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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.

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.

The American Academy of Neurology (AAN) Code of Professional Conduct (CPC)1 formalizes the standards of professional behavior for AAN members. The CPC provides the ethical principles and professional standards that neurologists and other neuroscience professionals should or must observe in their clinical and scientific activities. While ethical principles do not change with time, developments in technology and social structure may lead to a change in how these principles are applied. One such technological development is social media—a class of communication tools that has rapidly grown in number and popularity in recent years. The AAN developed this position statement to review in-depth how social media use has transformed clinical practice, with a particular focus on neurologic practice, and, by exploring the relevant principles in the CPC,1 to provide an ethical framework for neurology professionals and trainees to consider when engaging in social media. This statement complements the CPC; it is not a replacement for the AAN Web site's Code of Conduct, Privacy Policy, or Terms of Service.

The American Academy of Neurology (AAN) developed the Code of Professional Conduct to formalize the standards of professional behavior for AAN members to help them in their pursuit of providing the highest quality of patient-centered neurologic care. The goal of this code is to establish the professional standards that AAN members must or should observe in their clinical, academic, scientific, and personal activities.

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.

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.

BackgroundNew-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.MethodsWe 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.ResultsOf 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).ConclusionsRemote 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.

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.

Although death by neurologic criteria (brain death) is legally recognized throughout the United States, state laws and clinical practice vary concerning three key issues: (1) the medical standards used to determine death by neurologic criteria, (2) management of family objections before determination of death by neurologic criteria, and (3) management of religious objections to declaration of death by neurologic criteria. The American Academy of Neurology and other medical stakeholder organizations involved in the determination of death by neurologic criteria have undertaken concerted action to address variation in clinical practice in order to ensure the integrity of brain death determination. To complement this effort, state policymakers must revise legislation on the use of neurologic criteria to declare death. We review the legal history and current laws regarding neurologic criteria to declare death and offer proposed revisions to the Uniform Determination of Death Act (UDDA) and the rationale for these recommendations.

With organ-sustaining technology, patients declared dead by neurologic criteria can display some normal bodily functions, rendering acceptance of death conceptually difficult. Nonetheless, when patients fail to demonstrate neurologic recovery after catastrophic brain injury, physicians have a professional duty to evaluate for death by neurologic criteria (DNC). In their essay, “Can a Parent Refuse the Brain Death Examination?” Lee and colleagues present a patient without neurologic recovery following cardiac arrest as a platform to discuss legal and ethical considerations for requiring informed consent for DNC evaluation.1 We agree that this request is reason to delay the evaluation. While there is no statutory law prohibiting evaluation against parents’ wishes, … E-mail: kirschenm{at}chop.edu

Thoughtful and reasonable people disagree about the boundaries of a physician’s responsibility to dying patients. A vexing case in point is the morality of a physician’s participation in patient requests for hastened death.

Classic autism has gradually evolved into the concept of a larger “spectrum disorder.” The rising prevalence of autism and autism spectrum disorder (autism/ASD) diagnoses can be largely attributed to broader diagnostic criteria, adoption of dimensional assessment strategies, increased awareness, linking of services to diagnosis, and the inclusion of milder neurodevelopmental differences bordering on normality. The spectrum disorder diagnosis raises numerous bioethical issues for individuals and society. Three groups of caregivers have important ethical, legal, and social obligations to individuals with autism/ASD: (1) families and advocates of individuals with autism/ASD; (2) health care and other professionals; and (3) governments. Each group may have different views of autism/ASD diagnostic criteria, screening, testing, and the effectiveness of various interventions. All see timely diagnosis as desirable, but earlier diagnosis may not be better, morally or practically. The growing practice of genetic testing in milder ASD raises ethical questions because of its uncertain scientific validity and limited clinical utility. Individuals with autism/ASD have various kinds of needs but all want acceptance and most deserve better accommodations. Governments struggle to provide a fair allocation of appropriate special education and supportive services. This article examines the evolving dimensions of the autism/ASD diagnosis, outlines certain bioethics principles related to its evaluation and management, reviews relevant laws and disability rights, and emphasizes the societal obligation to recognize neurodevelopmental variation and human neurodiversity. Future directions in the evaluation and care of autism/ASD should attempt to integrate the roles and responsibilities of all agents caring for each unique autistic individual.

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.

We thank Drs. Dewar and Shamy for their comment on our article1 and applaud their attention to the ethical and scientific question of when a randomized controlled trial (RCT) is justified. The 7 principles endorsed in our position statement—social value, scientific validity, fair participant selection, favorable risk-benefit ratio, independent review, informed consent, and respect for participants—provide a framework for deciding when an RCT is ethically justified.1 We agree that systematic reviews can help to evaluate the social value and scientific validity of a proposed RCT. However, we disagree with a requirement that a systematic review is a necessary prerequisite to an RCT. Observational studies and randomized trials have different and complementary advantages and roles in the clinical research enterprise. Well-conducted randomized trials have advantages over observational studies in internal validity and the ability to balance known and unknown confounders between study arms.2 Consequently, randomized trials have at times overturned the results of previous observational studies.3,4 Similarly, our inability to replicate the findings of many high-impact studies—the “replication crisis”—raises the need for more replication of existing studies.5 Therefore, we respectfully disagree with a universal mandate that randomized trials be conducted only where systematic reviews have been performed and demonstrated uncertainty surrounding the hypothesis.

Objective The objective of this study was to determine early developmental and cognitive outcomes of children with febrile status epilepticus (FSE) one month and one year after FSE. Methods One hundred ninety four children with FSE were evaluated on measures of cognition, receptive language, and memory as part of the FEBSTAT study and compared with 100 controls with simple febrile seizures (FSs). Results Children with FSE did not differ dramatically on tasks compared with FS controls at one month after FSE but demonstrated slightly weaker motor development (p = 0.035) and receptive language (p = 0.034) at one year after FSE. Performances were generally within the low average to average range. Within the FSE cohort, non-White children performed weaker on many of the tasks compared with Caucasian children. At the one-year visit, acute hippocampal T2 findings on MRI were associated with weaker receptive language skills (p = 0.0009), and human herpes virus 6 or 7 (HHV6/7) viremia was associated with better memory performances (p = 0.047). Conclusion Febrile status epilepticus does not appear to be associated with significant cognitive impairment on early developmental measures, although there is a trend for possible receptive language and motor delay one year after FSE. Further follow-up, which is in progress, is necessary to track long-term cognitive functioning.

PHACE ( posterior fossa brain malformation, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities) syndrome is a neurocutaneous disorder often involving the cerebral vasculature. PHACE patients appear to have early-onset and severe headaches more commonly than children without PHACE. The objective of this study was to characterize the clinical features and prevalence of headache by conducting a cross-sectional survey of families in 2 large PHACE registries. Sixty-six percent of eligible families completed the survey in which 62.7% of respondents reported headaches. Average age of headache onset was 48.8 months. Females were more likely to have headaches (68.6% vs 30.8%, P = .014). Families reported associated migrainous features including nausea (62.5%), vomiting (37.5%), photophobia (75%), and phonophobia (75%). Headaches occurred at least weekly in 29.4%, lasted ≥1 hour in 85.4%, and led to ≥1 hospital admission in 15.7%. Three respondents with headaches had at least 1 ischemic stroke. We demonstrated that headaches are common among PHACE patients, develop at an early age, and have migrainous features.

Central nervous system infections in children can be life threatening. It is imperative to suspect and identify these early in their course to manage them appropriately and improve outcomes. This article will focus on the clinical definitions, etiologies, and pathogenic mechanisms of some of the most common central nervous system infections in childhood. In addition, key parts of the initial evaluation including physical examination, laboratory investigations, and neuroimaging as well as treatment and outcomes are discussed.

Objective Brain involvement is a serious complication of HIV infection. The earliest changes in the brain, which represents an anatomic site for viral persistence, are largely unknown. Methods This investigation used quantitative Magnetic Resonance methodologies, including high resolution and diffusion tensor (DTI) imaging, to evaluate the brain in 15 HIV and 20 seronegative subjects. All HIV subjects were antibody nonreactive with assay-estimated infection duration of less than 100 days. Results Brain volumetric analysis revealed reduced parenchyma with enlargement of the third ventricle and brainstem. DTI quantified loss of white matter integrity in the corpus callosum and diffusion alterations in caudate. Cognitive differences were indicated in psychomotor speed and visual recall. There were no differences between antiretroviral-initiated and naive HIV subgroups. Interpretation These findings, quantified within 100 days of infection, shed light on the earliest brain changes in HIV infection. Onset of neural injury may date to initial viral invasion and the transient early period of unchecked viremia and marked immunosuppression of the seroconversion period.

We describe our 10-year experience developing the Ruth D. & Ken M. Davee Pediatric Neurocritical Care Program at Northwestern University Feinberg School of Medicine. The neurocritical care team includes intensivists, neurologists, and an advanced practice nurse who have expertise in critical care neurology and who continue care in long-term follow-up of intensive care unit patients in a dedicated neurocritical care outpatient clinic. Brain-directed critical care requires collaboration between intensivists and neurologists with specific expertise in neurocritical care, using protocol-directed consistent care, and physiological measures to protect brain function. The heterogeneity of neurologic disorders in the pediatric intensive care unit requires a background in the relevant basic science and pathophysiology that is beyond the scope of standard neurology or critical care fellowships. To address this need, we also created a fellowship in neurocritical care for intensivists, neurologists, and advanced practice nurses. Last, we discuss the implications for pediatric neurocritical care from the experience of management of pediatric stroke and the development of stroke centers.

The roseoloviruses, human herpesvirus-6A -6B and -7 (HHV-6A, HHV-6B and HHV-7) cause acute infection, establish latency, and in the case of HHV-6A and HHV-6B, whole virus can integrate into the host chromosome. Primary infection with HHV-6B occurs in nearly all children and was first linked to the clinical syndrome roseola infantum. However, roseolovirus infection results in a spectrum of clinical disease, ranging from asymptomatic infection to acute febrile illnesses with severe neurologic complications and accounts for a significant portion of healthcare utilization by young children. Recent advances have underscored the association of HHV-6B and HHV-7 primary infection with febrile status epilepticus as well as the role of reactivation of latent infection in encephalitis following cord blood stem cell transplantation.

We thank Machado et al. for the comments on our review,1 and for the observations of abnormal anatomic and functional connectivity using diffusion-weighted MRI (DW-MRI). Innumerable studies have compared patients with autism spectrum disorders (ASD) and nonaffected controls at rest or while performing particular tasks, most often in small selected subject samples. For example, studies linked autism with the retino-collicular magnocellular visual pathways that project via the pulvinar to the amygdala, occipital V1, and multiple other areas, including the dorsal occipito-parietal/midtemporal streams, which participate with the frontal eye fields in processing spatial attention, moving targets, and dynamic facial expression (with inputs from the amygdala and other limbic pathways).2 However, no results consistently demonstrated specific neural networks that are uniquely pathognomonic of autism in the brain despite the fact that broad networks were linked with deficient social cognition in autism.3 Complex behaviors, like ASD, do not have a single endophenotype linked to one discrete neocortical location.4 The critical need for more research in autism should be balanced by caution about generalizing interpretations of neuroimaging findings that suggest the dysregulation of specific neural pathways. At present, DW-MRI and similar techniques, such as diffusion compartment imaging, are considered beneficial for research but not for routine clinical diagnostics.

In response to a number of recent lawsuits related to brain death determination, the American Academy of Neurology Ethics, Law, and Humanities Committee convened a multisociety quality improvement summit in October 2016 to address, and potentially correct, aspects of brain death determination within the purview of medical practice that may have contributed to these lawsuits. This article, which has been endorsed by multiple societies that are stakeholders in brain death determination, summarizes the discussion at this summit, wherein we (1) reaffirmed the validity of determination of death by neurologic criteria and the use of the American Academy of Neurology practice guideline to determine brain death in adults; (2) discussed the development of systems to ensure that brain death determination is consistent and accurate; (3) reviewed strategies to respond to objections to determination of death by neurologic criteria; and (4) outlined goals to improve public trust in brain death determination.

SummaryObjective Our aim was to explore the association between plasma cytokines and febrile status epilepticus (FSE) in children, as well as their potential as biomarkers of acute hippocampal injury. Methods Analysis was performed on residual samples of children with FSE (n = 33) as part of the Consequences of Prolonged Febrile Seizures in Childhood study (FEBSTAT) and compared to children with fever (n = 17). Magnetic resonance imaging (MRI) was obtained as part of FEBSTAT within 72 h of FSE. Cytokine levels and ratios of antiinflammatory versus proinflammatory cytokines in children with and without hippocampal T2 hyperintensity were assessed as biomarkers of acute hippocampal injury after FSE. Results Levels of interleukin (IL)-8 and epidermal growth factor (EGF) were significantly elevated after FSE in comparison to controls. IL-1β levels trended higher and IL-1RA trended lower following FSE, but did not reach statistical significance. Children with FSE were found to have significantly lower ratios of IL-1RA/IL-1β and IL-1RA/IL-8. Specific levels of any one individual cytokine were not associated with FSE. However, lower ratios of IL-1RA/IL-1β, IL-1RA/1L-6, and IL-1RA/ IL-8 were all associated with FSE. IL-6 and IL-8 levels were significantly higher and ratios of IL-1RA/IL-6 and IL-1RA/IL-8 were significantly lower in children with T2 hippocampal hyperintensity on MRI after FSE in comparison to those without hippocampal signal abnormalities. Neither individual cytokine levels nor ratios of IL-1RA/IL-1β or IL-1RA/IL-8 were predictive of MRI changes. However, a lower ratio of IL-1RA/IL-6 was strongly predictive (odds ratio [OR] 21.5, 95% confidence interval [CI] 1.17–393) of hippocampal T2 hyperintensity after FSE. Significance Our data support involvement of the IL-1 cytokine system, IL-6, and IL-8 in FSE in children. The identification of the IL-1RA/IL-6 ratio as a potential biomarker of acute hippocampal injury following FSE is the most significant finding. If replicated in another study, the IL-1RA/IL-6 ratio could represent a serologic biomarker that offers rapid identification of patients at risk for ultimately developing mesial temporal lobe epilepsy (MTLE).

Background: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre–messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. Methods: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. Results: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P Conclusions: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug.

Objective Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine if FSE produces acute hippocampal injury that evolves to HS.

Matrix metalloproteinases (MMPs) have been implicated in human immunodeficiency virus (HIV)-associated neurological injury; however, this relationship has not been studied early in infection. Plasma levels of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-10 measured using Luminex technology (Austin, TX, USA) were compared in 52 HIV and 21 seronegative participants of the Chicago Early HIV Infection study. MMP levels were also examined in HIV subgroups defined by antibody reactivity, viremia, and antiretroviral status, as well as in available cerebrospinal fluid (CSF) samples (n = 9). MMPs were evaluated for patterns of relationship to cognitive function and to quantitative magnetic resonance measurements of the brain derived in vivo. Plasma MMP-2 levels were significantly reduced in early HIV infection and correlated with altered white matter integrity and atrophic brain changes. MMP-9 levels were higher in the treated subgroup than in the naïve HIV subgroup. Only MMP-2 and MMP-9 were detected in the CSF; CSF MMP-2 correlated with white matter integrity and with volumetric changes in basal ganglia. Relationships with cognitive function were also identified. MMP-2 levels in plasma and in CSF correspond to early changes in brain structure and function. These findings establish a link between MMPs and neurological status previously unidentified in early HIV infection.

The use of prescription medication to augment cognitive or affective function in healthy persons—or neuroenhancement—is increasing in adult and pediatric populations. In children and adolescents, neuroenhancement appears to be increasing in parallel to the rising rates of attention-deficit disorder diagnoses and stimulant medication prescriptions, and the opportunities for medication diversion. Pediatric neuroenhancement remains a particularly unsettled and value-laden practice, often without appropriate goals or justification. Pediatric neuroenhancement presents its own ethical, social, legal, and developmental issues, including the fiduciary responsibility of physicians caring for children, the special integrity of the doctor–child–parent relationship, the vulnerability of children to various forms of coercion, distributive justice in school settings, and the moral obligation of physicians to prevent misuse of medication. Neurodevelopmental issues include the importance of evolving personal authenticity during childhood and adolescence, the emergence of individual decision-making capacities, and the process of developing autonomy. This Ethics, Law, and Humanities Committee position paper, endorsed by the American Academy of Neurology, Child Neurology Society, and American Neurological Association, focuses on various implications of pediatric neuroenhancement and outlines discussion points in responding to neuroenhancement requests from parents or adolescents. Based on currently available data and the balance of ethics issues reviewed in this position paper, neuroenhancement in legally and developmentally nonautonomous children and adolescents without a diagnosis of a neurologic disorder is not justifiable. In nearly autonomous adolescents, the fiduciary obligation of the physician may be weaker, but the prescription of neuroenhancements is inadvisable because of numerous social, developmental, and professional integrity issues.

To identify risk and risk factors for developing a subsequent febrile seizure (FS) in children with a first febrile status epilepticus (FSE) compared to a first simple febrile seizure (SFS). To identify home use of rescue medications for subsequent FS.Cases included a first FS that was FSE drawn from FEBSTAT and Columbia cohorts. Controls were a first SFS. Cases and controls were classified according to established FEBSTAT protocols. Cumulative risk for subsequent FS over a 5-year period was compared in FSE versus SFS, and Cox proportional hazards regression was conducted. Separate analysis examined subsequent FS within FSE. The use of rescue medications at home was assessed for subsequent FS.Risk for a subsequent FSE was significantly increased in FSE versus SFS. Any magnetic resonance imaging (MRI) abnormality increased the risk 3.4-fold (p0.05), adjusting for age at first FS and FSE and in analyses restricted to children whose first FS was FSE (any MRI abnormality hazard ratio [HR] 2.9, p0.05). The risk for a second FS of any type or of subsequent FS lasting10 min over the 5-year follow-up did not differ in FSE versus SFS. Rectal diazepam was administered at home to 5 (23.8%) of 21 children with subsequent FS lasting ≥10 min.Compared to controls, FSE was associated with an increased risk for subsequent FSE, suggesting the propensity of children with an initial prolonged seizure to experience a prolonged recurrence. Any baseline MRI abnormality increased the recurrence risk when FSE was compared to SFS and when FSE was studied alone. A minority of children with a subsequent FS lasting 10 min or longer were treated with rectal diazepam at home, despite receiving prescriptions after the first FSE. This indicates the need to further improve the education of clinicians and parents in order to prevent subsequent FSE.

Objective: Brain changes occurring early in HIV infection are not well characterized. The Chicago Early HIV Infection Study aimed to evaluate the presence and extent of structural brain alterations using quantitative MRI. Methods: Forty-three HIV and 21 control subjects were enrolled. Mean length of infection was estimated as less than 1 year based on assay results. High-resolution neuroanatomical images were acquired. Automated image analysis was used to derive measurements for total brain, ventricular volume, and for tissue classes (total and cortical gray matter, white matter, and CSF). A separate image analysis algorithm was used to calculate measurements for individual brain regions. Cognitive function was assessed by neuropsychological evaluation. Results: Reductions were quantified in total ( p = 0.0547) and cortical ( p = 0.0109) gray matter in the HIV group. Analysis of individual brain regions with a separate image analysis algorithm revealed consistent findings of reductions in cerebral cortex ( p = 0.042) and expansion of third ventricle ( p = 0.046). The early HIV group also demonstrated weaker performance on several neuropsychological tests, with the most pronounced difference in psychomotor speed ( p = 0.001). Conclusions: This cross-sectional brain volumetric study indicates structural alterations early in HIV infection. The findings challenge the prevailing assumption that the brain is spared in this period. Revisiting the question of the brain9s vulnerability to processes unfolding in the initial virus-host interaction and the early natural history may yield new insights into neurologic injury in HIV infection and inform neuroprotection strategies.

Summary Purpose: Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent hippocampal sclerosis (HS) and temporal lobe epilepsy. The FEBSTAT study was designed to prospectively examine the association between prolonged febrile seizures and development of HS and associated temporal lobe epilepsy, one of the most controversial issues in epilepsy. We report on the baseline phenomenology of the final cohorts as well as detailed aims and methodology. Methods: The “Consequences of Prolonged Febrile Seizures in Childhood” (FEBSTAT) study is a prospective, multicenter study. Enrolled are children, aged 1 month to 6 years of age, presenting with a febrile seizure lasting 30 min or longer based on ambulance, emergency department, and hospital records, and parental interview. At baseline, procedures included a magnetic resonance imaging (MRI) study and electroencephalography (EEG) recording done within 72 h of FSE, and a detailed history and neurologic examination. Baseline development and behavior are assessed at 1 month. The baseline assessment is repeated, with age-appropriate developmental testing at 1 and 5 years after enrollment as well as at the development of epilepsy and 1 year after that. Telephone calls every 3 months document additional seizures. Two other groups of children are included: a “control” group consisting of children with a first febrile seizure ascertained at Columbia University and with almost identical baseline and 1-year follow-up examinations and a pilot cohort of FSE from Duke University. Key Findings: The FEBSTAT cohort consists of 199 children with a median age at baseline of 16.0 months (interquartile range [IQR] 12.0–24.0) and a median duration of FSE of 70.0 min (IQR 47.0–110.0). Seizures were continuous in 57.3% and behaviorally intermittent (without recovery in between) in 31.2%; most were partial (2.0%) or secondary generalized (65.8%), and almost all (98.0%) culminated in a generalized tonic–clonic seizure. Of the 199 children, 86.4% had normal development and 20% had prior febrile seizures. In one third of cases, FSE was unrecognized in the emergency department. The Duke existing cohort consists of 23 children with a median age of FSE onset of 18.0 months (IQR 14.0–28.0) and median duration of FSE of 90.0 min (IQR 50.0–170.0). The Columbia control cohort consists of 159 children with a first febrile seizure who received almost the same workup as the FEBSTAT cohort at baseline and at 1 year. They were followed by telephone every 4 months for a median of 42 months. Among the control cohort, 64.2% had a first simple FS, 26.4% had a first complex FS that was not FSE, and 9.4% had FSE. Among the 15 with FSE, the median age at onset was 14.0 months (IQR 12.0–20.0) and the median duration of FSE was 43.0 min (IQR 35.0–75.0). Significance: The FEBSTAT study presents an opportunity to prospectively study the relationship between FSE and acute hippocampal damage, the development of mesial temporal sclerosis, epilepsy (particularly temporal lobe epilepsy), and impaired hippocampal function in a large cohort. It is hoped that this study may illuminate a major mystery in clinical epilepsy today, and permit the development of interventions designed to prevent the sequelae of FSE.

Purpose In a prospective study of the consequences of prolonged febrile seizures (FEBSTAT), we determined the frequency of Human Herpesvirus (HHV)-6 and HHV-7 infection as a cause of febrile status epilepticus (FSE).

Since 2006, the National Institutes of Health has provided institutional infrastructure grants, called Clinical and Translational Science Awards (CTSAs), to support adult and pediatric clinical and translational research in United States institutions. A CTSA Consortium Child Health Oversight Committee workgroup developed metrics to measure the impact of CTSAs on child health (CH) research. A cross-sectional survey to collect metric data was distributed to the 46 institutions that received CTSAs during 2006-09. Thirty-seven (80%) institutions responded to the survey. Data regarding 7 metrics were reported by >70% of responding institutions: the proportion of overall funding (median, interquartile range; 0.12, 0.06–0.19) and pilot grants (0.15, 0.11–0.21) supporting CH research; the proportion of active clinical research center studies involving children (0.23, 0.15–0.35); the proportion of IRB-approved (0.24, 0.16–0.30) and funded (0.22, 0.18–0.30) studies involving children; the proportion of mentored research training awards to CH investigators (0.18, 0.11–0.28); and, the proportion of CTSA leadership positions held by pediatricians (0.18, 0.12–0.28). CTSAs provide substantial support for CH research, although additional investment in CH research is needed to improve the health of children. These metrics provide an initial means to track the impact of CTSAs on CH research.

Circulating levels of matrix metalloproteinases (MMP-1 and 7) have been found to correlate with the severity of brain injury in HIV-infected subjects. This study used high-resolution neuroanatomic imaging and automated segmentation algorithms to clarify this relationship. Both metalloproteinases were significantly correlated with increased cerebrospinal fluid volume fraction. Comprehensive brain volumetric analysis revealed a more marked relationship with atrophy for MMP-7, which was significantly correlated with neural injury in multiple brain regions and nearly all ventricular measurements. MMP-7 was also correlated with measures of virologic and cognitive status.

In this investigation, circulating cytokines and chemokines were screened as correlates of brain injury in individuals with advanced Human Immunodeficiency Virus (HIV) infection. Markers were quantified using high throughput multiplexed analysis at baseline and three years later in the clinical course. Neurological status was ascertained based on objective measurements of the brain derived in vivo with Magnetic Resonance (MR) segmentation algorithms and with Diffusion Tensor Imaging (DTI). Of the markers examined, Monocyte Chemoattractant Protein-1 (n.b. MCP-1 or CCL-2) was the most prominent correlate of brain injury. At the initial assessment, elevated MCP-1 levels correlated with alterations in brain white matter. The relationship to brain injury was more extensive three years later; MCP-1 was significantly correlated with both microstructural measures (fractional anisotropy and mean diffusivity) and with brain atrophy (in gray matter and overall parenchyma). Conclusion These findings provide further evidence of the potential importance of MCP-1 as a marker of neurological injury in HIV infection. These observations build on our prior descriptions suggesting that elevated levels of MCP-1 may be a useful predictive marker for HIV-associated neurocognitive disorder (HAND). As a potent chemoattractant, MCP-1 may mediate injury through participation in self-reinforcing cycles of chronic immune activation and cytokine/chemokine-mediated neurotoxicity.

Nearly ubiquitous infection, including central nervous system invasion, with human herpesvirus 6 occurs in childhood. There are two variants, HHV6A and HHV6B. Usually asymptomatic, it is associated with the common, self-limited childhood illness roseola infantum, and rarely with more severe syndromes. In patients with immune compromise, reactivation of viral activity may lead to severe limbic encephalitis. HHV6 has been identified as a possible etiologic agent in multiple sclerosis. A preponderance of evidence supports an association between HHV6 and febrile seizures. An ongoing multicenter study is investigating possible links between HHV6 infection, febrile status epilepticus, and development of mesial temporal sclerosis (MTS). Investigation of temporal lobectomy specimens showed evidence of active HHV6B but not HHV6A replication in hippocampal astrocytes in about two-thirds of patients with MTS, but not other causes of epilepsy. HHV6 has been detected in similar clinical syndromes by other investigators, although less frequently, and additional viruses have been detected as well. It has been suggested that HHV6B may cause ‘excitotoxicity’ by interfering with astrocyte excitatory amino acid transport. Although conventional inflammatory changes are not found in most MTS specimens, inflammatory modulators may play a role in neuronal injury leading to MTS as well. If the link between early viral infection and later development of intractable temporal lobe epilepsy is confirmed, possibly associated with febrile seizures, new therapeutic approaches to a common intractable epilepsy syndrome may be possible.

BACKGROUND De novo constitutional chromosomal anomalies provide important insights into the genetic loci responsible for congenital neurological disorders. However, most phenotypic descriptions of patients with rare chromosomal abnormalities are published as individual case reports or small group studies, making genotype-phenotype correlations unclear. Moreover, many clinical genetic reports do not include neuroimaging. METHODS We conducted a retrospective case series study of all children who had genetic testing done at Children's Memorial Hospital in Chicago, Illinois between 1985 and 2006. The case series was selected from a database containing all chromosomal testing results, clinical data, and neuroimaging. Clinical examination results were assigned by board certified geneticists and/or neurologists and neuroimages were reviewed by both a neurologist or neuroradiologist and a blinded neurologist. RESULTS Of the 28,108 children in the series, we identified 34 children with novel or apparently novel de novo chromosomal abnormalities. Several of the cases represent potentially new genetic loci for neurological malformations and novel syndromic conditions. CONCLUSIONS This study demonstrates the utility of large clinical databases in assessing genotype-phenotype correlations and mapping loci for congenital neurological disorders. We describe a case-series strategy to analyze existing databases to reveal new genotype-phenotype correlations.

In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND.

Investigators from New York Presbyterian Morgan Stanley Children's Hospital examined whether having an isolated headache following minor blunt head trauma was suggestive of traumatic brain injury (TBI) among a large cohort of children 2-18 years of age.

Investigators from Danish Headache Centre, Glostrup Hospital, and the University of Copenhagen investigated whether intracellular cyclic AMP accumulation induced migraine attacks among 14 migraine patients without aura.