Intrathecal magnesium delivery for Mg++-insensitive NMDA receptor activity due to GRIN1 mutation.

BACKGROUND: Mutations in the NMDA receptor are known to disrupt glutamatergic signaling crucial for early neurodevelopment, often leading to severe global developmental delay/intellectual disability, epileptic encephalopathy, and cerebral palsy phenotypes. Both seizures and movement disorders can be highly treatment-refractory. RESULTS: We describe a targeted ABA n-of-1 treatment trial with intrathecal MgSO4, rationally designed based on the electrophysiologic properties of this gain of function mutation in the GRIN1 NMDA subunit. CONCLUSION: Although the invasive nature of the trial necessitated a short-term, non-randomized, unblinded intervention, quantitative longitudinal neurophysiologic monitoring indicated benefit, providing class II evidence in support of intrathecal MgSO4 for select forms of GRIN disorders.

Quantitative Electroencephalography After Pediatric Anterior Circulation Stroke.

OBJECTIVE: Regional differences were investigated in quantitative EEG (QEEG) characteristics and associations of QEEG to hemodynamics after pediatric acute stroke. METHODS: Quantitative EEG was analyzed, including power in delta, theta, alpha, and beta bands, alpha-delta power ratio, total power, and spectral edge frequency from 11 children with unilateral, anterior circulation strokes during the first 24 hours of continuous EEG recording. Differences between injured and uninjured hemispheres were assessed using multivariate dynamic structural equations modeling. Dynamic structural equations modeling was applied to six children with hemorrhagic stroke undergoing arterial blood pressure, heart rate, and cerebral oximetry monitoring to investigate associations between hemodynamics with QEEG adjacent to anterior circulation regions. RESULTS: All patients with acute ischemic stroke ( n = 5) had lower alpha and beta power and spectral edge frequency on injured compared with uninjured regions. This was not consistent after hemorrhagic stroke ( n = 6). All hemorrhagic stroke patients demonstrated negative association of total power with arterial blood pressure within injured regions. No consistency was observed for direction or strength of association in other QEEG measures to arterial blood pressure nor were such consistent relationships observed for any QEEG measure studied in relation to heart rate or cerebral oximetry. CONCLUSIONS: After pediatric anterior circulation acute ischemic stroke, reduced spectral edge frequency and alpha and beta power can be observed on injured as compared with noninjured regions. After pediatric anterior circulation hemorrhagic stroke, total power can be negatively associated with arterial blood pressure within injured regions. Larger studies are needed to understand conditions in which QEEG patterns manifest and relate to hemodynamics and brain penumbra.

Pediatric Acute Stroke Protocols in the United States and Canada.

OBJECTIVE: To describe existing pediatric acute stroke protocols to better understand how pediatric centers might implement such pathways within the context of institution-specific structures. STUDY DESIGN: We administered an Internet-based survey of pediatric stroke specialists. The survey included questions about hospital demographics, child neurology and pediatric stroke demographics, acute stroke response, imaging, and hyperacute treatment. RESULTS: Forty-seven surveys were analyzed. Most respondents practiced at a large, freestanding children's hospital with a moderate-sized neurology department and at least 1 neurologist with expertise in pediatric stroke. Although there was variability in how the hospitals deployed stroke protocols, particularly in regard to staffing, the majority of institutions had an acute stroke pathway, and almost all included activation of a stroke alert page. Most institutions preferred magnetic resonance imaging (MRI) over computed tomography (CT) and used abbreviated MRI protocols for acute stroke imaging. Most institutions also had either CT-based or magnetic resonance-based perfusion imaging available. At least 1 patient was treated with intravenous tissue plasminogen activator (IV-tPA) or mechanical thrombectomy at the majority of institutions during the year before our survey. CONCLUSIONS: An acute stroke protocol is utilized in at least 41 pediatric centers in the US and Canada. Most acute stroke response teams are multidisciplinary, prefer abbreviated MRI over CT for diagnosis, and have experience providing IV-tPA and mechanical thrombectomy. Further studies are needed to standardize practices of pediatric acute stroke diagnosis and hyperacute management.

Implementation of Multimodality Neurologic Monitoring Reporting in Pediatric Traumatic Brain Injury Management.

BACKGROUND/OBJECTIVE: Multimodality neurologic monitoring (MMM) is an emerging technique for management of traumatic brain injury (TBI). An increasing array of MMM-derived biomarkers now exist that are associated with injury severity and functional outcomes after TBI. A standardized MMM reporting process has not been well described, and a paucity of evidence exists relating MMM reporting in TBI management with functional outcomes or adverse events. METHODS: Prospective implementation of standardized MMM reporting at a single pediatric intensive care unit (PICU) is described that included monitoring of intracranial pressure (ICP), cerebral oxygenation and electroencephalography (EEG). The incidence of clinical decisions made using MMM reporting is described, including timing of neuroimaging, ICP monitoring discontinuation, use of paralytic, hyperosmolar and pentobarbital therapies, neurosurgical interventions, ventilator and CPP adjustments and neurologic prognostication discussions. Retrospective analysis was performed on the association of MMM reporting with initial Glasgow Coma Scale (GCS) and Pediatric Risk of Mortality III (PRISM III) scores, duration of total hospitalization and PICU hospitalization, duration of mechanical ventilation and invasive ICP monitoring, inpatient complications, time with ICP > 20 mmHg, time with cerebral perfusion pressure (CPP) < 40 mmHg and 12-month Glasgow Outcome Scale-Extended Pediatrics (GOSE-Peds) scores. Association of outcomes with MMM reporting was investigated using the Wilcoxon rank-sum test or Fisher's exact test, as appropriate. RESULTS: Eighty-five children with TBI underwent MMM over 6 years, among which 18 underwent daily MMM reporting over a 21-month period. Clinical decision-making influenced by MMM reporting included timing of neuroimaging (100.0%), ICP monitoring discontinuation (100.0%), timing of extubation trials of surviving patients (100.0%), body repositioning (11.1%), paralytic therapy (16.7%), hyperosmolar therapy (22.2%), pentobarbital therapy (33.3%), provocative cerebral autoregulation testing (16.7%), adjustments in CPP thresholds (16.7%), adjustments in PaCO2 thresholds (11.1%), neurosurgical interventions (16.7%) and neurologic prognostication discussions (11.1%). The implementation of MMM reporting was associated with a reduction in ICP monitoring duration (p = 0.0017) and mechanical ventilator duration (p = 0.0018). No significant differences were observed in initial GCS or PRISM III scores, total hospitalization length, PICU hospitalization length, total complications, time with ICP > 20 mmHg, time with CPP < 40 mmHg, use of tier 2 therapy, or 12-month GOS-E Peds scores. CONCLUSION: Implementation of MMM reporting in pediatric TBI management is feasible and can be impactful in tailoring clinical decisions. Prospective work is needed to understand the impact of MMM and MMM reporting systems on functional outcomes and clinical care efficacy.

Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.

Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1ß) are recommended.

Treatment Timing, EEG, Neuroimaging, and Outcomes After Acute Necrotizing Encephalopathy in Children.

BACKGROUND: Acute necrotizing encephalopathy (ANE) is a rare condition associated with rapid progression to coma and high incidence of morbidity and mortality. METHODS: Clinical, electroencephalographic (EEG), and brain magnetic resonance imaging (MRI) characteristics and immunomodulatory therapy timing were retrospectively analyzed in children with ANE. ANE severity scores (ANE-SS) and MRI scores were also assessed. The associations of patient characteristics with 6-month modified Rankin scale (mRS) and length of hospitalization were determined using either univariate linear regression or one-way analysis of variance. RESULTS: 7 children were retrospectively evaluated. Normal EEG sleep spindles (P = .024) and early treatment (R2 = .57, P = .030) were associated with improved outcomes (ie, decreased mRS). Higher ANE-SS (R2 = .79, P = .011), higher age (R2 = .62, P = .038), and presence of brainstem lesions (P = .015) were associated with longer length of hospitalization. Other patient characteristics were not significantly associated with mRS or length of hospitalization. CONCLUSION: Early immunomodulatory therapy and normal sleep spindles are associated with better functional outcome in children with ANE.

Arteritis and Large Vessel Occlusive Strokes in Children After COVID-19 Infection.

We describe 2 previously healthy children who suffered disabling arterial ischemic strokes because of acute intracranial large vessel occlusion within 3 to 4 weeks of coronavirus disease 2019 (COVID-19) infection. Both children presented from communities with high COVID-19 case rates in the Southwest United States. An 8-year-old American Indian girl experienced severe iron deficiency anemia requiring blood transfusion and presented with bilateral middle cerebral artery (MCA) distribution strokes 3 weeks later. She underwent emergent mechanical thrombectomy of the left MCA with successful clot retrieval but experienced reocclusion of that artery 5 hours after intervention. She also had evidence of cerebral arteritis on catheter angiography and vessel wall imaging, and clot pathology revealed recently formed, unorganized platelet- and fibrin-rich thrombus with sparse clusters of erythrocytes, degenerated histiocytes, few eosinophils, and rare neutrophils. A 16-year old African American boy demonstrated evidence of arteritis on brain magnetic resonance angiography and serological markers of cardiac and renal injury accompanied by positive lupus anticoagulant antibodies. The children described in this report express clinical features inconsistent with focal cerebral arteriopathy, including elevated markers of systemic inflammation in both bilateral MCA strokes in one case and multiple organ system dysfunction in the other case. Neither patient fulfilled criteria for multisystem inflammatory syndrome in children, given absence of fever. These cases illustrate that systemic postinfectious arteritis with cerebrovascular involvement may complicate COVID-19 infection in previously healthy school-aged children, and their presentations may overlap but not fulfill criteria for multisystem inflammatory syndrome in children or focal cerebral arteriopathy.

Multimodal Assessment of Cerebral Autoregulation and Autonomic Function After Pediatric Cerebral Arteriovenous Malformation Rupture.

BACKGROUND: Management after cerebral arteriovenous malformation (AVM) rupture aims toward preventing hemorrhagic expansion while maintaining cerebral perfusion to avoid secondary injury. We investigated associations of model-based indices of cerebral autoregulation (CA) and autonomic function (AF) with outcomes after pediatric cerebral AVM rupture. METHODS: Multimodal neurologic monitoring data from the initial 3 days after cerebral AVM rupture were retrospectively analyzed in children (< 18 years). AF indices included standard deviation of heart rate (HRsd), root-mean-square of successive differences in heart rate (HRrmssd), low-high frequency ratio (LHF), and baroreflex sensitivity (BRS). CA indices include pressure reactivity index (PRx), wavelet pressure reactivity indices (wPRx and wPRx-thr), pulse amplitude index (PAx), and correlation coefficient between intracranial pressure pulse amplitude and cerebral perfusion pressure (RAC). Percent time of cerebral perfusion pressure (CPP) below lower limits of autoregulation (LLA) was also computed for each CA index. Primary outcomes were determined using Pediatric Glasgow Outcome Score Extended-Pediatrics (GOSE-PEDs) at 12 months and acquired epilepsy. Association of biomarkers with outcomes was investigated using linear regression, Wilcoxon signed-rank, or Chi-square. RESULTS: Fourteen children were analyzed. Lower AF indices were associated with poor outcomes (BRS [p = 0.04], HRsd [p = 0.04], and HRrmssd [p = 0.00]; and acquired epilepsy (LHF [p = 0.027]). Higher CA indices were associated with poor outcomes (PRx [p = 0.00], wPRx [p = 0.00], and wPRx-thr [p = 0.01]), and acquired epilepsy (PRx [p = 0.02] and wPRx [p = 0.00]). Increased time below LLA was associated with poor outcome (percent time below LLA based on PRx [p = 0.00], PAx [p = 0.04], wPRx-thr [p = 0.03], and RAC [p = 0.01]; and acquired epilepsy (PRx [p = 0.00], PAx [p = 0.00], wPRx-thr [p = 0.03], and RAC [p = 0.01]). CONCLUSIONS: After pediatric cerebral AVM rupture, poor outcomes are associated with AF and CA when applying various neurophysiologic model-based indices. Prospective work is needed to assess these indices of CA and AF in clinical decision support.

Glucose Transporter 1 Deficiency: A Treatable Cause of Opsoclonus and Epileptic Myoclonus.

BACKGROUND: Epileptic myoclonus in infancy is associated with various pathological conditions. In the absence of an identifiable central nervous system lesion, an underlying metabolic genetic cause is often suspected. PATIENTS: We describe two infants with glucose transporter 1 deficiency syndrome who presented with epileptic myoclonus. One infant presented with an electroclinical phenotype mimicking benign myoclonic epilepsy of infancy; the other infant had a novel mutation and presented with opsoclonus and epileptic myoclonus with a robust response to high-dose steroids. Both infants began the ketogenic diet after the diagnosis of glucose transporter 1 deficiency syndrome, with good yet variable treatment responses. CONCLUSIONS: These infants demonstrate that an evaluation for glucose transporter 1 deficiency syndrome is warranted in patients presenting with an electroclinical picture compatible with benign myoclonic epilepsy of infancy as well as in patients with intractable epilepsy who demonstrate a significant response to steroid therapy.

Migraine management in children.

Migraine management in children relies on understanding the difference between adult and childhood migraine, being able to identify childhood migraine variants and knowledge of both the pediatric and adult literature regarding treatment.