the same period in 2019, while other PSCs reported an increase of 0.8%. No case of a patient with stroke and confirmed COVID-19 was reported during the study period.

Conclusion: Kobe City was able to maintain operation of its stroke care systems thanks to close cooperation among all city PSCs and a temporal decrease in the total number of stroke cases.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526598PMC
December 2020

Anti-Ma-associated paraneoplastic cerebellar degeneration in a patient with nodular lymphocyte-predominant Hodgkin lymphoma: a case report.

BMC Neurol 2020 Sep 23;20(1):355. Epub 2020 Sep 23.

Department of Hematology, 2-1-1 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.

Background: Paraneoplastic cerebellar degeneration (PCD) is a devastating paraneoplastic syndrome that occasionally occurs in patients with Hodgkin lymphoma (HL). Anti-Ma2 is a well-characterized onconeuronal antibody and one of the causes of PCD. There has been only one previous report of anti-Ma2-associated paraneoplastic syndrome as a complication of HL. Here we present a rare case of anti-Ma2-associated PCD in a patient with nodular lymphocyte-predominant HL (NLPHL).

Case Presentation: A 77-year-old man with a 3-month history of gait instability and a 2-month history of oscillopsia was referred to our hospital for further investigation. On examination, his cognition was normal. He had nystagmus in all directions of gaze; specifically, he had horizontal and rotatory nystagmus in the primary position, downbeat nystagmus after right, left, and up gaze, and upbeat nystagmus after down gaze. Although his limb ataxia was mild, his trunk ataxia was so pronounced that he was unable to walk without support. We strongly suspected paraneoplastic syndrome and tested for neuronal autoantibodies. The anti-Ma2 antibody was strongly positive in the blood and cerebrospinal fluid but other antineuronal autoantibodies were negative. Computed tomography showed an enlarged lymph node in the right axilla but no masses. Biopsy confirmed a diagnosis of NLPHL. The NLPHL cells stained with anti-Ma-2 antibody in the cytoplasm, suggesting these abnormal cells contained protein that was cross-reactive with Ma-2.

Conclusions: To the best of our knowledge, this is the first case of anti-Ma2-associated PCD in a patient with NLPHL that was confirmed using immunostaining of the lymph node tissue with anti-Ma2 antibody. Our case confirms an association between anti-Ma2-associated PCD and NLPHL.
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http://dx.doi.org/10.1186/s12883-020-01929-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513504PMC
September 2020

A case report of fulminant cytokine release syndrome complicated by dermatomyositis after the combination therapy with immune checkpoint inhibitors.

Medicine (Baltimore) 2020 Apr;99(15):e19741

Department of Neurology, Kobe City Medical Center General Hospital, 650-0047, 2-1-1 Minatojima-Minamimachi, Chuou-ku, Kobe, Hyogo.

Introduction: Immune-related adverse events (ir-AEs) are increasingly becoming a concern, as immune checkpoint inhibitors (ICIs) are used more frequently. Herein, we present a case of fulminant cytokine release syndrome (CRS) complicated by dermatomyositis after the combination therapy with ICIs.

Patient Concerns: A 70-year-old male developed dermatomyositis during the course of treatment with two ICIs, nivolumab and ipilimumab. He was treated by steroid pulse therapy, but the effect was limited. Afterwards, he had acute-onset high fever, hypotension, respiratory failure, impaired consciousness, renal failure, and coagulation abnormality at the same time. C reactive protein (CRP), creatinine kinase (CK), D-dimer, and ferritin levels were considerably elevated: CRP, 24 mg/dL; CK, 40,500 U/L; D-dimer, 290 μg/mL; ferritin, 329,000 ng/mL.

Diagnosis: CRS induced by ICI combination therapy.

Interventions: Given that high fever and elevated CRP level indicated potential sepsis, an antibiotic was used until the confirmation of negative blood cultures. All the simultaneous acute symptoms were supposed to be CRS. He was admitted to the intensive care unit (ICU), and temporary intubation and hemodialysis were needed. Immunosuppressive therapy was reinforced by mycophenolate mofetil together with steroid, and plasma exchange was performed for the elimination of abnormal proteins.

Outcomes: The patient's clinical symptoms and laboratory parameters gradually improved and he was discharged from the ICU in a month.

Conclusion: Fulminant CRS can be induced by ICI combination therapy. As the initial symptoms of CRS resemble sepsis, it is important to consider CRS as a differential diagnosis and to initiate immunosuppressive therapy early when needed. In steroid-resistant cases, early introduction of other immunosuppressive therapy and plasma exchange can be effective.
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http://dx.doi.org/10.1097/MD.0000000000019741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220092PMC
April 2020

[Severe ketoacidosis induced by short-term starvation in a patient with spinal muscular atrophy].

Rinsho Shinkeigaku 2020 Apr 31;60(4):268-271. Epub 2020 Mar 31.

Department of Neurology, Kobe City Medical Center General Hospital.

We report a case of a 29-year-old woman with spinal muscular atrophy (SMA) type II who developed severe ketoacidosis after short-term starvation. She was hospitalized with lower respiratory tract infection. Although her symptoms improved after administration of intravenous antibiotic agents, her food intake gradually decreased. On the 7th day of hospitalization, she experienced abdominal pain followed by vomiting, after which she was unable to eat. Approximately 12 h later, she suffered from shock, accompanied with disturbance of consciousness, and she was admitted to the intensive care unit. She was diagnosed with ketoacidosis based on arterial blood gas analyses and urine test results. On receiving continuous infusion of glucose and insulin, her ketoacidosis was rapidly resolved and her symptoms completely recovered by the next day. To prevent the recurrence of ketoacidosis, we provided a diet plan based on indirect calorimetry results. However, ketoacidosis recurred twice, at 12 months and 16 months after discharge, both within 24 h of the onset of the fasting state. In addition to insufficient glycogen storage because of chronic malnutrition, poor gluconeogenesis or poor ketone body consumption due to skeletal muscle atrophy was believed to increase the risk of acute-onset, severe ketoacidosis after short-term starvation. Clinicians must note that patients with SMA are prone to ketoacidosis and that they must be promptly treated.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001382DOI Listing
April 2020

Improving detection of JC virus by ultrafiltration of cerebrospinal fluid before polymerase chain reaction for the diagnosis of progressive multifocal leukoencephalopathy.

BMC Neurol 2019 Oct 25;19(1):252. Epub 2019 Oct 25.

Department of Virology 1, National Institute of Infectious Diseases, Toyama 1-23-1, Shinjuku-ku, Tokyo, 162-8640, Japan.

Background: Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by JC virus (JCV). Although detecting JCV DNA in the cerebrospinal fluid (CSF) by real-time polymerase chain reaction (PCR) is useful, diagnosis is difficult when JCV concentrations are low. We therefore aimed to lower the detection limit of real-time PCR testing by enriching JCV in the CSF via ultrafiltration.

Methods: Virus suspensions and CSF specimens from 20 untreated patients with suspected PML were collected and total DNAs were extracted. The JCV large T gene was detected by quantitative real-time PCR under condition with and without prior centrifugal ultrafiltration.

Results: The JCV DNA was reliably detected to a lower limit of 10 copies/mL of virus suspension by real-time PCR with ultrafiltration. When using this method, the quantity of JCV DNA per PCR reaction increased 3.2- to 8.7-fold compared with the standard procedure. Seven patients were positive for JCV when using the standard procedure, and an additional patient was positive when using ultrafiltration. All JCV-positive patients had neurological features and magnetic resonance imaging findings compatible with PML.

Conclusions: The detection limit of JCV DNA by real-time PCR can be lowered by viral enrichment using ultrafiltration. Our simple protocol offers a valuable tool for PML diagnosis when extremely low copy numbers of JCV are released into the CSF or when brain biopsy is not feasible.
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http://dx.doi.org/10.1186/s12883-019-1476-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815041PMC
October 2019

Complement and inflammasome overactivation mediates paroxysmal nocturnal hemoglobinuria with autoinflammation.

J Clin Invest 2019 12;129(12):5123-5136

Research Institute for Microbial Diseases and.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored (GPI-anchored) proteins, resulting from a mutation in the X-linked gene PIGA. Here we report on a set of patients in whom PNH results instead from biallelic mutation of PIGT on chromosome 20. These PIGT-PNH patients have clinically typical PNH, but they have in addition prominent autoinflammatory features, including recurrent attacks of aseptic meningitis. In all these patients we find a germ-line point mutation in one PIGT allele, whereas the other PIGT allele is removed by somatic deletion of a 20q region comprising maternally imprinted genes implicated in myeloproliferative syndromes. Unlike in PIGA-PNH cells, GPI is synthesized in PIGT-PNH cells and, since its attachment to proteins is blocked, free GPI is expressed on the cell surface. From studies of patients' leukocytes and of PIGT-KO THP-1 cells we show that, through increased IL-1β secretion, activation of the lectin pathway of complement and generation of C5b-9 complexes, free GPI is the agent of autoinflammation. Eculizumab treatment abrogates not only intravascular hemolysis, but also autoinflammation. Thus, PIGT-PNH differs from PIGA-PNH both in the mechanism of clonal expansion and in clinical manifestations.
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http://dx.doi.org/10.1172/JCI123501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877298PMC
December 2019

Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease.

Nat Genet 2019 08 22;51(8):1215-1221. Epub 2019 Jul 22.

Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult, but skin biopsy enables its ante-mortem diagnosis. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.
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http://dx.doi.org/10.1038/s41588-019-0459-yDOI Listing
August 2019

Elevated Adenosine Deaminase Levels in the Cerebrospinal Fluid in Immune Checkpoint Inhibitor-induced Autoimmune Encephalitis.

Intern Med 2019 Oct 27;58(19):2871-2874. Epub 2019 Jun 27.

Department of Neurology, Kobe City Medical Center General Hospital, Japan.

Immune checkpoint inhibitors (ICIs) are promising drugs for various cancers. However, immune activation by ICIs can lead to immune-related adverse events (irAEs). Autoimmune encephalitis is a rare irAE, and its clinical features remain unknown. We herein report two patients with ICI-associated autoimmune encephalitis who, saliently, showed elevated adenosine deaminase (ADA) levels in the cerebrospinal fluid (CSF). This is the first report of increased ADA levels in the CSF of patients with ICI-induced autoimmune encephalitis. Although the mechanism of the ADA increase is poorly understood, elevated ADA in the CSF may be informative in the diagnosis of this rare disorder.
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http://dx.doi.org/10.2169/internalmedicine.2537-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815906PMC
October 2019

Successful Reperfusion with Endovascular Therapy Has Beneficial Effects on Long-Term Outcome Beyond 90 Days.

Cerebrovasc Dis 2019 9;47(3-4):127-134. Epub 2019 Apr 9.

Stroke Center, Osaka University Graduate School of Medicine, Osaka, Japan.

Background And Purpose: Recent studies have demonstrated that endovascular reperfusion therapy improves clinical outcomes at 90 days after ischemic stroke. However, the effects on long-term outcomes are not well known. We hypothesized that successful reperfusion might be associated with long-term improvement beyond 90 days after endovascular therapy. To assess the long-term effects beyond 90 days, we analyzed the association of successful reperfusion with a temporal change in modified Rankin Scale (mRS) score from 90 days to 1 year after endovascular therapy.

Methods: We retrospectively analyzed a database of consecutive patients with acute ischemic stroke who received endovascular therapy between April 2006 and March 2016 at 4 centers. We compared the incidences of improvement and deterioration in patients with successful reperfusion (i.e., modified thrombolysis in cerebral infarction score of 2b or 3) with those in patients with unsuccessful reperfusion. We defined improvement and deterioration as decrease and increase on the mRS score by 1 point or more from 90 days to 1 year after endovascular therapy respectively.

Results: A total of 268 patients were included in the current study. The rate of patients with improvement tended to be higher in patients with successful reperfusion than in patients with unsuccessful reperfusion (20% [34/167 patients] vs. 12% [12/101], p = 0.07). The rate of patients with deterioration was lower in patients with successful reperfusion than in patients with unsuccessful reperfusion (25% [42/167] vs. 42% [42/101], p < 0.01). After adjustment for confounders, successful reperfusion was associated with improvement (adjusted OR 2.65; 95% CI 1.23-5.73; p < 0.05) and deterioration (adjusted OR 0.33; 95% CI 0.18-0.62; p < 0.01), independent of the 90-day mRS score.

Conclusions: Successful reperfusion has further beneficial legacy effects on long-term outcomes beyond 90 days after stroke.
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http://dx.doi.org/10.1159/000499190DOI Listing
February 2020

Ischemic stroke in a young woman with anti-phosphatidylserine/prothrombin (aPS/PT) complex antibody: a case report.

J Neurol Sci 2019 Feb 7;397:77-79. Epub 2018 Dec 7.

Department and institution, Department of Neurology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-Minamimachi, Chuo-ku Kobe, Hyogo 650-0047, Japan.

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http://dx.doi.org/10.1016/j.jns.2018.12.012DOI Listing
February 2019

Short "Infraslow" Activity (SISA) With Burst Suppression in Acute Anoxic Encephalopathy: A Rare, Specific Ominous Sign With Acute Posthypoxic Myoclonus or Acute Symptomatic Seizures.

J Clin Neurophysiol 2018 Nov;35(6):496-503

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Objective: Slow wave with frequency <0.5 Hz are recorded in various situations such as normal sleep, epileptic seizures. However, its clinical significance has not been fully clarified. Although infra-slow activity was recently defined as activity between 0.01 and 0.1 Hz, we focus on the activity recorded with time constant of 2 seconds for practical usage. We defined short "infraslow" activity (SISA) less than 0.5 Hz recorded with time constant of 2 seconds and investigated the occurrence and clinical significance of SISA in acute anoxic encephalopathy.

Methods: This study evaluated the findings of electroencephalography in consecutive 98 comatose patients with acute anoxic encephalopathy after cardiac arrest. We first classified electroencephalography findings conventionally, then investigated SISA by time constant of 2 second and a high-cut filter of 120 Hz, to clarify the relationship between SISA and clinical profiles, especially of clinical outcomes and occurrence of acute posthypoxic myoclonus or acute symptomatic seizures.

Results: Short infra-slow activity was found in six patients (6.2%), superimposed on the burst phase of the burst-suppression pattern. All six patients showed acute posthypoxic myoclonus or acute symptomatic seizures (generalized tonic-clonic seizures) and its prognosis was poor. This 100% occurrence of acute posthypoxic myoclonus or acute symptomatic seizures was significantly higher than that in patients without SISA (39.1%; P < 0.05).

Conclusions: Short infra-slow activity in acute anoxic encephalopathy could be associated with acute posthypoxic myoclonus and acute symptomatic seizures. Short infra-slow activity could be a practically feasible biomarker for myoclonus or seizures and poor prognosis in acute anoxic encephalopathy, if it occurs with burst suppression.
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http://dx.doi.org/10.1097/WNP.0000000000000507DOI Listing
November 2018

Recurrent aseptic meningitis with mutations: a novel pathogenesis of recurrent meningitis successfully treated by eculizumab.

BMJ Case Rep 2018 Sep 27;2018. Epub 2018 Sep 27.

Department of Neurology, Kobe City Medical Center General Hospital, Kobe, Japan.

We report the case of a patient with mutations who experienced recurrent aseptic meningitis 121 times over 16 years before developing paroxysmal nocturnal haemoglobinuria (PNH). Each episode was preceded by urticaria and arthralgia. After developing PNH, haemolysis occurred prior to meningitis. Flow cytometry revealed deficiency of the glycophosphatidylinositol (GPI)-anchored complement regulatory proteins, CD59 and CD55, and he was diagnosed with PNH. All the symptoms disappeared on administering eculizumab, an anti-C5 antibody. We did not detect mutation in , which is regarded as the cause of PNH. However, we detected a germ-line mutation and a somatic microdeletion in chromosome 20q including ; PIGT is essential for transferring GPI anchor to the precursors of CD59 and CD55, which play important roles in complement regulation. Loss of these proteins leads to complement overactivation, causing inflammatory symptoms, including recurrent meningitis. mutations should be considered a novel pathogenesis of recurrent meningitis of unknown aetiology.
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http://dx.doi.org/10.1136/bcr-2018-225910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6169622PMC
September 2018

Post-hyperventilation Apnea with Spindle Activity on Electroencephalogram.

Intern Med 2018 Dec 10;57(24):3659-3662. Epub 2018 Aug 10.

Department of Neurology, Kobe City Medical Center General Hospital, Japan.

Loss of consciousness occurs in post-hyperventilation apnea, but its pathophysiology remains unclear. We herein report a patient with post-hyperventilation apnea showing spindle activity on electroencephalogram (EEG). The patient was alert and breathing spontaneously before the hyperventilation test, but loss of consciousness and apnea with spindle activity on EEG occurred when the end-tidal CO decreased during the hyperventilation test. She recovered consciousness and spontaneous breathing with the disappearance of the spindle activity on EEG when the end-tidal CO increased after the hyperventilation test. The loss of consciousness during post-hyperventilation apnea might be due to the focal involvement of the ascending-activating mesodiencephalic reticular formation.
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http://dx.doi.org/10.2169/internalmedicine.1161-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355414PMC
December 2018

A Punctate Magnetic Resonance Imaging Pattern in a Patient with Systemic Lupus Erythematosus Is an Early Sign of Progressive Multifocal Leukoencephalopathy: A Clinicopathological Study.

Intern Med 2018 Sep 27;57(18):2727-2734. Epub 2018 Apr 27.

Department of Neurology, Kobe City Medical Center General Hospital, Japan.

A 37-year-old woman with systemic lupus erythematosus presented with gait disturbance and cognitive dysfunction. Brain magnetic resonance imaging (MRI) revealed small, punctate, T2-/fluid-attenuated inversion recovery-hyperintense and T1-hypointense lesions without gadolinium enhancement, which is atypical for progressive multifocal leukoencephalopathy (PML). On a pathological examination of biopsied brain tissues, JC virus-infected cells were hardly detected via immunohistochemistry but were certainly detected via in situ hybridization, conclusively verifying the PML diagnosis. After tapering off the immunosuppressant and mefloquine administration, the MRI findings revealed gradual improvement, and she has been stable for over 18 months. A punctate MRI pattern is not specific to natalizumab-associated PML but may be a ubiquitous early sign useful for the early diagnosis of PML.
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http://dx.doi.org/10.2169/internalmedicine.0696-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191581PMC
September 2018

Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial.

Lancet Neurol 2018 06 21;17(6):519-529. Epub 2018 Apr 21.

Department of Neurology, Tokushima University, Tokushima, Japan.

Background: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome.

Methods: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725.

Findings: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred.

Interpretation: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials.

Funding: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.
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http://dx.doi.org/10.1016/S1474-4422(18)30114-5DOI Listing
June 2018

[Tapia's syndrome following transesophageal echocardiography during an open-heart operation: a case report].

Rinsho Shinkeigaku 2017 Dec 28;57(12):785-787. Epub 2017 Nov 28.

Department of Neurology, Kobe City Medical Center General Hospital.

A 67-year-old man presented with hoarseness, dysarthria and deviation of the tongue to the left side the day after the open-heart operation under general anesthesia. Brain MRI demonstrated no causal lesion, and laryngoscope showed left vocal cord abductor palsy, so we diagnosed him with Tapia's syndrome (i.e., concomitant paralysis of the left recurrent and hypoglossal nerve). His neurological symptoms recovered gradually and improved completely four months after the onset. Tapia's syndrome is a rare condition caused by the extra cranial lesion of the recurrent laryngeal branch of the vagus nerve and the hypoglossal nerve, and mostly described as a complication of tracheal intubation. In this case, transesophageal echo probe has been held in the left side of the pharynx, so compression to the posterior wall of pharynx by the probe resulted in this condition, and to the best of our knowledge, this is the first report of Tapia's syndrome due to transesophageal echocardiography during an open-heart operation. This rare syndrome should be considered as a differential diagnosis of dysarthria and tongue deviation after a procedure associated with compression to the pharynx.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001097DOI Listing
December 2017

Serial EEG findings in anti-NMDA receptor encephalitis: correlation between clinical course and EEG.

Epileptic Disord 2017 Dec;19(4):465-470

Department of Neurology, Kobe City Medical Centre General Hospital, 2-1-1, Minatojimaminamimachi, Chuo-ku, Kobe city 650-0047.

Anti-NMDA receptor encephalitis is a paraneoplastic encephalitis characterised by psychiatric features, involuntary movement, and autonomic instability. Various EEG findings in patients with anti-NMDA receptor encephalitis have been reported, however, the correlation between the EEG findings and clinical course of anti-NMDA receptor encephalitis remains unclear. We describe a patient with anti-NMDA receptor encephalitis with a focus on EEG findings, which included: status epilepticus, generalised rhythmic delta activity, excess beta activity, extreme delta brush, and paroxysmal alpha activity upon arousal from sleep, which we term"arousal alpha pattern". Initially, status epilepticus was observed on the EEG when the patient was comatose with conjugate deviation. The EEG then indicated excess beta activity, followed by the emergence of continuous slow activity, including generalised rhythmic delta activity and extreme delta brush, in the most severe phase. Slow activity gradually faded in parallel with clinical amelioration. Excess beta activity persisted, even after the patient became almost independent in daily activities, and finally disappeared with full recovery. In summary, our patient with anti-NMDA receptor encephalitis demonstrated slow activity on the EEG, including extreme delta brush during the most severe phase, which gradually faded in parallel with clinical amelioration, with excess beta activity persisting into the recovery phase.
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http://dx.doi.org/10.1684/epd.2017.0942DOI Listing
December 2017

Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.

Brain 2016 12 25;139(Pt 12):3170-3186. Epub 2016 Oct 25.

17 Department of Neuropathology, Institute for Medical Sciences of Aging, Aichi Medical University, Nagakute, Aichi, Japan.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs. NIID has been considered to be a heterogeneous disease because of the highly variable clinical manifestations, and ante-mortem diagnosis has been difficult. However, since we reported the usefulness of skin biopsy for the diagnosis of NIID, the number of NIID diagnoses has increased, in particular adult-onset NIID. In this study, we studied 57 cases of adult-onset NIID and described their clinical and pathological features. We analysed both NIID cases diagnosed by post-mortem dissection and by ante-mortem skin biopsy based on the presence of characteristic eosinophilic, hyaline and ubiquitin-positive intanuclear inclusion: 38 sporadic cases and 19 familial cases, from six families. In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness. Muscle weakness and sensory disturbance were also observed. It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia. In familial cases with more than 40 years of onset age, dementia was most prominent (100%). Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases. Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis. All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging. Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores. Based on these clinicopathological features, we proposed a diagnosis flow chart of adult-onset NIID. Our study suggested that the prevalence rate of adult-onset NIID may be higher than previously thought, and that NIID may be underdiagnosed. We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy.
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http://dx.doi.org/10.1093/brain/aww249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382941PMC
December 2016

Status epilepticus in the elderly: Prognostic implications of rhythmic and periodic patterns in electroencephalography and hyperintensities on diffusion-weighted imaging.

J Neurol Sci 2016 Nov 4;370:284-289. Epub 2016 Oct 4.

Department of Neurology, Kobe City Medical Center General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan.

Objective: To delineate the clinical characteristics and functional outcome of status epilepticus (SE) in elderly people, and elucidate prognostic implications of SE-associated rhythmic and periodic patterns (RPPs) in electroencephalography and hyperintensities on diffusion-weighted imaging.

Methods: We retrospectively investigated 107 consecutive patients with SE aged≥65years in a comprehensive community hospital. RPPs were classified using the 2012 American Clinical Neurophysiology Society's Standardized Critical Care EEG Terminology. Poor outcome was defined as an increase in modified Rankin Scale (mRS) score at discharge compared with that at baseline, including death.

Results: Median age of patients was 80.0years. Median mRS score at baseline was 3. Thirty-four patients (31.8%) had a previous diagnosis of epilepsy. Cerebrovascular disease and dementia were major etiologies. Poor outcome occurred in 41 (38.3%). In electroencephalography, periodic discharges (PDs) were present in 21.0% (22/105), rhythmic delta activity (RDA) in 10.5% (11/105), and conventional seizure patterns in 9.5% (10/105). Diffusion-weighted hyperintensities associated with SE were observed in 28.0% (26/93). With univariate analysis, poor outcome was significantly associated with no previous diagnosis of epilepsy, etiology, refractory SE, specific electroencephalographic patterns (PDs and conventional seizure patterns, but not RDA), and diffusion-weighted hyperintensities. With multivariate logistic regression analysis, diffusion-weighted hyperintensities (OR 6.13 [95% CI 1.72-21.9]) and refractory SE (OR 5.36 [95% CI 1.28-22.4]) were independently associated with poor outcome.

Conclusions: SE often occurred as the first seizure in already disabled elderly people, further worsening their functional disabilities. Diffusion-weighted hyperintensities and refractory SE, but not RPPs in electroencephalography, were independent functional prognostic factors.
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http://dx.doi.org/10.1016/j.jns.2016.09.062DOI Listing
November 2016

Recurrent Guillain-Barré syndrome, Miller Fisher syndrome and Bickerstaff brainstem encephalitis.

J Neurol Sci 2016 May 3;364:59-64. Epub 2016 Mar 3.

Department of Neurology, Kobe City Medical Center General Hospital, Japan. Electronic address:

Objective: Guillain-Barré syndrome (GBS), Miller Fisher syndrome (MFS), and Bickerstaff brainstem encephalitis (BBE) are usually monophasic, but some patients experience recurrences after long asymptomatic intervals. We aimed to investigate clinical features of recurrent GBS, MFS, and BBE at a single hospital.

Methods: Records from 97 consecutive patients with GBS, MFS or BBE who were admitted to a tertiary hospital between 2001 and 2013 were reviewed. Clinical and laboratory features of patients with recurrent GBS, MFS, or BBE were investigated.

Results: Patients included 55 (32 males) with GBS, 34 (22 males) with MFS, and 8 (6 males) with BBE. Recurrent cases occurred in 2 (4%) of the 55 patients with GBS, 4 (12%) of the 34 patients with MFS, and 2 (25%) of the 8 patients with BBE. Patients with recurrent MFS had a tendency to be younger at the first episode than patients with non-recurrent MFS (median, 22 versus 37years old). Symptoms and signs were less severe during relapses than during the initial episode in recurrent patients.

Conclusions: Recurrences occurred more frequently in patients with MFS or BBE compared with those with GBS. Patients with recurrent MFS might be younger than those with non-recurrent MFS.
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http://dx.doi.org/10.1016/j.jns.2016.03.008DOI Listing
May 2016
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