Publications by authors named "Haruki Koike"

152 Publications

Emerging infectious diseases, vaccines and Guillain-Barré syndrome.

Clin Exp Neuroimmunol 2021 May 17. Epub 2021 May 17.

Department of Neurology Nagoya University Graduate School of Medicine Nagoya Japan.

The recent outbreak of Zika virus infection increased the incidence of Guillain-Barré syndrome (GBS). Following the first reported case of GBS after Zika virus infection in 2013, there has been a considerable increase in the incidence of GBS in endemic countries, such as French Polynesia and Latin American countries. The association between coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and GBS is another emerging research hotspot. Electrophysiological studies have suggested that GBS patients associated with Zika virus infection or COVID-19 tend to manifest acute inflammatory demyelinating polyneuropathy, rather than acute motor axonal neuropathy (AMAN). Causative autoantibodies, such as anti-ganglioside antibodies in AMAN associated with infection, have not been identified in GBS associated with these emerging infectious diseases. Nevertheless, recent studies suggested molecular mimicry between these viruses and human proteins related to GBS. Recent studies have shown the efficacy of new vaccines, containing artificial messenger RNA encoding the spike protein of SARS-CoV-2, against. These vaccines are now available in many countries and massive vaccination campaigns are currently ongoing. Although there are long-standing concerns about the increased risk of GBS after inoculation of conventional vaccines, the risk of GBS is not considered a legitimate reason to limit administration of currently available vaccines, because the benefits outweigh the risks.
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http://dx.doi.org/10.1111/cen3.12644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250889PMC
May 2021

Emerging Infection, Vaccination, and Guillain-Barré Syndrome: A Review.

Neurol Ther 2021 Jun 12. Epub 2021 Jun 12.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.

Guillain-Barré syndrome (GBS) is an autoimmune disorder of the peripheral nervous system that typically develops within 4 weeks after infection. In addition to conventional infectious diseases with which we are familiar, emerging infectious diseases, such as Zika virus infection and coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have also been suggested to be associated with GBS. GBS is mainly categorized into a demyelinating subtype known as acute inflammatory demyelinating polyneuropathy (AIDP) and an axonal subtype known as acute motor axonal neuropathy (AMAN). Most patients who develop GBS after Zika virus infection or COVID-19 have AIDP. The concept of molecular mimicry between pathogens and human peripheral nerve components was established through studies of AMAN with anti-ganglioside GM1 antibodies occurring after Campylobacter jejuni infection. Although such mimicry between specific pathogens and myelin or Schwann cell components has not been clearly demonstrated in AIDP, a similarity of Zika virus and SARS-CoV-2 proteins to human proteins has been suggested. With the development of global commerce and travel, emerging infectious diseases will continue to threaten public health. From this viewpoint, the development of vaccines and antiviral drugs is important to prepare for and control emerging infectious diseases. Although a decrease in the number of patients after the 2015-2016 Zika epidemic increased the difficulty in conducting phase 3 trials for Zika virus vaccines, the efficacy and safety of new vaccines have recently been demonstrated for COVID-19. In general, vaccines can decrease the risk of infectious disease by stimulating the immune system, and discussions regarding an increased risk of autoimmune disorders, such as GBS, have been ongoing for many years. However, the risk of GBS is not considered a legitimate reason to limit the administration of currently available vaccines, as only a trivial association or no association with GBS has been demonstrated.
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http://dx.doi.org/10.1007/s40120-021-00261-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196284PMC
June 2021

Multidisciplinary Approaches for Transthyretin Amyloidosis.

Cardiol Ther 2021 Jun 4. Epub 2021 Jun 4.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Amyloidosis caused by systemic deposition of transthyretin (TTR) is called ATTR amyloidosis and mainly includes hereditary ATTR (ATTRv) amyloidosis and wild-type ATTR (ATTRwt) amyloidosis. Until recently, ATTRv amyloidosis had been considered a disease in the field of neurology because neuropathic symptoms predominated in patients described in early reports, whereas advances in diagnostic techniques and increased recognition of this disease revealed the presence of patients with cardiomyopathy as a predominant feature. In contrast, ATTRwt amyloidosis has been considered a disease in the field of cardiology. However, recent studies have suggested that some of the patients with ATTRwt amyloidosis present tenosynovial tissue complications, particularly carpal tunnel syndrome, as an initial manifestation of amyloidosis, necessitating an awareness of this disease among neurologists and orthopedists. Although histopathological confirmation of amyloid deposits has traditionally been considered mandatory for the diagnosis of ATTR amyloidosis, the development of noninvasive imaging techniques in the field of cardiology, such as echocardiography, magnetic resonance imaging, and nuclear imaging, enabled nonbiopsy diagnosis of this disease. The mechanisms underlying characteristic cardiac imaging findings have been deciphered by histopathological studies. Novel disease-modifying therapies for ATTR amyloidosis, such as TTR stabilizers, short interfering RNA, and antisense oligonucleotides, were initially approved for ATTRv amyloidosis patients with polyneuropathy. However, the indications for the use of these disease-modifying therapies gradually widened to include ATTRv and ATTRwt amyloidosis patients with cardiomyopathy. Since the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, occurred, the minimization of hospital visits and telemedicine have become increasingly important. As older age and cardiovascular disease are major factors associated with increased disease severity and mortality of COVID-19, many ATTR amyloidosis patients are at increased risk of disease aggravation when they are infected with SARS-CoV-2. From this viewpoint, close interspecialty communication to determine the optimal interval of evaluation is needed for the management of patients with ATTR amyloidosis.
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http://dx.doi.org/10.1007/s40119-021-00222-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177037PMC
June 2021

Macrophages and Autoantibodies in Demyelinating Diseases.

Cells 2021 Apr 8;10(4). Epub 2021 Apr 8.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.

Myelin phagocytosis by macrophages has been an essential feature of demyelinating diseases in the central and peripheral nervous systems, including Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), and multiple sclerosis (MS). The discovery of autoantibodies, including anti-ganglioside GM1 antibodies in the axonal form of GBS, anti-neurofascin 155 and anti-contactin 1 antibodies in typical and distal forms of CIDP, and anti-aquaporin 4 antibodies in neuromyelitis optica, contributed to the understanding of the disease process in a subpopulation of patients conventionally diagnosed with demyelinating diseases. However, patients with these antibodies are now considered to have independent disease entities, including acute motor axonal neuropathy, nodopathy or paranodopathy, and neuromyelitis optica spectrum disorder, because primary lesions in these diseases are distinct from those in conventional demyelinating diseases. Therefore, the mechanisms underlying demyelination caused by macrophages remain unclear. Electron microscopy studies revealed that macrophages destroy myelin as if they are the principal players in the demyelination process. Recent studies suggest that macrophages seem to select specific sites of myelinated fibers, including the nodes of Ranvier, paranodes, and internodes, for the initiation of demyelination in individual cases, indicating that specific components localized to these sites play an important role in the behavior of macrophages that initiate myelin phagocytosis. Along with the search for autoantibodies, the ultrastructural characterization of myelin phagocytosis by macrophages is a crucial step in understanding the pathophysiology of demyelinating diseases and for the future development of targeted therapies.
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http://dx.doi.org/10.3390/cells10040844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068327PMC
April 2021

Association between neurosarcoidosis with autonomic dysfunction and anti-ganglionic acetylcholine receptor antibodies.

J Neurol 2021 Apr 21. Epub 2021 Apr 21.

Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, 1-1-1, Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.

Objective: To determine whether autonomic dysfunction in neurosarcoidosis is associated with anti-ganglionic acetylcholine receptor (gAChR) antibodies, which are detected in autoimmune autonomic ganglionopathy.

Methods: We retrospectively extracted cases of sarcoidosis from 1787 serum samples of 1,381 patients between 2012 and 2018. Anti-gAChR antibodies against the α3 and β4 subunit were measured by luciferase immunoprecipitation to confirm the clinical features of each case. We summarized literature reviews of neurosarcoidosis with severe dysautonomia to identify relevant clinical features and outcomes.

Results: We extracted three new cases of neurosarcoidosis with severe dysautonomia, among which two were positive for anti-gAChR antibodies: Case 1 was positive for antibodies against the β4 subunit, and Case 2 was positive for antibodies against both the α3 and β4 subunits. We reviewed the cases of 15 patients with neurosarcoidosis and severe dysautonomia, including the three cases presented herein. Orthostatic hypotension and orthostatic intolerance were the most common symptoms. Among the various types of neuropathy, small fiber neuropathy (SFN) was the most prevalent, with seven of nine cases exhibiting definite SFN. Six of eight cases had impaired postganglionic fibers, of which the present three cases revealed abnormality of I-MIBG myocardial scintigraphy. Of the 11 cases, 10 were responsive to immunotherapy, except one seropositive case (Case 2).

Conclusions: The presence of gAChR antibodies may constitute one of the mechanisms by which dysautonomia arises in neurosarcoidosis.
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http://dx.doi.org/10.1007/s00415-021-10551-4DOI Listing
April 2021

Association of serum neurofilament light chain levels with clinicopathology of chronic inflammatory demyelinating polyneuropathy, including NF155 reactive patients.

J Neurol 2021 Apr 2. Epub 2021 Apr 2.

Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.

Objectives: To clarify whether serum neurofilament light chains (NfLs) serve as a biomarker of axonal damage in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), especially in patients with anti-neurofascin 155 (NF155) antibodies.

Methods: The Simoa system was used to examine serum NfL levels from 58 patients with CIDP, including 13 anti-NF155 antibody-positive patients, and from 14 age- and sex-matched healthy individuals. Serum NfL levels were evaluated before and after treatment in eight patients with anti-NF155 antibodies. Clinical features, electrophysiological findings, and cerebrospinal fluid (CSF) protein levels, were evaluated. The pathological features of sural nerves from 40 patients were also examined.

Results: Serum NfL levels were significantly higher in patients with CIDP than in healthy individuals (median 29.63 vs. 7.71 pg/mL, p < 0.001) and were correlated with both modified Rankin Scale scores (r = 0.584, p < 0.001) and CSF protein levels (r = 0.432, p = 0.001). The NfL levels of anti-NF155 antibody-positive patients were higher than those of antibody-negative patients (p = 0.005). Serum NfL levels were negatively correlated with compound muscle action potential amplitudes of the tibial nerves (r =  - 0.404, p = 0.004) and positively correlated with the degree of active axonal degeneration in the pathological findings (r = 0.485, p = 0.001). In the antibody-positive group, NfL levels and antibody titers decreased after treatment in all examined patients.

Conclusion: Serum NfL correlated with pathological indices of axonal degeneration, and may serve as a biomarker that reflects active axonal damage of CIDP.
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http://dx.doi.org/10.1007/s00415-021-10537-2DOI Listing
April 2021

Ratio of urinary N-terminal titin fragment to urinary creatinine is a novel biomarker for amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2021 Mar 18. Epub 2021 Mar 18.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan

Objective: We aimed to investigate the validity of urinary N-terminal titin fragment as a biomarker for amyotrophic lateral sclerosis (ALS).

Methods: We consecutively enrolled patients with ALS (n=70) and healthy controls (HC) (n=43). We assessed the urinary titin N-terminal fragment, urinary neurotrophin receptor p75 extracellular domain, serum neurofilament light chain (NfL), motor functional measurements and prognosis. We used urinary creatinine (Cr) levels to normalise the urinary levels of titin fragment.

Results: Compared with HC, patients with ALS had significantly increased urinary levels of titin N-terminal fragment normalised with Cr (titin/Cr) (ALS, 27.2 pmol/mg/dL; HC, 5.8 pmol/mg/dL; p<0.001), which were correlated with the scores of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (=-0.422, p<0.001). A Cox proportional hazards model demonstrated that the high urinary level of titin/Cr was a survival predictor in patients with ALS. Multivariate analysis of prognostic factors showed that the urinary titin/Cr and serum NfL were independent factors for poor prognosis.

Conclusions: Our findings indicate that urinary N-terminal titin fragment is a non-invasive measure of muscle damage in ALS, which could be applied in disease monitoring and prediction of disease progression, in combination with serum NfL.
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http://dx.doi.org/10.1136/jnnp-2020-324615DOI Listing
March 2021

Two distinct mechanisms of neuropathy in immunoglobulin light chain (AL) amyloidosis.

J Neurol Sci 2021 Feb 2;421:117305. Epub 2021 Jan 2.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Introduction: Although polyneuropathy in patients with immunoglobulin light chain (AL) amyloidosis has been considered to be attributable to axonal degeneration resulting from amyloid deposition, patients with nerve conduction parameters indicating demyelination that mimics chronic inflammatory demyelinating polyneuropathy (CIDP) have also been reported anecdotally.

Methods: We evaluated the electrophysiological and pathological features of 8 consecutive patients with AL amyloidosis who were referred for sural nerve biopsy.

Results: Although findings of axonal neuropathy predominantly in the lower limbs were the cardinal feature, all patients showed one or more abnormalities of nerve conduction velocities or distal motor latencies. In particular, 2 of these patients fulfilled the definite electrophysiological for CIDP defined by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS). On electron microscopic examination of sural nerve biopsy specimens, Schwann cells apposed to amyloid fibrils became atrophic in all patients, suggesting that amyloid deposits directly affect neighboring tissues. Additionally, detachment of the neurilemma from the outermost compacted myelin lamella was seen where amyloid fibrils were absent in 4 patients. Electrophysiological findings suggestive of demyelination were more conspicuous in these patients compared with the other patients. The detachment of the neurilemma from the outermost compacted myelin lamella was particularly conspicuous in patients who fulfilled the definite EFNS/PNS electrophysiological criteria for CIDP.

Conclusion: Abnormalities of myelinated fibers unrelated to amyloid deposition may frequently occur in AL amyloidosis. Disjunction between myelin and the neurilemma may induce nerve conduction abnormalities suggestive of demyelination.
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http://dx.doi.org/10.1016/j.jns.2020.117305DOI Listing
February 2021

The wide-ranging clinical and genetic features in Japanese families with valosin-containing protein proteinopathy.

Neurobiol Aging 2021 04 14;100:120.e1-120.e6. Epub 2020 Nov 14.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan. Electronic address:

Mutations in the valosin-containing protein (VCP) gene are known to cause various neurodegenerative disorders. Here, we report 8 Japanese patients [6 men, 2 women; median age at onset: 49.5 (range, 35-58) years] from 5 unrelated families with VCP missense mutations. Although 7 of 8 patients were diagnosed with either inclusion body myopathy or amyotrophic lateral sclerosis, 1 patient showed demyelinating polyneuropathy, which was confirmed by longitudinal nerve conduction studies. Sural nerve biopsy of the patient revealed intranuclear ubiquitin staining in Schwann cells. Three known pathogenic VCP mutations (p.Arg191Gln, p.Arg155Cys, and p.Ile126Phe) were detected. A novel mutation, c.293 A>T (p.Asp98Val), was also identified in a patient with amyotrophic lateral sclerosis and frontotemporal dementia. This mutation was predicted to be "deleterious" or "disease causing" using in silico mutation analyses. In conclusion, demyelinating polyneuropathy may be a novel phenotype caused by VCP mutations. The p.Asp98Val mutation was found to be a novel pathogenic mutation of VCP proteinopathy. We believe our cases represent a wide clinical spectrum of VCP mutations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.10.028DOI Listing
April 2021

[A case of post-surgical inflammatory neuropathy with lower-extremity weakness after surgery for anorectal malignant melanoma that showed the effectiveness of immunotherapy].

Rinsho Shinkeigaku 2020 Nov 27;60(11):762-767. Epub 2020 Oct 27.

Department of Neurology, University of Fukui Hospital.

A 59-year-old man with past histories of bronchial asthma and chronic sinusitis underwent transanal resection of anorectal malignant melanoma with general anesthesia. On the third day after surgery, he presented with subacute weakness with right dominant hypoesthesia in the bilateral lower limbs. Tendon reflexes were diminished without pathological reflexes. Blood examination showed increased eosinophils (2,058/μl) and elevated serum immunoglobulin E (675.0 IU/ml). Cerebrospinal fluid examination showed elevated protein (200 mg/dl) without pleocytosis (<5/μl). A nerve conduction study suggested multiple mononeuropathy with motor and axonal dominance in the right tibial, peroneal, and sural nerves. Because of eosinophilia and his past medical history (i.e., bronchial asthma and chronic sinusitis), we initially suspected eosinophilic polyangiitis granulomatosis (EGPA) as the cause of postoperative polyneuropathy. However, his neurological symptoms did not improve despite the decreased eosinophil count after tumor resection, which was inconsistent with EGPA. We biopsied the left sural nerve to exclude EGPA and make a diagnosis. Pathological findings revealed no demyelination, axonal degeneration, or eosinophil infiltration with granuloma formation; however, lymphocyte-dominated inflammation was observed around the epineurial small vessels. Thus, the patient was diagnosed with early onset post-surgical inflammatory neuropathy (PIN) based on his clinical course and the pathological findings. On post-surgery day 48, oral administration of prednisolone (40 mg/day) was started. His neurological symptoms improved quickly and remarkably. Our case suggests that, when multiple mononeuropathy develops early after surgery, PIN should be considered as a differential diagnosis to initiate appropriate treatment based on the pathological condition of neuropathy.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001441DOI Listing
November 2020

Association Between IL-5 Levels and the Clinicopathologic Features of Eosinophilic Granulomatosis With Polyangiitis.

Neurology 2021 02 27;96(5):226-229. Epub 2020 Oct 27.

From the Department of Neurology (R.N., H.K., K.O., Y.F., M.I., M.K.), Nagoya University Graduate School of Medicine; Department of Neurology (K.O.), Okazaki City Hospital; and Research Division of Dementia and Neurodegenerative Disease (G.S.), Nagoya University Graduate School of Medicine, Japan.

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http://dx.doi.org/10.1212/WNL.0000000000011142DOI Listing
February 2021

Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies.

Neurol Ther 2020 Dec 18;9(2):317-333. Epub 2020 Sep 18.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

ATTR amyloidosis is caused by systemic deposition of transthyretin (TTR) and comprises ATTRwt (wt for wild-type) amyloidosis, ATTRv (v for variant) amyloidosis, and acquired ATTR amyloidosis after domino liver transplantation. ATTRwt amyloidosis has classically been regarded as cardiomyopathy found in the elderly, whereas carpal tunnel syndrome has also become a major initial manifestation. The phenotypes of ATTRv amyloidosis are diverse and include neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation and age of onset. In addition to variant TTR, the deposition of wild-type TTR plays a significant role, even in patients with ATTRv amyloidosis. The formation of amyloid fibrils tends to occur in association with the basement membrane. The thickening or reduplication of the basement membrane surrounding endoneurial microvessels, which is similar to diabetic neuropathy, is observed in ATTRv amyloidosis, suggesting that common mechanisms, such as an accumulation of advanced glycation end products, may participate in the disease process. In addition to direct damage caused by amyloid fibrils, recent studies have suggested that the toxicity of nonfibrillar TTRs, such as TTR oligomers, participates in the process of tissue damage. Although liver transplantation has been performed for patients with ATTRv amyloidosis since 1990, late-onset patients were not eligible for this treatment. However, as the efficacy of orally administered tafamidis and diflunisal, which stabilize TTR tetramers, was suggested in the early 2010s, such late-onset patients have also become targets for disease-modifying therapies. Additionally, recent studies of small interfering RNA (patisiran) and antisense oligonucleotide (inotersen) therapies have demonstrated the efficacy of these gene-silencing agents. A strategy for monitoring patients that enables the choice of an appropriate treatment from comprehensive and long-term viewpoints should be established. As many patients with ATTR amyloidosis are aged and have heart failure, they are at increased risk of aggravation if they are infected by SARS-CoV2. The optimal interval of evaluation should also be considered, particularly in this COVID-19 era.
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http://dx.doi.org/10.1007/s40120-020-00210-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500251PMC
December 2020

Aberrant Expression of Nodal and Paranodal Molecules in Neuropathy Associated With IgM Monoclonal Gammopathy With Anti-Myelin-Associated Glycoprotein Antibodies.

J Neuropathol Exp Neurol 2020 12;79(12):1303-1312

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya.

To clarify the pathogenesis of anti-myelin-associated glycoprotein (MAG) antibody neuropathy associated with IgM monoclonal gammopathy (anti-MAG neuropathy), sural nerve biopsy specimens from 15 patients were investigated. Sodium channels, potassium channels, contactin-associated protein 1 (Caspr1), contactin 1, and neurofascin were evaluated by immunofluorescence in teased-fiber preparations. Immunoreactivity to the pan-sodium channel in both anti-MAG neuropathy patients and in normal controls was concentrated at the node of Ranvier unless there was demyelination, which was defined as the widening of the node of Ranvier. However, this immunoreactivity became weak or disappeared as demyelination progressed. In contrast, KCNQ2 immunostaining was nearly absent even in the absence of demyelination. The lengths of Caspr1, contactin 1, and pan-neurofascin immunostaining sites at the paranode were significantly increased compared with those of normal controls despite the absence of demyelination. The length of paranodal neurofascin staining correlated with the anti-MAG antibody titer, nerve conduction indices, the frequency of de/remyelination in teased-fiber preparations, and the frequency of widely spaced myelin (p < 0.05, p < 0.05, p < 0.01, and <0.05, respectively). These findings suggest that nodal and paranodal molecular alterations occur in early stages preceding the morphological changes associated with demyelination in anti-MAG neuropathy.
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http://dx.doi.org/10.1093/jnen/nlaa085DOI Listing
December 2020

Hepatitis B Virus-related Vasculitic Neuropathy in an Inactive Virus Carrier Treated with Intravenous Immunoglobulin.

Intern Med 2020 Dec 4;59(23):3075-3078. Epub 2020 Aug 4.

Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Japan.

We herein report a 33-year-old woman who was an asymptomatic hepatitis B virus (HBV) carrier and presented with distal muscle weakness in the legs and asymmetrical paresthesia in the distal extremities. A nerve biopsy specimen revealed fibrinoid necrosis associated with inflammatory infiltration in the perineural space, and deposition of hepatitis B core antigen and C4d complement was detected in the vascular endothelial cells as well as around the vessels. She was diagnosed with HBV-related vasculitic neuropathy and treated with intravenous immunoglobulin (IVIG). Her symptoms completely subsided after eight weeks. Vasculitic neuropathy rarely develops in the chronic inactive stages of HBV infection. This is the first report of an HBV-inactive carrier with vasculitic neuropathy successfully treated with IVIG.
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http://dx.doi.org/10.2169/internalmedicine.4498-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759712PMC
December 2020

Pathophysiology of Chronic Inflammatory Demyelinating Polyneuropathy: Insights into Classification and Therapeutic Strategy.

Neurol Ther 2020 Dec 14;9(2):213-227. Epub 2020 May 14.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is classically defined as polyneuropathy with symmetric involvement of the proximal and distal portions of the limbs. In addition to this "typical CIDP", the currently prevailing diagnostic criteria proposed by the European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) define "atypical CIDP" as encompassing the multifocal acquired demyelinating sensory and motor (MADSAM), distal acquired demyelinating symmetric (DADS), pure sensory, pure motor, and focal subtypes. Although macrophage-induced demyelination is considered pivotal to the pathogenesis of CIDP, recent studies have indicated the presence of distinctive mechanisms initiated by autoantibodies against paranodal junction proteins, such as neurofascin 155 and contactin 1. These findings led to the emergence of the concept of nodopathy or paranodopathy. Patients with these antibodies tend to show clinical features compatible with typical CIDP or DADS, particularly the latter. In contrast, classical macrophage-induced demyelination is commonly found in some patients in each major subtype, including the typical CIDP, DADS, MADSAM, and pure sensory subtypes. Differences in the distribution of lesions and the repair processes underlying demyelination by Schwann cells may determine the differences among subtypes. In particular, the preferential involvement of proximal and distal nerve segments has been suggested to occur in typical CIDP, whereas the involvement of the middle nerve segments is conspicuous in MADSAM. These findings suggest that humoral rather than cellular immunity predominates in the former because nerve roots and neuromuscular junctions lack blood-nerve barriers. Treatment for CIDP consists of intravenous immunoglobulin (IVIg) therapy, steroids, and plasma exchange, either alone or in combination. However, patients with anti-neurofascin 155 and contactin 1 antibodies are refractory to IVIg. It has been suggested that rituximab, a monoclonal antibody to CD20, could have efficacy in these patients. Further studies are needed to validate the CIDP subtypes defined by the EFNS/PNS from the viewpoint of pathogenesis and establish therapeutic strategies based on the pathophysiologies specific to each subtype.
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http://dx.doi.org/10.1007/s40120-020-00190-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606443PMC
December 2020

Monitoring of asymptomatic family members at risk of hereditary transthyretin amyloidosis for early intervention with disease-modifying therapies.

J Neurol Sci 2020 Jul 2;414:116813. Epub 2020 Apr 2.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto-shi, Kumamoto 860-8556, Japan; Department of Amyloidosis Research, Nagasaki International University, Japan. Electronic address:

Background: Hereditary transthyretin (ATTRv) amyloidosis is an adult-onset, systemic disorder caused by mutations in the transthyretin (TTR) gene. As ATTRv amyloidosis is inherited in an autosomal dominant manner, family members of the patients are at risk of developing the disease.

Methods: With an objective of discussing recommendations on monitoring of family members for early diagnosis of ATTRv amyloidosis, we held a medical advisory board meeting in Tokyo, Japan, in October 2017.

Results: Our recommendations are summarized as follows: periodic follow-up genetic counseling should be offered to asymptomatic gene mutation carriers; follow-up assessments should be started when the carriers are still asymptomatic to test for amyloidosis onset, irrespective of TTR genotype and age at onset in the particular family. We suggest annual routine assessments and in-depth assessments every 3-5 years, with the frequency of these increased as required. Periodical monitoring of asymptomatic gene mutation carriers is crucial for attending physicians to detect early signs or symptoms of the disease and start disease-modifying therapy (DMT).

Conclusions: The monitoring strategy for asymptomatic TTR gene mutation carriers should progress toward rapid diagnosis and early intervention with DMT. This approach may be more appropriate for countries with more resources.
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http://dx.doi.org/10.1016/j.jns.2020.116813DOI Listing
July 2020

Ultrastructural mechanisms of macrophage-induced demyelination in Guillain-Barré syndrome.

J Neurol Neurosurg Psychiatry 2020 06 3;91(6):650-659. Epub 2020 Apr 3.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objective: To describe the pathological features of Guillain-Barré syndrome focusing on macrophage-associated myelin lesions.

Methods: Longitudinal sections of sural nerve biopsy specimens from 11 patients with acute inflammatory demyelinating polyneuropathy (AIDP) exhibiting macrophage-associated demyelinating lesions were examined using electron microscopy. A total of 1205 nodes of Ranvier were examined to determine the relationship of the macrophage-associated demyelinating lesions with the nodal regions. Additionally, immunohistochemical and immunofluorescent studies were performed to elucidate the sites of complement deposition.

Results: Overall, 252 macrophage-associated myelin lesions were identified in longitudinal sections. Of these, 40 lesions exhibited complete demyelination with no association with the lamellar structures of myelin. In 183 lesions, macrophage cytoplasm was located at internodes without association with the nodes of Ranvier or paranodes. In particular, these internodal lesions were more frequent in one patient (152 lesions). In the remaining 29 lesions, the involvement of nodal regions was obvious. Lesions involving nodal regions were more frequently observed than those involving internodes in four patients. Invasion of the macrophage cytoplasmic processes into the space between the paranodal myelin terminal loops and the axolemma from the nodes of Ranvier was observed in three of these patients. Immunostaining suggested complement deposition corresponding to putative initial macrophage-associated demyelinating lesions.

Conclusions: The initial macrophage-associated demyelinating lesions appeared to be located at internodes and at nodal regions. The sites at which the macrophages initiated phagocytosis of myelin might be associated with the location of complement deposition in certain patients with AIDP.
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http://dx.doi.org/10.1136/jnnp-2019-322479DOI Listing
June 2020

Efficacy and Safety of Rituximab in Refractory CIDP With or Without IgG4 Autoantibodies (RECIPE): Protocol for a Double-Blind, Randomized, Placebo-Controlled Clinical Trial.

JMIR Res Protoc 2020 Apr 1;9(4):e17117. Epub 2020 Apr 1.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune-mediated peripheral neuropathy that is currently classified into several clinical subtypes, which are presumed to have different pathogenic mechanisms. Recently, studies identified a subgroup of patients with CIDP who were positive for IgG4 autoantibodies against paranodal proteins, such as neurofascin-155 and contactin-1, who respond poorly to first-line therapies for typical CIDP, including intravenous immunoglobulin therapy.

Objective: This study aims to evaluate the efficacy and safety of intravenous rituximab according to IgG4 autoantibody status in patients with refractory CIDP.

Methods: The Evaluation of the Efficacy and Safety of Rituximab in Refractory CIDP Patients with IgG4 Autoantibodies in the Exploratory Clinical (RECIPE) trial consists of 2 cohorts: a multicenter, placebo-controlled, randomized study cohort of 15 patients with IgG4 autoantibody-positive CIDP (rituximab:placebo = 2:1) and an open-label trial cohort of 10 patients with antibody-negative CIDP. The primary endpoint is improvement in functional outcome assessed using the adjusted Inflammatory Neuropathy Cause and Treatment Disability Scale score at 26, 38, or 52 weeks after the start of treatment with rituximab in patients with CIDP and anti-paranodal protein antibodies. Secondary outcome measures include grip strength, manual muscle testing sum scores, results of nerve conduction studies, and other functional scales.

Results: We plan to enroll 25 cases for the full analysis set. Recruitment is ongoing, with 14 patients enrolled as of January 2020. Enrollment will close in September 2020, and the study is planned to end in December 2021.

Conclusions: This randomized controlled trial will determine if rituximab is safe and effective in patients with anti-paranodal antibodies. An open-label study will provide additional data on the effects of rituximab in patients with antibody-negative CIDP. The results of the RECIPE trial are expected to provide evidence for the positioning of rituximab as a pathogenesis-based therapeutic for refractory CIDP.

Trial Registration: ClinicalTrials.gov NCT03864185, https://clinicaltrials.gov/ct2/show/NCT03864185 ; The Japan Registry of Clinical Trials jRCT2041180037, https://jrct.niph.go.jp/en-latest-detail/jRCT2041180037.

International Registered Report Identifier (irrid): DERR1-10.2196/17117.
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http://dx.doi.org/10.2196/17117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160709PMC
April 2020

Differential clinicopathologic features of EGPA-associated neuropathy with and without ANCA.

Neurology 2020 04 26;94(16):e1726-e1737. Epub 2020 Mar 26.

From the Department of Neurology (R.N., H.K., K.O., Y.F., S.I., Y.K., M.I., M.K.) and Research Division of Dementia and Neurodegenerative Disease (G.S.), Nagoya University Graduate School of Medicine; and Department of Neurology (K.O.), Okazaki City Hospital, Japan.

Objective: To investigate the clinicopathologic features of eosinophilic granulomatosis with polyangiitis (EGPA)-associated neuropathy with a focus on the presence or absence of anti-neutrophil cytoplasmic antibodies (ANCAs).

Methods: We examined the clinical features and pathologic findings of sural nerve biopsy specimens from 82 patients with EGPA-associated neuropathy. Of these patients, 32.9% were myeloperoxidase (MPO)-ANCA positive, and 67.1% were MPO-ANCA negative. PR3-ANCA was negative in all of 78 examined patients.

Results: Upper limb symptoms were more frequently reported as initial neuropathic manifestations in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (44.4% vs 14.6%, < 0.01). The serum levels of C-reactive protein were significantly higher in the MPO-ANCA-positive group than in the MPO-ANCA-negative group ( < 0.05). Sural nerve biopsy specimens showed findings suggestive of vasculitis (i.e., destruction of vascular structures) in epineurial vessels; these results were seen more frequently in the MPO-ANCA-positive group than in the MPO-ANCA-negative group ( < 0.0001). Conversely, the numbers of eosinophils in the lumen of the epineurial vessels ( < 0.01) and epineurial vessels occluded by intraluminal eosinophils ( < 0.05) were higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group. Furthermore, the incidence of eosinophil infiltration in the endoneurium was higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group ( < 0.01).

Conclusions: This study suggests that the pathogenesis of EGPA comprises at least 2 distinct mechanisms: ANCA-associated vasculitis resulting in ischemic effects and inflammation, which is prominent in MPO-ANCA-positive patients, and eosinophil-associated vascular occlusion leading to ischemia and eosinophil-associated tissue damage, which is conspicuous in MPO-ANCA-negative patients.
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http://dx.doi.org/10.1212/WNL.0000000000009309DOI Listing
April 2020

Complement deposition and macrophage-induced demyelination in CIDP with anti-LM1 antibodies.

J Neurol Sci 2020 01 17;408:116509. Epub 2019 Oct 17.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jns.2019.116509DOI Listing
January 2020

Expanding the spectrum of transthyretin amyloidosis.

Muscle Nerve 2020 01 6;61(1):3-4. Epub 2019 Nov 6.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

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http://dx.doi.org/10.1002/mus.26741DOI Listing
January 2020

Demyelinating Neuropathy Due to Intravascular Large B-cell Lymphoma.

Intern Med 2020 Feb 7;59(3):435-438. Epub 2019 Oct 7.

Department of Neurology, Nagoya University Graduate School of Medicine, Japan.

We herein report the case of a 67-year-old man who presented with the acute onset of limb weakness. Brain magnetic resonance imaging revealed multiple abnormal-signal-intensity lesions. Steroids were administered, and the patient initially responded. Nerve conduction testing findings were consistent with demyelinating polyneuropathy. A sural nerve biopsy specimen revealed fascicles with extensive onion-bulb formation. Although skin and sural nerve biopsies showed no atypical cellular infiltration, the histopathological diagnosis of intravascular large B-cell lymphoma was obtained by a brain biopsy. The neuropathy in this patient may be attributed to a demyelinating process independent of ischemic damage by lymphoma.
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http://dx.doi.org/10.2169/internalmedicine.3228-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028418PMC
February 2020

[Multiple mononeuropathy associated with systemic sclerosis with vasculitis confirmed by nerve biopsy: a case report].

Rinsho Shinkeigaku 2019 Sep 30;59(9):604-606. Epub 2019 Aug 30.

Department of Neurology, Tosei General Hospital.

A 68-year-old woman with a medical history of interstitial pneumonia associated with systemic sclerosis (SSc) presented with numbness of the lower limbs and left drop foot. She was diagnosed with multiple mononeuropathy based on the laterality of her symptoms, muscle weakness, thermal hypoalgesia, and nerve conduction study findings. Left sural nerve biopsy showed vasculitis, and steroid therapy was effective. This case highlights the importance of histopathological assessment to select an appropriate treatment strategy.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001320DOI Listing
September 2019

Evolution of amyloid fibrils in hereditary transthyretin amyloidosis: an ultrastructural study.

Amyloid 2019;26(sup1):26

a Department of Neurology, Nagoya University Graduate School of Medicine , Nagoya , Japan.

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http://dx.doi.org/10.1080/13506129.2019.1582496DOI Listing
January 2020

Cardiovascular autonomic functions in late-onset hereditary transthyretin amyloidosis with Val30Met mutation.

Amyloid 2019;26(sup1)

b Research Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of Medicine , Nagoya , Japan.

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http://dx.doi.org/10.1080/13506129.2019.1582018DOI Listing
January 2020

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

Intractable axonal neuropathy with multifocal peripheral nerve swelling in neuromyelitis optica spectrum disorders: A case report.

Mult Scler Relat Disord 2019 Oct 29;35:16-18. Epub 2019 Jun 29.

Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address:

We report a patient with neuromyelitis optica spectrum disorders (NMOSD) with anti-aquaporin 4 (AQP4) antibodies, who developed intractable axonal neuropathy presenting with multifocal peripheral nerve swelling by magnetic resonance (MR) neurography. A 52-year-old woman with a 12-year history of polymyositis and rheumatoid arthritis had been treated with prednisolone, tacrolimus, and abatacept (CTLA-4-Ig). She developed progressive numbness and tingling sensations in the distal parts of all limbs at the age of 50 years, followed by weakness of both upper limbs 6 months later. Neurological examination revealed severe muscle weakness and atrophy of the right upper limb with proximal dominance, diffuse moderate weakness of the left upper limb, severe sensory impairment of all modalities of four limbs in glove and stocking distribution, wide-based gait with positive Romberg's sign, and absence of all tendon reflexes. She was diagnosed with NMOSD due to positive serum anti-AQP4 antibodies and a longitudinally extensive cervical spinal cord lesion on MR images. Intravenous methylprednisolone pulse therapy, plasma exchange and intravenous immunoglobulin administration were performed, which improved the spinal cord lesion on MRI, but did not ameliorate her symptoms. Notably, she also had axonal neuropathy characterized by asymmetrical, multifocal swelling of peripheral nerves by MR neurography. Histopathological examination of the biopsied sural nerve revealed axonal degeneration and endoneurial edema but no inflammatory cell infiltration. Although she was treated with intravenous methylprednisolone, intravenous immunoglobulin, oral prednisolone, tacrolimus and tocilizumab, her symptoms gradually progressed. Neurologists should be aware of co-existing intractable axonal neuropathy in NMOSD cases presenting as immunotherapy-resistant sensorimotor disturbances.
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http://dx.doi.org/10.1016/j.msard.2019.06.033DOI Listing
October 2019

Clinicopathological characteristics of subtypes of chronic inflammatory demyelinating polyradiculoneuropathy.

J Neurol Neurosurg Psychiatry 2019 09 21;90(9):988-996. Epub 2019 Jun 21.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objective: To evaluate the clinical and pathological correlations characterising each clinical subtype of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

Methods: We assessed 106 consecutive patients who had CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria and had been referred for sural nerve biopsy. Patients with anti-neurofascin 155, anti-contactin 1 and anti-LM1 antibodies were excluded.

Results: 55 patients were classified as having typical CIDP. Regarding atypical CIDP, the multifocal acquired demyelinating sensory and motor (MADSAM) (n=15), distal acquired demyelinating symmetric (DADS) (n=16) and pure sensory (n=15) forms were major subtypes, while the pure motor (n=4) and focal (n=1) forms were rare. Nerve conduction studies revealed that distal motor latencies and F-wave latencies were markedly prolonged in the typical CIDP group but relatively preserved in the MADSAM group. Motor conduction velocity was conspicuously slowed in the DADS group, and distal motor latencies were markedly prolonged in the pure sensory group. Sural nerve biopsy specimens from patients with MADSAM, DADS and pure sensory type tended to show extreme variation in myelinated fibre density among fascicles due to focal myelinated fibre loss or onion-bulb formation, whereas patients with typical CIDP tended to show mild fascicular variation. Epineurial lymphocytic infiltration was conspicuous in cases with marked fascicular variation in myelinated fibre density.

Conclusions: Preferential involvement of distal and proximal segments and uniform pathological features in typical CIDP indicate a role of humoral factors at sites where the blood-nerve barrier is deficient. By contrast, focal lesions in MADSAM, DADS and pure sensory forms may share neuropathic mechanisms primarily affecting the nerve trunk.
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http://dx.doi.org/10.1136/jnnp-2019-320741DOI Listing
September 2019
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