Central nervous system involvement in adults with epidemic hemolytic uremic syndrome.
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ABSTRACT:
SUBMITTER: Wengenroth M
PROVIDER: S-EPMC7964673 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In typical hemolytic uremic syndrome (HUS) approximately 25% of patients show central nervous system (CNS) involvement often leading to serious long-term disabilities. We used the C5-complement inhibitor Eculizumab as rescue therapy. From 2011 to 2014, 11 children (median age 22 months, range 11-175) with enterohemorrhagic Escherichia coli-positive HUS requiring dialysis who had seizures (11/11) and/or were in a stupor or coma (10/11) were treated with Eculizumab. Two patients enrolled on the Safety and Efficacy Study of Eculizumab in Shiga-Toxin Producing E coli Hemolytic-Uremic Syndrome (STEC-HUS) each received 6 doses of Eculizumab, 3 patients 2 doses, and 6 patients 1 dose. Laboratory diagnostics of blood samples and magnetic resonance imaging (MRI) were performed as per center practice. Data were analyzed retrospectively. Cranial MRI was abnormal in 8 of 10 patients with findings in the basal ganglia and/or white matter. A 2-year-old boy with severe cardiac involvement and status epilepticus needed repeated cardio-pulmonary resuscitation and extracorporeal membrane oxygenation. He died 8 days after start of Eculizumab treatment. Two patients with hemorrhagic colitis and repeated seizures required artificial ventilation for 6 and 16 days, respectively. At the time of discharge, 1 patient showed severe neurological impairment and 1 mild neurological impairment. The 8 surviving patients experienced no further seizures after the first dose of Eculizumab. Three patients showed mild neurological impairment at discharge, whilst the remaining 5 showed no impairment. The platelets normalized 4 days (median) after the first dose of Eculizumab (range 0-20 days). The mean duration of dialysis after the first dose of Eculizumab was 14.1 ± 6.1 days. In children with typical HUS and CNS involvement early use of Eculizumab appears to improve neurological outcome. In severe HUS cases which progress rapidly with multiple organ involvement, late treatment with Eculizumab seems to show less benefit. We speculate that prophylactic Eculizumab therapy before development of neurological symptoms could be advantageous.
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Project description:Hemolytic uremic syndrome (HUS) is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. The atypical form of HUS is a disease characterized by complement overactivation. Inherited defects in complement genes and acquired autoantibodies against complement regulatory proteins have been described. Incomplete penetrance of mutations in all predisposing genes is reported, suggesting that a precipitating event or trigger is required to unmask the complement regulatory deficiency. The underlying genetic defect predicts the prognosis both in native kidneys and after renal transplantation. The successful trials of the complement inhibitor eculizumab in the treatment of atypical HUS will revolutionize disease management.
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Project description:We conducted a retrospective study on hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC) in 96 adults enrolled in the cohort of the National Reference Center for Thrombotic Microangiopathies network in France during 2009-2017. Most infections were caused by STEC strains not belonging to the O157 or O104 serogroups. Thirty (31.3%) patients had multiple risk factors for thrombotic microangiopathy. In total, 61 (63.5%) patients required dialysis, 50 (52.1%) had a serious neurologic complication, 34 (35.4%) required mechanical ventilation, and 19 (19.8%) died during hospitalization. We used multivariate analysis to determine that the greatest risk factors for death were underlying immunodeficiency (hazard ratio 3.54) and severe neurologic events (hazard ratio 3.40). According to multivariate analysis and propensity score-matching, eculizumab treatment was not associated with survival. We found that underlying conditions, especially immunodeficiency, are strongly associated with decreased survival in adults who have hemolytic uremic syndrome caused by STEC.
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Project description:Eighty two patients of leukaemia consisting of 25 cases of acute lymphocytic leukaemia, 38 cases of acute myeloid leukaemia, 14 cases of chronic myeloid leukaemia and 5 cases of chronic lymphocytic leukaemia were evaluated for central nervous system (CNS) involvement. Speech disorders, cranial nerve palsies, encephalopathy, ataxia, intracranial haemorrhage, peripheral neuropathy and spinal cord involvement were the main neurological findings detected in 23 (28.1%) cases. All except one were subjected to autopsy after death. Leukaemic infiltrations (36.6%) and intracranial haemorrhage (26.8%) were the prominent CNS autopsy findings. In addition, demyelination with astrocytosis (9.7%) and gliosis (2.4%) were seen. In all, 45 (54.9%) of the patients showed CNS involvement at autopsy. Thus a large number of CNS lesions were missed clinically and detected only on autopsy.
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Project description:Central nervous system (CNS) involvement is reportedly more common in acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARL). We describe factors and outcomes associated with CNS involvement at baseline (CNS(B) ) and relapse (CNS(R) ) in 886 patients with newly diagnosed ARL. Of 886 patients, 800 received either intrathecal (IT) therapy for CNS(B) or IT prophylaxis. CNS(B) was found in 13%. CNS(B) was not associated with reduced overall survival (OS). There was no difference in the prevalence of CNS(B) between the pre-combination antiretroviral therapy (cART) and cART eras. 5·3% of patients experienced CNS(R) at a median of 4·2 months after diagnosis (12% if CNS(B) ; 4% if not). Median OS after CNS(R) was 1·6 months. On multivariate analysis, only CNS(B) [hazard ratio (HR) 3·68, P = 0·005] and complete response to initial therapy (HR 0·14, P < 0·0001) were significantly associated with CNS(R) . When restricted to patients without CNS(B) , IT CNS prophylaxis with 3 vs. 1 agent did not significantly impact the risk of CNS(R) . Despite IT CNS prophylaxis, 5% of patients experienced CNS(R) . Our data confirms that CNS(R) in ARL occurs early and has a poor outcome. Complete response to initial therapy was associated with a reduced frequency of CNS(R) . Although CNS(B) conferred an increased risk for CNS(R) , it did not impact OS.
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Project description:Atypical hemolytic uremic syndrome (aHUS) is a disease characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury. The histopathologic lesions of aHUS include thrombotic microangiopathy involving the glomerular capillaries and thrombosis involving arterioles or interlobar arteries. Extra-renal manifestations occur in up to 20% of patients. The majority of aHUS is caused by complement system defects impairing ordinary regulatory mechanisms. Activating events therefore lead to unbridled, ongoing complement activity producing widespread endothelial injury. Pathologic mutations include those resulting in loss-of-function in a complement regulatory gene (CFH, CFI, CD46 or THBD) or gain-of-function in an effector gene (CFB or C3). Treatment with the late complement inhibitor, eculizumab - a monoclonal antibody directed against C5 - is effective.
| S-EPMC5472348 | biostudies-other
Project description:Atypical hemolytic uremic syndrome (aHUS) is a disorder characterized by thrombocytopenia and microangiopathic hemolytic anemia due to endothelial injury. aHUS is felt to be caused by defective complement regulation due to underlying genetic mutations in complement regulators or activators, most often of the alternative pathway. Mutations causing aHUS can be subdivided into two groups, loss of function mutations (affecting factor H, factor H-related proteins, membrane co-factor protein, and factor I), and gain of function mutations (affecting factor B and C3). As more information becomes available on the relationship between specific mutations and clinical outcome, complete genetic workup of aHUS patients becomes more and more important. In this review, we will discuss the genetic background of aHUS, the role of complement for aHUS pathogenesis, and the different groups of specific mutations known to be involved in the pathogenesis of aHUS.
| S-EPMC6404389 | biostudies-literature
Project description:The hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. The common form of the syndrome is triggered by infection with Shiga toxin-producing bacteria and has a favorable outcome. The less common form of the syndrome, called atypical hemolytic-uremic syndrome, accounts for about 10% of cases, and patients with this form of the syndrome have a poor prognosis. Approximately half of the patients with atypical hemolytic-uremic syndrome have mutations in genes that regulate the complement system. Genetic factors in the remaining cases are unknown. We studied the role of thrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, and cytoprotective properties, in atypical hemolytic-uremic syndrome.We sequenced the entire thrombomodulin gene (THBD) in 152 patients with atypical hemolytic-uremic syndrome and in 380 controls. Using purified proteins and cell-expression systems, we investigated whether thrombomodulin regulates the complement system, and we characterized the mechanisms. We evaluated the effects of thrombomodulin missense mutations associated with atypical hemolytic-uremic syndrome on complement activation by expressing thrombomodulin variants in cultured cells.Of 152 patients with atypical hemolytic-uremic syndrome, 7 unrelated patients had six different heterozygous missense THBD mutations. In vitro, thrombomodulin binds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-mediated inactivation of C3b in the presence of cofactors, CFH or C4b binding protein. By promoting activation of the plasma procarboxypeptidase B, thrombomodulin also accelerates the inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulin variants associated with atypical hemolytic-uremic syndrome had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and were thus less protected from activated complement.Mutations that impair the function of thrombomodulin occur in about 5% of patients with atypical hemolytic-uremic syndrome.
| S-EPMC3530919 | biostudies-literature
Project description:BackgroundPregnancy is associated with various forms of thrombotic microangiopathy, including hemolytic uremic syndrome. A previous small French study suggested that pregnancy-associated hemolytic uremic syndrome was to be included in the spectrum of atypical hemolytic uremic syndrome linked to complement alternative pathway dysregulation.Design, setting, participants, & measurementsWe sought to retrospectively analyze the presentation, outcome, and frequency of complement alternative pathway gene variants in a larger international (France, United Kingdom, Italy) cohort of patients with pregnancy-associated hemolytic uremic syndrome.ResultsEighty-seven patients with pregnancy-associated hemolytic uremic syndrome were included. Hemolytic uremic syndrome occurred mainly during the first pregnancy (58%) and in the postpartum period (76%). At diagnosis, 56 (71%) patients required dialysis. Fifty-six (78%) patients underwent plasma exchanges, 21 (41%) received plasma infusions, and four (5%) received eculizumab. During follow-up (mean duration of 7.2 years), 41 (53%) patients reached ESRD, 15 (19%) had CKD, and 18 (28%) patients experienced hemolytic uremic syndrome relapse. Twenty-four patients (27%) received a kidney transplant and a recurrence of hemolytic uremic syndrome occurred in 13 (54%) patients. Variants in complement genes were detected in 49 (56%) patients, mainly in the CFH (30%) and CFI genes (9%).ConclusionsPregnancy-associated hemolytic uremic syndrome and atypical hemolytic uremic syndrome nonrelated to pregnancy have the same severity at onset and during follow-up and the same frequency of complement gene variants.
| S-EPMC5544502 | biostudies-literature
Project description:We reviewed the evidence on features of central nervous system (CNS) involvement in trichinellosis, systematically searching five databases (to January 2021). We categorized clinical features based on their diagnostic value as warning signs for severe CNS infection (with outcome death) or non-specific signs (outcome improvement). They were suggestive of severe infection if they substantially raised death probability. The review included 87 papers published from 1906 through 2019, with data on 168 patients. Mydriasis, paraparesis, dysphagia, psychomotor seizures, or delirium present a 30-45% increased death likelihood. The best poor prognosis predictor is mydriasis (positive likelihood ratio 9.08). Slow/absent light reflex, diminished/absent knee reflexes, globally decreased tendon reflexes present a moderate increase (20-25%) of death risk. Anisocoria, acalculia, or seizures could also indicate an increased death risk. We provided a detailed presentation of clinical and paraclinical signs that alert physicians of a possible neurotrichinellosis, emphasizing signs that might indicate a poor prognosis.
| S-EPMC8227095 | biostudies-literature