Papers by Yoshiki Sekijima
Human Pathology, Nov 1, 2011
Carpal tunnel syndrome is the most common type of entrapment neuropathy. However, the cause of ca... more Carpal tunnel syndrome is the most common type of entrapment neuropathy. However, the cause of carpal tunnel syndrome remains unclear in most cases. Senile systemic amyloidosis, induced by wild-type transthyretin deposition, is a prevalent aging-related disorder and often accompanied by carpal tunnel syndrome. In this study, we measured the frequency of unrecognized wild-type transthyretin deposition in idiopathic carpal tunnel syndrome patients. One-hundred and twenty-three patients with carpal tunnel syndrome, including 100 idiopathic patients, treated by carpal tunnel release surgery were analyzed. Tenosynovial tissues obtained at surgery were analyzed by Congo red and immunohistochemical staining. If staining for transthyretin was positive, the entire TTR gene was analyzed by direct DNA sequencing. We also analyzed tenosynovial tissues from 32 autopsy cases as controls. Thirty-four (34.0%) patients with idiopathic carpal tunnel syndrome showed amyloid deposition in the tenosynovial tissue, and all amyloid showed specific immunolabelling with anti-transthyretin antibody. Direct DNA sequencing of the entire TTR gene did not reveal any mutations, indicating that all amyloid deposits were derived form wild-type transthyretin. Statistical analysis using logistic regression showed that the prevalence of transthyretin deposition in the idiopathic carpal tunnel syndrome group was significantly higher than that in controls (odds ratio 15.8, 95% CI 3.3-75.7), and age and male gender were independent risk factors for transthyretin amyloid deposition. Our results demonstrate that wild-type transthyretin deposition is a common cause of carpal tunnel syndrome in elderly men. It is likely that many patients develop carpal tunnel syndrome as an initial symptom of senile systemic amyloidosis.
medRxiv (Cold Spring Harbor Laboratory), Feb 16, 2023
Objective: Providing appropriate health information to patients with systemic lupus erythematosus... more Objective: Providing appropriate health information to patients with systemic lupus erythematosus (SLE) is advantageous in the treatment decision-making process. We aimed to investigate how online health information-seeking behavior affects shared decision-making (SDM) in patients with SLE. Methods: This cross-sectional study included 464 patients with SLE from five institutions. The main exposure was time spent on the Internet per day, which was divided into four categories (none, <1 h, 1-<2 h, and ≥2 h). Participants categorized their preferred first source of health information as physicians, the Internet, or other media. The outcome was the degree of SDM measured via the 9-item Shared Decision-Making Questionnaire (SDM-Q-9). A general linear model was applied. Results: Compared with no Internet use, longer internet use was associated with a higher SDM-Q-9 score: <1 h, 6.9 points (95% confidence interval [CI] 0.32 to 13.6) and ≥2 h, 8.75 points, (95% CI 0.61 to 16.9). The SDM-Q-9 did not differ between those who chose physicians and those who chose the Internet as their preferred first source of health information
Internal Medicine, Oct 15, 2020
A 61-year-old Japanese man with the pure spinal form of cerebrotendinous xanthomatosis developed ... more 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.
Internal Medicine, 2020
Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by a recurrent fe... more Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by a recurrent fever and multiple serositis. In the present report, we discuss the case of a 42-year-old man diagnosed with FMF accompanied by recurrent aseptic meningitis (RAM). The patient experienced RAM at intervals of several years without any serositis or synovitis. We detected Mediterranean fever (MEFV) gene mutations (E148Q homozygotes) and diagnosed FMF in perfect accordance with clinical diagnostic criteria. FMF, in which RAM is a major symptom, has also been described in previous reports. Therefore, FMF should be considered in the differential diagnosis of causative diseases for RAM.
BMC Nephrology, Jun 26, 2023
Background Light and heavy chain deposition disease (LHCDD) is a rare condition characterised by ... more Background Light and heavy chain deposition disease (LHCDD) is a rare condition characterised by the deposition of immunoglobulin components in the kidneys. Similarly, Amyloidosis is also caused by the deposition of light chain and/or heavy chain components of immunoglobulins which are folded into amyloid fibrils characterised by Congophilic deposits that exhibit apple-green birefringence under polarised light. Only a handful of reports describing LHCDD with amyloid fibril deposition have been previously published, however, none have characterized the composition of the deposited immunoglobulin components via mass spectrometry. We report a case of a 79-year-old Japanese woman with nephrotic syndrome. Bone marrow aspiration revealed a slight proliferation of plasma cells (under 10%). Immunofluorescence assessment of renal biopsy showed amyloid-like deposits in the glomerulus that were positive for IgA and kappa. Further, the Congo red staining of the deposits was faintly positive, and only a slight birefringence was detected. Electron microscopy confirmed fine fibrillar structures and non-amyloid deposits. Finally, mass spectrometry revealed that the deposits were composed of abundant amounts of light chain with small amounts of heavy chain. Therefore, the patient was diagnosed with LHCDD and focal amyloid deposition. Chemotherapy was subsequently initiated, which resulted in haematological and renal response. Under polarised light, faint birefringence with Congo red staining and periodic acid-methenamine silver positivity indicated that the deposits were mostly non-amyloid fibrils with a small component of amyloid fibrils. Generally, the diagnosis of heavy-and light-chain amyloidosis is defined by greater heavy chain deposition compared to the light chain. However, in our case, contrary to the definition, the light-chain deposition was far greater than that of the heavy-chain. Conclusions This is the first case of LHCDD with focal amyloid deposition diagnosed by analysing the glomerular deposits by mass spectrometry.
Circulation journal, Nov 24, 2018
Clinical Rheumatology, Feb 8, 2020
Objective: Hypertrophic pachymeningitis (HP) related to anti-neutrophil cytoplasmic antibody (ANC... more Objective: Hypertrophic pachymeningitis (HP) related to anti-neutrophil cytoplasmic antibody (ANCA) is the most frequently seen immune-mediated HP. We investigated cerebrospinal fluid (CSF) biomarkers related to the pathogenesis of ANCA-related HP (ANCA-HP). Methods: The levels of B-cell activation factor of the tumor necrosis factor family (BAFF), a proliferation-inducing ligand (APRIL), and transforming growth factor beta 1 (TGF-β1) in the CSF were compared between patients with ANCA-HP (n = 12), other types of immune-mediated HP (other HP; n = 12), multiple sclerosis (MS; n = 14), and non-inflammatory neurological disorders (NIND; n = 10). In addition, we evaluated whether ANCA would be detected in CSF. Results: CSF levels of BAFF, APRIL, and TGF-β1 were significantly increased in ANCA-HP and other HP. In particular, BAFF and APRIL levels were significantly correlated with the IgG index in ANCA-HP. In other HP, BAFF and APRIL levels were significantly correlated with cell counts and protein levels in CSF. Of 12 patients with ANCA-HP, the CSF of 7 patients (58%) tested positive for myeloperoxidase (MPO)-or proteinase 3 (PR3)-ANCA, while none of the CSF samples from other HP, MS, or NIND patients tested positive. The levels of BAFF, APRIL, and TGF-β1 may serve as useful CSF biomarkers for assessing the disease activity of immune-mediated HP. Moreover, BAFF and APRIL in the CSF may be implicated in the pathogenesis of ANCA-HP via promoting autoreactive B cells, while detecting Ikeda J, et al. 3 MPO-or PR3-ANCA in the CSF may be found in some patients with ANCA-HP.
International Heart Journal, Jan 29, 2022
The diagnosis of cardiac amyloidosis is frequently delayed because histological confirmation is o... more The diagnosis of cardiac amyloidosis is frequently delayed because histological confirmation is often challenging. Few studies have attempted to clarify the utility and safety of abdominal fat pad fine-needle aspiration (FPFNA) for an initial screening test in patients with suspected cardiac amyloidosis. This study included 77 consecutive patients with suspected non-ischemic cardiomyopathy who had left ventricular dysfunction and/or hypertrophy. All patients underwent abdominal FPFNA and an endomyocardial biopsy. In all patients, the abdominal FPFNA could be performed within less than 5 minutes with no complications; however, in 1 patient (1.3%), the obtained specimen was too small to evaluate. Among the remaining 76 patients, 5 (6.6%) were positive for amyloid (FPFNA[+]) and 7 (9.2%), including the 5 FPFNA[+], were diagnosed with cardiac amyloidosis (AL = 1, ATTR = 6) by endomyocardial biopsy. Positive abdominal FPFNAs indicated cardiac amyloidosis with high accuracy (sensitivity, 71.4%; specificity, 100%). Positive abdominal FPFNAs are directly linked to diagnoses of cardiac amyloidosis. Abdominal FPFNA is simple and useful for the initial screening test for cardiac amyloidosis in patients with non-ischemic cardiomyopathy.
Journal of the Neurological Sciences, Apr 1, 2019
We report a novel nonsense variant in the CACNA1A gene. Our patients showed paroxysmal exerti... more We report a novel nonsense variant in the CACNA1A gene. Our patients showed paroxysmal exertion-induced dyskinesia with mild ataxia and intellectual disability. The present study might broaden the clinical overlap between SLC2A1-and CACNA1A-related disorders.
Journal of Atherosclerosis and Thrombosis, Sep 1, 2021
diverse clinical symptoms cause a substantial diagnostic delay . Replacement treatment with cheno... more diverse clinical symptoms cause a substantial diagnostic delay . Replacement treatment with chenodeoxycholic acid (CDCA) in the early stage of the disease has been reported to improve or even prevent clinical symptoms of CTX ; however, after significant neurological pathology is established, the effect of the treatment is limited and deterioration of clinical manifestations may continue . Therefore, it is crucial to treat CTX patients at the initial stage of the disease. In this article, we provide the current understanding of the underlying pathomechanisms, clinical manifestations, diagnosis, and treatment of CTX. CTX is caused by mutations in the CYP27A1 gene encoding sterol 27-hydroxylase, a key enzyme in the bile acid synthesis pathway. A schematic Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disorder caused by mutations in the CYP27A1 gene, which encodes the mitochondrial enzyme sterol 27-hydroxylase. Decreased sterol 27-hydroxylase activity results in impaired bile acid synthesis, leading to reduced production of bile acids, especially chenodeoxycholic acid (CDCA), as well as elevated serum cholestanol and urine bile alcohols. The accumulation of cholestanol and cholesterol mainly in the brain, lenses, and tendons results in the characteristic clinical manifestations of CTX. Clinical presentation is characterized by systemic symptoms including neonatal jaundice or cholestasis, refractory diarrhea, juvenile cataracts, tendon xanthomas, osteoporosis, coronary heart disease, and a broad range of neuropsychiatric manifestations. The combinations of symptoms vary from patient to patient and the presenting symptoms, especially in the early disease phase, may be nonspecific, which leads to a substantial diagnostic delay or underdiagnosis. Replacement of CDCA has been approved as a first-line treatment for CTX, and can lead to biochemical and clinical improvements. However, the effect of CDCA treatment is limited once significant neuropsychiatric manifestations are established. The age at diagnosis and initiation of CDCA treatment correlate with the prognosis of patients with CTX. Therefore, early diagnosis and subsequent treatment initiation are essential.
Frontiers in Immunology, Dec 7, 2021
We investigated the characteristics of regulatory T cells (Tregs), focusing on the relationship b... more We investigated the characteristics of regulatory T cells (Tregs), focusing on the relationship between their stability and reactive oxygen species (ROS), in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Intracellular expressions of effector cytokines, forkhead box protein 3 (FoxP3), ROS, phosphorylated mammalian target of rapamycin (mTOR), and sirtuin 1 (SIRT1) in Tregs from peripheral blood mononuclear cells (PBMCs) of patients with AAV and healthy controls (HC) were analyzed. The alterations in and functional ability of Tregs were compared before and after resveratrol (RVL) treatment of PBMCs in patients with AAV. Significantly higher expressions of interferon (IFN)-g, interleukin (IL)-17, IL-4, ROS, and phosphorylated mTOR (pho-mTOR) and lower expression of SIRT1 in CD4+CD25+FoxP3+ cells were found in patients with AAV than in the HC. FoxP3 expression in CD4+CD25+ cells and suppressive function of Tregs were significantly lower in patients with AAV than in the HC. Tregs after RVL treatment demonstrated significant decreases in IFN-g, ROS, and pho-mTOR levels and increases in FoxP3, SIRT1 levels, and functional activity. Conversely, the direct activation of SIRT1 by SRT1720 resulted in decreased FoxP3 expression, with no reduction in ROS levels. The pho-mTOR levels were significantly higher in Tregs after activation by SRT1720 than in those after RVL treatment. This study suggested that imbalanced changes in Tregs could be attributed to mTOR activation, in which ROS overproduction was predominantly implicated. Therefore, ROS is a key mediator for promoting Tregs instability in AAV.
Internal Medicine, 2017
The current standard diagnostic approach for progressive multifocal leukoencephalopathy (PML) is ... more The current standard diagnostic approach for progressive multifocal leukoencephalopathy (PML) is to perform a DNA test to identify the presence of the JC virus in cerebrospinal fluid (CSF). A 32-year-old woman with a 5-year history of systemic lupus erythematosus developed right hemiplegia and motor aphasia. MRI revealed a large white matter lesion in the left frontal lobe. JC virus DNA was undetectable in the CSF, but a brain biopsy showed typical histopathology and a high DNA load of the JC virus. The patient was treated with mefloquine and mirtazapine, and is currently alive at 24 months after onset. An early brain biopsy may therefore be important for making a timely diagnosis of PML.
Circulation journal, Dec 25, 2019
Ministry of Health, Labour and Welfare (JMHLW) approved tafamidis (Vyndaqel ® , Pfizer) the treat... more Ministry of Health, Labour and Welfare (JMHLW) approved tafamidis (Vyndaqel ® , Pfizer) the treatment of cardiomyopathy caused by both wild-type TTR (TTRwt) and variant TTR (TTRv)-derived amyloidoses. The approval was based on the Tafamidis Phase 3 Transthyretin Amyloid Cardiomyopathy Study, which was presented at the European Society of Cardiology 2018 Congress in Munich, Germany, and published in the New England Journal of Medicine. 2 In that trial, 441 patients with ATTR amyloid cardiomyopathy (either hereditary ATTR [ATTRv] or ATTRwt) were randomized in a 2:1:2 ratio to 80 mg tafamidis meglumine (48.8 mg tafamidis), 20 mg tafamidis meglumine (12.2 mg tafamidis), or matching placebo and assessed for the A myloidosis is a group of diseases in which amyloid fibrils deposit in the extracellular spaces of different organs, ultimately leading to progressive organ dysfunction. Amyloid fibrils are formed by an aggregation of misfolded proteins. The most common amyloid fibril proteins that can infiltrate the heart and lead to cardiac amyloidosis are immunoglobulin light-chain amyloid fibril protein (AL) and transthyretin (TTR) amyloid fibril protein (ATTR). Wild-type TTR-derived cardiac amyloidosis occurs mostly in older patients, in whom misfolded transthyretin proteins deposit in the heart. TTR is a soluble human plasma protein that can be converted into amyloid by dissociation of the homotetramer into monomers. The drug tafamidis binds to the TTR tetramer and dramatically slows dissociation, thereby efficiently inhibiting aggregation. 1
International Journal of Rheumatic Diseases, Feb 20, 2017
Aim: To elucidate the characteristics of patients with hypertrophic pachymeningitis (HP) in a pop... more Aim: To elucidate the characteristics of patients with hypertrophic pachymeningitis (HP) in a population with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We retrospectively investigated the clinical records of 39 patients who were diagnosed with AAV. To determine the characteristics of HP in AAV, the epidemiological and clinical data from patients with HP were statistically compared with those from patients without HP. Results: Of 39 patients with AAV, seven (17.9%) had associated HP. All patients with HP were classified as having granulomatosis with polyangiitis (GPA), whereas only five of 32 patients without HP were diagnosed as having GPA (P < 0.0001). The frequencies of myeloperoxidase (MPO)-ANCA and proteinase 3-ANCA positivity in patients with HP were equivalent, while MPO-ANCA positivity was obviously dominant in patients without HP. HP occurred as the initial clinical episode of AAV in three patients (7.7% of all AAV). Frequent significant characteristics of patients with HP were headache, cranial neuropathy and paranasal involvement (P < 0.05), and histopathological findings from paranasal involvement were useful for the diagnosis of GPA in some patients with HP. Combination therapy of corticosteroid and an immunosuppressant, such as methotrexate, cyclophosphamide or rituximab, was effective for achieving remission and improving radiographic findings of HP. AAV is a common cause of HP; epidemiological features of AAV patients with HP are different from those of patients without HP. Additionally, HP impacts diagnosis because it may be an initial clinical sign of AAV.
Journal of the Neurological Sciences, Sep 1, 2010
Background: Calcium pyrophosphate dehydrate (CPPD) crystal deposition disease is one of the most ... more Background: Calcium pyrophosphate dehydrate (CPPD) crystal deposition disease is one of the most common forms of crystal-associated arthropathy in the elderly. However, CPPD deposition on the cervical spine is less well known, and only a limited number of cases have been reported to date. Here, we report our recent clinical experience with CPPD crystal deposition disease of the cervical spine and describe the clinical features of this disease. Methods: Fourteen patients with clinically diagnosed CPPD crystal deposition disease of the cervical spine at our department during the period from January 2005 to December 2008 were analyzed retrospectively. Results: Patients ranged in age from 54 to 92 (mean ± SD, 77.5 ± 8.5). Chief symptoms of patients were acute posterior neck pain and fever. All patients had markedly restricted neck rotation. Serum CRP level was highly elevated in all patients (10.16 ± 5.35 mg/dL). Computed tomography of the cervical spine demonstrated linear calcific deposits in the transverse ligament of atlas (crowned dens syndrome) in all patients. Calcific deposits were also found in other periodontoid structures and the ligamenta flava in some patients. Posterior neck pain, fever, and increased serum inflammatory indicators were relieved within 1 to 3 weeks by nonsteroidal antiinflammatory drugs (NSAIDs) or a combination of NSAIDs and prednisolone. Most of the patients were misdiagnosed as having other diseases before consultation. Conclusions: CPPD crystal deposition disease of the cervical spine is one of the most common underrecognized causes of acute neck pain in the neurology department, especially in elderly patients.
Internal Medicine, Mar 1, 2019
We herein report the case of an 84-year-old woman with transthyretin (TTR) Val30Met-associated fa... more We herein report the case of an 84-year-old woman with transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP-ATTR Val30Met), representing a very old case. The patient had muscle weakness and sensory disturbances in her extremities caused by severe peripheral neuropathy. She also had vitreous opacity and orthostatic hypotension, and pyrophosphate scintigraphy showed a myocardial accumulation. Esophagogastroduodenoscopy revealed mucosal amyloid deposits, positive in anti-TTR antibody staining. A TTR gene analysis isolated the Val30Met mutation. More than a few cases of FAP-ATTR develop late, like our own, and their familial histories are often obscure in non-endemic areas, which might make a diagnosis difficult.
Internal Medicine, Jan 15, 2019
We herein report the case of a 59-year-old man with anti-leucine-rich glioma-inactivated 1 (LGI1)... more We herein report the case of a 59-year-old man with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis who presented with slowly progressive cognitive impairment mimicking dementia for over 3 years and then developed seizures. Unique brain magnetic resonance imaging (MRI) findings of fluctuating striatal lesions were observed during the disease course. He was treated with intravenous methylprednisolone pulse therapy followed by oral prednisolone, which dramatically improved his neurological function. Taken together, these findings indicate that anti-LGI1 encephalitis may present as slowly progressive cognitive impairment mimicking dementia and that fluctuating MRI striatal lesions may be a characteristic radiological finding of this disorder.
Clinical Therapeutics, Nov 1, 2010
Enzyme replacement therapy (ERT) with imiglucerase is a well-established, effective treatment for... more Enzyme replacement therapy (ERT) with imiglucerase is a well-established, effective treatment for Gaucher disease. However, there have been no reports regarding the excretion of imiglucerase into human breast milk and its effects on the nursing infant. Here, we report a Gaucher disease patient who had successful pregnancies and lactation under ERT, and describe the distribution and excretion of imiglucerase in human milk. Following the peak of serum β-glucocerebrosidase activity, slightly increased enzymatic activity (0.0.16 nmol/h/mL) was observed in the first breast milk after imiglucerase infusion. Our data indicate that a small amount of imiglucerase is excreted into human breast milk.
European Heart Journal Supplements, May 1, 2023
Internal Medicine, Oct 1, 2020
A 29-year-old woman presented with headache, urinary dysfunction, in addition to weakness and hyp... more A 29-year-old woman presented with headache, urinary dysfunction, in addition to weakness and hyperreflexia in the lower limbs. A cerebrospinal fluid analysis revealed pleocytosis (total cells, 403/μL; mononuclear cells 96 %) and an increase in the myelin basic protein level (17,000 pg/ mL). Cerebral magnetic resonance imaging (MRI) revealed a high signal intensity localized to the cerebral cortex on both sides of the frontal lobe on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Picture 1A). Spinal MRI showed a high signal intensity in the spinal cord from Th3 to Th9 on T2-weighted images (Picture 1B). The high signal intensity was observed mainly in the gray matter forming an "H sign" (Picture 1C) (1). Methylprednisolone pulse therapy ameliorated her clinical and radiological findings (Picture 2). Her serum sample was found to be negative for anti-aquaporin-4 antibody, but positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibody. Our case is unique since she simultaneously demonstrated the occurrence of anti-MOG cortical encephalitis and gray matter myelitis (2).
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Papers by Yoshiki Sekijima