Taeun Chang

The American clinical neurophysiology society's guideline on continuous electroencephalography monitoring in neonates

This article offers the preferred methods and indications for longterm, conventional electroencephalography (EEG) monitoring for selected, high-risk neonates of postmenstrual age less than 48 weeks. The authors recognize that there may be significant practical barriers to the implementation of these recommendations for many caregivers and institutions, particularly with regard to the availability of equipment, and technical and interpretive personnel. A wide range of clinical circumstances dictates the implementation of EEG monitoring, frequency of EEG review, and the subsequent treatment of seizures or EEG background abnormalities detected by neonatal EEG. Consequently, this article should be considered as an expression of idealized goals and not as a mandated standard of care.

The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats

Experimental models of traumatic brain injury have been developed to replicate selected aspects of human head injury, such as contusion, concussion, and/or diffuse axonal injury. Although diffuse axonal injury is a major feature of clinical head injury, relatively few experimental models of diffuse traumatic brain injury (TBI) have been developed, particularly in smaller animals such as rodents. Here, we describe the pathophysiological consequences of moderate diffuse TBI in rats generated by a newly developed, highly controlled, and reproducible model. This model of TBI caused brain edema beginning 20 min after injury and peaking at 24 h post-trauma, as shown by wet weight/dry weight ratios and diffusion-weighted magnetic resonance imaging. Increased permeability of the blood-brain barrier was present up to 4 h post-injury as evaluated using Evans blue dye. Phosphorus magnetic resonance spectroscopy showed significant declines in brain-free magnesium concentration and reduced cytosolic phosphorylation potential at 4 h post-injury. Diffuse axonal damage was demonstrated using manganese-enhanced magnetic resonance imaging, and intracerebral injection of a fluorescent vital dye (Fluoro-Ruby) at 24-h and 7-day post-injury. Morphological evidence of apoptosis and caspase-3 activation were also found in the cerebral hemisphere and brainstem at 24 h after trauma. These results show that this model is capable of reproducing major biochemical and neurological changes of diffuse clinical TBI.

Symptomatic Neonatal Arterial Ischemic Stroke: The International Pediatric Stroke Study

BACKGROUND: Neonatal arterial ischemic stroke (AIS) has emerged as a leading cause of perinatal brain injury, cerebral palsy, and lifelong disability. The pathogenesis is poorly understood, which limits the development of treatment and prevention strategies. Multicenter studies must define epidemiology, risk factors, treatment practices, and outcomes to advance clinical trials and improve the adverse outcomes suffered by most survivors. METHODS: The International Pediatric Stroke Study is a global research initiative of 149 coinvestigators (30 centers in 10 countries). Patients with clinical and neuroimaging confirmation of symptomatic neonatal AIS were enrolled (2003–2007). Standardized, Web-based data entry collected clinical presentations, risk factors, investigations, treatments, and early outcomes. We examined predictors of infarct characteristics and discharge outcome by using multivariate logistic regression. RESULTS: Two hundred forty-eight neonates were studied (57% male, 10% premature). Most of them presented with seizure (72%) and nonfocal neurologic signs (63%). MRI was completed for 92% of the infants, although <50% had vascular imaging. Infarcts preferentially involved the anterior circulation and left hemisphere and were multifocal in 30%. Maternal health and pregnancies were usually normal. Neonates often required resuscitation (30%) and had systemic illnesses (23%). Cardiac and prothrombotic abnormalities were identified in <20% of the infants. Antithrombotic treatment was uncommon (21%) and varied internationally. Half (49%) of the infants had deficits at discharge, and data on their long-term outcomes are pending. CONCLUSIONS: Newborns with AIS are often systemically sick, whereas their mothers are usually healthy. Definitive causes for most neonatal AISs have not been established, and large-scale case-control studies are required to understand pathogenesis if outcomes are to be improved.

Erythropoietin for Neuroprotection in Neonatal Encephalopathy: Safety and Pharmacokinetics

OBJECTIVE: To determine the safety and pharmacokinetics of erythropoietin (Epo) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy (HIE). We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies (ie, maximum concentration = 6000–10 000 U/L; area under the curve = 117 000–140 000 U*h/L). METHODS: In this multicenter, open-label, dose-escalation, phase I study, we enrolled 24 newborns undergoing hypothermia for HIE. All patients had decreased consciousness and acidosis (pH < 7.00 or base deficit ≥ 12), 10-minute Apgar score ≤ 5, or ongoing resuscitation at 10 minutes. Patients received 1 of 4 Epo doses intravenously: 250 (N = 3), 500 (N = 6), 1000 (N = 7), or 2500 U/kg per dose (N = 8). We gave up to 6 doses every 48 hours starting at <24 hours of age and performed pharmacokinetic and safety analyses. RESULTS: Patients received mean 4.8 ± 1.2 Epo doses. Although Epo followed nonlinear pharmacokinetics, excessive accumulation did not occur during multiple dosing. At 500, 1000, and 2500 U/kg Epo, half-life was 7.2, 15.0, and 18.7 hours; maximum concentration was 7046, 13 780, and 33 316 U/L, and total Epo exposure (area under the curve) was 50 306, 131 054, and 328 002 U*h/L, respectively. Drug clearance at a given dose was slower than reported in uncooled preterm infants. No deaths or serious adverse effects were seen. CONCLUSIONS: Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals. A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE.

Prospective study of new-onset seizures presenting as status epilepticus in childhood

Objective: To characterize children with new-onset seizures presenting as status epilepticus at a tertiary care childrens hospital. Methods: Prospectively collected data were reviewed from a database derived from a mandated critical care pathway. A total of 1,382 patients presented with new-onset seizures between 2001 and 2007. Results: A total of 144 patients presented in status epilepticus. The average age was 3.4 years. The majority of seizures (72%) lasted between 21 and 60 minutes. The majority of patients had no significant past medical history; one-fourth had a family history of epilepsy. Five (4%) patients with EEGs had electrographic seizures during the study, captured only with prolonged monitoring. The most common etiology was febrile convulsion, followed by cryptogenic. The most common acute symptomatic cause was CNS infection; the most common remote symptomatic cause was cerebral dysgenesis. Combined CT and MRI provided a diagnosis in 30%. CT was helpful in identifying acute vascular lesions and acute edema, whereas MRI was superior in identifying subtle abnormalities and remote symptomatic etiologies such as dysplasia and mesial temporal sclerosis. Conclusions: Children who present in status epilepticus that is not a prolonged febrile convulsion should undergo neuroimaging in the initial evaluation. For any child who presents in status epilepticus and has not yet returned to baseline, the possibility of nonconvulsive status epilepticus should be considered. Although CT is often more widely accepted, especially in the urgent setting, strong consideration for MRI should be given when available, due to the superior yield.

High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial

OBJECTIVE: To determine if multiple doses of erythropoietin (Epo) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy. METHODS: In a phase II double-blinded, placebo-controlled trial, we randomized newborns to receive Epo (1000 U/kg intravenously; n = 24) or placebo (n = 26) at 1, 2, 3, 5, and 7 days of age. All infants had moderate/severe encephalopathy; perinatal depression (10 minute Apgar <5, pH <7.00 or base deficit ≥15, or resuscitation at 10 minutes); and received hypothermia. Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale and Warner Initial Developmental Evaluation. Two independent observers rated MRI brain injury severity by using an established scoring system. RESULTS: The mean age at first study drug was 16.5 hours (SD, 5.9). Neonatal deaths did not significantly differ between Epo and placebo groups (8% vs 19%, P = .42). Brain MRI at mean 5.1 days (SD, 2.3) showed a lower global brain injury score in Epo-treated infants (median, 2 vs 11, P = .01). Moderate/severe brain injury (4% vs 44%, P = .002), subcortical (30% vs 68%, P = .02), and cerebellar injury (0% vs 20%, P = .05) were less frequent in the Epo than placebo group. At mean age 12.7 months (SD, 0.9), motor performance in Epo-treated (n = 21) versus placebo-treated (n = 20) infants were as follows: Alberta Infant Motor Scale (53.2 vs 42.8, P = .03); Warner Initial Developmental Evaluation (28.6 vs 23.8, P = .05). CONCLUSIONS: High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function.

STOCHASTIC VERSUS DETERMINISTIC VARIABILITY IN SIMPLE NEURONAL CIRCUITS. I: MONOSYNAPTIC SPINAL CORD REFLEXES

Long time series of monosynaptic Ia-afferent to alpha-motoneuron reflexes were recorded in the L7 or S1 ventral roots in the cat. Time series were collected before and after spinalization at T13 during constant amplitude stimulations of group Ia muscle afferents in the triceps surae muscle nerves. Using autocorrelation to analyze the linear correlation in the time series demonstrated oscillations in the decerebrate state (4/4) that were eliminated after spinalization (5/5). Three tests for determinism were applied to these series: 1) local flow, 2) local dispersion, and 3) nonlinear prediction. These algorithms were validated with time series generated from known deterministic equations. For each experimental and theoretical time series used, matched time-series of stochastic surrogate data were generated to serve as mathematical and statistical controls. Two of the time series collected in the decerebrate state (2/4) demonstrated evidence for deterministic structure. This structure could not be accounted for by the autocorrelation in the data, and was abolished following spinalization. None of the time series collected in the spinalized state (0/5) demonstrated evidence of determinism. Although monosynaptic reflex variability is generally stochastic in the spinalized state, this simple driven system may display deterministic behavior in the decerebrate state.

Risk factors for EEG seizures in neonates treated with hypothermia: a multicenter cohort study.

Objective: To assess the risk factors for electrographic seizures among neonates treated with therapeutic hypothermia for hypoxic-ischemic encephalopathy (HIE). Methods: Three-center observational cohort study of 90 term neonates treated with hypothermia, monitored with continuous video-EEG (cEEG) within the first day of life (median age at onset of recording 9.5 hours, interquartile range 6.3–14.5), and continued for >24 hours (total recording 93.3 hours, interquartile range 80.1–112.8 among survivors). A pediatric electroencephalographer at each site reviewed cEEGs for electrographic seizures and initial EEG background category. Results: A total of 43 (48%) had electrographic seizures, including 9 (10%) with electrographic status epilepticus. Abnormal initial EEG background classification (excessively discontinuous, depressed and undifferentiated, burst suppression, or extremely low voltage), but not clinical variables (including pH <6.8, base excess ≤−20, or 10-minute Apgar ≤3), was strongly associated with seizures. Conclusions: Electrographic seizures are common among neonates with HIE undergoing hypothermia and are difficult to predict based on clinical features. These results justify the recommendation for cEEG monitoring in neonates treated with hypothermia.

New-onset afebrile seizures in infants Role of neuroimaging

Objective: To investigate the presenting characteristics of new-onset afebrile seizures in infants (age 1–24 months) and the yield of neuroimaging. Methods: Prospective data were obtained from a standardized evaluation and management plan mandated by a critical care pathway. A total of 317 infants presented with new-onset afebrile seizures between 2001 and 2007. EEG was performed on 90.3%, head CT was obtained on 94%, and MRI was obtained on 57.4%. Results: We found half of the infants had partial features to their seizures, yet evidence for primary generalized seizures was rare. The majority had more than 1 seizure upon presentation. Seizures in this age group tended to be brief, with 44% lasting less than 1 minute. EEG abnormalities were found in half. One-third of CTs were abnormal, with 9% of all CTs requiring acute medical management. Over half of MRIs were abnormal, with cerebral dysgenesis being the most common abnormality (p < 0.05). One-third of normal CTs had a subsequent abnormal MRI—only 1 resulted in altered medical management. Conclusions: Infantile seizures are usually brief, but commonly recurrent, and strong consideration should be made for inpatient observation. Acute imaging with CT can alter management in a small but important number of infants. Due to the superior yield, strong consideration for MRI should be given for all infants, as primary generalized seizures are rare, and there is a high rate of cerebral dysgenesis.

Is cerebral palsy preventable

Purpose of reviewTo use evidence of good medical quality to update information on strategies for prevention of cerebral palsy, and on the success of these preventive efforts to date. Recent findingsCauses of cerebral palsy, and therefore promising approaches to prevention, differ by gestational age group and by clinical subtype. Neuroimaging and neuropathology indicate the importance of white matter disorders and of ischemic stroke in cerebral palsy; birth asphyxia, congenital malformations, placental pathology, and genetic variants also contribute to cerebral palsy risk. Multiplicity of risk factors markedly increases risk. Recent studies indicate that mild hypothermia lessens cerebral palsy risk in term infants with moderate neonatal encephalopathy, and the possibility that administration of magnesium sulphate to women in preterm labor may aid in primary prevention of cerebral palsy in very preterm infants. SummaryPast efforts to prevent cerebral palsy have not had the benefits sought, but recent results provide new hope and new challenges.