Use of neurological criteria to declare death in children.

Accurate determination of death is a necessary responsibility of the medical profession. Brain death, or death by neurological criteria (DNC), can be legally declared after the determination of permanent loss of clinical brain function, including the capacity for consciousness, brainstem reflexes, and the ability to breathe spontaneously. Despite longstanding debates over the exact definition of brain death or DNC and how it is determined, most middle- and high-income countries have compatible medical protocols and legal policies for brain death or DNC. This review summarizes the 2023 updated guidelines for brain death or DNC determination, which integrate adult and pediatric diagnostic criteria. We discuss the clinical challenges related to brain death or DNC determination in infants and young children. We emphasize that physicians must follow the standardized and meticulous evaluation processes outlined in these guidelines to reduce diagnostic error and ensure no false positive determinations. An essential component of the brain death or DNC evaluation is appropriate and transparent communication with families. Ongoing efforts to promote consistency and legal uniformity in the declaration of death are needed.

Hippocampal sclerosis and temporal lobe epilepsy following febrile status epilepticus: The FEBSTAT study.

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. SIGNIFICANCE: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.

A case report of riboflavin transporter deficiency: A novel heterozygous pathogenic variant in the SLC52A3 gene.

Riboflavin transporter deficiency (RTD) is a neurodegenerative disorder that presents from infancy to adulthood with a progressive axonal neuropathy characterized by a variety of neurologic symptoms including hearing loss, weakness, bulbar palsy, and respiratory insufficiency. Pathogenic variants in SLC52A2 and SLC52A3 are implicated in the pathogenesis of RTD type 2 and 3, respectively. Early identification of this disorder is critical, as it is treatable with riboflavin supplementation. We describe a 16-year-old female with a phenotype consistent with RTD3 found to have a novel heterozygous SLC52A3 variant. Though RTD is typically considered an autosomal recessive condition, her heterozygous variant was thought to be disease causing after further genetic analysis and given her improvement in response to riboflavin supplementation. This case highlights the importance of reinterpretation of genetic testing, particularly when there is a high clinical suspicion for disease.

Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema.

Brain oedema is a life-threatening complication of various neurological conditions. Understanding molecular mechanisms of brain volume regulation is critical for therapy development. Unique insight comes from monogenic diseases characterized by chronic brain oedema, of which megalencephalic leukoencephalopathy with subcortical cysts (MLC) is the prototype. Variants in MLC1 or GLIALCAM, encoding proteins involved in astrocyte volume regulation, are the main causes of MLC. In some patients, the genetic cause remains unknown. We performed genetic studies to identify novel gene variants in MLC patients, diagnosed by clinical and MRI features, without MLC1 or GLIALCAM variants. We determined subcellular localization of the related novel proteins in cells and in human brain tissue. We investigated functional consequences of the newly identified variants on volume regulation pathways using cell volume measurements, biochemical analysis and electrophysiology. We identified a novel homozygous variant in AQP4, encoding the water channel aquaporin-4, in two siblings, and two de novo heterozygous variants in GPRC5B, encoding the orphan G protein-coupled receptor GPRC5B, in three unrelated patients. The AQP4 variant disrupts membrane localization and thereby channel function. GPRC5B, like MLC1, GlialCAM and aquaporin-4, is expressed in astrocyte endfeet in human brain. Cell volume regulation is disrupted in GPRC5B patient-derived lymphoblasts. GPRC5B functionally interacts with ion channels involved in astrocyte volume regulation. In conclusion, we identify aquaporin-4 and GPRC5B as old and new players in genetic brain oedema. Our findings shed light on the protein complex involved in astrocyte volume regulation and identify GPRC5B as novel potentially druggable target for treating brain oedema.

Fetal anomaly diagnosis and termination of pregnancy.

The aim of this review was to discuss bioethics in prenatal diagnosis and health care after recent legislative and judicial changes affecting reproductive rights, such as the repeal of 'Roe v. Wade' in the United States. We recognize that abortion involves particular moralities that are not universal or shared by all cultures, groups, and individuals. We reviewed the historical aspects of embryology and personhood, fetal morbidity and mortality, and parental options for prenatal diagnostic testing. We examined relevant ethical issues including informed consent, the emergence of fetal pain, reproductive autonomy, the fiduciary responsibilities of pregnant mothers, and the obligations of physicians caring for the maternal-fetal dyad. The code of medical ethics includes respect for decisional privacy and the protection of information shared in confidence. When a fetal anomaly is diagnosed, pregnant mothers must be informed about the risks, burdens, and alternatives in either continuing or terminating the pregnancy. Parental choice should include the right to refuse testing, the informed choice not to know about certain genetic test results, and the right to make informed decisions about the best interests of the future child. In the diagnosis and care of fetal anomalies, moral dilemmas arise. Before fetal viability, the mother's autonomy, sense of beneficence, and personal values should be trusted and respected. Perinatal palliative care should be available to pregnant mothers whose anomalous fetus is carried to birth.

Ethical Perspectives on Costly Drugs and Health Care: AAN Position Statement.

High drug prices have created substantial challenges for patients, physicians, health systems, and payers. High drug prices can affect patient care in many ways, including limiting access to treatment, increasing the burden of administrative tasks, and contributing to physician burnout. Exorbitant drug pricing poses direct challenges for distributive justice, which is concerned with fairly distributing benefits and burdens across society. In this position statement, we discuss ethical concerns raised by high drug costs, primarily focusing on concerns around distributive justice. We consider forms of rationing, approaches to allocation, potential complexities in real-life application, and structural forces contributing to high drug costs. Finally, we consider potential policy solutions and ramifications for individual clinicians.

AAN position statement: The COVID-19 pandemic and the ethical duties of the neurologist.

Patients, clinicians, and hospitals have undergone monumental changes during the coronavirus disease 2019 (COVID-19) pandemic. This crisis has forced us to consider the obligations that we neurologists have to our individual patients as well as the greater community. By returning to our fundamental understanding of these duties, we can ensure that we are providing the most ethically appropriate contingency and crisis care possible. We recommend specific adaptations to both the inpatient and outpatient settings, as well as changes to medical and trainee education. Furthermore, we explore the daunting but potentially necessary implementation of scare resource allocation protocols. As the pandemic evolves, we will need to adapt continuously to these rapidly changing circumstances and consider both national and regional standards and variation.

AAN position statement: Ethical issues in clinical research in neurology.

This update to the American Academy of Neurology's 1998 position statement endeavors to provide guidance for the consistent ethical conduct and review of neurologic research involving human participants. It does so by outlining a widely used ethical framework of 7 principles derived from the foundational documents of modern bioethics, including the Nuremberg Code, the World Medical Association's Declaration of Helsinki, the Belmont Report, and the US Department of Health and Human Service's Common Rule. The position statement then applies this principle-based framework to analyze and produce recommendations for the management of common and important ethical issues encountered in neurologic clinical research. These include institutional review board oversight, equitable research participant inclusion, cognitive impairment in research participants, international studies, the replication crisis, and genetic testing and modification.

Remote poststroke headache in children: Characteristics and association with stroke recurrence.

BACKGROUND: New-onset headache after stroke is common among adult stroke survivors. However, pediatric data are limited. The primary aim of this study was to investigate the prevalence of new-headache after pediatric ischemic stroke. Secondary outcomes were to describe the characteristics of patients experiencing poststroke headache and the association between poststroke headache and stroke recurrence. METHODS: We conducted a single-center retrospective study on children aged 30 days to 18 years with a confirmed radiographic diagnosis of arterial ischemic stroke (AIS) from January 1, 2008, to December 31, 2016. Patients were identified from an internal database, with additional data abstracted from the electronic medical record. Poststroke headache (occurring >30 days after stroke) was identified through electronic searches of the medical record and confirmed by chart review. RESULTS: Of 115 patients with confirmed AIS, 41 (36%) experienced poststroke headache, with headache developing a median of 6 months after stroke. Fifty-one percent of patients with poststroke headache presented to the emergency department for headache evaluation; 81% of the patients had an inpatient admission for headache. Older age at stroke (odds ratio [OR] 21.5; p = 0.0001) and arteriopathy (OR 8.65; p = 0.0029) were associated with development of poststroke headache in a multivariable analysis. Seventeen patients (15%) had a recurrent stroke during the study period. Poststroke headache was associated with greater risk for stroke recurrence (p = 0.049). CONCLUSIONS: Remote poststroke headache is a common morbidity among pediatric stroke survivors, particularly in older children. Headaches may increase health care utilization, including neuroimaging and hospital admissions. We identified a possible association between poststroke headache and stroke recurrence.

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Brain death, the determination of brain death, and member guidance for brain death accommodation requests: AAN position statement.

The American Academy of Neurology holds the following positions regarding brain death and its determination, and provides the following guidance to its members who encounter resistance to brain death, its determination, or requests for accommodation including continued use of organ support technology despite neurologic determination of death.