Minor brain abnormalities in infants with congenital Cytomegalovirus infection

Background The spectrum of neuroimaging abnormalities associated with congenital CMV infection (cCMV) include subependymal pseudocysts (SEPCs) and white matter abnormalities (WMAs). There are scant data about outcome and effectiveness of antiviral treatment in patients with cCMV and isolated SEPCs (ISEPCs) or isolated WMAs (IWMAs). The aims of this study were: 1) to assess prevalence and outcome of ISEPCS and IWMAs detected by MRI in term infants with cCMV infection; 2) to compare hearing and neurodevelopmental outcomes between patients with symptomatic and asymptomatic cCMV; to compare hearing and neurodevelopmental outcomes between treated and untreated patients with cCMV. Methods This was a retrospective study of term infants with cCMV born before February 2021 from three European children’s hospitals. MRI studies were performed on a 1.5 or 3 Tesla system. MRI scans were independently reviewed by two experts blinded to clinical data, and any discrepancy was resolved by consensus. Symptomatic cCMV was defined according to Kimberlin DW, et al (N Engl J Med. 2015;372(10):933-43). SEPCs were defined as cystic lesions located along or adjacent to the wall of the lateral ventricle(s). Patients were considered to have ISEPCs when these were the only abnormal MRI finding. WMAs were established in the presence of abnormally high signal intensity on T2- and low signal intensity within the white matter on T1-weighted MRI. WMAs were classified as multifocal or diffuse. Patients were considered to have isolated WMAs (IWMAs) when these were the only abnormal finding detected by MRI, or were associated solely with SEPCs. Antiviral treatment (ganciclovir or valganciclovir) was proposed according to the best evidence-based standard practice at time of birth. Moderate or severe disability was defined as one of the following: cerebral palsy; GMDS DQ, BSID-II MDI or PDI, Bayley-III composite cognitive or motor score, or overall IQ at WISC or WPPSI <-2 SD; epilepsy requiring antiseizure medication; severe sensori-neural hearing loss (SNHL) (>70 dB threshold and/or requiring cochlear implants); or visual impairment. Non-severe SNHL or a score between -1 and -2 SD on the GMDS DQ, BSID-II MDI or PDI, Bayley-III composite cognitive or motor scales, or overall IQ were classified as mild disabilities. Results Among the 89 included patients, SEPCs were identified in 52 (58.4%) infants. In 19/89 cases (21.3%), they were isolated (ISEPCs). No patients with ISEPCs had moderate/severe disability at a mean age of 52.3±21.6 months. All 13 asymptomatic patients with ISEPCs had normal outcome, whilst 2/6 (33.3%) symptomatic patients with ISEPCs had mild disability at follow-up (non-severe SNHL). Treated and untreated patients with ISEPCs had similar rates of mild disability (table 1). WMAs were found in 36 (40.4%) infants. WMAs were associated with MRI abnormalities other than SEPCs in 16 (18.0%) infants, while in 20 (22.5%) infants they were isolated or associated solely with SEPCs (IWMAs). Mean follow-up duration was Among patients with IWMAs, 1/20 (5.0%) had a moderate/severe disability (severe SNHL) at last follow-up visit (mean age at last follow-up: 53.2 ± 24.0 months). Within the IWMA group, a trend towards a higher rate of disability was observed among patients with symptomatic cCMV (57.1%) compared to those with asymptomatic disease (15.4%), although not statistically significant. Treated and untreated patients with IWMAs had similar rates of disability (table 2). Discussion ISEPCs and IWMAs are common MRI findings among cCMV infants. Overall, patients with cCMV and ISEPCs carry a low risk of mild disability, regardless of antiviral treatment. Among patients with IWMAs, disability rates are higher, with no difference between treated and untreated subjects. Given the toxicity of the available antiviral agents and the absence of trials investigating the effectiveness of treatment in patients with cCMV and ISEPCs or IWMAs, these data may be helpful when facing the dilemma of treatment in these subgroups of infants with cCMV. Untreated ISEPCs (N = 11) Treated ISEPCs (N = 8) P Symptomatic disease, n (%) 3/11 (27.3) 3/8 (37.5) 1 Outcome data Age at follow-up, months, mean ± SD 49.9 ± 22.9 56.4 ± 22.9 0.55 Moderate or severe disability, n/total (%) 0/9 (0.0) 0/8 (0.0) - Cerebral palsy, n/total (%) 0/9 (0.0) 0/8 (0.0) - Moderate or severe cognitive or neurodevelopmental deficit, n/total (%) 0/9 (0.0) 0/8 (0.0) - Epilepsy requiring antiseizure medication, n/total (%) 0/9 (0.0) 0/8 (0.0) - Severe SNHL, n/total (%) 0/11 (0.0) 0/8 (0.0) - Visual impairment, n/total (%) 0/9 (0.0) 0/8 (0.0) - Death, n (%) 0/11 (0.0) 0/8 (0.0) - Mild disability, n/total (%) 1/9 (11.1) 1/8 (12.5) 1 Non-severe SNHL without other moderate or severe disabilities, n/total (%) 1/11 (9.1) 1/8 (12.5) 1 Mild cognitive or neurodevelopmental deficit, n/total (%) 0/9 (0.0) 0/8 (0.0) - Any disability, n/total (%) 1/9 (11.1) 1/8 (12.5) 1 Table 1. Hearing and neurodevelopmental outcomes of patients with ISEPCs according to antiviral treatment. Untreated IWMAs (N = 11) Treated IWMAs (N = 9) p Symptomatic disease, n (%) 2/11 (18.2) 5/9 (44.4) 0.20 Outcome data Age at follow-up, months, mean ± SD 58.6 ± 23.1 46.4 ± 23.0 0.40 Moderate or severe disability, n/total (%) 0/11 (0.0) 1/9 (11.1) 0.45 Cerebral palsy, n/total (%) 0/11 (0.0) 0/9 (0.0) - Moderate or severe cognitive or neurodevelopmental deficit, n/total (%) 0/11 (0.0) 0/9 (0.0) - Epilepsy requiring antiseizure medication, n/total (%) 0/11 (0.0) 0/9 (0.0) - Severe SNHL, n/total (%) 0/11 (0.0) 1/9 (11.1) 0.45 Visual impairment, n/total (%) 0/11 (0.0) 0/9 (0.0) - Death, n (%) 0/11 (0.0) 0/9 (0.0) - Mild disability, n/total (%) 3/11 (27.3) 2/9 (22.2) 1 Non-severe SNHL without other moderate or severe disabilities, n/total (%) 1/11 (9.1) 1/9 (11.1) 1 Mild cognitive or neurodevelopmental deficit, n/total (%) 2/11 (18.2) 1/9 (11.1) 1 Any disability, n/total (%) 3/11 (27.3) 3/9 (33.3) 1 Table 2. Hearing and neurodevelopmental outcomes of patients with IWMAs according to antiviral treatment.