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A congenital CMV infection model for follow-up studies of neurodevelopmental disorders, neuroimaging abnormalities, and treatment.

ABSTRACT: Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neurodevelopmental disorders. However, the neuropathogenesis remains largely elusive due to a lack of informative animal models. In this study, we developed a congenital murine CMV (cMCMV) infection mouse model with high survival rate and long survival period that allowed long-term follow-up study of neurodevelopmental disorders. This model involves in utero intracranial injection and mimics many reported clinical manifestations of cCMV infection in infants, including growth restriction, hearing loss, and impaired cognitive and learning-memory abilities. We observed that abnormalities in MRI/CT neuroimaging were consistent with brain hemorrhage and loss of brain parenchyma, which was confirmed by pathological analysis. Neuropathological findings included ventriculomegaly and cortical atrophy associated with impaired proliferation and migration of neural progenitor cells in the developing brain at both embryonic and postnatal stages. Robust inflammatory responses during infection were shown by elevated inflammatory cytokine levels, leukocyte infiltration, and activation of microglia and astrocytes in the brain. Pathological analyses and CT neuroimaging revealed brain calcifications induced by cMCMV infection and cell death via pyroptosis. Furthermore, antiviral treatment with ganciclovir significantly improved neurological functions and mitigated brain damage as shown by CT neuroimaging. These results demonstrate that this model is suitable for investigation of mechanisms of infection-induced brain damage and long-term studies of neurodevelopmental disorders, including the development of interventions to limit CNS damage associated with cCMV infection.

SUBMITTER: Zhou YP

PROVIDER: S-EPMC8765053 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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A congenital CMV infection model for follow-up studies of neurodevelopmental disorders, neuroimaging abnormalities, and treatment.

Zhou Yue-Peng YP Mei Meng-Jie MJ Wang Xian-Zhang XZ Huang Sheng-Nan SN Chen Lin L Zhang Ming M Li Xin-Yan XY Qin Hai-Bin HB Dong Xiao X Cheng Shuang S Wen Le L Yang Bo B An Xue-Fang XF He Ao-Di AD Zhang Bing B Zeng Wen-Bo WB Li Xiao-Jun XJ Lu Youming Y Li Hong-Chuang HC Li Haidong H Zou Wei-Guo WG Redwood Alec J AJ Rayner Simon S Cheng Han H McVoy Michael A MA Tang Qiyi Q Britt William J WJ Zhou Xin X Jiang Xuan X Luo Min-Hua MH

JCI insight 20220111 1

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neurodevelopmental disorders. However, the neuropathogenesis remains largely elusive due to a lack of informative animal models. In this study, we developed a congenital murine CMV (cMCMV) infection mouse model with high survival rate and long survival period that allowed long-term follow-up study of neurodevelopmental disorders. This model involves in utero intracranial injection and mimics many reported clinical man ...[more]

PMID: 35014624

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Project description:BackgroundBrain injury and neurodevelopmental impairment remain a concern in children with complex congenital heart disease (CHD). A practice guideline on neuromonitoring, neuroimaging, and neurodevelopmental follow-up in CHD patients undergoing cardiopulmonary bypass surgery is lacking. The aim of this survey was to systematically evaluate the current practice in centers across Europe.MethodsAn online-based structured survey was sent to pediatric cardiac surgical centers across Europe between April 2019 and June 2020. Results were summarized by descriptive statistics.ResultsValid responses were received by 25 European centers, of which 23 completed the questionnaire to the last page. Near-infrared spectroscopy was the most commonly used neuromonitoring modality used in 64, 80, and 72% preoperatively, intraoperatively, and postoperatively, respectively. Neuroimaging was most commonly performed by means of cranial ultrasound in 96 and 84% preoperatively and postoperatively, respectively. Magnetic resonance imaging was obtained in 72 and 44% preoperatively and postoperatively, respectively, but was predominantly reserved for clinically symptomatic patients (preoperatively 67%, postoperatively 64%). Neurodevelopmental follow-up was implemented in 40% of centers and planned in 24%.ConclusionsHeterogeneity in perioperative neuromonitoring and neuroimaging practice in CHD in centers across Europe is large. The need for neurodevelopmental follow-up has been recognized. A clear practice guideline is urgently needed.ImpactThere is large heterogeneity in neuromonitoring, neuroimaging, and neurodevelopmental follow-up practices among European centers caring for neonates with complex congenital heart disease. This study provides a systematic evaluation of the current neuromonitoring, neuroimaging, and neurodevelopmental follow-up practice in Europe. The results of this survey may serve as the basis for developing a clear practice guideline that could help to early detect and prevent neurological and neurodevelopmental sequelae in neonates with complex congenital heart disease.

Project description:BackgroundNeurodevelopmental outcomes programs for children with congenital heart disease (CHD) support early identification and intervention for developmental impairments; however, not all eligible children attend such programs. The purpose of our study was to examine factors, including sociodemographic, associated with cardiac neurodevelopmental outcomes program attendance.MethodsChildren with CHD born April 2013-April 2018 who underwent cardiac surgery before age 6 months were included. The primary outcome was at least one neurodevelopmental clinic visit, and secondary outcome was number of visits attended during the first two years of life. Predictor variables included maternal and infant characteristics, surgical data, geographic location of residence, and neighborhood-level socioeconomic metrics.ResultsOf 730 eligible infants, median age at surgery was 13 days (IQR 7-44), and 37% were Hispanic, 45% were non-Hispanic White, and 10% were non-Hispanic Black. Twenty-three percent lived >200 miles from the institution. A total of 462 (63%) attended at least one visit. On multivariable analysis, factors associated with attending at least once were Hispanic ethnicity (if living <200 miles from the institution or Spanish-speaking), older maternal age, and shorter driving time. On multivariable analysis of the secondary outcome, factors associated with a greater number of visits were Hispanic ethnicity (if living <200 miles from the institution), older maternal age, shorter driving time, and private health insurance.ConclusionsOur data demonstrate that Hispanic ethnicity and closer distance from the institution were associated with increased attendance in our neurodevelopmental program. Continued education on the importance of neurodevelopmental follow-up and making adaptations to current practices to reach all individuals with CHD will be important moving forward. Whether these higher rates of attendance improve neurodevelopmental outcomes for this specific population requires further research.

Project description:AimTo identify and map evidence describing components of neurodevelopmental follow-up care for children with congenital heart disease (CHD).MethodThis was a scoping review of studies reporting components of neurodevelopmental follow-up programmes/pathways for children with CHD. Eligible publications were identified through database searches, citation tracking, and expert recommendations. Two independent reviewers screened studies and extracted data. An evidence matrix was developed to visualize common characteristics of care pathways. Qualitative content analysis identified implementation barriers and enablers.ResultsThe review included 33 studies. Twenty-one described individual care pathways across the USA (n = 14), Canada (n = 4), Australia (n = 2), and France (n = 1). The remainder reported surveys of clinical practice across multiple geographical regions. While heterogeneity in care existed across studies, common attributes included enrolment of children at high-risk of neurodevelopmental delay; centralized clinics in children's hospitals; referral before discharge; periodic follow-up at fixed ages; standardized developmental assessment; and involvement of multidisciplinary teams. Implementation barriers included service cost/resourcing, patient burden, and lack of knowledge/awareness. Multi-level stakeholder engagement and integration with other services were key drivers of success.InterpretationDefining components of effective neurodevelopmental follow-up programmes and care pathways, along with enhancing and expanding guideline-based care across regions and into new contexts, should continue to be priorities.What this paper addsTwenty-two different neurodevelopmental follow-up care pathways/programmes were published, originating from four countries. Twelve additional publications described broad practices for neurodevelopmental follow-up across regions Common attributes across eligibility, service structure, assessment processes, and care providers were noted. Studies reported programme acceptability, uptake, cost, and effectiveness. Implementation barriers included service cost/resourcing, patient burden, and lack of knowledge/awareness.

Dataset Information

A congenital CMV infection model for follow-up studies of neurodevelopmental disorders, neuroimaging abnormalities, and treatment.

Publications

A congenital CMV infection model for follow-up studies of neurodevelopmental disorders, neuroimaging abnormalities, and treatment.

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