Headache in systemic lupus erythematosus: The LUNA registry cross-sectional study.

OBJECTIVES: This study investigated the clinically relevant factors for headaches in patients with systemic lupus erythematosus (SLE) using a registry from a Japanese multicenter cohort. METHODS: This cross-sectional study analysed the clinical information of patients with SLE who experienced headache episodes using the Migraine Disability Assessment (MIDAS) questionnaire. Significant findings in the comparisons between patients with headache (HA patients) and those without headache (non-HA patients) and in the comparisons depending on the grades of headache-induced disability in daily life based on the MIDAS scores were evaluated. Multivariate logistic regression analyses were performed to identify the relevant factors for headache. RESULTS: We analyzed 369 patients (median age, 45 years; female, 90.8%), including 113 HA patients who were significantly younger than non-HA patients (p < .005). HA patients had significantly higher frequencies of photosensitivity, rashes, and mucosal ulcers than non-HA patients (p < .05). Age and photosensitivity were significantly associated with headache (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.95-0.99; OR 2.11, 95% CI 1.29-3.49, respectively). In the HA patients, hypocomplementemia was significantly associated with a disability of more than mild grade (OR 2.89, 95% CI 1.14-7.74), while rash was significantly observed in those presenting with moderate and severe disability. CONCLUSION: This study suggests that photosensitivity is a relevant manifestation of headache in patients with SLE. Persistent hypocomplementemia can contribute to headache-induced disability in daily life, whereas a rash may be a dominant manifestation in patients presenting with moderate/severe headache-induced disability.

Spinal intradural pseudocyst formation in central nervous system superficial siderosis.

The figure shows tissue samples taken from three previous cases, revealing the cause of hemosiderin deposition in the central nervous system because of superficial siderosis.

Neurofilament Light Chains in Systemic Amyloidosis: A Systematic Review.

Peripheral and autonomic neuropathy are common disease manifestations in systemic amyloidosis. The neurofilament light chain (NfL), a neuron-specific biomarker, is released into the blood and cerebrospinal fluid after neuronal damage. There is a need for an early and sensitive blood biomarker for polyneuropathy, and this systematic review provides an overview on the value of NfL in the early detection of neuropathy, central nervous system involvement, the monitoring of neuropathy progression, and treatment effects in systemic amyloidosis. A literature search in PubMed, Embase, and Web of Science was performed on 14 February 2024 for studies investigating NfL levels in patients with systemic amyloidosis and transthyretin gene-variant (TTRv) carriers. Only studies containing original data were included. Included were thirteen full-text articles and five abstracts describing 1604 participants: 298 controls and 1306 TTRv carriers or patients with or without polyneuropathy. Patients with polyneuropathy demonstrated higher NfL levels compared to healthy controls and asymptomatic carriers. Disease onset was marked by rising NfL levels. Following the initiation of transthyretin gene-silencer treatment, NfL levels decreased and remained stable over an extended period. NfL is not an outcome biomarker, but an early and sensitive disease-process biomarker for neuropathy in systemic amyloidosis. Therefore, NfL has the potential to be used for the early detection of neuropathy, monitoring treatment effects, and monitoring disease progression in patients with systemic amyloidosis.

Multiple lymphadenopathies in eosinophilic granulomatosis with polyangiitis: differentiating from IgG4-related lymphadenopathy.

We report a case of eosinophilic granulomatosis with polyangiitis (EGPA) in a 75-year-old man who developed mononeuritis multiplex and purpura in the lower legs concomitantly presenting with lymphadenopathies. Biopsied lymph node tissue pathologically demonstrated fibrinoid necrotizing vasculitis with perivascular eosinophil infiltration, resulting in EGPA diagnosis. Additionally, abundant IgG4-positive plasma cell infiltration exhibiting >70% IgG4/IgG ratio, without storiform pattern fibrosis and obliterative phlebitis, was observed in the biopsied lymph node. Clinical improvement was observed after corticosteroid therapy. IgG4-related lymphadenopathy (IgG4-LAD) has been defined as a distinct clinical category regardless of fulfilling IgG4-related disease classification criteria. However, some autoimmune diseases, including EGPA, can develop lymphadenopathy pathologically similar to IgG4-LAD.

Amyloid-Forming Corpora Amylacea and Spheroid-Type Amyloid Deposition: Comprehensive Analysis Using Immunohistochemistry, Proteomics, and a Literature Review.

This study aimed to elucidate the similarities and differences between amyloid-forming corpora amylacea (CA) in the prostate and lung, examine the nature of CAs in cystic tumors of the atrioventricular node (CTAVN), and clarify the distinctions between amyloid-forming CA and spheroid-type amyloid deposition. We conducted proteomics analyses using liquid chromatography-tandem mass spectrometry with laser microdissection and immunohistochemistry to validate the characteristics of CAs in the lung and prostate. Our findings revealed that the CAs in these organs primarily consisted of common proteins (ß2-microglobulin and lysozyme) and locally produced proteins. Moreover, we observed a discrepancy between the histopathological and proteomic analysis results in CTAVN-associated CAs. In addition, while the histopathological appearance of the amyloid-forming CAs and spheroid-type amyloid deposits were nearly identical, the latter deposition lacked ß2-microglobulin and lysozyme and exhibited evident destruction of the surrounding tissue. A literature review further supported these findings. These results suggest that amyloid-forming CAs in the lung and prostate are formed through a shared mechanism, serving as waste containers (wasteosomes) and/or storage for excess proteins (functional amyloids). In contrast, we hypothesize that while amyloid-forming CA and spheroid-type amyloid deposits are formed, in part, through common mechanisms, the latter are pathological.

An Extremely Delayed Onset of Frey Syndrome: A Case Report and Literature Review.

We report the case of an 80-year-old man with Frey syndrome that developed 30 years postoperatively, which is an exceptionally long period before its occurrence. Sweating and flushing occurred on only the side of his face where the surgery was performed, and he had no other causative abnormalities. Following treatment with botulinum toxin, the patient's symptoms resolved. Extremely early- and late-onset cases do not fit the conventional paradigm of this pathology. Various surgical methods to prevent this syndrome have been explored, but complete prevention has not yet been achieved. These findings suggest that the underlying pathophysiology of Frey's syndrome may be more complex than previously recognized.

Enterocolic granulomatous phlebitis associated with epidermal growth factor-containing fibulin-like extracellular matrix protein 1 deposition and focal amyloid properties: A case report.

A woman in her 60s with rheumatoid arthritis was admitted with fever and abdominal pain. Laparoscopic examination with the differential diagnosis of peritoneal neoplasm and infection revealed granulomatous phlebitis in the resected greater omentum. Amorphous eosinophilic deposits observed in the resected tissue exhibited focal, weak positivity for Congo red but were strongly positive for thioflavin S, confirming their focal amyloid properties. Marked degeneration of elastic fibers was also evident. Electron microscopy revealed deposits around the affected elastic fibers. Immunohistochemistry revealed the deposition of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) along with T-cell-predominant lymphocytic inflammation. The definitive diagnosis was granulomatous enterocolic lymphocytic phlebitis (ELP) associated with EFEMP1 deposition exhibiting focal amyloid properties (EFEMP1/AEFEMP1), supported by proteomics analysis. This type of vasculitis is similar to amyloid-ß-related angiitis of the central nervous system. Thus, we speculate that granulomatous ELP also results from an immune response that recognizes EFEMP1/AEFEMP1 deposits as foreign material and attempts to remove them. Confirmation of EFEMP1/AEFEMP1 deposition with Congo red staining is challenging, particularly in the presence of inflammation, and warrants comprehensive evaluation.

Amyloid accumulation in cases of suspected comorbid cerebral amyloid angiopathy and isolated cortical venous thrombosis.

BACKGROUND AND AIM: The differentiation of isolated cortical venous thrombosis (ICVT) from cerebral amyloid angiopathy (CAA) can be difficult because both diseases share similar neurological symptoms and imaging findings. N-methyl-11C-2-(4'-methylaminophenyl)-6-hydroxybenzo-thiazole (11C-PiB) positron emission tomography (PET) functions as a diagnostic modality for CAA by detecting amyloid deposition. The present prospective study evaluated amyloid deposition using 11C-PiB-PET in consecutive patients with suspected ICVT. METHOD: This study was a prospective observational study. Patients who attended or were hospitalized between May 2019 and March 2020 were included in the analysis. Consecutive patients who met the criteria for suspicion of ICVT were enrolled in the study, and the clinical course, symptoms, imaging findings (including magnetic resonance imaging), and the 11C-PiB-PET findings of each case were analyzed. RESULTS: The study cohort included four patients (64-82 years of age, all women). In one younger patient, 11C-PiB-PET afforded no findings suggestive of CAA, whereas the remaining three patients exhibited 11C-PiB-PET findings suggestive of CAA. CONCLUSION: Although 11C-PiB-PET would be a reasonable modality for distinguishing ICVT from CAA, especially in younger patients, it might be difficult to differentiate ICVT from CAA in elderly patients because of the potential deposition of amyloid. CLINICAL TRIAL REGISTRATION: URL: https://www.umin.ac.jp/ctr/ Unique identifier: UMIN 000037101.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Following SARS-CoV-2 Infection.

We herein report the first case of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy after coronavirus disease 2019 (COVID-19). A 23-year-old man experienced fatigue, a fever, and headache 14 days after the resolution of COVID-19. He was severely disoriented and admitted to our hospital. On admission, the patient exhibited disorientation, headache, neck stiffness, myoclonus of both upper limbs, dysuria, and pyramidal signs. A blood examination revealed hyponatremia, and a cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis. The CSF test results were positive for anti-GFAPα antibodies. The patient was treated with methylprednisolone pulse therapy, followed by oral prednisolone, which quickly ameliorated his neurological abnormalities.

Tafamidis Efficacy Among Octogenarian Patients in the Phase 3 ATTR-ACT and Ongoing Long-Term Extension Study.

BACKGROUND: Tafamidis was approved to treat patients with transthyretin amyloid cardiomyopathy (ATTR-CM) on the basis of findings from the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). OBJECTIVES: This study was a post hoc analysis exploring tafamidis efficacy in octogenarian patients. METHODS: Analysis of patients aged <80 and ≥80 years in ATTR-ACT and its ongoing open-label long-term extension (LTE) study, where all patients receive tafamidis. RESULTS: After 30 months in ATTR-ACT, least squares (LS) mean change from baseline in 6-minute walk test (6MWT) distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score were smaller (all P < 0.05) in patients aged ≥80 years treated with tafamidis (n = 51) vs placebo (n = 37). At the LTE study interim analysis, patients aged ≥80 years treated continuously with tafamidis had a smaller decline in KCCQ-OS score (P < 0.05) and trended toward longer median survival (45 vs 27 months; all-cause mortality HR: 0.6828 [95% CI: 0.4048-1.1517]; P = 0.1526) than those initially treated with placebo in ATTR-ACT. Similar efficacy was observed in patients aged <80 years in ATTR-ACT, including smaller LS mean change from baseline in 6MWT distance, NT-proBNP concentration, and KCCQ-OS score, and lower rate of cardiovascular-related hospitalizations with tafamidis (n = 125) vs placebo (n = 140). In the LTE study, patients aged <80 years treated continuously with tafamidis had a longer median survival (80 vs 41 months; HR = 0.4513 [95% CI: 0.3176-0.6413]; P < 0.0001) and a smaller decline in KCCQ-OS score than those initially treated with placebo. CONCLUSIONS: The findings demonstrate tafamidis efficacy for patients with ATTR-CM both in those aged <80 and those aged ≥80 years. (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]; NCT01994889/Long-term Safety of Tafamidis in Subjects With Transthyretin Cardiomyopathy; NCT02791230).

Auditory Neuropathy Spectrum Disorder Progressing with Motor and Sensory Neuropathy Caused by an ATP1A1 Variant.

We encountered a 27-year-old Japanese woman with sensorineural deafness progressing to motor and sensory neuropathy. At 16 years old, she had developed weakness in her lower extremities and hearing impairment, which gradually deteriorated. At 22 years old, combined audiological, electrophysiological, and radiological examination results were consistent with auditory neuropathy spectrum disorder (ANSD). Genetic analyses identified a previously reported missense variant in the ATP1A1 gene (NM_000701.8:c.1799C>G, p.Pro600Arg). Although sensorineural deafness has been reported as a clinical manifestation of ATP1A1-related disorders, our case suggested that ANSD may underlie the pathogenesis of deafness in ATP1A1-related disorders. This case report broadens the genotype-phenotype spectrum of ATP1A1-related disorders.

Immune-mediated necrotizing myopathy with concomitant development of Kikuchi-Fujimoto disease.

Immune-mediated necrotizing myopathy (IMNM) is a distinct type of idiopathic inflammatory myositis, pathologically characterized by myofiber necrosis and degeneration in the absence of lymphocyte infiltration. Herein, we present a case of IMNM with concomitant development of Kikuchi-Fujimoto disease (KFD), characterized by histiocytic necrotizing lymphadenitis, in a 36-year-old woman who had a treatment history for rheumatoid arthritis (RA). Treatment with oral prednisolone and tacrolimus as immunosuppressants resulted in the remission of the skeletomuscular involvement and lymphadenopathy. To the best of our knowledge, this is the first report of IMNM and KFD developing concomitantly during the clinical course of RA.

Two Cases of Alice in Wonderland Syndrome with a Right Occipital Lobe Lesion Caused by Isolated Cortical Venous Thrombosis.

Alice in Wonderland syndrome (AIWS) is extremely rare, occurring more often in young individuals than in older adults. Symptoms of this syndrome typically include an altered body image, size perception, and time perception. However, the pathophysiology and lesions responsible for this syndrome remain unclear. In most cases, specific lesions cannot be identified using computed tomography or magnetic resonance imaging. Two patients with isolated cortical venous thrombosis in the right occipital area experienced transient visual symptoms of AIWS. Furthermore, a literature search indicated that AIWS with visual distortions is associated with right occipital lobe lesions, supporting the findings of our study.

Lysinuric protein intolerance exhibiting renal tubular acidosis/Fanconi syndrome in a Japanese woman.

Lysinuric protein intolerance (LPI), caused by pathogenic variants of SLC7A7, is characterized by protein aversion, failure to thrive, hyperammonemia, and hepatomegaly. Recent studies have reported that LPI can cause multiple organ dysfunctions, including kidney disease, autoimmune deficiency, pulmonary alveolar proteinosis, and osteoporosis. We report the case of a 47-year-old Japanese woman who was initially diagnosed with renal tubular acidosis (RTA), Fanconi syndrome, and rickets. At the age of 3 years, she demonstrated a failure to thrive. Urinary amino acid analysis revealed elevated lysine and arginine levels, which were masked by pan-amino aciduria. She was subsequently diagnosed with rickets at 5 years of age and RTA/Fanconi syndrome at 15 years of age. She was continuously treated with supplementation of vitamin D3, phosphate, and bicarbonate. A renal biopsy at 18 years of age demonstrated diffuse proximal and distal tubular damage with endocytosis-lysosome pathway abnormalities. Distinctive symptoms of LPI, such as protein aversion and postprandial hyperammonemia were not observed throughout the patient's clinical course. The patient underwent a panel-based comprehensive genetic testing and was diagnosed with LPI. As the complications of LPI involve many organs, patients lacking distinctive symptoms may develop various diseases, including RTA/Fanconi syndrome. Our case indicates that proximal and distal tubular damages are notable findings in patients with LPI. The possibility of LPI should be carefully considered in the management of RTA/Fanconi syndrome and/or incomprehensible pathological tubular damage, even in the absence of distinctive symptoms; furthermore, a comprehensive genetic analysis is useful for diagnosing LPI.

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Hereditary transthyretin amyloid neuropathies: advances in pathophysiology, biomarkers, and treatment.

Hereditary transthyretin (TTR) amyloid polyneuropathy is an autosomal dominant life-threatening disorder. TTR is produced mainly by the liver but also by the choroid plexus and retinal pigment epithelium. Detailed clinical characterisation, identification of clinical red flags for misdiagnosis, and use of biomarkers enable early diagnosis and treatment. In addition to liver transplantation and TTR stabilisers, three other disease-modifying therapies have regulatory approval: one antisense oligonucleotide (inotersen) and two small interfering RNAs (siRNAs; patisiran and vutrisiran). The siRNAs have been shown to stop progression of neuropathy and improve patients' quality of life. As none of the disease-modifying therapies can cross the blood-brain barrier, TTR deposition in the CNS, which can cause stroke and cognitive impairment, remains an important unaddressed issue. CRISPR-Cas9-based one-time TTR editing therapy is being investigated in a phase 1 clinical study. Identification of the earliest stages of pathogenesis in TTR variant carriers is a major challenge that needs addressing for optimal management.