Publications by authors named "Yoshiki Sekijima"

167 Publications

Absolute quantitative analysis of cardiac amyloidosis using SPECT/CT with Tc-pyrophosphate.

Amyloid 2021 Apr 7:1-2. Epub 2021 Apr 7.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.

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http://dx.doi.org/10.1080/13506129.2021.1903418DOI Listing
April 2021

Development of diagnostic antibodies against immunoglobulin heavy chain variable region for heavy chain amyloidosis (AH amyloidosis).

Pathol Int 2021 Mar 13. Epub 2021 Mar 13.

Institute for Biomedical Sciences, Shinshu University, Nagano, Japan.

It is difficult to diagnose immunoglobulin heavy chain amyloidosis (AH amyloidosis) without proteomic analysis due to no useful diagnostic antibodies. The aim of this study was to develop diagnostic antibodies available to immunohistochemistry and immunoblotting. Two rabbit anti-heavy chain variable region antibodies were generated and evaluated in immunohistochemical studies performed on 11 AH amyloidosis patients and 64 patients with other systemic amyloidoses. Additionally, immunoblotting was performed using extracted amyloid protein from one patient and serum samples from two patients with AH amyloidosis. Immunohistochemical analysis generated a positive outcome in 10 of 11 AH amyloidosis patients (sensitivity 90.9%). While positive staining was also observed in 9 of 64 non-AH amyloidosis patients (specificity 85.9%), substitution of the blocking agent reversed the positive reactivity in 5 of 9 patients. Amyloid protein band was clearly detected via immunoblotting analysis, and protein bands with similar molecular weights of amyloid protein were observed in serum samples from patients with AH amyloidosis. The two antibodies may represent a powerful diagnostic tool for AH amyloidosis. In addition, our data revealed the existence of amyloidogenic variable region fragments in the serum of patients, suggesting their potential as diagnostic markers for AH amyloidosis.
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http://dx.doi.org/10.1111/pin.13081DOI Listing
March 2021

Painless Panniculitis upon the Treatment of Clinically Amyopathic Dermatomyositis with Anti-MDA5 Antibody.

Intern Med 2021 Mar 8. Epub 2021 Mar 8.

Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, Japan.

Panniculitis, a rare cutaneous manifestation in patients with dermatomyositis (DM), usually presents as a painful erythematous lesion. We herein report a 32-year-old woman with panniculitis that appeared as an indurated plaque without pain or redness after a 4-month episode of clinically amyopathic DM during treatment with prednisolone and tacrolimus. She experienced no pain; however, the firmness and extent gradually worsened. Based on our findings, including the histopathological results, DM panniculitis was diagnosed. Azathioprine was additionally administered, leading to remission. DM panniculitis can develop as a painless induration during immunosuppressive treatment, and azathioprine may be a useful treatment.
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http://dx.doi.org/10.2169/internalmedicine.6931-20DOI Listing
March 2021

Pathologic basis of the preferential thinning of thecorpus callosum in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

eNeurologicalSci 2021 Mar 22;22:100310. Epub 2021 Jan 22.

Intractable Disease Care Center, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto 390-8621, Japan.

Background: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an early onset dementia characterized by axonal loss in the cerebral white matter with swollen axons (spheroids). It had been reported that the preferential thinning and "focal lesions" of the corpus callosum were observed on T2-weighted MRI in ALSP patients. The present study aimed to reveal the pathologic basis of them in relation to brain lesion staging (I ~ IV: Oyanagi et al. 2017).

Methods: Seven autopsied brains of ALSP and five controls were neuropathologically examined.

Results: Even at Stage I, corpus callosum body showed evident atrophy, and the atrophy advanced with stage progression. Spheroid size and density were maximal at Stage II in both centrum semiovale and corpus callosum body, but spheroids were larger in corpus callosum body than in centrum semiovale. Microglia in the body at Stage II had a larger cytoplasm than those in centrum semiovale. But spheroids and microglia in the "focal lesions" were identical with those of centrum semiovale.

Conclusion: Preferential thinning of corpus callosum was considered to be formed in relation to peculiar morphological alteration of microglia there in ALSP. Instead, "focal lesions" were formed in connection with the lesions in centrum semiovale.
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http://dx.doi.org/10.1016/j.ensci.2021.100310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844436PMC
March 2021

Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy.

Neurol Genet 2020 Dec 19;6(6):e531. Epub 2020 Nov 19.

Department of Neurology (T.I., T.O., Y. Saitoh, S.O., Y.T.), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Human Genetics (K.S., A.F., H.F., N. Miyake, T.M., N. Matsumoto), Yokohama City University Graduate School of Medicine, Kanagawa; Department of Pathology and Laboratory Medicine (T.S., Y. Saito), National Center Hospital, National Center of Neurology and Psychiatry, Tokyo; Department of Neurology (T.Y.), Iida Municipal Hospital, Shinshu University School of Medicine, Nagano; Department of Medicine (Neurology and Rheumatology) (Y.M., Y. Sekijima), Shinshu University School of Medicine, Nagano; and Department of Neurology and Stroke Medicine (H.F.), Yokohama City University, Japan.

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http://dx.doi.org/10.1212/NXG.0000000000000531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713717PMC
December 2020

Alteration of BAFF and APRIL in the cerebrospinal fluid based on the therapeutic response in primary central nervous system B-cell lymphoma.

J Clin Neurosci 2020 Nov 28;81:72-75. Epub 2020 Sep 28.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.

We evaluated the cerebrospinal fluid (CSF) levels of the B-cell activating factor of the tumor necrosis factor family (BAFF) and A proliferation-inducing ligand (APRIL) in two cases of primary central nervous system B-cell lymphoma (PCNSBL) before and after treatment. One patient achieved clinical remission, and demonstrated decrease in the CSF levels of both BAFF and APRIL after treatment. Meanwhile, the other patient with insufficient therapeutic response showed increase in the BAFF levels despite decrease in APRIL levels. This report suggests that the combination of BAFF and APRIL levels could be useful in estimating the therapeutic efficacy in treating PCNSBL as reliable CSF markers.
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http://dx.doi.org/10.1016/j.jocn.2020.09.005DOI Listing
November 2020

Triggering factors for febrile attacks in Japanese patients with familial Mediterranean fever.

Clin Exp Rheumatol 2020 Sep-Oct;38 Suppl 127(5):76-79. Epub 2020 Nov 4.

Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.

Objectives: We occasionally encounter patients with familial Mediterranean fever (FMF) whose attacks are triggered by specific factors; however, information regarding these factors is limited. Our purpose was to identify the factors that trigger febrile attacks in Japanese patients with FMF.

Methods: Our retrospective study included 372 patients (229 women, 143 men) with FMF, who were diagnosed between April 2007 and June 2018. We retrospectively investigated clinical features, genetic variants, and the factors that the patients perceived to have triggered their attacks. Patients completed a questionnaire that included the following triggering factors, anxiety, psychological stress, tiredness, excitement, environmental change, and menstruation.

Results: Of 372 patients, 180 (49.4%) reported some triggering factors. Psychological stress and tiredness were commonly reported factors regardless of sex; however, menstruation (39.7%, n=91) was the most commonly reported triggering factor in female patients with FMF. Menstrual-related patients had a younger age of onset and diagnosis, a higher frequency of peritonitis, and a higher rate of patients with endometriosis compared with the non-menstrual-related patients.

Conclusions: Gaining an understanding of these triggering factors could help to reduce attacks and educate the patients. Clinicians may need to consider FMF for patients who have fever and serositis that occurs with every menstrual period.
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December 2020

Distribution of amyloidosis subtypes based on tissue biopsy site - Consecutive analysis of 729 patients at a single amyloidosis center in Japan.

Pathol Int 2021 Jan 28;71(1):70-79. Epub 2020 Oct 28.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Nagano, Japan.

This study was performed to elucidate the distribution of amyloidosis subtypes based on tissue biopsy site. Samples obtained from 729 consecutive patients with amyloidosis were analyzed by immunohistochemical staining (IHC) and supplemental mass spectrometry (MS). The correlations between the type of organs from which samples were obtained and amyloidosis subtypes were investigated retrospectively. Among the patients, 95.1% were diagnosed by IHC and 4.9% were diagnosed by MS. The distribution of amyloidosis subtypes was as follows: AL, 59.1%; ATTR, 32.9%; AA, 4.0%; AH, 1.4%; Aβ2M, 0.8%; and others, 0.9%. AL was the most common subtype in most organs, including the liver, lung, kidney, lower urinary tract, bone marrow, gastrointestinal tract, and skin/subcutaneous tissue. ATTR was the most common subtype in the heart, carpal tunnel, and peripheral nerves. AH was the second most common subtype in renal biopsy. Three or more amyloidosis subtypes were detected in each organ. In conclusion, AL was the most common subtype in most biopsy sites except the heart, carpal tunnel, and peripheral nerve, in which ATTR was more common. Because several types of amyloidogenic protein were detected in each organ, amyloid typing must be pursued, no matter the site from where biopsy was obtained.
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http://dx.doi.org/10.1111/pin.13041DOI Listing
January 2021

Amyloid nomenclature 2020: update and recommendations by the International Society of Amyloidosis (ISA) nomenclature committee.

Amyloid 2020 Dec 26;27(4):217-222. Epub 2020 Oct 26.

Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.

The ISA Nomenclature Committee met electronically before and directly after the XVII ISA International Symposium on Amyloidosis, which, unfortunately, had to be virtual in September 2020 due to the ongoing COVID-19 pandemic instead of a planned meeting in Tarragona in March. In addition to confirmation of basic nomenclature, several additional concepts were discussed, which are used in scientific amyloid literature. Among such concepts are cytotoxic oligomers, protofibrils, primary and secondary nucleation, seeding and cross-seeding, amyloid signature proteins, and amyloid plaques. Recommendations for their use are given. Definitions of amyloid and amyloidosis are confirmed. Possible novel human amyloid fibril proteins, appearing as 'classical' amyloid, were discussed. It was decided to include fibulin-like extracellular matrix protein 1 (amyloid protein: AEFEMP1), which appears as localised amyloid in portal veins. There are several possible amyloid proteins under investigation, and these are included in a new Table.
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http://dx.doi.org/10.1080/13506129.2020.1835263DOI Listing
December 2020

Development of Arthritis as the Initial Involvement in Adult-Onset Cutaneous Polyarteritis Nodosa: Two Cases and Literature Review.

Case Rep Rheumatol 2020 16;2020:8897358. Epub 2020 Sep 16.

Department of Medicine, Neurology and Rheumatology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.

Articular symptoms are commonly present in polyarteritis nodosa (PAN). Meanwhile, they may occur as the initial and main involvement of PAN, raising a concern of a delay in a definitive diagnosis of disease unless the histological evidence is obtained. Herein, we report two cases of cutaneous PAN (c-PAN) in which arthritis developed as the initial clinical episode of disease and we argued, through a review of the literature, the clinical feature of patients presenting with arthritis as the initial symptom of PAN. To our knowledge, only six cases have been reported in the English literature, and all six patients were categorized as having c-PAN. Of those patients, four had arthritis with indicating destructive changes. A median of 9 years elapsed prior to the induction of immunosuppressive treatment despite the fact that the other reviewed cases as well as our two patients, who received treatment significantly earlier, showed no evidence of joint destruction. Taken together, this report suggests that the early induction of therapy based on the definitive diagnosis of PAN may be required for preventing joint disruption even though it is not easy to make a diagnosis of PAN unless biopsied tissue can provide the evidence of necrotizing vasculitis.
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http://dx.doi.org/10.1155/2020/8897358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516710PMC
September 2020

Late-onset Hereditary ATTR Amyloidosis with a Novel p.P63S (P43S) Transthyretin Variant.

Intern Med 2021 Feb 30;60(4):557-561. Epub 2020 Sep 30.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.

The patient was an 82-year-old Japanese man with no family history suggestive of amyloidosis. He developed bilateral leg edema and shortness of breath and was referred to our hospital. An electrocardiogram showed atrial fibrillation with right bundle branch block. Echocardiography showed concentric LV hypertrophy. An endomyocardial biopsy showed severe ATTR amyloid deposits. A genetic analysis of the transthyretin (TTR) gene revealed a heterozygous c.187C>T missense variant resulting in p.P63S (P43S). In silico analyses predicted that this variant only modestly altered the structure and function of the TTR protein. The p.P63S variant might be associated with an elderly-onset cardiac-dominant ATTRv phenotype.
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http://dx.doi.org/10.2169/internalmedicine.5615-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946494PMC
February 2021

Giant Hepatomegaly with Spleno-testicular Enlargement in a Patient with Apolipoprotein A-I Amyloidosis: An Uncommon Type of Amyloidosis in Japan.

Intern Med 2021 Feb 30;60(4):575-581. Epub 2020 Sep 30.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.

Hereditary systemic amyloidosis aside from transthyretin-related familial amyloid polyneuropathy is quite uncommon in Japan. We herein report a sporadic case of hereditary apolipoprotein A-I (apoAI) amyloidosis. The patient was a 43-year-old Japanese man who exhibited marked hepatomegaly with spleno-testicular enlargement. While he was initially thought to have primary AL amyloidosis, a proteomics analysis revealed that the amyloid was composed of variant apoAI with an E34K variant. To date, only one patient with apoAI amyloidosis has been reported in Japan. However, our study suggests that more patients may be present in Japan, and the majority may have been diagnosed with other types of amyloidosis due to its clinical similarity.
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http://dx.doi.org/10.2169/internalmedicine.5126-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946490PMC
February 2021

Dialysis-related amyloidosis associated with a novel β-microglobulin variant.

Amyloid 2021 Mar 2;28(1):42-49. Epub 2020 Sep 2.

Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan.

Till date, there had been no reported case of dialysis-related amyloidosis (DRA) associated with a β-microglobulin variant. We report here a 41-year-old haemodialysis patient with systemic amyloidosis, exhibiting macroglossia and swelling salivary glands, uncommon clinical manifestations for DRA. Molecular analysis showed that the patient had a new variant of β-microglobulin (V27M). Extracted amyloid protein was predominantly composed of variant β-microglobulin. analysis revealed that this variant β-microglobulin had a strong amyloidogenic propensity, probably owing to the decreased stability caused by a bulky methionine residue. Our data clearly show that V27M variant is amyloidogenic and this mutation results in unusual clinical manifestations. To date, only one amyloidogenic β-microglobulin variant (D76N) has been reported in non-dialysis patients. It is noteworthy that the V27M and D76N variants show substantial differences in both clinical phenotypes and pathomechanical features. This is the first case of DRA associated with a naturally occurring β-microglobulin variant.
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http://dx.doi.org/10.1080/13506129.2020.1813097DOI Listing
March 2021

Characteristics of Patients with Hereditary Transthyretin Amyloidosis and an Evaluation of the Safety of Tafamidis Meglumine in Japan: An Interim Analysis of an All-case Postmarketing Surveillance.

Clin Ther 2020 09 12;42(9):1728-1737.e6. Epub 2020 Aug 12.

Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Pharmacy, Nagasaki International University, Nagasaki, Japan.

Purpose: An all-case, single-arm, observational, postmarketing surveillance is underway to assess the safety of tafamidis in patients with hereditary transthyretin (ATTRv) amyloidosis with peripheral polyneuropathy, also called transthyretin-type familial amyloid polyneuropathy, in Japan. Results from an interim analysis (data cutoff date, May 15, 2018) are presented in this preliminary report.

Methods: Patients were registered and treated with tafamidis meglumine 20 mg/d in routine clinical practice (observation period, 156 weeks). Data on patient demographic and clinical characteristics and adverse drug reactions (ADRs) were captured using case-report forms.

Findings: Of 219 patients included (mean age, 59.7 years; patients with age at disease onset ≥50 years, 61.2%; mean treatment duration, 95.5 weeks), 143 (65.3%) were male, 126 (57.5%) had a family history of ATTRv amyloidosis, and 149 (68.0%) originated from nonendemic areas. The most common ADRs were diarrhea (1.4%) and hematuria (0.9%). Six serious ADRs (pneumonia, bacteremia, malignant melanoma, pancreatic carcinoma, hematuria, and hereditary neuropathic amyloidosis [primary disease exacerbation]) were reported; no ADRs leading to death were recorded.

Implications: This interim analysis successfully provided comprehensive, nationwide epidemiologic data from 219 Japanese patients with ATTRv amyloidosis. The safety profile of tafamidis was largely consistent with that obtained from previous research. No new safety concerns were identified to date. Data presented in this interim analysis are subject to change following completion of the study, and we will continue to assess the safety and effectiveness of tafamidis throughout the study. ClinicalTrials.gov identifier: NCT02146378.
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http://dx.doi.org/10.1016/j.clinthera.2020.07.001DOI Listing
September 2020

Non-invasive detection and differentiation of cardiac amyloidosis using Tc-pyrophosphate scintigraphy and C-Pittsburgh compound B PET imaging.

Amyloid 2020 Dec 28;27(4):266-274. Epub 2020 Jul 28.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.

Purpose: To investigate the utility of the combined use of C-Pittsburgh compound B (C-PiB) positron emission tomography (PET) imaging and Tc-pyrophosphate (Tc-PYP) scintigraphy for detection and differentiation of three major types of cardiac amyloidosis, i.e. immunoglobulin light chain (AL), hereditary transthyretin (ATTRv), and wild-type transthyretin (ATTRwt) amyloidosis.

Methods: Whole-body C-PiB PET and Tc-PYP scintigraphy were performed in 17 patients with AL amyloidosis, 22 patients with ATTRv, and eight patients with ATTRwt amyloidosis. The correlations between organ involvement and the uptake of C-PiB and Tc-PYP were analyzed in each patient.

Results: Cardiac amyloidosis was detectable by Tc-PYP scintigraphy or C-PiB PET in all systemic amyloidosis patients with cardiac involvement. Tc-PYP scintigraphy and C-PiB PET showed an interesting complementary relation. Strict combination of positive C-PiB and negative Tc-PYP uptake (PiB pattern) was observed in all AL amyloidosis patients with cardiac involvement. In contrast, strict combination of positive Tc-PYP and negative C-PiB uptake (PYP pattern) was observed in all ATTRwt amyloidosis patients with cardiac involvement. ATTRv amyloidosis patients with cardiac involvement were divided into two groups: PiB pattern or PYP pattern. All of the early-onset V30M (p.V50M) ATTRv patients showed the PiB pattern, whereas all of the late-onset V30M and non-V30M ATTRv patients showed the PYP pattern.

Conclusions: All three major types of cardiac amyloidosis can be detected and differentiated non-invasively by combined use of the two amyloid imaging methods and gene testing.
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http://dx.doi.org/10.1080/13506129.2020.1798223DOI Listing
December 2020

The identified clinical features of Parkinson's disease in homo-, heterozygous and digenic variants of PINK1.

Neurobiol Aging 2021 01 2;97:146.e1-146.e13. Epub 2020 Jul 2.

Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan; Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Tokyo, Japan. Electronic address:

To investigate the prevalence and genotype-phenotype correlations of phosphatase and tensin homolog induced putative kinase 1 (PINK1) variants in Parkinson's disease (PD) patients, we analyzed 1700 patients (842 familial PD and 858 sporadic PD patients from Japanese origin). We screened the entire exon and exon-intron boundaries of PINK1 using Sanger sequencing and target sequencing by Ion torrent system. We identified 30 patients with heterozygous variants, 3 with homozygous variants, and 3 with digenic variants of PINK1-PRKN. Patients with homozygous variants presented a significantly younger age at onset than those with heterozygous variants. The allele frequency of heterozygous variants in patients with age at onset at 50 years and younger with familial PD and sporadic PD showed no differences. [I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy indicated that half of patients harboring PINK1 heterozygous variants showed a decreased heart to mediastinum ratio (12/23). Our findings emphasize the importance of PINK1 variants for the onset of PD in patients with age at onset at 50 years and younger and the broad spectrum of clinical symptoms in patients with PINK1 variants.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.06.017DOI Listing
January 2021

Clinical characteristics of patients with myalgia as the initial manifestation of small and medium-sized vasculitis: a retrospective study.

Rheumatol Int 2020 Oct 24;40(10):1667-1674. Epub 2020 Jul 24.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.

Myalgia is a common symptom in small and medium-sized systemic vasculitis, sometimes occurring as the initial or only clinical manifestation of vasculitis. This study investigated the clinical features and diagnostic process in patients presenting with myalgia as the initial symptom of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) or polyarteritis nodosa (PAN). We included 93 patients diagnosed with AAV or PAN by retrospectively reviewing their clinical records at the initial diagnosis. Clinical findings and diagnostic methods were assessed in patients with myalgia. Of 93 patients, myalgia was observed in 21 (22.6%) patients, with diagnostic classifications of microscopic polyangiitis (MPA) in 12 (52.4%), granulomatosis with polyangiitis in 2 (9.5%), eosinophilic granulomatosis with polyangiitis in 2 (9.5%), and PAN in 5 (23.8%). Myalgia was present in the lower extremities of all patients; more than 80% of patients had pain in the calf muscle. In 10 patients with myalgia, including 7 with MPA and 3 with PAN, muscle biopsy was performed because myalgia was the main symptom and no other impaired organs were suitable for biopsy. Consequently, 8 patients had necrotizing vasculitis, leading to MPA or PAN diagnosis, although muscle pathology was not evaluated in patients without myalgia. Muscle magnetic resonance imaging was useful in determining the biopsy site. Myalgia, especially in the lower limbs, may be an initial clinical sign of vasculitis, particularly in MPA or PAN patients. Moreover, the histological evidence of muscular vasculitis can contribute to a definite diagnosis especially in patients presenting with myalgia as an early symptom of AAV or PAN.
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http://dx.doi.org/10.1007/s00296-020-04652-yDOI Listing
October 2020

Cerebrospinal fluid levels of BAFF and APRIL as direct indicators of disease activity in anti-neutrophil cytoplasmic antibody-related hypertrophic pachymeningitis.

Clin Rheumatol 2020 Oct 4;39(10):3145-3148. Epub 2020 Jul 4.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.

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http://dx.doi.org/10.1007/s10067-020-05270-6DOI Listing
October 2020

A case of novel amyloidosis: glucagon-derived amyloid deposition associated with pancreatic neuroendocrine tumour.

Amyloid 2021 Mar 29;28(1):72-73. Epub 2020 Jun 29.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.

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http://dx.doi.org/10.1080/13506129.2020.1785417DOI Listing
March 2021

A Late-onset and Relatively Rapidly Progressive Case of Pure Spinal Form Cerebrotendinous Xanthomatosis with a Novel Mutation in the CYP27A1 Gene.

Intern Med 2020 Oct 23;59(20):2587-2591. Epub 2020 Jun 23.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.

A 61-year-old Japanese man with the pure spinal form of cerebrotendinous xanthomatosis developed dysesthesia of the lower limbs and gait disturbance at 57 years of age. At 61 years old, he was unable to walk without support. A neurological examination showed spasticity and sensory disturbance in the lower limbs. Spinal MRI showed long hyperintense lesions involving the lateral and posterior funiculus in the cervical and thoracic cord on T2-weighted images. His serum cholestanol level was markedly elevated. A CYP27A1 gene analysis identified two missense variants, p.R474W, and a novel p.R262C variant. Combination therapy with chenodeoxycholic acid and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase decreased his serum cholestanol level.
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http://dx.doi.org/10.2169/internalmedicine.5037-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662043PMC
October 2020

Gray Matter Encephalomyelitis with Anti-Myelin Oligodendrocyte Glycoprotein Antibody.

Intern Med 2020 10 23;59(19):2435-2436. Epub 2020 Jun 23.

Department of Neurology and Rheumatology, Shinshu University School of Medicine, Japan.

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http://dx.doi.org/10.2169/internalmedicine.5011-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644494PMC
October 2020

Moyamoya syndrome related to systemic lupus erythematosus developing during pregnancy: a case-based review.

Clin Rheumatol 2020 Dec 19;39(12):3861-3867. Epub 2020 Jun 19.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.

Moyamoya syndrome (MMS) is a chronic cerebrovascular disorder characterized by occlusion or stenosis of the internal carotid arteries with the formation of abnormal collateral vascular networks. Moreover, the development of MMS, which is a distinct category from "moyamoya disease," is attributed to the underlying disease, while some cases of MMS related to systemic lupus erythematosus (SLE) have been previously reported. Herein, we present the case of a 29-year-old Japanese woman with SLE in whom intracranial hemorrhage ascribable to MMS developed during pregnancy. Craniotomy was performed to remove hematoma, and prednisolone, tacrolimus, and hydroxychloroquine were consecutively administered. She ultimately achieved remission and childbearing without the relapse of cerebrovascular event. To our knowledge, this is the first report of MMS associated with SLE in pregnancy. Through reviewing published English articles and our case, it was suggested that the pathogenesis of SLE is implicated in the development of moyamoya vasculopathy leading to cerebrovascular events. Moreover, pregnancy may affect the bleeding from the fragile collateral vessel wall.
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http://dx.doi.org/10.1007/s10067-020-05246-6DOI Listing
December 2020

An Elderly Case of Paraneoplastic Anti-NMDA Receptor Encephalitis Associated with Small-cell Lung Cancer Expressing NR1 Subunits.

Intern Med 2020 Sep 2;59(18):2307-2309. Epub 2020 Jun 2.

Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, Japan.

A 61-year-old Japanese man presented with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. NR1 antibodies were detected in his cerebrospinal fluid. Chest computed tomography revealed lung tumor. The patient was diagnosed with paraneoplastic anti-NMDAR encephalitis associated with lung cancer and treated with two cycles of intravenous high-dose methylprednisolone and one cycle of intravenous immunoglobulin. However, he died one year later without improvement. An autopsy confirmed small-cell lung cancer (SCLC). Immunohistochemistry revealed the expression of NR1 subunits in the tumor cells, suggesting that SCLC may trigger NR1 autoimmunity though the expression of NR1 subunits as onconeural antigens, expanding the phenotypic spectrum of paraneoplastic neurological syndrome associated with SCLC.
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http://dx.doi.org/10.2169/internalmedicine.4860-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578603PMC
September 2020

Elderly patient with 5q spinal muscular atrophy type 4 markedly improved by Nusinersen.

J Neurol Sci 2020 08 17;415:116901. Epub 2020 May 17.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto 390-8621, Japan.

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http://dx.doi.org/10.1016/j.jns.2020.116901DOI Listing
August 2020

Macrophage activation syndrome in adult dermatomyositis: a case-based review.

Rheumatol Int 2020 Jul 30;40(7):1151-1162. Epub 2020 Apr 30.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.

Macrophage activation syndrome (MAS) is a severe and life-threatening syndrome associated with autoimmune diseases, characterized by fever, hepatosplenomegaly, and pancytopenia. Dermatomyositis (DM) is one of the causes of MAS; however, its clinical characteristics in DM patients remain unclear. This study aimed to present a case of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM complicated by MAS in a 29-year-old woman and to review the literatures including similar cases. Even though symptoms and cytopenia of our patient were refractory to combination therapy, including glucocorticoids, immunosuppressants, and plasma exchange, the administration of rituximab (RTX) resulted in rapid clinical improvement and glucocorticoid reduction. The literature review revealed 18 adult patients with DM associated MAS. Most patients developed MAS within 3 months from DM onset. A monotherapy of glucocorticoid was insufficient to control the disease, and the mortality of MAS in DM was higher than that of MAS in other rheumatic diseases, despite being treated by various means. RTX may be an effective treatment for patients with DM complicated by MAS who are refractory to conventional therapy. Anti-MDA5 antibody could influence the development of MAS; however, further investigations are needed to elucidate the association between myositis-specific antibody and MAS.
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http://dx.doi.org/10.1007/s00296-020-04590-9DOI Listing
July 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

Primary central nervous system lymphoma in neuropsychiatric systemic lupus erythematosus: case-based review.

Rheumatol Int 2021 May 6;41(5):1009-1017. Epub 2020 Apr 6.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan.

Primary central nervous system lymphoma (PCNSL) sometimes occurs in immune-compromised hosts or patients with autoimmune diseases. Some cohort studies have previously reported an increased risk of non-Hodgkin's lymphoma in systemic lupus erythematosus (SLE), while some cases of PCNSL in patients with SLE were reported. We present the case of PCNSL which developed in a patient with the active phase of neuropsychiatric SLE (NPSLE). Furthermore, we reviewed published English articles to confirm the characteristics of PCNSL related to SLE. To our knowledge, this is the first report of PCNSL occurring in NPSLE. Histology demonstrated B-cell lymphoma with a positive Epstein-Barr virus-encoded RNA. This patient recovered following surgical resection of the lymphoma, whole brain radiation therapy, intravenous infusion of rituximab (RTX), and administration of belimumab after RTX. Given the series of reviews, our report suggests that the persistence of damage in the central nervous system (CNS) and long-term exposure to immunosuppressants may impact oncogenic immune responses within the CNS, leading to PCNSL development.
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http://dx.doi.org/10.1007/s00296-020-04569-6DOI Listing
May 2021

Limbic Encephalitis with Anti-myelin Oligodendrocyte Glycoprotein Antibody.

Intern Med 2020 06 5;59(11):1465-1466. Epub 2020 Mar 5.

Department of Neurology and Rheumatology, Shinshu University School of Medicine, Japan.

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http://dx.doi.org/10.2169/internalmedicine.4216-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332617PMC
June 2020

Taste disorder in facial onset sensory and motor neuronopathy: a case report.

BMC Neurol 2020 Feb 29;20(1):71. Epub 2020 Feb 29.

Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.

Background: Taste disorder is a common symptom in the general population. Several studies have shown that patients with neurological disorders, such as amyotrophic lateral sclerosis and Parkinson's disease, develop taste disturbance. Facial onset sensory and motor neuronopathy (FOSMN) is a rare disease characterized by sensory disturbance and weakness spreading from the face to the limbs caudally. We describe a patient with FOSMN who showed taste disorder as the sole initial symptom.

Case Presentation: A 49-year-old man who smoked cigarettes developed taste disturbance. Despite using zinc supplements, an herbal medication, and an ointment, his taste disorder worsened. 4 years later, a tingling feeling emerged at the tip of his tongue and gradually spread to his entire lips. At 55 years of age, he showed difficulty in swallowing, followed by facial paresthesia, muscle atrophy, and weakness in the face and upper limbs without apparent upper motor neuron sign. Cessation of smoking did not improve his taste disturbance, and he was unable to discriminate different tastes on the entire tongue. In an electrogustometric study, electrical stimulation did not induce any type of taste sensation. Blink reflex showed delayed or diminished R2 responses. Needle electromyography revealed severe chronic neurogenic changes in the tongue and masseter muscles. Mild chronic neurogenic changes were also observed in the limbs. In the thoracic paraspinal muscles, active neurogenic changes were detected. Findings of hematological and cerebrospinal fluid analyses, and magnetic resonance images of the brain and spinal cord were unremarkable. One cycle of intravenous immunoglobulin therapy did not improve his symptoms. We diagnosed him as having FOSMN with the sole initial symptom of taste disorder. Nine years after the onset of taste disorder, he developed impaired sensation of touch in the right upper limb and required tube feeding and ventilator support.

Conclusion: Taste disorder can be the initial manifestation of FOSMN and might involve the solitary nucleus.
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http://dx.doi.org/10.1186/s12883-020-01639-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049225PMC
February 2020