Cristina Uria-Avellanal

Outcome following neonatal seizures

Neonatal seizures are the most common manifestation of neurological disorders in the newborn period and an important determinant of outcome. Overall, for babies born at full term, mortality following seizures has improved in the last decade, typical current mortality rates being 10% (range: 7-16%), down from 33% in reports from the 1990s. By contrast, the prevalence of adverse neurodevelopmental sequelae remains relatively stable, typically 46% (range: 27-55%). The strongest predictors of outcome are the underlying cause, together with the background electroencephalographic activity. In preterm babies, for whom the outlook tends to be worse as background mortality and disability are high, seizures are frequently associated with serious underlying brain injury and therefore subsequent impairments. When attempting to define the prognosis for a baby with neonatal seizures, we propose a pathway involving history, examination, and careful consideration of all available results (ideally including brain magnetic resonance imaging) and the response to treatment before synthesizing the best estimate of risk to be conveyed to the family.

Relationship Between Cerebral Oxygenation and Metabolism During Rewarming in Newborn Infants After Therapeutic Hypothermia Following Hypoxic-Ischemic Brain Injury

Therapeutic hypothermia (TH) has become a standard of care following hypoxic ischemic encephalopathy (HIE). After TH, body temperature is brought back to 37 °C over 14 h. Lactate/N-acetylasperatate (Lac/NAA) peak area ratio on proton magnetic resonance spectroscopy (1H MRS) is the best available outcome biomarker following HIE. We hypothesized that broadband near infrared spectroscopy (NIRS) measured changes in the oxidation state of cytochrome-c-oxidase concentration (Δ[oxCCO]) and cerebral hemodynamics during rewarming would relate to Lac/NAA. Broadband NIRS and systemic data were collected during rewarming from 14 infants following HIE over a mean period of 12.5 h. 1H MRS was performed on day 5–9. Heart rate increased by 20/min during rewarming while blood pressure and peripheral oxygen saturation (SpO2) remained stable. The relationship between mitochondrial metabolism and oxygenation (measured as Δ[oxCCO] and Δ[HbD], respectively) was calculated by linear regression analysis. This was reviewed in three groups: Lac/NAA values <0.5, 0.5–1, >1. Mean regression coefficient (r 2) values in these groups were 0.41 (±0.27), 0.22 (±0.21) and 0.01, respectively. The relationship between mitochondrial metabolism and oxygenation became impaired with rising Lac/NAA. Cardiovascular parameters remained stable during rewarming.

Changes in Cerebral Oxidative Metabolism during Neonatal Seizures Following Hypoxic–Ischemic Brain Injury

Seizures are common following hypoxic–ischemic brain injury in newborn infants. Prolonged or recurrent seizures have been shown to exacerbate neuronal damage in the developing brain; however, the precise mechanism is not fully understood. Cytochrome-c-oxidase is responsible for more than 90% of ATP production inside mitochondria. Using a novel broadband near-infrared spectroscopy system, we measured the concentration changes in the oxidation state of cerebral cytochrome-c-oxidase (Δ[oxCCO]) and hemodynamics during recurrent neonatal seizures following hypoxic–ischemic encephalopathy in a newborn infant. A rapid increase in Δ[oxCCO] was noted at the onset of seizures along with a rise in the baseline of amplitude-integrated electroencephalogram. Cerebral oxygenation and cerebral blood volume fell just prior to the seizure onset but recovered rapidly during seizures. Δ[oxCCO] during seizures correlated with changes in mean electroencephalogram voltage indicating an increase in neuronal activation and energy demand. The progressive decline in the Δ[oxCCO] baseline during seizures suggests a progressive decrease of mitochondrial oxidative metabolism.

Pressure passivity of cerebral mitochondrial metabolism is associated with poor outcome following perinatal hypoxic ischemic brain injury

Hypoxic ischemic encephalopathy (HIE) leads to significant morbidity and mortality. Impaired autoregulation after hypoxia-ischaemia has been suggested to contribute further to injury. Thalamic lactate/N-Acetylasperate (Lac/NAA) peak area ratio of > 0.3 on proton (1H) magnetic resonance spectroscopy (MRS) is associated with poor neurodevelopment outcome following HIE. Cytochrome-c-oxidase (CCO) plays a central role in mitochondrial oxidative metabolism and ATP synthesis. Using a novel broadband NIRS system, we investigated the impact of pressure passivity of cerebral metabolism (CCO), oxygenation (haemoglobin difference (HbD)) and cerebral blood volume (total haemoglobin (HbT)) in 23 term infants following HIE during therapeutic hypothermia (HT). Sixty-minute epochs of data from each infant were studied using wavelet analysis at a mean age of 48 h. Wavelet semblance (a measure of phase difference) was calculated to compare reactivity between mean arterial blood pressure (MABP) with oxCCO, HbD and HbT. OxCCO-MABP semblance correlated with thalamic Lac/NAA (r = 0.48, p = 0.02). OxCCO-MABP semblance also differed between groups of infants with mild to moderate and severe injury measured using brain MRI score (p = 0.04), thalamic Lac/NAA (p = 0.04) and neurodevelopmental outcome at one year (p = 0.04). Pressure passive changes in cerebral metabolism were associated with injury severity indicated by thalamic Lac/NAA, MRI scores and neurodevelopmental assessment at one year of age.

PC.30 3T proton magnetic resonance spectroscopy in neonatal encephalopathy: lactate/n-acetylaspartate prognosis

Introduction Lactate (Lac) / N-acetyl-aspartate (Naa) peak area ratio measured at long echo time on proton magnetic resonance spectroscopy (1H MRS) in the thalamus is a robust biomarker of outcome between day 5–14 in babies presenting with neonatal encephalopathy (NE).1 Previous studies have been done at 2.35 and 1.5 Tesla; a specific median Lac/Naa threshold of 0.29 differentiated those infants with subsequent good and adverse outcome at 2 years. The optimum threshold may differ at higher field strengths (eg 3 Tesla) as the T2 values of Lac and Naa will be different to those at lower field. Aim To determine whether the threshold for assigning prognosis is altered at 3 Tesla. Patients and methods 42 infants with NE were scanned using 1H MRS (PRESS: TR = 2298 ms, TE = 288 ms, 1.5cm3 voxel in thalamus) at 3 Tesla. Of these, 26 (gestational age: 39.6 +/- 0.3 weeks, birth weight: 3155 ± 425 grams, postnatal age at scan 5.6 +/- 1.7 days; mean +/- SD) had 12 month clinical follow up using Bayley III scales. 20 infants had good outcomes (normal or mild impairment) and 6 had adverse outcomes (death or severe disability). Results Figure 1 shows the ROC curve for Lac/Naa. Using a 0.29 threshold yielded a true positive rate of 100% for adverse outcomes with 2 false positive results. (PPV: 0.75; NPV: 1.00) Abstract PC.30 Figure 1 ROC curve for Lac/Naa at 3T Conclusion A thalamic 1H MRS Lac/Naa peak area ratio threshold of 0.29 differentiates babies with subsequent normal and adverse outcomes at 3T. Reference Thayyil S, Chandrasekaran M, Taylor AM, Bainbridge A, Cady EB, Chong WK, Murad S, Omar RZ, Robertson NJ. In-vivo cerebral magnetic resonance biomarkers for predicting long-term neurodevelopmental outcome following neonatal encephalopathy: A meta-analysis. Pediatrics. 2010;125(2):e382–e395

Proton magnetic resonance spectroscopy lactate/N-acetylaspartate within 2 weeks of birth accurately predicts 2-year motor, cognitive and language outcomes in neonatal encephalopathy after therapeutic hypothermia

Objective Brain proton (1H) magnetic resonance spectroscopy (MRS) lactate/N-acetylaspartate (Lac/NAA) peak area ratio is used for prognostication in neonatal encephalopathy (NE). At 3 Tesla in NE babies, the objectives were to assess: (1) sensitivity and specificity of basal ganglia and thalamus (BGT) 1H MRS Lac/NAA for the prediction of Bayley III outcomes at 2 years using optimised metabolite fitting (Tarquin) with threonine and total NAA; (2) prediction of motor outcome with diffusion-weighted MRI; (3) BGT Lac/NAA correlation with the National Institute of Child Health and Human Development (NICHD) MRI score. Subjects and methods 55 (16 inborn, 39 outborn) infants at 39w+5 d (35w+5d–42w+0d) with NE admitted between February 2012 and August 2014 to University College London Hospitals for therapeutic hypothermia underwent MRI and 1H MRS at 3T on day 2–14 (median day 5). MRIs were scored. Bayley III was assessed at 24 (22–26) months. Results 16 babies died (1 inborn, 15 outborn); 20, 19 and 21 babies had poor motor, cognitive and language outcomes. Using a threshold of 0.39, sensitivity and specificity of BGT Lac/NAA for 2-year motor outcome was 100% and 97%, cognition 90% and 97% and language 81% and 97%, respectively. Sensitivity and specificity for motor outcome of mean diffusivity (threshold 0.001 mm2/s) up to day 9 was 72% and 100% and fractional anisotropy (threshold 0.198) was 39% and 94%, respectively. Lac/NAA correlated with BGT injury on NICHD scores (2A, 2B, 3). Conclusion BGT Lac/NAA on 1H MRS at 3T within 14 days accurately predicts 2-year motor, cognitive and language outcome and may be a marker directing decisions for therapies after cooling.