Hemichoreo-hemibalism as a Manifestation of Central Nervous System Chronic Graft-versus-Host Disease.
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ABSTRACT:
SUBMITTER: Enriquez-Marulanda A
PROVIDER: S-EPMC6353313 | biostudies-literature | 2017 Jul-Aug
REPOSITORIES: biostudies-literature
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Hemichoreo-hemibalism as a Manifestation of Central Nervous System Chronic Graft-versus-Host Disease.
Enriquez-Marulanda Alejandro A Sierra-Ruiz Melibea M Jaramillo Francisco Javier FJ Escobar Luis Alberto LA Granados Ana María AM Rodríguez-Rojas Lisa Ximena LX Lees Andrew J AJ Orozco Jorge Luis JL
Movement disorders clinical practice 20170525 4
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Project description:As an adverse immune phenomenon, graft-versus-host disease often occurs after allogeneic hematopoietic stem cell transplantation. The incidence of acute and chronic graft-versus-host disease is about 40-60% and the mortality rate can reach 15%, which is a potentially fatal disease. There are rare GvHD cases involving the central nervous system. We reported a rare case of diffuse white matter changes after haploid bone marrow transplantation, summarizing its clinical manifestations and diagnosis and treatment in conjunction with the literature.
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Project description:Central nervous system (CNS) involvement of graft versus host disease (GvHD) is a rare cause of CNS disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic CNS GvHD symptoms are heterogeneous and include cerebrovascular manifestations, demyelinating disease and immune-mediated encephalitis. CNS-Acute GvHD is not formally defined in literature.We report 7 cases of CNS-GvHD among which two had histological-proven disease. We reviewed 32 additional cases of CNS GvHD published in literature since 1990. In this cohort, 34 patients were transplanted for hematologic malignancies, and 5 for non-malignant hematopoiesis disorders. Of these patients, 25 had a history of chronic GvHD and immunosuppressive treatment had been decreased or discontinued in 14 patients before neurological symptoms onset. Median neurological disorder onset was 385 days [7-7320]. Patients had stroke-like episodes (n?=?7), lacunar syndromes (n?=?3), multiple sclerosis-like presentations (n?=?7), acute demyelinating encephalomyelitis-like symptoms (n?=?4), encephalitis (n?=?14), mass syndrome (n?=?1), and 3 had non-specific symptoms. Median neurological symptoms onset was 81.5 days [7-1095] for patients without chronic GVHD history versus 549 days [11-7300] for patients with chronic GVHD (P?=?0.001). Patients with early involvement of CNS after allo-HSCT and no chronic GVHD symptoms were more frequently suffering from encephalitis (64% versus 28%, P?=?0.07), whereas stroke-like episodes and lacunar symptoms were less frequent (9% versus 36%, P?=?0.13).34 patients with CNS-GvHD were treated with immunosuppressive therapy, including corticosteroids for 31 of them. Other treatments were intravenous immunoglobulin, plasmapheresis, cyclophosphamide, calcineurin inhibitors, mycophenolic acid, methotrexate and etoposide.27 patients achieved a response: 10 complete responses, 15 partial responses and 2 transient responses. Of 25 patients with sufficient follow-up, 7 were alive and 18 patients deceased after CNS-GvHD diagnosis.CNS-related GvHD is a rare cause of CNS disorders after allo-HSCT and is associated with a poor prognosis.
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Project description:Chronic graft-versus-host disease (cGVHD ) is a leading cause of allogeneic hematopoietic stem-cell transplantation-related mortality and morbidity. It is an immune-mediated disorder that can target almost any organ in the body, often with devastating consequences. The immune-suppressive medications currently used to treat it are equally toxic and are often not very effective. At this time, our understanding of its pathophysiology is limited. The discovery of potential biomarkers offers new possibilities in the clinical management of cGVHD. They could potentially be used for diagnosing cGVHD, for predicting or evaluating response to therapy and for unique insights into the pathophysiology underlying the clinical manifestations of cGVHD. Understanding the biological origins of these biomarkers can help us construct a more comprehensive and clinically relevant model for the pathogenesis of this disease. In this article, we review existing evidence for candidate biomarkers that have been identified in the framework of how they may contribute to the pathophysiology of cGVHD. Issues regarding the discovery and application of biomarkers are discussed.
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Project description:Chronic graft-versus-host disease (GVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Symptoms and manifestations of chronic GVHD are heterogeneous and pleomorphic, and there are no standard treatments beyond corticosteroids. Therapy is typically prolonged, and chronic GVHD and its treatment are associated with adverse effects that have a significant impact on long-term quality of life and functional status. Several advances have been made over the last 2 decades to define the diagnosis of chronic GVHD as well as its severity and response criteria for clinical trials. Further understanding into the biologic mechanisms of the development of chronic GVHD has led to the investigation of several novel immunomodulatory and targeted therapies. Multi-institutional collaboration and pharmaceutical support in the development of therapies based on sound biologic mechanisms and clinical trials with defined end points and responses have led to several promising agents on the horizon of approval for treatment of chronic GVHD. This article reviews advances in our knowledge of chronic GVHD and its biologic framework to improve approaches to prevention and treatment.
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2016-05-27 | PXD002762 | Pride
Project description:At least half of patients with chronic graft-versus-host-disease (cGVHD), the leading cause of morbidity and non-relapse mortality after allogeneic stem cell transplantation, have oral manifestations: mucosal lesions, salivary dysfunction, and limited mouth-opening. cGVHD may manifest in a single organ or affect multiple organ systems, including the mouth, eyes, and the skin. The interrelationship of the 3 oral manifestations of cGVHD with each other and with the specific manifestations of extraoral cGVHD has not been studied. In this analysis, we explored, in a large group of patients with cGVHD, the potential associations between: (1) oral mucosal disease and erythematous skin disease, (2) salivary gland dysfunction and lacrimal gland dysfunction, and (3) limited mouth-opening and sclerotic skin cGVHD. Study participants, enrolled in a cGVHD Natural History Protocol (NCT00331968, n = 212), underwent an oral examination evaluating: (1) mucosal cGVHD [NIH Oral Mucosal Score (OMS)], (2) salivary dysfunction (saliva flow and xerostomia), and (3) maximum mouth-opening measurement. Parameters for dysfunction (OMS > 2, saliva flow ≤ 1 mL/5 min, mouth-opening ≤ 35 mm) were analyzed for association with skin cGVHD involvement (erythema and sclerosis, skin symptoms), lacrimal dysfunction (Schirmer's tear test, xerophthalmia), Lee cGVHD Symptom Scores, and NIH organ scores. Oral mucosal disease (31% prevalence) was associated with skin erythema (P < 0.001); salivary dysfunction (11% prevalence) was associated with lacrimal dysfunction (P = 0.010) and xerostomia with xerophthalmia (r = 0.32, P = 0.001); and limited mouth-opening (17% prevalence) was associated with skin sclerosis (P = 0.008) and skin symptoms (P = 0.001). There was no association found among these 3 oral cGVHD manifestations. This analysis supports the understanding of oral cGVHD as 3 distinct diseases: mucosal lesions, salivary gland dysfunction, and mouth sclerosis. Clear classification of oral cGVHD as 3 separate manifestations will improve clinical diagnosis, observational research data collection, and the definitions of outcome measures in clinical trials.
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Project description:Chronic graft-versus-host disease (cGVHD) is a heterogenous syndrome whose symptoms and treatment are often associated with decreases in functional status and quality of life among survivors of transplantation. We explored definitions of cGVHD-related disability and factors associated with disability in cGVHD. We analyzed 371 patients with cGVHD requiring a new systemic therapy with enrollment and 18-month assessments through the Chronic GVHD Consortium, evaluating disability as a composite endpoint including any 1 of 5 impairments previously defined by Fatobene et al [1] (score 2 or 3 keratoconjunctivitis sicca, score 2 or 3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation). We also evaluated disability, defined as an ≥8-point decline in a human activity profile (HAP) score or a ≥20% decline in Karnofsky Performance Status (KPS) from enrollment to 18 months. At enrollment, 47% of patients had at least 1 of the 5 Flowers disability features, with 50% of this group acquiring additional impairments at 18 months. Of the 197 patients (53%) with no Flowers disability at enrollment, 50% progressed with disability features at 18 months. We found that any progressive Flowers impairment was associated with a decline in HAP/KPS as well as with increased National Institutes of Health severity scores at 18 months. Enrollment mouth scores and patient-reported eye and skin scores were significantly associated with progressive impairment at 18 months. Progressive disability at 18 months did not predict subsequent nonrelapse mortality. Additional studies to define chronic GVHD related-disability and risk factors are needed to develop this important patient-centered outcome.
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Project description:Substantial preclinical and clinical research into chronic graft-versus-host disease (cGVHD) has come to fruition in the last five years, generating a clear understanding of a complex cytokine-driven cellular network. cGVHD is mediated by naive T cells differentiating within IL-17-secreting T cell and follicular Th cell paradigms to generate IL-21 and IL-17A, which drive pathogenic germinal center (GC) B cell reactions and monocyte-macrophage differentiation, respectively. cGVHD pathogenesis includes thymic damage, impaired antigen presentation, and a failure in IL-2-dependent Treg homeostasis. Pathogenic GC B cell and macrophage reactions culminate in antibody formation and TGF-β secretion, respectively, leading to fibrosis. This new understanding permits the design of rational cytokine and intracellular signaling pathway-targeted therapeutics, reviewed herein.
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Project description:The increasing clinical indications for hematopoietic stem cell transplantation (HSCT) and improved clinical care throughout and following HSCT have led to not only long-term survival but also to an increasing incidence and prevalence of graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) affects almost 50% of adult patients post-HSCT, with increasing incidence in pediatric patients as well. Oral cGVHD specifically has a reported prevalence ranging from 45% to 83% in patients who develop cGVHD and is more extensive in adult patients than in children. Oral cGVHD affects patients through clinically significant oral symptoms that may lead to significantly decreased caloric intake, oral infections, and increased health service utilization, and may thus affect overall health and survival. The most commonly used therapy for mucosal involvement of oral cGVHD is topical high-dose and ultra-high potency corticosteroids, and calcineurin inhibitors. This review of oral complications of cGVHD presents the clinical significance of oral cGVHD to HSCT survivors, our current understanding of the pathobiology of oral cGVHD and gaps in this evidence, and the global targeted interdisciplinary clinical research efforts, including the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. Current challenges regarding the management of oral cGVHD and strategies to advance our scientific understanding of this clinically significant chronic oral disease are presented.
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Project description:PurposeTo identify diagnostic and prognostic markers of chronic graft-versus-host disease (cGVHD), the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT).Patients and methodsUsing a quantitative proteomics approach, we compared pooled plasma samples obtained at matched time points after HCT (median, 103 days) from 35 patients with cGVHD and 18 without cGVHD (data are available via ProteomeXchange with identifier PXD002762). Of 105 proteins showing at least a 1.25-fold difference in expression, 22 were selected on the basis of involvement in relevant pathways and enzyme-linked immunosorbent assay availability. Chemokine (C-X-C motif) ligand 9 (CXCL9) and suppression of tumorigenicity 2 (ST2) also were measured on the basis of previously determined associations with GVHD. Concentrations of the four lead biomarkers were measured at or after diagnosis in plasma from two independent verification cohorts (n = 391) to determine their association with cGVHD. Their prognostic ability when measured at approximately day +100 after HCT was evaluated in plasma of a second verification cohort (n = 172).ResultsOf 24 proteins measured in the first verification cohort, nine proteins were associated with cGVHD, and only four (ST2, CXCL9, matrix metalloproteinase 3, and osteopontin) were necessary to compose a four-biomarker panel with an area under the receiver operating characteristic curve (AUC) of 0.89 and significant correlation with cGVHD diagnosis, cGVHD severity, and nonrelapse mortality. In a second verification cohort, this panel distinguished patients with cGVHD (AUC, 0.75), and finally, the panel measured at day +100 could predict cGVHD occurring within the next 3 months with an AUC of 0.67 and 0.79 without and with known clinical risk factors, respectively.ConclusionWe conclude that the biomarker panel measured at diagnosis or day +100 after HCT may allow patient stratification according to risk of cGVHD.
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