Neurorehabilitation across the Continuum: From the Neurocritical care unit to home.

Children admitted to neurocritical care units often experience new neurodevelopmental disabilities due to both their acquired neurologic injuries and deconditioning from prolonged hospitalizations. Rehabilitation for critically ill children is multifactorial and begins in the intensive care unit itself. The goals of rehabilitation include prevention of complications associated with immobilization and evolving tone, comprehensive evaluation and treatment of functional deficits, and implementation of adaptive strategies with the goal of maximizing recovery. As a child progresses along the medical continuum from the neurocritical care unit to acute care to post-hospitalization settings, their rehabilitative needs and interventions should also evolve. A child in the neurocritical care unit is likely to have sustained an acquired brain injury. Whether resulting from traumatic or non-traumatic causes, all etiologies of pediatric acquired brain injury can result in significant challenges for the child and their family. Post-intensive care syndrome-pediatrics is a clinical construct that that systematically organizes the range of physical, cognitive, psychological, and social symptoms that emerge in both a child and their family members following a critical illness. Ideally, outpatient care for this population evaluates and supports all areas of post-intensive care syndrome-pediatrics through an interdisciplinary clinical care model. Proactive and comprehensive rehabilitation across the continuum provides the opportunity to support the child and their family in all areas affected, thereby minimizing distress, maximizing function, and optimizing outcomes.

Fulminant Anti-Myelin Oligodendrocyte Glycoprotein-Associated Cerebral Cortical Encephalitis: Case Series of a Severe Pediatric Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease Phenotype.

BACKGROUND: We describe a cohort of children with severe myelin oligodendrocyte glycoprotein (MOG)-IgG-associated cerebral cortical encephalitis (CCE), manifesting with bilateral cortical cytotoxic edema and critical neurological illness. METHODS: We retrospectively reviewed our pediatric MOG antibody-associated disease (MOGAD) database and identified patients with specific radiographic pattern of bilateral, multifocal cortical cytotoxic lesions. We collected demographic, clinical, and outcomes data from these patients and compared select variables with radiographically distinct cerebral MOGAD syndromes (case-control analysis). We assessed the correlation of quantitative clinical variables with severity/outcomes measures using simple linear regression. RESULTS: Sixty-five of 88 total MOGAD cases had cerebral disease, and six of 88 met inclusion criteria for fulminant CCE (f-CCE). Age range was 2 to 7 years; five of six were male. Six of six were critically ill with severe encephalopathy and seizures, two of six required barbiturate coma, and two of six required invasive intracranial pressure monitoring. Six of six required treatment escalation beyond steroids. Four of six had favorable outcome; two of six had moderate-severe disability. Compared with other cerebral MOGAD cases (n = 59), children with f-CCE were more likely to have critical illness and poor neurological outcomes scores. Neurofilament light chain and treatment latency positively correlated with intensive care unit length of stay and outcomes scores; cerebrospinal fluid (CSF) white blood cell count and neutrophil-to-lymphocyte ratio did not. CONCLUSIONS: Pediatric CCE with bilateral cytotoxicity is associated with more fulminant disease and worse outcomes than other cerebral MOGAD syndromes.

A Toddler With New Seizures, Progressive White Matter Lesions, and Multifocal Microhemorrhages.

A 16-month-old, previously healthy male is hospitalized for new onset seizures. Initial investigation is significant for enterovirus/rhinovirus respiratory infection, abnormal T2 signal predominantly in the white matter and scattered microhemorrhages on brain MRI, transaminitis, and thrombocytopenia. His symptoms initially improve on steroid therapy and he is discharged from the hospital. During the ensuing month with the tapering of the steroids, he develops new motor deficits for which he is rehospitalized. His laboratory investigation on readmission is unremarkable. However, there is significant progression of white matter lesions and microhemorrhages on repeat MRI. While in the hospital, he becomes febrile and has seizure recurrence and worsening neurologic symptoms, including cerebral salt wasting and encephalopathy. Subsequent neuroimaging demonstrates cerebral edema and diffuse brain injury. A high index of suspicion for a rare condition ultimately leads us to perform the specialized testing that confirms the diagnosis. We will discuss the diagnostic challenges that arise from an atypical presentation of an uncommon condition, and from the disease progression that is modified by previous interventions.

Eosinophilic Meningitis: Eleven-Year Experience at Texas Children's Hospital.

Eosinophilic meningitis can be caused by various etiologies and is reported mostly in tropical climates. The diagnosis is rare in the continental US, presenting challenges for management. Following a case of pediatric eosinophilic meningitis, we reviewed our 11-year experience with this diagnosis at a large US children's hospital.

KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism.

BACKGROUND: Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. METHODS: Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. FINDINGS: Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. INTERPRETATION: Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. FUNDING: Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.

Continuing Care For Critically Ill Children Beyond Hospital Discharge: Current State of Follow-up.

OBJECTIVES: Survivors of the PICU face long-term morbidities across health domains. In this study, we detail active PICU follow-up programs (PFUPs) and identify perceptions and barriers about development and maintenance of PFUPs. METHODS: A web link to an adaptive survey was distributed through organizational listservs. Descriptive statistics characterized the sample and details of existing PFUPs. Likert responses regarding benefits and barriers were summarized. RESULTS: One hundred eleven respondents represented 60 institutions located in the United States (n = 55), Canada (n = 3), Australia (n = 1), and the United Kingdom (n = 1). Details for 17 active programs were provided. Five programs included broad PICU populations, while the majority were neurocritical care (53%) focused. Despite strong agreement on the need to assess and treat morbidity across multiple health domains, 29% were physician only programs, and considerable variation existed in services provided by programs across settings. More than 80% of all respondents agreed PFUPs provide direct benefits and are essential to advancing knowledge on long-term PICU outcomes. Respondents identified "lack of support" as the most important barrier, particularly funding for providers and staff, and lack of clinical space, though successful programs overcome this challenge using a variety of funding resources. CONCLUSIONS: Few systematic multidisciplinary PFUPs exist despite strong agreement about importance of this care and direct benefit to patients and families. We recommend stakeholders use our description of successful programs as a framework to develop multidisciplinary models to elevate continuity across inpatient and outpatient settings, improve patient care, and foster collaboration to advance knowledge.

From Telemedicine to the ICU-Fever and Rash in a 9-Year-Old Girl.

A 9-year-old girl presented to her primary care pediatrician via telemedicine during the initial months of the coronavirus disease 2019 pandemic because of 4 days of warmth perceived by her mother, decreased energy, and a new rash on her upper extremities. After 10 additional days of documented fever >38°C, worsening fatigue, and 1 day of nausea, vomiting, and diarrhea, she was allowed to schedule an in-person visit with her pediatrician after testing negative for severe acute respiratory syndrome coronavirus 2. She appeared ill on arrival to clinic, and her pediatrician recommended evaluation in an emergency department. Her initial laboratory testing revealed nonspecific elevation in several inflammatory markers and leukopenia, and she responded well to intravenous hydration. Over the next 2 weeks, her fever persisted, constitutional symptoms worsened, and she developed progressively painful cervical lymphadenopathy and pancytopenia. She was evaluated in clinic by several specialists and eventually was urged to present to the emergency department again, at which time she was admitted to the PICU. After consulting additional specialists and waiting for laboratory results, the team reached a definitive diagnosis and initiated therapy; however, she experienced rapid clinical decline shortly thereafter. The specialists who assisted with identification of the underlying etiology of her symptoms were able to work together to manage the subsequent complications.

Coronavirus Infections in the Nervous System of Children: A Scoping Review Making the Case for Long-Term Neurodevelopmental Surveillance.

BACKGROUND: The objective of this study was to describe the case literature of human coronavirus infections in the nervous system of children, including from SARS-CoV-2, and to provide guidance to pediatric providers for managing the potential long-term effects on neurodevelopment of human coronavirus infections in the nervous system. METHODS: Using a structured strategy, the PubMed and Ovid:Embase databases were queried for articles about the clinical presentation and pathophysiology of coronavirus infections in the nervous system of children and young adults, aged 0 to 24 years. RESULTS: Of 2302 articles reviewed, 31 described SARS-CoV-2 infections in the nervous system of children and 21 described other human coronaviruses: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, MERS-CoV, SARS-CoV-1. Excepting MERS-CoV, we found cases of neurological disease in children from each human coronavirus. Children with non-SARS-CoV-2 infections have suffered acute flaccid paralysis, acute disseminated encephalomyelitis, encephalitis, and seizures. In addition, cases of ischemic, hemorrhagic, and microvascular strokes have occurred in children with SARS-CoV-2. Patients with multisystem inflammatory syndrome in children have suffered encephalitis, stroke, pseudotumor cerebri syndrome, and cytotoxic lesions of deep brain structures. Despite these reports, few articles evaluated the impact of human coronavirus infections on long-term neurodevelopmental domains including cognitive, language, academic, motor, and psychosocial outcomes. CONCLUSIONS: Neurological manifestations of human coronavirus infections can cause severe disease in children. The case literature suggests a critical gap in knowledge of the long-term effects on child neurodevelopment of these infections. As the current SARS-CoV-2 pandemic continues, this gap must be filled to facilitate optimal outcomes in recovering children.

Variation in Treatment and Outcomes of Children With Acute Disseminated Encephalomyelitis.

OBJECTIVES: To characterize variation in treatments and outcomes of pediatric patients admitted to children's hospitals with acute disseminated encephalomyelitis (ADEM). METHODS: In this retrospective cohort study, we used data from the Pediatric Health Information System. Children >30 days old who were hospitalized from 2010 to 2015 with ADEM were included. Variables analyzed were treatments and admission to an ICU. Primary outcomes were discharge disposition and readmissions for relapses (ADEM readmissions) or for continued comorbidities (non-ADEM readmissions). RESULTS: A total of 954 patients with ADEM had 1117 admissions. Treatments included steroids (80%), immunoglobulin (22%), and plasmapheresis (6.6%); 15% of admissions included none of these treatments. Treatments varied by center (P < .001). Thirty-four percent of admissions included ICU admission, which was associated with an increased number and duration of treatments (P < .01). The discharge disposition was home in 85% of admissions; home with health services, rehab facility, or other in 13.6%; and mortality in 1.4%. Twelve percent (117 of 954) of patients had >1 admission for ADEM. Treatment choice and ICU stay were not associated with ADEM readmissions. Sixteen percent (181 of 1101) of ADEM admissions had a non-ADEM readmission within 90 days. Prolonged ICU hospitalization was associated with non-ADEM readmission (adjusted odds ratio 1.9; P = .017) and decreased likelihood of discharge from the hospital to home (adjusted odds ratio 0.1; P < .001). After adjusting for ICU duration, treatment choice and duration were not associated with non-ADEM readmission or hospital disposition. CONCLUSIONS: Significant variation in ADEM treatment exists across centers. Admission to an ICU for ADEM was associated with increased immunotherapy, additional health services at discharge, and readmission for diagnoses other than ADEM.

MRI Findings in Pediatric Abusive Head Trauma: A Review.

Trauma is the most common cause of death and significant morbidity in childhood; abusive head trauma (AHT) is a prominent cause of significant morbidity and mortality in children younger than 2 years old. Correctly diagnosing AHT is challenging both clinically and radiologically. The primary diagnostic challenges are that the abused children are usually too young to provide an adequate history, perpetrators are unlikely to provide truthful account of trauma, and clinicians may be biased in their assessment of potentially abused children. The main radiological challenge is that there is no single imaging finding that is independently specific for or diagnostic of AHT. The radiological evaluation should be based on the multiplicity and severity of findings and an inconsistency with the provided mechanism of trauma. While the most common neuroimaging finding in AHT is subdural hemorrhage, other less well-known magnetic resonance imaging (MRI) findings such as the "lollipop sign" or "tadpole sign," parenchymal or cortical lacerations, subpial hemorrhage, cranio-cervical junction injuries including retroclival hematomas, as well as diffuse hypoxic brain injury have been identified and described in the recent literature. While AHT is ultimately a clinical diagnosis combining history, exam, and neuroimaging, familiarity with the typical as well as the less-well known MRI findings will improve recognition of AHT by radiologists.

Phenotypic characterization of individuals with SYNGAP1 pathogenic variants reveals a potential correlation between posterior dominant rhythm and developmental progression.

BACKGROUND: The SYNGAP1 gene encodes for a small GTPase-regulating protein critical to dendritic spine maturation and synaptic plasticity. Mutations have recently been identified to cause a breadth of neurodevelopmental disorders including autism, intellectual disability, and epilepsy. The purpose of this work is to define the phenotypic spectrum of SYNGAP1 gene mutations and identify potential biomarkers of clinical severity and developmental progression. METHODS: A retrospective clinical data analysis of individuals with SYNGAP1 mutations was conducted. Data included genetic diagnosis, clinical history and examinations, neurophysiologic data, neuroimaging, and serial neurodevelopmental/behavioral assessments. All patients were seen longitudinally within a 6-year period; data analysis was completed on June 30, 2018. Records for all individuals diagnosed with deleterious SYNGAP1 variants (by clinical sequencing or exome sequencing panels) were reviewed. RESULTS: Fifteen individuals (53% male) with seventeen unique SYNGAP1 mutations are reported. Mean age at genetic diagnosis was 65.9 months (28-174 months). All individuals had epilepsy, with atypical absence seizures being the most common semiology (60%). EEG abnormalities included intermittent rhythmic delta activity (60%), slow or absent posterior dominant rhythm (87%), and epileptiform activity (93%), with generalized discharges being more common than focal. Neuroimaging revealed nonspecific abnormalities (53%). Neurodevelopmental evaluation revealed impairment in all individuals, with gross motor function being the least affected. Autism spectrum disorder was diagnosed in 73% and aggression in 60% of cases. Analysis of biomarkers revealed a trend toward a moderate positive correlation between visual-perceptual/fine motor/adaptive skills and language development, with posterior dominant rhythm on electroencephalogram (EEG), independent of age. No other neurophysiology-development associations or correlations were identified. CONCLUSIONS: A broad spectrum of neurologic and neurodevelopmental features are found with pathogenic variants of SYNGAP1. An abnormal posterior dominant rhythm on EEG correlated with abnormal developmental progression, providing a possible prognostic biomarker.

A 14-Year-Old Boy With Fevers, Cytopenias, and Neurocognitive Decline.

A 14-year-old boy presented to our institution with a 1-month history of neurocognitive decline and intermittent fevers. His history was significant for fevers, headaches, and a 10-lb weight loss. Previous examinations by multiple medical providers were significant only for bilateral cervical lymphadenopathy. Previous laboratory workup revealed leukopenia, neutropenia, and elevated inflammatory markers. Despite improvement in his laboratory values after his initial presentation, his fevers persisted, and he developed slowed and "jerky" movements, increased sleep, slurred speech, delusions, visual hallucinations, and deterioration in his school performance. A brain MRI performed at an outside hospital before admission at our institution was concerning for patchy, increased T2 and fluid-attenuated inversion recovery signal intensity in multiple areas, including the basal ganglia. After transfer to our institution and admission to the pediatric hospital medicine team, the patient had an acute decompensation. Our subspecialists will discuss the initial evaluation, workup, differential diagnosis, definitive diagnosis, and subsequent management of this patient.

A 15-Year-Old Boy With Refractory Status Epilepticus.

In this case report, we discuss a 15-year-old previously healthy boy who presented with acute onset encephalopathy with refractory status epilepticus requiring pentobarbital-induced burst suppression for seizure control. We review the differential diagnosis and important diagnostic considerations for pediatric patients presenting with acute encephalopathy. We then review Hashimoto encephalopathy (SREAT) and discuss presentation, diagnosis, and treatment.

Preliminary findings of altered functional connectivity of the default mode network linked to functional outcomes one year after pediatric traumatic brain injury.

PURPOSE AND METHOD: This study examined functional connectivity of the default mode network (DMN) and examined brain-behavior relationships in a pilot cohort of children with chronic mild to moderate traumatic brain injury (TBI). RESULTS: Compared to uninjured peers, children with TBI demonstrated less anti-correlated functional connectivity between DMN and right Brodmann Area 40 (BA 40). In children with TBI, more anomalous less anti-correlated) connectivity between DMN and right BA 40 was linked to poorer performance on response inhibition tasks. CONCLUSION: Collectively, these preliminary findings suggest that functional connectivity between DMN and BA 40 may relate to longterm functional outcomes in chronic pediatric TBI.

A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.