The cytomegalovirus gB/MF59 vaccine candidate induces antibodies against an antigenic domain controlling cell-to-cell spread.

Vaccination against human cytomegalovirus (CMV) infection remains high priority. A recombinant form of a protein essential for CMV entry, glycoprotein B (gB), demonstrated partial protection in a clinical trial (NCT00299260) when delivered with the MF59 adjuvant. Although the antibody titre against gB correlated with protection poor neutralising responses against the 5 known antigenic domains (AD) of gB were evident. Here, we show that vaccination of CMV seronegative patients induces an antibody response against a region of gB we term AD-6. Responses to the polypeptide AD-6 are detected in >70% of vaccine recipients yet in <5% of naturally infected people. An AD-6 antibody binds to gB and to infected cells but not the virion directly. Consistent with this, the AD-6 antibody is non-neutralising but, instead, prevents cell-cell spread of CMV in vitro. The discovery of AD-6 responses has the potential to explain part of the protection mediated by gB vaccines against CMV following transplantation.

Ganglionic Eminence Anomalies and Coexisting Cerebral Developmental Anomalies on Fetal MR Imaging: Multicenter-Based Review of 60 Cases.

BACKGROUND AND PURPOSE: The ganglionic eminences are transient fetal brain structures that produce a range of neuron types. Ganglionic eminence anomalies have been recognized on fetal MR imaging and anecdotally found in association with a number of neurodevelopmental anomalies. The aim of this exploratory study was to describe and analyze the associations between ganglionic eminence anomalies and coexisting neurodevelopmental anomalies. MATERIALS AND METHODS: This retrospective study includes cases of ganglionic eminence anomalies diagnosed on fetal MR imaging during a 20-year period from 7 centers in Italy and England. Inclusion criteria were cavitation or increased volume of ganglionic eminences on fetal MR imaging. The studies were analyzed for associated cerebral developmental anomalies: abnormal head size and ventriculomegaly, reduced opercularization or gyration, and abnormal transient layering of the developing brain mantle. The results were analyzed using χ2 and Fisher exact tests. RESULTS: Sixty fetuses met the inclusion criteria (21 females, 24 males, 15 sex unknown). Thirty-four had ganglionic eminence cavitations (29 bilateral and 5 unilateral), and 26 had increased volume of the ganglionic eminences (19 bilateral, 7 unilateral). Bilateral ganglionic eminence cavitations were associated with microcephaly (P = .01), reduced opercularization, (P < .001), reduced gyration (P < .001), and cerebellar anomalies (P = .01). Unilateral ganglionic eminence cavitations were not significantly associated with any particular feature. Bilateral increased volume of the ganglionic eminences showed an association with macrocephaly (P = .03). Unilateral increased volume was associated with macrocephaly (P = .002), abnormal transient layering (P = .001), unilateral polymicrogyria (P = .001), and hemimegalencephaly (P < .001). CONCLUSIONS: Ganglionic eminence anomalies are associated with specific neurodevelopmental anomalies with ganglionic eminence cavitations and increased ganglionic eminence volume apparently having different associated abnormalities.

Post-mortem confirmation of fetal brain abnormalities: challenges highlighted by the MERIDIAN cohort study.

OBJECTIVES: To assess and analyse the concordance between post-mortem findings and in utero magnetic resonance imaging (iuMRI) in the MERIDIAN (MRI to enhance the diagnosis of fetal developmental brain abnormalities in utero) cohort. DESIGN: Prospective cohort study. SETTING: Fetal medicine units in the UK. POPULATION: Pregnant women with a diagnosis of fetal brain abnormality identified on ultrasound at 18 weeks of gestation or later. METHODS: All pregnancies from the MERIDIAN study that resulted in a abortion were included and the rate of uptake and success of post-mortem examinations were calculated. In the cases in which diagnostic information about the fetal brain was obtained by post-mortem, the results were compared with the diagnoses from iuMRI. MAIN OUTCOME MEASURE: Outcome reference diagnosis from post-mortem examination. RESULTS: A total of 155 from 823 pregnancies (19%) ended in a termination of pregnancy and 71 (46%) had post-mortem brain examinations, 62 of which were diagnostically adequate. Hence, the overall rate of successful post-mortem investigation was 40%, and for those cases there was a concordance rate of 84% between iuMRI and post-mortem examination. Detailed information is provided when the results of the post-mortem examination and the iuMRI study differed. CONCLUSIONS: We have shown tissue-validation of radiological diagnosis is hampered by a low rate of post-mortem studies in fetuses aborted with brain abnormalities, a situation further compounded by a 12% rate of autopsy being technically unsuccessful. The agreement between iuMRI and post-mortem findings is high, but our analysis of the discrepant cases provides valuable clues for improving how we provide information for parents. TWEETABLE ABSTRACT: iuMRI should be considered a reliable indicator of fetal brain abnormalities when post-mortem is not performed.

Review of the MRI brain findings of septo-optic dysplasia.

AIM: To report the magnetic resonance imaging (MRI) findings from a retrospective case analysis of children with septo-optic dysplasia (SOD), a rare congenital disorder characterised by any combination of midline brain defects, optic nerve hypoplasia (ONH), and hypothalamic-pituitary dysfunction. MATERIALS AND METHODS: SOD was defined radiologically as complete or partial septum pellucidum (SP) absence with hypoplasia of at least one of the optic nerves and/or chiasm. Local MRI databases were searched for SOD cases in children over an 18-year period, and studies reviewed by two consultant paediatric neuroradiologists. The extent of structural SP, optic nerve, chiasm, and hypothalamic-pituitary involvement was recorded, along with coexisting brain abnormalities. RESULTS: Forty-eight cases of SOD were found; 44/48 (92%) demonstrated complete SP absence whereas 4/48 (8%) had partial absence. Eight of 48 cases (17%) exhibited unilateral ONH. Fifty-one percent of cases, where the pituitary was identified on MRI, demonstrated a structural pituitary abnormality, which included an ectopic posterior bright spot in 6%. The olfactory nerves were hypoplastic in 5/48 cases (10%). Twenty-seven of the 48 cases (56%) had another brain abnormality, resulting from some form of cortical formation abnormality/schizencephaly in 21/48 (44%). CONCLUSION: A high rate of associated brain abnormalities was found in the present cohort, including structural pituitary abnormalities in 51% and cortical formation abnormalities/schizencephaly in 44%. This suggests there is not a single cause for SOD, rather SOD is the phenotypic end point from multiple aetiological events. Individual children with SOD may have coexisting intracranial abnormalities, and, hence, high-quality MRI is required in all.

Analysis of 270 fetuses with non-visualization of cavum septi pellucidi and vergae on in-utero magnetic resonance imaging.

OBJECTIVE: To analyze a large retrospective cohort of fetuses in which the cavum septi pellucidi and vergae (CSPV) was not present or was not in its expected position on in-utero magnetic resonance imaging (iuMRI), in order to describe the possible causes of that finding and provide a diagnostic approach to assess such cases in clinical practice using iuMRI. METHODS: This was a retrospective study of fetuses that underwent iuMRI at a single institution, over an 18-year period (2000-2017 inclusive), in which the CSPV was not visualized or was abnormal. All iuMRI studies were reviewed and classified as CSPV being not present, disrupted (visualization of remnants of an otherwise normally placed CSPV) or malpositioned (CSPV was present, but not in its expected position). We describe the neuropathology present in each of the groups. RESULTS: Of the 270 fetuses that met the inclusion criteria, the CSPV was described as malpositioned in 150 (56%), disrupted in 71 (26%) and not present in 49 (18%). Malpositioned CSPV was present only in cases with agenesis of the corpus callosum and three specific patterns of malpositioning are described, depending on the location of the leaflets of the CSPV and fornix. Disrupted CSPV was present in fetuses with hydrocephalus or pathologies causing extensive brain parenchymal injury. Not present CSPV was found in cases with holoprosencephaly or when absence of the CSPV appeared to be an isolated finding. CONCLUSION: We have described a large cohort of fetuses with non-visualization of a normal CSPV on iuMRI and present a categorical classification system based on the CSPV being not present, disrupted or malpositioned. This approach should help in the diagnosis of the underlying cause of a CSPV abnormality. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The rate of brain abnormalities on in utero MRI studies in fetuses with normal ultrasound examinations of the brain and calculation of indicators of diagnostic performance.

AIM: To estimate the rate of unexpected brain abnormalities detected by in utero magnetic resonance imaging (iuMRI) in fetuses without abnormalities at ultrasonography (USS). MATERIALS AND METHODS: A prospective cohort study of pregnant women whose fetus had no structural brain (or body) abnormalities recognised on antenatal ultrasonography. Women were recruited from 12 centres across the UK and underwent iuMRI at 18 gestational weeks or more in the [blinded for review]. The imaging studies were reviewed by an experienced neuroradiologist. The positive and negative predictive values of both USS and iuMRI have been calculated by combining the results of this study with the results from the main [blinded for review] study. RESULTS: One hundred and ninety-eight pregnant women were recruited and underwent iuMRI of 205 fetuses. Brain abnormalities were shown on iuMRI in two fetuses that were not recognised on USS (one case of a focal cortical abnormality and one case of mild ventriculomegaly). The negative predictive value for USS was 99.5% and 100% for iuMRI. CONCLUSIONS: To the authors' knowledge, this is the first study comparing USS and iuMRI in low-risk pregnancies. USS has a comparatively high rule-out for fetal brain abnormalities and should remain the screening tool of choice.

T2 prolongation in the cerebellar vermis on prenatal MRI of fetuses with Chiari 2 malformations.

AIM: To describe a new finding in fetuses with Chiari 2 malformations recognised at in utero (iu) magnetic resonance imaging (MRI), specifically T2 prolongation (high signal) in the cerebellar vermis. MATERIALS AND METHODS: This was a prospective observational study of iuMRI studies performed at two time points on 20 fetuses with Chiari 2 malformations and 10 control fetuses at the same time points. High T2 signal in the cerebellar vermis was noted and correlated with posterior fossa dimensions was assessed. RESULTS: High T2 signal in the cerebellar vermis was found in over half of the fetuses with a Chiari 2 malformation, but was not correlated with the degree of reduction in size of the bony posterior fossa. CONCLUSION: The present findings suggest that abnormal high T2 signal in the cerebellum is common in fetuses with Chiari 2 malformations and although the cause of the signal change is not known at present it may represent vasogenic oedema as a result of restricted venous drainage.

Should we perform in utero MRI on a fetus at increased risk of a brain abnormality if ultrasonography is normal or shows non-specific findings?

There are a number of reasons why a pregnant woman might be considered to have an increased risk of carrying a fetus with a brain abnormality, but they fall broadly into two groups. First, there may be a relevant family history usually, but not always, when a fetus/child from a previous pregnancy has a developmental brain abnormality and a clinical geneticist judges that there is a risk of recurrence. Second, there may be findings in their current pregnancy that increases the risk of the fetus either having a developmental brain abnormality or accruing acquired brain pathology. Antenatal ultrasonography remains the mainstay of fetal screening and anomaly scanning, but there is now persuasive evidence that in utero magnetic resonance imaging should have an important supporting role. This is important, as more accurate and more certain diagnoses are central to providing parents with accurate information about the likely clinical outcome. In pregnancies at increased risk of brain abnormalities, it is also important to provide the best quality information that the fetal brain is normal to provide reassurance to parents. In this paper, we review the proposition that in utero magnetic resonance imaging should be used in pregnancies at increased risk of brain abnormalities, even if the consultant-led ultrasound examination is normal or showed non-specific findings only.

Anatomical subgroup analysis of the MERIDIAN cohort: failed commissuration.

OBJECTIVE: To assess the contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with either agenesis or hypogenesis of the corpus callosum (referred to collectively as failed commissuration) on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with failed commissuration (with or without ventriculomegaly) diagnosed on ultrasound in women who had MRI assessment within 2 weeks of ultrasound and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI was studied, as well as indicators of diagnostic confidence and effects on prognosis/clinical management. Appropriate diagnostic confidence was assessed by the score-based weighted average method, which combines diagnostic accuracy with diagnostic confidence data. RESULTS: In the MERIDIAN cohort, 79 fetuses were diagnosed with failed commissuration on ultrasound (55 with agenesis and 24 with hypogenesis of the corpus callosum). The diagnostic accuracy for detecting failed commissuration was 34.2% for ultrasound and 94.9% for MRI (difference, 60.7% (95% CI, 47.6-73.9%), P < 0.0001). The diagnostic accuracy for detecting hypogenesis of the corpus callosum as a discrete entity was 8.3% for ultrasound and 87.5% for MRI, and for detecting agenesis of the corpus callosum as a distinct entity was 40.0% for ultrasound and 92.7% for MRI. There was a statistically significant improvement in 'appropriate' diagnostic confidence when using MRI as assessed by the score-based weighted average method (P < 0.0001). Prognostic information given to the women changed in 36/79 (45.6%) cases after MRI and its overall effect on clinical management was 'significant', 'major' or 'decisive' in 35/79 cases (44.3%). CONCLUSIONS: Our data suggest that any woman whose fetus has failed commissuration as the only intracranial finding detected on ultrasound should have MRI examination for further evaluation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Anatomical subgroup analysis of the MERIDIAN cohort: posterior fossa abnormalities.

OBJECTIVE: To assess the diagnostic and clinical contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with abnormalities of the posterior fossa as the only intracranial abnormality recognized on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with abnormalities of the posterior fossa (with or without ventriculomegaly) diagnosed on antenatal ultrasound in women who had MRI within 2 weeks of ultrasound and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI is reported, as well as indicators of diagnostic confidence and effects on prognosis and clinical management. Appropriate diagnostic confidence was assessed by the score-based weighted average method, which combines diagnostic accuracy with diagnostic confidence data. RESULTS: Abnormalities confined to the posterior fossa according to ultrasound were found in 81 fetuses (67 with parenchymal and 14 with cerebrospinal fluid-containing lesions). The overall diagnostic accuracy for detecting an isolated posterior fossa abnormality was 65.4% for ultrasound and 87.7% for MRI (difference, 22.3% (95% CI, 14.0-30.5%); P < 0.0001). There was an improvement in 'appropriate' diagnostic confidence, as assessed by the score-based weighted average method (P < 0.0001), and a three-fold reduction in 'high confidence but incorrect diagnosis' was achieved using MRI. Prognostic information given to the women changed after MRI in 44% of cases, and the overall effect of MRI on clinical management was considered to be 'significant', 'major' or 'decisive' in 35% of cases. CONCLUSIONS: Our data suggest that any woman whose fetus has a posterior fossa abnormality as the only intracranial finding on ultrasound should have MRI for further evaluation. This is on the basis of improved diagnostic accuracy and confidence, which impacts substantially on the prognostic information given to women as well as their clinical management. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Anatomical subgroup analysis of the MERIDIAN cohort: ventriculomegaly.

OBJECTIVE: To assess the contribution of fetal magnetic resonance imaging (MRI) in fetuses of the MERIDIAN cohort diagnosed with ventriculomegaly (VM) as the only abnormal intracranial finding on antenatal ultrasound. METHODS: This was a subgroup analysis of the MERIDIAN study of fetuses with only VM diagnosed on ultrasound in women who had a subsequent MRI examination within 2 weeks and for whom outcome reference data were available. The diagnostic accuracy of ultrasound and MRI was reported in relation to the severity of VM. The difference in measurements of trigone size on the two imaging methods and the clinical impact of adding MRI to the diagnostic pathway were also studied. RESULTS: In 306 fetuses with VM, ultrasound failed to detect 31 additional brain abnormalities, having an overall diagnostic accuracy of 89.9% for ultrasound, whilst MRI correctly detected 27 of the additional brain abnormalities, having a diagnostic accuracy of 98.7% (P < 0.0001). There were other brain abnormalities in 14/244 fetuses with mild VM on ultrasound (diagnostic accuracy, 94.3%) and MRI correctly diagnosed 12 of these (diagnostic accuracy, 99.2%; P = 0.0005). There was a close agreement between the size of trigones measured on ultrasound and on MRI, with categorical differences in only 16% of cases, showing that MRI did not systematically overestimate or underestimate trigone size. Complete prognostic data were available in 295/306 fetuses and the prognosis category changed after MRI in 69/295 (23.4%) cases. The overall effect of MRI on clinical management was considered to be 'significant', 'major' or 'decisive' in 76/295 (25.8%) cases. CONCLUSION: Our data suggest that a woman carrying a fetus with VM as the only intracranial finding on ultrasound should be offered an adjuvant investigation by MRI for further evaluation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Change in diagnostic confidence brought about by using in utero MRI for fetal structural brain pathology: analysis of the MERIDIAN cohort.

AIM: To measure possible change in diagnostic confidence by performing in utero magnetic resonance imaging (iuMRI) studies on fetuses with brain abnormalities recognised on ultrasonography (US). MATERIALS AND METHODS: The analyses are based on the primary cohort from the prospective MERIDIAN study, which consisted of 570 fetuses with brain abnormalities detected on US, with iuMRI performed within 2 weeks of US and complete outcome reference data. The cohort was recruited between July 2011 and August 2014, and written informed consent was obtained for all participants. They all had indicators of diagnostic confidence measured on US by fetal medicine experts and iuMRI by the reporting radiologists. Three assessments were carried out using the conventional uncorrected (C2-C1%) method, the conventional (C2-C1%) with the Omary correction, and the score-based weighted average method. RESULTS: All three assessments showed statistically significant (p<0·0001) positive effects indicating that iuMRI was potentially beneficial when included in the diagnostic pathway for prenatal structural brain anomalies (in terms of diagnostic confidence). CONCLUSION: These results strongly support the routine clinical use of iuMRI as an adjunct to US when assessing fetuses with structural brain abnormalities.