Factors associated with drug retention of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis: A multicentre REVEAL cohort study.

OBJECTIVES: To determine the current retention rate of mepolizumab (MPZ) and identify factors associated with drug retention in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in the Kansai multicentre cohort (REVEAL cohort). METHODS: Sixty patients diagnosed with EGPA and treated with MPZ between December 2016 and June 2023 were enrolled. The clinical characteristics, including laboratory data, treatments administered, and disease course outcomes were collected retrospectively. The patients were stratified into MPZ continuation (n=53) and discontinuation (n=7) groups, and drug retention was statistically compared using the log-rank test. RESULTS: The median age of patients was 54.5 years, with 55% females, and 33% antineutrophil cytoplasmic antibody-positive at disease onset. MPZ exhibited a retention rate of 78.7% after five years. The reasons for discontinuation included treatment of coexisting diseases, inadequate response, and remission. Patient characteristics at disease onset were comparable between the groups. Patients receiving immunosuppressants (IS) before MPZ introduction demonstrated significantly higher retention rates (P = 0.038). During the final observation, the MPZ continuation group had a lower vasculitis damage index score (P = 0.027). CONCLUSIONS: MPZ exhibited a high 5-year retention rate, particularly in patients requiring IS. This study implies that long-term use of MPZ may mitigate irreversible organ damage.

An autopsy case of type A FTLD-TDP with a GRN mutation presenting with the logopenic variant of primary progressive aphasia at onset and with corticobasal syndrome subsequently.

A 68-year-old woman presented with difficulty finding words and writing characters. Neurological examination led to clinical diagnosis at onset of the logopenic variant of primary progressive aphasia accompanied with ideomotor apraxia, visuospatial agnosia on the right, and Gerstmann syndrome. Bradykinesia and rigidity on the right with shuffling gait developed after one year. Treatment with L-dopa had no effect. The patient was diagnosed with corticobasal syndrome (CBS). Brain magnetic resonance imaging revealed diffuse cortical atrophy dominantly on the left, especially in the temporal, parietal, and occipital lobes. Positron emission tomography did not reveal any significant accumulation of amyloid ß or tau protein. She died five years later. Neuropathological examination revealed diffuse cortical atrophy with severe neuronal loss and fibrous gliosis in the cortex. Neuronal cytoplasmic inclusions, short dystrophic neurites, and, most notably, neuronal intranuclear inclusions, all immunoreactive for phosphorylated TDP-43, were observed. Western blotting revealed a full length and fragments of phosphorylated TDP-43 at 45 and 23 kDa, respectively, confirming the pathological diagnosis of type A FTLD-TDP. Whole exome sequencing revealed a pathogenic mutation in GRN (c.87dupC). FTLD-TDP should be included in the differential diagnosis of CBS.

Effectiveness of Anti-Calcitonin Gene-Related Peptide Medication in Vestibular Migraine: A Retrospective Cohort Study in an Asian Population.

BACKGROUND: Migraine and dizziness often coexist, with vestibular migraine (VM) presenting with vestibular symptoms and headaches. Calcitonin gene-related peptide (CGRP) may be involved in motion-induced symptoms; however, studies on the use of anti-CGRP monoclonal antibodies (mAbs) for the treatment of VM have yielded conflicting results. This study aimed to clarify the effectiveness of anti-CGRP mAbs in VM treatment. METHODS: This retrospective observational cohort study, conducted between 1 January 2021 and 31 March 2023, assessed 12 Japanese patients with VM who were treated with anti-CGRP mAbs (CGRP group) for 6 months and 11 Japanese patients who received standard of care for VM and served as controls. Clinical questionnaires and equilibrium tests were administered, with primary outcomes including changes in Dizziness Handicap Inventory (DHI) scores compared with baseline values. Objective variables included the DHI score and explanatory variables included demographic data, balance test results, head-up tilt (HUT) test results, vestibular test results and questionnaire survey results. Analysis of variance was used to assess the treatment effects of anti-CGRP mAbs, and multivariate regression analysis was performed to identify mAb responders. RESULTS: After 6 months, the CGRP group showed significant improvements in DHI scores [0 versus 6 months, odds ratio (95% confidence interval): 22.01 (0.13-43.88)] and number of vertigo/dizziness attacks per month [0 versus 6 months: 10.28 (2.80-17.76)]. No significant difference was observed in the control group [DHI scores, 0 versus 6 months: 0.65 (-26.84 to 28.14); number of vertigo/dizziness attacks per month, 0 versus 6 months: - 8.07 (- 23.77 to 7.62)]. Multivariate regression analysis showed that autonomic function at baseline was associated with mAb response in patients [ß estimates (95% confidence interval): 3.63 (0.21-7.06)]. CONCLUSIONS: Treatment with anti-CGRP mAbs was more effective than conventional treatment in preventing migraine in patients with VM. While the identified factors associated with treatment responsiveness offer valuable insights into personalised treatment approaches, further prospective studies are warranted to validate the findings due to our study's retrospective design and limited sample size.

Diffusion Mediates Molecular Transport through the Perivascular Space in the Brain.

The perivascular space has been proposed as a clearance pathway for degradation products in the brain, including amyloid ß, the accumulation of which may induce Alzheimer's disease. Live images were acquired using a two-photon microscope through a closed cranial window in mice. In topical application experiments, the dynamics of FITC-dextran were evaluated from 30 to 150 min after the application and closure of the window. In continuous injection experiments, image acquisition began before the continuous injection of FITC-dextran. The transport of dextran molecules of different sizes was evaluated. In topical application experiments, circumferential accumulation around the penetrating arteries, veins, and capillaries was observed, even at the beginning of the observation period. No further increases were detected. In continuous injection experiments, a time-dependent increase in the fluorescence intensity was observed around the penetrating arteries and veins. Lower-molecular-weight dextran was transported more rapidly than higher-molecular-weight dextran, especially around the arteries. The largest dextran molecules were not transported significantly during the observation period. The size-dependent transport of dextran observed in the present study strongly suggests that diffusion is the main mechanism mediating substance transport in the perivascular space.

Recapitulated Late-Onset Inflammatory Toxicities and Progressive Dysautonomia with Persistence of Central Memory CD4+ Chimeric Antigen Receptor T Cells in a Case of Transformed Follicular Lymphoma: Case Report.

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has been widely used and is highly effective for B-cell lymphoid malignancies. Immune-mediated adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occur in the acute phase and are monophasic after CAR T-cell therapy. However, late-onset inflammatory and neurological toxicities have not been well studied. We encountered a patient with recurrent late-onset inflammatory toxicities and progressive dysautonomia after CD19-directed CAR T-cell therapy. A 69-year-old man was treated with CD19-directed CAR T-cell therapy for transformed follicular lymphoma. Triphasic inflammation with stomatitis, cytopenia, and noninfectious pneumonia was first observed 7 months after CAR T-cell infusion. Progressive dysautonomia was also observed and eventually fatal. Residual CAR T cells, predominantly central memory CD4+ cells, were detectable in peripheral blood approximately 1 year after CAR T-cell infusion. The cytokine profile with the lack of tumor necrosis factor-α, interferon-γ, and interleukin-1ß elevation in the peripheral blood and cerebrospinal fluid was inconsistent with that of typical CRS or ICANS. The persistence of central memory CD4+ CAR T cells might be associated with unique manifestations of late-onset immune-mediated adverse effects. More cases should be accumulated to elucidate the mechanism and establish the optimal management strategy of late-onset immune-mediated toxicities previously unrecognized.

An autopsy case of progressive multifocal leukoencephalopathy with massive iron deposition in juxtacortical lesions.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by JC virus infection of oligodendrocytes. Little has been reported on iron deposits in patients with PML. Herein, we report a case of PML with massive iron deposition in the juxtacortical regions attaching white matter lesions in a 71-year-old woman who developed bilateral visual disturbance and progressive aphasia after 16 months of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone treatment for follicular lymphoma. Magnetic resonance imaging revealed white matter lesions in the left parietal and other lobes with massive iron deposition in the juxtacortical lesions. A PCR test for JC virus was positive, confirming the diagnosis of PML. Despite treatment with mefloquine and mirtazapine, the patient died six months later. At autopsy, demyelination was found dominantly in the left parietal lobe. Moreover, hemosiderin-laden macrophages and reactive astrocytes containing ferritin were abundant in the juxtacortical regions adjacent to the white matter lesions. This is a previously unreported case of PML after lymphoma, in which iron deposition was confirmed both radiologically and pathologically.

Correlation between Phase-difference-enhanced MR Imaging and Amyloid Positron Emission Tomography: A Study on Alzheimer's Disease Patients and Normal Controls.

PURPOSE: While amyloid-ß deposition in the cerebral cortex for Alzheimer's disease (AD) is often evaluated by amyloid positron emission tomography (PET), amyloid-ß-related iron can be detected using phase difference enhanced (PADRE) imaging; however, no study has validated the association between PADRE imaging and amyloid PET. This study investigated whether the degree of hypointense areas on PADRE imaging correlated with the uptake of amyloid PET. METHODS: PADRE imaging and amyloid PET were performed in 8 patients with AD and 10 age-matched normal controls. ROIs in the cuneus, precuneus, superior frontal gyrus (SFG), and superior temporal gyrus (STG) were automatically segmented. The degree of hypointense areas on PADRE imaging in each ROI was evaluated using 4-point scaling of visual assessment or volumetric semiquantitative assessment (the percentage of hypointense volume within each ROI). The mean standardized uptake value ratio (SUVR) of amyloid PET in each ROI was also calculated. The Spearman's correlation coefficient between the 4-point scale of PADRE imaging and SUVR of amyloid PET or between the semiquantitative hypointense volume percentage and SUVR in each ROI was evaluated. RESULTS: In the precuneus, a significant positive correlation was identified between the 4-point scale of PADRE imaging and SUVR of amyloid PET (Rs = 0.5; P = 0.034) in all subjects. In the cuneus, a significant positive correlation was identified between the semiquantitative volume percentage of PADRE imaging and SUVR of amyloid PET (Rs = 0.55; P = 0.02) in all subjects. CONCLUSION: Amyloid-ß-enhancing PADRE imaging can be used to predict the SUVR of amyloid PET, especially in the cuneus and precuneus, and may have the potential to be used for diagnosing AD by detecting amyloid deposition.

Muscle Biopsy-proven Drug-induced Microscopic Polyangiitis in a Patient with Tuberculosis.

We herein report a case of muscle biopsy-proven microscopic polyangiitis (MPA) in a patient with tuberculosis. The patient had developed a persistent fever after the initiation of treatment for tuberculosis and was positive for myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA). However, because conventional symptoms were lacking, determination of the biopsy site was difficult. Based on the findings of a biopsy of the biceps femoris, which confirmed small vessel vasculitis, the patient was diagnosed with MPA. The fever was alleviated by glucocorticoids. Tuberculosis and antituberculosis drugs can cause ANCA-associated vasculitis (AAV). A muscle biopsy is useful for the diagnosis of AAV.

[Sibling cases of four and a half LIM domains 1 (FHL1) myopathy who developed respiratory failure without apparent limb weakness].

A 60-year-old man developed dyspnea without apparent limb weakness. He had cardiomyopathy in his 30s and was treated for chronic heart failure since 42. He was diagnosed as having four and a half LIM domains 1 (FHL1) mutation at 53 following the same diagnosis of his younger brother. He was first admitted to the cardiology department for possible worsening of chronic cardiac failure. Blood gas analysis showing respiratory acidosis prompted his treatment with a respirator. Neurological examination revealed that he had mild weakness limited to the shoulder girdle muscles and contracture at jaw, spine, elbows and ankles. Skeletal muscle CT showed truncal atrophy. He, as well as his younger brother, was diagnosed with FHL1 myopathy resulting in ventilation failure and was discharged after successful weaning from the respirator in the daytime. The present sibling cases are the first with FHL1 mutation to develop respiratory failure without limb weakness and suggest that FHL1 myopathy as a differentially diagnosis of hereditary myopathies with early respiratory failure.

In Vivo Dynamic Movement of Polymerized Amyloid ß in the Perivascular Space of the Cerebral Cortex in Mice.

Disposition of amyloid ß (Aß) into the perivascular space of the cerebral cortex has been recently suggested as a major source of its clearance, and its disturbance may be involved in the pathogenesis of cerebral amyloid angiopathy and Alzheimer's disease. Here, we explored the in vivo dynamics of Aß in the perivascular space of anesthetized mice. Live images were obtained with two-photon microscopy through a closed cranial window. Either fluorescent-dye-labeled Aß oligomers prepared freshly or Aß fibrils after 6 days of incubation at 37 °C were placed over the cerebral cortex. Accumulation of Aß was observed in the localized perivascular space of the penetrating arteries and veins. Transportation of the accumulated Aß along the vessels was slow and associated with changes in shape. Aß oligomers were transported smoothly and separately, whereas Aß fibrils formed a mass and moved slowly. Parenchymal accumulation of Aß oligomers, as well as Aß fibrils along capillaries, increased gradually. In conclusion, we confirmed Aß transportation between the cortical surface and the deeper parenchyma through the perivascular space that may be affected by the peptide polymerization. Facilitation of Aß excretion through the system can be a key target in treating Alzheimer's disease.

Prolonged extrapyramidal symptoms induced by long-term, intermittent administration of low-dose olanzapine along with metoclopramide for emesis: A case report.

BACKGROUND: Antipsychotics with dopamine (D2) receptor antagonism can be effective for emesis in cancer patients. Extrapyramidal symptoms (EPS) induced by typical antipsychotics can be exacerbated by other D2 receptor antagonists. We describe a case of persistent EPS induced by long-term, intermittent administration of low-dose olanzapine along with metoclopramide for emesis. CASE PRESENTATION: A 59-year-old pancreatic cancer patient underwent chemotherapy for 7 months. He was referred to the psychiatry department because of restlessness and insomnia. Although he did not have obvious depressive symptoms, he was anxious about the cancer treatment. For chemotherapy-induced nausea, he had been prescribed 5 mg of olanzapine intermittently for 7 months. He had last used the drug 9 days before presenting it to us. Additionally, he received metoclopramide and palonosetron as antiemetics. We considered akathisia and cancer-related anxiety/agitation as possible causes of restlessness and insomnia, and prescribed clonazepam. However, his symptoms worsened, resulting in hospitalization. We reconsidered his symptoms as cancer-related anxiety/agitation and prescribed quetiapine. Although it was effective, he had tremors and was assessed by a neurologist. Considering the clinical manifestations of rigidity, postural reflex disorder, and a mask-like face, we suspected drug-induced parkinsonism and replaced quetiapine with biperiden on the next day, leading to his discharge after 2 weeks. He did not have symptom recurrence even after discontinuation of biperiden. CONCLUSIONS: Long-term, intermittent administration of low-dose antipsychotics with other antiemetics having D2 receptor antagonism can cause prolonged EPS. Especially in cancer patients, who often require polypharmacy, clinicians should consider exacerbated adverse effects due to drug interactions.

Japan Stroke Society Guideline 2021 for the Treatment of Stroke.

The revised Japan Stroke Society Guidelines for the Treatment of Stroke were published in Japanese in July 2021. In this article, the extracted recommendation statements are published. The revision keeps pace with the great progress in stroke control based on the recently enacted Basic Act on Stroke and Cardiovascular Disease in Japan. The guideline covers the following areas: primary prevention, general acute management of stroke, ischemic stroke and transient ischemic attack, intracerebral hemorrhage, subarachnoid hemorrhage, asymptomatic cerebrovascular disease, other cerebrovascular disease, and rehabilitation.

[Cerebrovascular Diseases and Autonomic Failure].

Cerebral vessels are innervated by sympathetic and parasympathetic nerves, as well as the trigeminal nerve. Under physiological conditions, neural regulation contributes to coupling of cerebral blood flow (CBF) and metabolism and autoregulation of CBF against systemic blood pressure. It also plays a key role in vasodilatation distal to narrowed vascular lesions associated with atherosclerosis, hyperperfusion syndrome that occurs after vascular reconstruction in patients with chronic ischemic diseases, reversible cerebral vasoconstriction syndrome, and migraine. Moreover, cerebrovascular disease can cause autonomic dysfunction; frontal lobe and brain stem lesions are known to result in urinary incontinence, mydriasis, and Horner's syndrome.

Multiple Cerebral Infarctions Accompanied by Subcortical and Subarachnoid Hemorrhaging in Bilateral Border Zone Areas in a Patient with Eosinophilic Granulomatosis with Polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with peripheral neuropathy, but reports of central nervous system involvement are quite rare. We herein report a patient with EGPA first identified as having hypereosinophilia who later developed asthma, eosinophilic otitis media, sinusitis, and hemorrhagic colitis. She subsequently developed hemiparesis. Head magnetic resonance imaging revealed multiple cerebral infarctions with subcortical and subarachnoid hemorrhaging colocalized at the bilateral border zone areas. She was diagnosed with EGPA-induced stroke and successfully treated with oral prednisolone. Inflammation in the small cerebral arteries in EGPA may induce bilateral border zone infarction with colocalizing subcortical and subarachnoid hemorrhaging.

Heavy Tau Burden with Subtle Amyloid ß Accumulation in the Cerebral Cortex and Cerebellum in a Case of Familial Alzheimer's Disease with APP Osaka Mutation.

We previously identified a novel mutation in amyloid precursor protein from a Japanese pedigree of familial Alzheimer's disease, FAD (Osaka). Our previous positron emission tomography (PET) study revealed that amyloid ß (Aß) accumulation was negligible in two sister cases of this pedigree, indicating a possibility that this mutation induces dementia without forming senile plaques. To further explore the relationship between Aß, tau and neurodegeneration, we performed tau and Aß PET imaging in the proband of FAD (Osaka) and in patients with sporadic Alzheimer's disease (SAD) and healthy controls (HCs). The FAD (Osaka) patient showed higher uptake of tau PET tracer in the frontal, lateral temporal, and parietal cortices, posterior cingulate gyrus and precuneus than the HCs (>2.5 SD) and in the lateral temporal and parietal cortices than the SAD patients (>2 SD). Most noticeably, heavy tau tracer accumulation in the cerebellum was found only in the FAD (Osaka) patient. Scatter plot analysis of the two tracers revealed that FAD (Osaka) exhibits a distinguishing pattern with a heavy tau burden and subtle Aß accumulation in the cerebral cortex and cerebellum. These observations support our hypothesis that Aß can induce tau accumulation and neuronal degeneration without forming senile plaques.

Disseminated Mycobacterium abscessus subsp. massiliense infection in a Good's syndrome patient negative for human immunodeficiency virus and anti-interferon-γ autoantibody: a case report.

BACKGROUND: Good's syndrome (GS) is characterized by immunodeficiency, and can lead to severe infection, which is the most significant complication. Although Mycobacterium rarely causes infection in patients with GS, disseminated nontuberculous mycobacterial (NTM) infection frequently occurs in GS patients that are also positive for the human immunodeficiency virus (HIV) or anti-interferon (IFN)-γ autoantibodies. Here, we report a rare case of GS with NTM without HIV or IFN-γ autoantibodies. CASE PRESENTATION: A 57-year-old Japanese male with GS and myasthenia gravis (treated with prednisolone and tacrolimus) was diagnosed with disseminated NTM infection caused by Mycobacterium abscessus subsp. massiliense. He presented with fever and back pain. Blood, lumbar tissue, urine, stool, and sputum cultures tested positive for M. abscessus. Bacteremia, spondylitis, intestinal lumber abscess, and lung infection were confirmed by bacteriological examination and diagnostic imaging; urinary and intestinal tract infections were suspected by bacteriological examination but not confirmed by imaging. Despite multidrug combination therapy, including azithromycin, imipenem/cilastatin, levofloxacin, minocycline, linezolid, and sitafloxacin, the patient ultimately died of the infection. The patient tested negative for HIV and anti-IFN-γ autoantibodies. CONCLUSIONS: Since myasthenia gravis symptoms interfere with therapy, patients with GS and their physicians should carefully consider the antibacterial treatment options against disseminated NTM.

A Case of Creutzfeldt-Jakob Disease with Stroke-Like Onset.

Creutzfeldt-Jakob disease (CJD) is a prion disease characterized by rapidly progressive dementia that is often followed by behavioral disturbances, ataxia, myoclonus, and akinetic mutism. The initial symptoms of CJD reportedly vary, but the onset is usually gradual. Here, we report a case of CJD with a sudden, stroke-like onset of right hemiparesis to alert readers that CJD can mimic a stroke during its early stage.

Liver injury after methylprednisolone pulse therapy in multiple sclerosis is usually due to idiosyncratic drug-induced toxicity rather than autoimmune hepatitis.

BACKGROUND: In patients with multiple sclerosis (MS), development of hepatic injury has been sporadically reported after methylprednisolone (MP) pulse therapy. Some studies suggest autoimmune hepatitis, while other studies reported direct hepatotoxicity as a cause for hepatic injury. Here, we studied the pathological mechanism of such liver injury in patients with MS. METHODS: From 2005 to 2016, eight patients with MS developed liver injury after MP pulse therapy. Their average age was 38 years (range: 28-49 years, all female). Autoimmune antibodies were measured and a liver biopsy was performed in seven patients. RESULTS: Liver injury developed within two weeks in two patients and later (30-90 days after MP) in six patients. No hepatitis-related autoantibody or hepatitis virus were found. All cases were classified as hepatocellular injury and none as cholestatic or mixed. A liver biopsy in five cases revealed centrilobular necrosis with lobular infiltrates of inflammatory cells, suggesting drug-induced acute hepatitis. The biopsy findings in another case suggested a residual stage of acute hepatitis. Only one patient showed portal expansion with periportal fibrosis, suggesting autoimmune hepatitis. All patients recovered spontaneously or with only hepatoprotective drugs, although one patient with possible autoimmune hepatitis recovered slowly. CONCLUSION: Liver injury develops usually later than two weeks after MP treatment. The prognosis is good in most cases and rarely autoimmune hepatitis may be involved.

Corrigendum: Age-Dependent Relationship Between Plasma Aß40 and Aß42 and Total Tau Levels in Cognitively Normal Subjects.

[This corrects the article DOI: 10.3389/fnagi.2019.00222.].