Value of pre- and postnatal magnetic resonance imaging in the evaluation of congenital central nervous system anomalies.

Fetal MRI and neonatal MRI of the central nervous system (CNS) are complementary tools that can help to accurately counsel and direct the management of children with anomalies of the central nervous system. Postnatal MRI can add to fetal MRI by allowing for monitoring of changes in the severity of disease, better delineation of a suspected prenatal anomaly, evaluation for secondary pathologies related to the primary diagnosis, and surgical management direction. In this review we discuss the roles of fetal and neonatal MRI in the diagnosis and treatment of congenital anomalies of the CNS through a series of case examples and how both are important in patient management.

Prenatal evaluation of the Sakoda complex.

Sakoda complex is a rare but distinct combination of birth defects consisting of a basal cephalocele, agenesis of the corpus callosum, and midline cleft lip/palate. It has been reported in association with ophthalmologic abnormalities, cognitive deficits and severe epilepsy. Here we describe both prenatal and postnatal MRI findings of a classic case of Sakoda complex in a child with characteristic findings on fetal MRI; prenatal findings have not been described in the literature. Diagnosis of this entity has important implications for prenatal counseling and perinatal management, as is demonstrated in this case.

Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features.

Kv7.2 subunits encoded by the KCNQ2 gene provide a major contribution to the M-current (IKM), a voltage-gated K+ current crucially involved in the regulation of neuronal excitability. Heterozygous missense variants in Kv7.2 are responsible for epileptic diseases characterized by highly heterogeneous genetic transmission and clinical severity, ranging from autosomal-dominant Benign Familial Neonatal Seizures (BFNS) to sporadic cases of severe epileptic and developmental encephalopathy (DEE). Here, we describe a patient with neonatal onset DEE, carrying a previously undescribed heterozygous KCNQ2 c.418G > C, p.Glu140Gln (E140Q) variant. Patch-clamp recordings in CHO cells expressing the E140Q mutation reveal dramatic loss of function (LoF) effects. Multistate structural modelling suggested that the E140Q substitution impeded an intrasubunit electrostatic interaction occurring between the E140 side chain in S2 and the arginine at position 210 in S4 (R210); this interaction is critically involved in stabilizing the activated configuration of the voltage-sensing domain (VSD) of Kv7.2. Functional results from coupled charge reversal or disulfide trapping experiments supported such a hypothesis. Finally, retigabine restored mutation-induced functional changes, reinforcing the rationale for the clinical use of Kv7 activators as personalized therapy for DEE-affected patients carrying Kv7.2 LoF mutations.

Interdisciplinary fetal neurology care: Current practice, challenges, and future directions.

As the field of fetal-neonatal neurology has expanded over the past 2 decades with increasingly complex diagnoses, multidisciplinary collaboration with many subspecialties including genetics, neonatology, obstetrics, maternal fetal medicine, surgical sub-specialties, cardiology, radiology, palliative care, and ethics has needed to evolve to strive to offer optimal patient care. While comprehensive care delivery with an inter-disciplinary approach is preferred, there are often barriers based on numerous health disparities especially in resource limited settings. Even in the context of comprehensive care, diagnostic and prognostic uncertainty lead to challenges for providers during fetal neurology consultations. We present a case that highlights advantages of a comprehensive multi-disciplinary team in caring for the medical and social challenges of patients faced with a fetal neurologic diagnosis. Inter-disciplinary training focusing on maternal, fetal, neonatal, and childhood neurodevelopmental course and collaboration among the numerous stakeholders that contribute to fetal neurology practice is needed to provide optimal counseling and care for families faced with a fetal neurological diagnosis.

Recognition and Management of Delirium in the Neonatal Intensive Care Unit: Case Series From a Single-Center Level 4 Intensive Care Unit.

Delirium often goes unrecognized in neonates and children because of lack of experience in evaluating behavior and cognition, insufficient awareness of the prevalence, and nondistinctive symptoms in this population. Although there are increasing reports of the presence of delirium in neonates, there are few data to guide the pharmacologic treatment in this population. In this retrospective single-center case series, we present our experience using quetiapine to treat delirium in 9 medically complex neonates. Based on an extensive literature review, expert opinion, and institutional experience, we propose an approach for monitoring and treating delirium in neonates and infants.

Impact of Race in Missed Appointments in Pediatric Neurology Resident Clinic at a Large Tertiary Medical Center.

Missed medical appointments are a common problem across specialties. The discontinuity of care leads to unplanned health care utilization, increased costs, and poor health outcomes. Previous studies evaluating pediatric epilepsy have shown significant socioeconomic barriers to care. In several specialties, resident clinic no-show rates are higher than faculty clinics because of socioeconomic barriers. We sought to understand the relationship between race, socioeconomic factors, and missed appointments in a pediatric neurology resident clinic at a large tertiary care hospital. Resident clinic encounters for 1 year were extracted and analyzed for missed appointments, socioeconomic factors, and health care utilization. We found that missed appointments occur for 1 in 5 patients and correlate with socioeconomic factors (eg, income and insurance) and race. Race was a more significant factor than socioeconomic factors for missed appointments. These results provide areas to target and track interventions to improve health outcomes in children in pediatric neurology clinics.

Recognition and Management of Delirium in the Neonatal Intensive Care Unit: Case Series From a Single-Center Level IV Intensive Care Unit.

Delirium often goes unrecognized in neonates and children because of lack of experience in evaluating behavior and cognition, insufficient awareness of the prevalence, and nondistinctive symptoms in this population. Although there are increasing reports of the presence of delirium in neonates, there are little data to guide the pharmacologic treatment in this population. In this retrospective single-center case series, we present our experience using quetiapine to treat delirium in 9 medically complex neonates. Based on an extensive literature review, expert opinion, and institutional experience, we propose an approach for monitoring and treating delirium in neonates and infants.

Fetal Brain MRI Abnormalities in Pyruvate Dehydrogenase Complex Deficiency.

BACKGROUND AND OBJECTIVES: Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1. Typical neonatal brain imaging findings have been described, with a focus on malformative and encephaloclastic features. Fetal brain MRI in PDCD has not been comprehensively described. The aims of this study were (1) to further characterize the fetal brain MRI findings in PDCD using comprehensive fetal imaging and genetic testing and (2) to determine whether markers of diagnosis of PDCD could be identified on prenatal imaging. METHODS: Fetuses with a diagnosis of PDCD related to a genetic etiology that had undergone fetal MRI were included. Fetuses were identified retrospectively from local databases of 4 fetal diagnostic clinics within tertiary pediatric health care centers. Electronic medical records were reviewed retrospectively: demographics, maternal and pregnancy history, fetal outcomes, and neonatal outcomes (if available) were reviewed and recorded. Fetal and neonatal imaging reports were reviewed; source fetal and neonatal brain MRI scans were reviewed by a single pediatric neuroradiologist (J.W.S.) for consistency. Genetic testing strategies and results including variant type, zygosity, inheritance pattern, and pathogenicity were recorded. Deidentified data were combined and reported descriptively. RESULTS: A total of 10 fetuses with a diagnosis of PDCD were included. 8 fetuses had corpus callosum dysgenesis, 6 had an abnormal gyration pattern, 10 had reduced brain volumes, and 9 had cystic lesions. 1 fetus had intraventricular hemorrhages. 1 fetus had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. 6 fetuses imaged in the second trimester had cystic lesions involving the ganglionic eminences (GEs) while GE cysts were not present in the 4 fetuses imaged in the third trimester. DISCUSSION: Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings are subtle early in pregnancy. Additional features, such as cystic lesions of the GEs, are noted in the second trimester in fetuses with PDCD. These may represent an early diagnostic marker of PDCD, although more data are needed to validate this association. Early diagnosis of PDCD using fetal MRI may inform genetic counseling, pregnancy decision making, and neonatal care planning.

Characteristic Fetal Brain MRI Abnormalities in Pyruvate Dehydrogenase Complex Deficiency.

Pyruvate dehydrogenase complex deficiency (PDCD) is a disorder of mitochondrial metabolism that is caused by pathogenic variants in multiple genes, including PDHA1. Typical neonatal brain imaging findings in PDCD have been described, with a focus on malformative features and chronic encephaloclastic changes. However, fetal brain MRI imaging in confirmed PDCD has not been comprehensively described. We sought to demonstrate the prenatal neurological and systemic manifestations of PDCD determined by comprehensive fetal imaging and genomic sequencing. All fetuses with a diagnosis of genetic PDCD who had undergone fetal MRI were included in the study. Medical records, imaging data, and genetic testing results were reviewed and reported descriptively. Ten patients with diagnosis of PDCD were included. Most patients had corpus callosum dysgenesis, abnormal gyration pattern, reduced brain volumes, and periventricular cystic lesions. One patient had associated intraventricular hemorrhages. One patient had a midbrain malformation with aqueductal stenosis and severe hydrocephalus. Fetuses imaged in the second trimester were found to have enlargement of the ganglionic eminences with cystic cavitations, while those imaged in the third trimester had germinolytic cysts. Fetuses with PDCD have similar brain MRI findings to neonates described in the literature, although some of these findings may be subtle early in pregnancy. Additional features, such as cystic cavitations of the ganglionic eminences, are noted in the second trimester in fetuses with PDCD, and these may represent a novel early diagnostic marker for PDCD. Using fetal MRI to identify these radiological hallmarks to inform prenatal diagnosis of PDCD may guide genetic counseling, pregnancy decision-making, and neonatal care planning.

Fetal Cerebral Ventriculomegaly: A Narrative Review and Practical Recommendations for Pediatric Neurologists.

Fetal cerebral ventriculomegaly is one of the most common fetal neurological disorders identified prenatally by neuroimaging. The challenges in the evolving landscape of conditions like fetal cerebral ventriculomegaly involve accurate diagnosis and how best to provide prenatal counseling regarding prognosis as well as postnatal management and care of the infant. The purpose of this narrative review is to discuss the literature on fetal ventriculomegaly, including postnatal management and neurodevelopmental outcome, and to provide practice recommendations for pediatric neurologists.

Advancing the Field of Fetal Neurology: A Call for Global Collaborations.

Fetal Neurology continues to grow as a distinct subspecialty informed by evolving precision diagnosis with advancements in prenatal neuroimaging, genetic and infectious testing. While there are inherent limitations and challenges in prenatal diagnostic testing and prognostic counseling, the interdisciplinary approach allows comprehensive guidance for perinatal and postnatal management of neurological disorders detected early in development. The current practice of fetal neurology is heterogenous and variable across centers. In low- and middle-income countries (LMICs), fetal neurology practice is under the umbrella of neonatal and perinatal medicine. Since infrastructure and capacity for prenatal diagnostic and prognostic counseling may be variable, the practice approach may have to be modified regionally based on resources, education, and setting. There is a need for collaborative development of educational opportunities, training, guidelines, and research exploring short- and long-term outcome of prenatally identified neurological conditions. Interdisciplinary collaborations and global professional networks are crucial to advance this unique subspecialty.

Muslim perspectives on palliative care in perinatal and neonatal patients: a mini-review.

Muslims comprise nearly a quarter of the worldwide population, with significant populations in the United States, Canada, and Europe. As clinicians, it is important to be familiar with Islamic religious and cultural perspectives on medical treatment, life-prolonging measures and comfort and palliative care, but historically, this has been a gap in the literature. Recently, there have been multiple papers discussing Islamic bioethics, particularly in regards to end of life care in adults; however, there has been a lack of literature discussing the Islamic perspective on issues related to neonatal and perinatal end of life care. This paper uses clinical scenarios to review key relevant principles of Islamic law, discussing the primary and secondary sources used in formulating fatawa, including the Quran, hadith, qiyas, and 'urf, and the importance of preservation of life and upholding of human dignity (karamah). Neonatal and perinatal scenarios are used to specifically explore the Islamic perspective on withholding and withdrawal of life-sustaining measures and determining what constitutes an acceptable quality of life. In some Islamic cultures the expertise of the patient's physician is given significant weight in making these judgments, and as such, families may appreciate frank assessment of the situation by the clinical team. Because of the various factors involved in issuing religious ruling, or fatwa, there is a wide spectrum of opinions on these rulings, and physicians should be aware of these differences, seek counsel and guidance from local Islamic leaders, and support families in their decision-making process.

Role of palliative care in fetal neurological consultations: Guiding through uncertainty and hope.

Fetal neurology is a rapidly evolving and expanding field. Discussions about diagnosis, prognosis, treatment options, and goals of care often begin in the antenatal period. However, there are inherent challenges to fetal counseling of neurological diagnoses due to limitations of fetal imaging, prognostic uncertainty, and variability in neurodevelopmental outcomes. In the midst of uncertainty, families are challenged with preparing a care plan for their baby while simultaneously experiencing profound grief. The paradigms of perinatal palliative care can assist with the grieving process and help frame diagnostic testing and complex decision-making within the context of a family's spiritual, cultural, and social belief system. This ultimately leads to a shared decision-making process and value driven medical care. While perinatal palliative care programs have expanded, many families faced with such diagnoses never meet with a palliative care team prior to delivery. Moreover, there is significant variability in the availability of palliative care services throughout the country. Using an illustrative vignette of a patient with a prenatally diagnosed encephalocele, this review aims to provide a basic framework of perinatal palliative care for fetal neurology diagnoses that emphasizes 1) importance of clear, consistent, and transparent communication among all subspecialists and families, 2) creation of a palliative care birth plan, 3) importance of consistent care providers and longitudinal points of contact prenatally and post-delivery, 4) close communication between the prenatal and post-natal providers to allow for optimal continuity of care, and 5) recognize that information, care plans, and goals of care often evolve over time.

Prenatal Neurological Diagnosis: Challenges in Neuroimaging, Prognostic Counseling, and Prediction of Neurodevelopmental Outcomes.

Prenatal diagnosis of fetal brain abnormalities is rapidly evolving with the advancement of neuroimaging techniques, thus adding value to prognostic counseling and perinatal management. However, challenges and uncertainties persist in prenatal counseling due to limitations of prenatal imaging, continued development and maturation of the brain structure, and the heterogeneity and paucity of outcome studies. This topical review of fetal neurological consultations highlights prenatally diagnosed brain abnormalities that challenged prognostic counseling and perinatal management. Representative cases across multiple centers that highlighted diagnostic challenges were selected. Charts were reviewed for neuroimaging, genetic evaluation, prenatal prognostic discussion, postnatal imaging and testing, and infant outcome. We present case studies with prenatal and postnatal information discussing prenatal testing, fetal MRI interpretation, and complexities in the prognostic counseling process. Advocating for large-scale multicenter studies and a national collaborative fetal neurological registry to help guide the ever-expanding world of prenatal diagnostics and prognostic counseling is critical to this field. Study of large-scale outcomes data from such a registry can better guide fetal neurological consultations and facilitate comprehensive multidisciplinary planning and program development for educational curriculum for fetal-neonatal neurology.

Imaging Similarities Between Oral-Facial-Digital Syndrome Type 1 and Aicardi Syndrome: Prenatal and Postnatal Magnetic Resonance Imaging (MRI) Findings in 4 Patients.

Prenatal identification by magnetic resonance imaging (MRI) of callosal anomalies, particularly with accompanying intracranial abnormalities, poses a challenge for accurate prognostication and fetal counseling as outcome can vary widely depending on underlying etiology. In female patients, Aicardi syndrome is an important consideration, and prompt postnatal ophthalmologic assessment to identify ocular stigmata of Aicardi syndrome can aid with anticipatory guidance and greater vigilance for seizures. We present a case of a female with fetal and postnatal MRI findings of agenesis of corpus callosum and type 2b interhemispheric cysts, characteristically found in Aicardi syndrome, but was found to have oral-facial-digital syndrome type 1 (OFD1). We also present 3 other companion cases with pre- and postnatal imaging of patients with Aicardi syndrome. These cases highlight the importance of widening the differential diagnosis to also include OFD1 for female patients with callosal anomalies.

Fetal Neurology Practice Survey: Current Practice and the Future Directions.

BACKGROUND: Fetal neurology is a rapidly evolving field. Consultations aim to diagnose, prognosticate, and coordinate prenatal and perinatal management along with other specialists and counsel expectant parents. Practice parameters and guidelines are limited. METHODS: A 48-question online survey was administered to child neurologists. Questions targeted current care practices and perceived priorities for the field. RESULTS: Representatives from 43 institutions in the United States responded; 83% had prenatal diagnosis centers, and the majority performed on-site neuroimaging. The earliest gestational age for fetal magnetic resonance imaging was variable. Annual consultations ranged from <20 to >100 patients. Fewer than half (n = 17.40%) were subspecialty trained. Most respondents (n = 39.91%) were interested in participating in a collaborative registry and educational initiatives. CONCLUSIONS: The survey highlights heterogeneity in clinical practice. Large multisite and multidisciplinary collaborations are essential to gather data that inform outcomes for fetuses evaluated across institutions through registries as well as creation of guidelines and educational material.

Albumin causes increased myosin light chain kinase expression in astrocytes via p38 mitogen-activated protein kinase.

Myosin light chain kinase (MLCK) plays an important role in the reorganization of the cytoskeleton, leading to disruption of vascular barrier integrity in multiple organs, including the blood-brain barrier (BBB), after traumatic brain injury (TBI). MLCK has been linked to transforming growth factor (TGF) and rho kinase signaling pathways, but the mechanisms regulating MLCK expression following TBI are not well understood. Albumin leaks into the brain parenchyma following TBI, activates glia, and has been linked to TGF-ß receptor signaling. We investigated the role of albumin in the increase of MLCK in astrocytes and the signaling pathways involved in this increase. After midline closed-skull TBI in mice, there was a significant increase in MLCK-immunoreactive (IR) cells and albumin extravasation, which was prevented by treatment with the MLCK inhibitor ML-7. Using immunohistochemical methods, we identified the MLCK-IR cells as astrocytes. In primary astrocytes, exposure to albumin increased both isoforms of MLCK, 130 and 210. Inhibition of the TGF-ß receptor partially prevented the albumin-induced increase in both isoforms, which was not prevented by inhibition of smad3. Inhibition of p38 MAPK, but not ERK, JNK, or rho kinase, also prevented this increase. These results are further evidence of a role of MLCK in the mechanisms of BBB compromise following TBI and identify astrocytes as a cell type, in addition to endothelium in the BBB, that expresses MLCK. These findings implicate albumin, acting through p38 MAPK, in a novel mechanism by which activation of MLCK following TBI may lead to compromise of the BBB.

Fetal Magnetic Resonance Imaging (MRI) in Holoprosencephaly and Associations With Clinical Outcome: Implications for Fetal Counseling.

Holoprosencephaly is the most common malformation of forebrain development and includes a wide spectrum of severity. The objective of this retrospective study was to evaluate fetal magnetic resonance imaging (MRI) associations with outcome. Of the 63 cases identified on antenatal ultrasonography, 28 cases were confirmed on fetal MRI. There were 17 live births; 9 patients died within the first month of life. There were 7 survivors. The vast majority were nonambulatory and required feeding support; none required respiratory support. We found that presence and number of non-holoprosencephaly-associated malformations was also associated with survival. Of 5 patients with 3 or more systemic anomalies, 4 died regardless of holoprosencephaly subtype and 1 was lost to follow-up. Patients with suspected holoprosencephaly on ultrasonography should have full body fetal MRI and echocardiogram to better evaluate systemic anomalies. Counseling should involve pediatric palliative care services to prepare families in caring for babies with limited life span.

Short- and Long-Term Outcomes of Prenatally Diagnosed Dandy-Walker Malformation, Vermian Hypoplasia, and Blake Pouch Cyst.

Dandy-Walker continuum, which includes Dandy-Walker malformation, vermian hypoplasia, and Blake pouch cyst, is among the most commonly diagnosed posterior fossa malformation by fetal magnetic resonance imaging (MRI). The objective of our retrospective study was to evaluate fetal and postnatal MRI scan and clinical outcomes. Seventy-two patients were identified; 40 patients had postnatal imaging and follow-up (7 Dandy-Walker malformation, 26 vermian hypoplasia, and 7 Blake pouch cyst). Although all patients with Dandy-Walker malformation required ventriculoperitoneal shunts and 66% were intubated at birth, none required tracheostomy tube and 2 of 5 surviving children had no neurologic deficits. Vermian hypoplasia was strongly associated with genetic conditions and cardiac malformations; odds of not ambulating normally were 12 times greater if a syndrome or injury was present. Echocardiogram and genetic screening are recommended with vermian hypoplasia. There is a risk for epilepsy in both Dandy-Walker malformation and vermian hypoplasia. Blake pouch cyst can be complicated by hydrocephalus, but outcome is favorable.