Isolated Absent Septum Pellucidum: A Retrospective Study of Fetal Diagnosis and Postnatal Outcomes.

BACKGROUND: Absent septum pellucidum (ASP) is a brain abnormality often associated with neuroanatomic abnormalities including septo-optic dysplasia (SOD). We aimed to determine how frequently prenatally diagnosed isolated ASP is confirmed by postnatal imaging and to examine clinical outcomes for ASP. METHODS: This was a retrospective study of maternal-fetal dyads referred to Children's National Hospital from January 1, 2012, to June 30, 2019. We included cases with fetal diagnosis of isolated or complex ASP. Diagnosis was based on ASP and the presence or absence of additional neuroanatomic findings. Data included obstetric and birth history, genetic testing, imaging, and neurodevelopmental outcomes. RESULTS: ASP was diagnosed in 35 fetuses. Of 17 fetuses with isolated ASP, 10 had postnatal evaluation. In five (50%) isolated ASP cases, postnatal imaging revealed additional brain abnormalities. The five children with postnatally confirmed isolated ASP had lower rates of hydrocephalus (0% vs 54%) and abnormal feeding (0% vs 20%), hearing (0% vs 14%), and vision (0% vs 14%) than those with complex ASP (n = 17). Children with isolated ASP had lower rates of developmental delay (33% vs 50%) and seizures (11% vs 30%) than children with complex ASP. One child with prenatal isolated ASP was diagnosed with SOD (10%). CONCLUSIONS: Few children with prenatally diagnosed isolated ASP had SOD diagnosed postnatally. Overall, children with isolated ASP demonstrate better outcomes than children with complex ASP. Fetal magnetic resonance imaging is a useful tool to evaluate the septum pellucidum and may reveal additional abnormalities that can impact prognosis and affect prenatal counseling.

Complexities of Zika Diagnosis and Evaluation in a U.S. Congenital Zika Program.

The objective of the study was to describe the complexity of diagnosis and evaluation of Zika-exposed pregnant women/fetuses and infants in a U.S. Congenital Zika Program. Pregnant women/fetuses and/or infants referred for clinical evaluation to the Congenital Zika Program at Children's National (Washington, DC) from January 2016 to June 2018 were included. We recorded the timing of maternal Zika-virus (ZIKV) exposure and ZIKV laboratory testing results. Based on laboratory testing, cases were either confirmed, possible, or unlikely ZIKV infection. Prenatal and postnatal imaging by ultrasound and/or magnetic resonance imaging (MRI) were categorized as normal, nonspecific, or as findings of congenital Zika syndrome (CZS). Of 81 women-fetus/infant pairs evaluated, 72 (89%) had confirmed ZIKV exposure; 18% of women were symptomatic; only a minority presented for evaluation within the time frame for laboratory detection. Zika virus could only be confirmed in 29 (40%) cases, was possible in 26 (36%) cases, and was excluded in 17 (24%) cases. Five cases (7%) had prenatal ultrasound and MRI findings of CZS, but in only three was ZIKV confirmed by laboratory testing. Because of timing of exposure to presentation, ZIKV infection could not be excluded in many cases. Neuroimaging found CZS in 7% of cases, and in many patients, there were nonspecific imaging findings that warrant long-term follow-up. Overall, adherence to postnatal recommended follow-up evaluations was modest, representing a barrier to care. These challenges may be instructive to future pediatric multidisciplinary clinics for congenital infectious/noninfectious threats to pregnant women and their infants.

Taenia-tela choroidea complex and choroid plexus location help distinguish Dandy-Walker malformation and Blake pouch cysts.

BACKGROUND: Dandy-Walker malformation and Blake pouch cysts can have overlapping imaging features. The choroid plexus and associated taenia-tela choroidea complex are displaced inferolaterally in Dandy-Walker malformation and below the vermis in Blake pouch cysts. OBJECTIVE: To determine the normal fetal and postnatal MR appearance of the choroid plexus and taenia-tela choroidea complex, and whether their location can help distinguish Dandy-Walker malformation from Blake pouch cysts. MATERIALS AND METHODS: In this retrospective study, we evaluated brain MR exams from normal-appearing fetuses (gestational age 19-38 weeks) and infants, fetal and postnatal exams in Blake pouch cysts and Dandy-Walker malformation, and ambiguous cases equivocal for mild Dandy-Walker malformation and Blake pouch cysts. We documented choroid plexus and the taenia-tela choroidea complex location and axial and sagittal angles in each case. Then we contrasted and compared the original and updated fetal diagnoses based on taenia-tela choroidea complex and choroid plexus positions. RESULTS: The choroid plexus location and the taenia-tela choroidea complex location and angles varied significantly among normal exams, Blake pouch cyst exams and Dandy-Walker malformation exams (P<0.01). Dandy-Walker malformation showed inferolateral displacement of the taenia-tela choroidea complex and choroid plexus distant from the vermis. Adding the taenia-tela choroidea complex and choroid plexus into the assessment improved diagnostic accuracy, especially in ambiguous cases. CONCLUSION: The location of the taenia-tela choroidea complex and choroid plexus provided additional diagnostic neuroimaging clues that could be used in conjunction with other conventional findings to distinguish Dandy-Walker malformation and Blake pouch cysts. Normal, Blake pouch cyst, and Dandy-Walker malformation cases differed with regard to taenia-tela choroidea complex and choroid plexus position. Inferolateral taenia-tela choroidea complex displacement distant from the vermian margin was characteristic of Dandy-Walker malformation.

The Role of Fetal MRI for Suspected Anomalies of the Posterior Fossa.

BACKGROUND: Posterior fossa anomalies can be diagnostic dilemmas during the fetal period. The prognosis for different diagnoses of the posterior fossa varies widely. We investigated whether fetal magnetic resonance imaging (MRI) and prenatal neurology consultation led to an alternate prognosis for fetuses referred due to concern for a fetal posterior fossa anomaly and concordance between pre- and postnatal diagnoses. METHODS: This is a retrospective study of cases referred to the Prenatal Pediatrics Institute at Children's National Hospital from January 2012 to June 2018 due to concern for posterior fossa anomaly. Each encounter was scored for change in prognosis based upon clinical and fetal MRI report. Postnatal imaging was compared with prenatal imaging when available. RESULTS: In total, 180 cases were referred for fetal posterior fossa anomalies based on outside obstetric ultrasound and had both fetal MRI and a neurology consultation. Fetal MRI and neurology consultation resulted in a change in fetal prognosis in 70% of cases. The most common referral diagnosis in our cohort was Dandy-Walker continuum, but it was not often confirmed by fetal MRI. In complex cases, posterior fossa diagnosis and prognosis determined by fetal MRI impacted choices regarding pregnancy management. Postnatal imaging was obtained in 57 (47%) live-born infants. Fetal and postnatal prognoses were similar in 60%. CONCLUSIONS: Fetal diagnosis affects pregnancy management decisions. The fetal-postnatal imaging agreement of 60% highlights the conundrum of balancing the timing of fetal MRI to provide the most accurate diagnosis of the posterior fossa abnormalities in time to make pregnancy management decisions.

Surgical Faculty Perception of Service-Based Advanced Practice Provider Impact: A Southwestern Surgical Congress Multicenter Survey.

BACKGROUND: A previous single-center survey of trauma and general surgery faculty demonstrated perceived positive impact of trauma and surgical subspecialty service-based advanced practice providers (SB APPs). The aim of this multicenter survey was to further validate these findings. METHODS: Faculty surgeons on teams that employ SB APPs at 8 academic centers completed an electronic survey querying perception about advanced practice provider (APP) competency and impact. RESULTS: Respondents agreed that SB APPs decrease workload (88%), length of stay (72%), contribute to continuity (92%), facilitate care coordination (87%), enhance patient satisfaction (88%), and contribute to best practice/safe patient care (83%). Fewer agreed that APPs contribute to resident education (50%) and quality improvement (QI)/research (36%). Although 93% acknowledged variability in the APP level of function, 91% reported trusting their clinical judgment. CONCLUSION: This study supports the perception that SB APPs have a positive impact on patient care and quality indicators. Areas for potential improvement include APP contribution to resident education and research/QI initiatives.

Dried blood spot compared to plasma measurements of blood-based biomarkers of brain injury in neonatal encephalopathy.

BACKGROUND: Data correlating dried blood spots (DBS) and plasma concentrations for neonatal biomarkers of brain injury are lacking. We hypothesized that candidate biomarker levels determined from DBS can serve as a reliable surrogate for plasma levels. METHODS: In the context of a phase II multi-center trial evaluating erythropoietin for neuroprotection in neonatal encephalopathy (NE), DBS were collected at enrollment ( < 24 h), day 2, 4, and 5. Plasma was collected with the first and last DBS. The relationship between paired DBS-plasma determinations of brain-specific proteins and cytokines was assessed by correlation and Bland-Altman analyses. For analytes with consistent DBS-plasma associations, DBS-derived biomarker levels were related to brain injury by MRI and 1-year outcomes. RESULTS: We enrolled 50 newborns with NE. While S100B protein, tumor necrosis factor α, interleukin (IL)1 ß, IL-6, IL-8 demonstrated significant DBS-plasma correlations, Bland-Altman plots demonstrated that the methods are not interchangeable, with a 2 to 4-fold error between measurements. No significant relationships were found between DBS levels of TNFα, IL-6, and IL-8 and outcomes. CONCLUSION: Further work is needed to optimize elution and assay methods before using DBS specimens as a reliable surrogate for plasma levels of candidate brain injury biomarkers in NE.

Sequential Neuroimaging of the Fetus and Newborn With In Utero Zika Virus Exposure.

Importance: The evolution of fetal brain injury by Zika virus (ZIKV) infection is not well described. Objectives: To perform longitudinal neuroimaging of fetuses and infants exposed to in utero maternal ZIKV infection using concomitant magnetic resonance imaging (MRI) and ultrasonography (US), as well as to determine the duration of viremia in pregnant women with ZIKV infection and whether the duration of viremia correlated with fetal and/or infant brain abnormalities. Design, Setting, and Participants: A cohort of 82 pregnant women with clinical criteria for probable ZIKV infection in Barranquilla, Colombia, and Washington, DC, were enrolled from June 15, 2016, through June 27, 2017, with Colombian women identified by community recruitment and physician referral and travel-related cases of American women recruited from a Congenital Zika Program. Interventions and Exposures: Women received 1 or more MRI and US examinations during the second and/or third trimesters. Postnatally, infants underwent brain MRI and cranial US. Blood samples were tested for ZIKV. Main Outcomes and Measures: The neuroimaging studies were evaluated for brain injury and cerebral biometry. Results: Of the 82 women, 80 were from Colombia and 2 were from the United States. In 3 of 82 cases (4%), fetal MRI demonstrated abnormalities consistent with congenital ZIKV infection. Two cases had heterotopias and malformations in cortical development and 1 case had a parietal encephalocele, Chiari II malformation, and microcephaly. In 1 case, US results remained normal despite fetal abnormalities detected on MRI. Prolonged maternal polymerase chain reaction positivity was present in 1 case. Of the remaining 79 cases with normal results of prenatal imaging, postnatal brain MRI was acquired in 53 infants and demonstrated mild abnormalities in 7 (13%). Fifty-seven infants underwent postnatal cranial US, which detected changes of lenticulostriate vasculopathy, choroid plexus cysts, germinolytic/subependymal cysts, and/or calcification in 21 infants (37%). Conclusions and Relevance: In a cohort of pregnant women with ZIKV infection, prenatal US examination appeared to detect all but 1 abnormal fetal case. Postnatal neuroimaging in infants who had normal prenatal imaging revealed new mild abnormalities. For most patients, prenatal and postnatal US may identify ZIKV-related brain injury.

Plasma Biomarkers of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy.

OBJECTIVES: To evaluate plasma brain specific proteins and cytokines as biomarkers of brain injury in newborns with hypoxic-ischemic encephalopathy (HIE) and, secondarily, to assess the effect of erythropoietin (Epo) treatment on the relationship between biomarkers and outcomes. STUDY DESIGN: A study of candidate brain injury biomarkers was conducted in the context of a phase II multicenter randomized trial evaluating Epo for neuroprotection in HIE. Plasma was collected at baseline (<24 hours) and on day 5. Brain injury was assessed by magnetic resonance imaging (MRI) and neurodevelopmental assessments at 1 year. The relationships between Epo, brain-specific proteins (S100B, ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], total Tau, neuron specific enolase), cytokines (interleukin [IL]-1ß, IL-6, IL-8, IL-10, IL-12P70, IL-13, interferon-gamma [IFN-γ], tumor necrosis factor alpha [TNF-α], brain-derived neurotrophic factor [BDNF], monocyte chemoattractant protein-1), and brain injury were assessed. RESULTS: In 50 newborns with encephalopathy, elevated baseline S100B, Tau, UCH-L1, IL-1ß, IL-6, IL-8, IL-10, IL-13, TNF-α, and IFN-γ levels were associated with increasing brain injury severity by MRI. Higher baseline Tau and lower day 5 BDNF were associated with worse 1 year outcomes. No statistically significant evidence of Epo treatment modification on biomarkers was detected in this small cohort. CONCLUSIONS: Elevated plasma brain-specific proteins and cytokine levels in the first 24 hours of life are associated with worse brain injury by MRI in newborns with HIE. Only Tau and BDNF levels were found to be related to neurodevelopmental outcomes. The effect of Epo treatment on the relationships between biomarkers and brain injury in HIE requires further study. TRIAL REGISTRATION: ClinicalTrials.gov: 01913340.

Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H.

OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course. RESULTS: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. SIGNIFICANCE: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches.

School-Age Test Proficiency and Special Education After Congenital Heart Disease Surgery in Infancy.

OBJECTIVE: To evaluate test proficiency and the receipt of special education services in school-age children who had undergone surgery for congenital heart disease (CHD) at age <1 year. STUDY DESIGN: Data from Arkansas-born children who underwent surgery for CHD at Arkansas Children's Hospital at age <1 year between 1996 and 2004 were linked to state birth certificates and the Arkansas Department of Education longitudinal database containing achievement test scores in literacy and mathematics for grades 3-4 and special education codes. The primary negative outcome was not achieving grade-level proficiency on achievement tests. Logistic regression accounting for repeated measures was used to evaluate for associations between achieving proficiency and demographic data, maternal education, and clinical factors. RESULTS: A total of 362 of 458 (79%) children who underwent surgery for CHD were matched to the Arkansas Department of Education database, 285 of whom had grade 3 and/or 4 achievement tests scores. Fewer students with CHD achieved proficiency in literacy and mathematics (P < .05) compared with grade-matched state students. Higher 5-minute Apgar score, shorter duration of hospitalization, and higher maternal education predicted proficiency in literacy (P < .05). White race, no cardiopulmonary bypass, and shorter hospitalization predicted proficiency in mathematics (P < .05). Sex, gestational age, age at surgery, CHD diagnosis, and type and number of surgeries did not predict test proficiency. Compared with all public school students, more children with CHD received special education services (26.9% vs 11.6%; P < .001). CONCLUSION: Children with CHD had poorer academic achievement and were more likely to receive special education services than all state students. Results from this study support the need for neurodevelopmental evaluations as standard practice in children with CHD.

Amplitude-integrated EEG in newborns with critical congenital heart disease predicts preoperative brain magnetic resonance imaging findings.

OBJECTIVE: The study aims are to evaluate cerebral background patterns using amplitude-integrated electroencephalography in newborns with critical congenital heart disease, determine if amplitude-integrated electroencephalography is predictive of preoperative brain injury, and assess the incidence of preoperative seizures. We hypothesize that amplitude-integrated electroencephalography will show abnormal background patterns in the early preoperative period in infants with congenital heart disease that have preoperative brain injury on magnetic resonance imaging. METHODS: Twenty-four newborns with congenital heart disease requiring surgery at younger than 30 days of age were prospectively enrolled within the first 3 days of age at a tertiary care pediatric hospital. Infants had amplitude-integrated electroencephalography for 24 hours beginning close to birth and preoperative brain magnetic resonance imaging. The amplitude-integrated electroencephalographies were read to determine if the background pattern was normal, mildly abnormal, or severely abnormal. The presence of seizures and sleep-wake cycling were noted. The preoperative brain magnetic resonance imaging scans were used for brain injury and brain atrophy assessment. RESULTS: Fifteen of 24 infants had abnormal amplitude-integrated electroencephalography at 0.71 (0-2) (mean [range]) days of age. In five infants, the background pattern was severely abnormal. (burst suppression and/or continuous low voltage). Of the 15 infants with abnormal amplitude-integrated electroencephalography, 9 (60%) had brain injury. One infant with brain injury had a seizure on amplitude-integrated electroencephalography. A severely abnormal background pattern on amplitude-integrated electroencephalography was associated with brain atrophy (P = 0.03) and absent sleep-wake cycling (P = 0.022). CONCLUSION: Background cerebral activity is abnormal on amplitude-integrated electroencephalography following birth in newborns with congenital heart disease who have findings of brain injury and/or brain atrophy on preoperative brain magnetic resonance imaging.

White matter injury in newborns with congenital heart disease: a diffusion tensor imaging study.

BACKGROUND: Brain injury is observed on cranial magnetic resonance imaging preoperatively in up to 50% of newborns with congenital heart disease. Newer imaging techniques such as diffusion tensor imaging provide sensitive measures of the white matter integrity. The objective of this study was to evaluate the diffusion tensor imaging analysis technique of tract-based spatial statistics in newborns with congenital heart disease. METHODS: Term newborns with congenital heart disease who would require surgery at less than 1 month of age were prospectively enrolled (n = 19). Infants underwent preoperative and postoperative brain magnetic resonance imaging with diffusion tensor imaging. Tract-based spatial statistics, an objective whole-brain diffusion tensor imaging analysis technique, was used to determine differences in white matter fractional anisotropy between infant groups. Term control infants were also compared with congenital heart disease infants. Postmenstrual age was equivalent between congenital heart disease infant groups and between congenital heart disease and control infants. RESULTS: Ten infants had preoperative brain injury, either infarct or white matter injury, by conventional brain magnetic resonance imaging. The technique of tract-based spatial statistics showed significantly lower fractional anisotropy (P < 0.05, corrected) in multiple major white matter tracts in the infants with preoperative brain injury compared with infants without preoperative brain injury. Fractional anisotropy values increased in the white matter tracts from the preoperative to the postoperative brain magnetic resonance imaging correlating with brain maturation. Control infants had higher fractional anisotropy in multiple white matter tracts compared with infants with congenital heart disease. CONCLUSION: Tract-based spatial statistics is a valuable diffusion tensor imaging analysis technique that may have better sensitivity in detecting white matter injury compared with conventional brain magnetic resonance imaging in term newborns with congenital heart disease.

Academic proficiency in children after early congenital heart disease surgery.

Children with early surgery for congenital heart disease (CHD) are known to have impaired neurodevelopment; their performance on school-age achievement tests and their need for special education remains largely unexplored. The study aimed to determine predictors of academic achievement at school age and placement in special education services among early CHD surgery survivors. Children with CHD surgery at <1 year of age from January 1, 1998 to December 31, 2003, at the Arkansas Children's Hospital were identified. Out-of-state births and infants with known genetic and/or neurologic conditions were excluded. Infants were matched to an Arkansas Department of Education database containing standardized assessments at early school age and special-education codes. Predictors for achieving proficiency in literacy and mathematics and the receipt of special education were determined. Two hundred fifty-six children who attended Arkansas public schools and who had surgery as infants were included; 77.7 % had either school-age achievement-test scores or special-education codes of mental retardation or multiple disabilities. Scores on achievement tests for these children were 7-13 % lower than those of Arkansas students (p < 0.01). They had an eightfold increase in receipt of special education due to multiple disabilities [odds ratio (OR) 10.66, 95 % confidence interval (CI) 4.23-22.35] or mental retardation (OR 4.96, 95 % CI 2.6-8.64). Surgery after the neonatal period was associated with decreased literacy proficiency, and cardiopulmonary bypass during the first surgery was associated with decreased mathematics proficiency. Children who had early CHD surgery were less proficient on standardized school assessments, and many received special education. This is concerning because achievement-test scores at school age are "real-world" predictors of long-term outcomes.

Multi-tiered analysis of brain injury in neonates with congenital heart disease.

Early brain injury occurs in newborns with congenital heart disease (CHD) placing them at risk for impaired neurodevelopmental outcomes. Predictors for preoperative brain injury have not been well described in CHD newborns. This study aimed to analyze, retrospectively, brain magnetic resonance imaging (MRI) in a heterogeneous group of newborns who had CHD surgery during the first month of life using a detailed qualitative CHD MRI Injury Score, quantitative imaging assessments (regional apparent diffusion coefficient [ADC] values and brain volumes), and clinical characteristics. Seventy-three newborns who had CHD surgery at 8 ± 5 (mean ± SD) days of life and preoperative brain MRI were included; 38 also had postoperative MRI. Thirty-four (34 of 73, 47 %) had at least one type of preoperative brain injury, and 28 of 38 (74 %) had postoperative brain injury. The 5-min APGAR score was negatively associated with preoperative injury, but there was no difference between CHD types. Infants with intraparenchymal hemorrhage, deep gray matter injury, and/or watershed infarcts had the highest CHD MRI Injury Scores. ADC values and brain volumes were not different in infants with different CHD types or in those with and without brain injury. In a mixed group of CHD newborns, brain injury was found preoperatively on MRI in almost 50 %, and there were no significant baseline characteristic differences to predict this early brain injury except 5-min APGAR score. We conclude that all infants, regardless of CHD type, who require early surgery should be evaluated with MRI because they are all at high risk for brain injury.

Therapeutic hypothermia in a neonate with perinatal asphyxia and transposition of the great arteries.

Despite advances in surgical techniques and perioperative management, many newborns with complex congenital heart disease (CCHD) continue to have adverse neurodevelopmental outcomes. With increasing survival of these infants, neuroprotective therapies at various time points, should be considered as an important area of investigation. As some brain injury has been shown to precede surgery, the preoperative period may be a key time to direct protective therapy. Selective hypothermia is used as a neuroprotective therapy for neonates with moderate-to-severe hypoxic-ischemic encephalopathy. We report a case of an asphyxiated term newborn with severe neonatal encephalopathy following neonatal resuscitation and subsequently found to have transposition of the great arteries with a relatively intact atrial septum, who underwent CoolCap(®) therapy following emergent balloon atrial septostomy. Brain injury observed on magnetic resonance imaging preoperatively after cooling was focal and did not extend following neonatal arterial switch operation. The patient's neurologic outcome appeared to be favorable at hospital discharge and at age 6 months. This case presents a therapeutic intervention which may represent a valuable neuroprotective strategy to limit brain injury, and therefore, improve neurodevelopmental outcomes in neonates with CCHD with perinatal asphyxia.