Serum Biomarkers of MRI Brain Injury in Neonatal Hypoxic Ischemic Encephalopathy Treated With Whole-Body Hypothermia

Abstract

Objectives To determine if candidate biomarkers, ubiquitin carboxyl-terminal esterase L1 and glial fibrillary acidic protein, are elevated in neonates with hypoxic ischemic encephalopathy who die or have severe MRI injury compared with surviving infants with minimal or no injury on brain MRI. Design Prospective observational study. Setting Level IIIC outborn neonatal ICU in a free-standing children's hospital. Patients Term newborns with moderate-to-severe hypoxic ischemic encephalopathy referred for therapeutic hypothermia Interventions Serum specimens were collected at 0, 12, 24, and 72 hours of cooling. MRI was performed in surviving infants at target 7–10 days of life and was scored by a pediatric neuroradiologist masked to biomarker and clinical data. Measurements and Main Results Serial biomarker levels were determined in 20 hypoxic ischemic encephalopathy patients. Ubiquitin carboxyl-terminal esterase L1 was higher at initiation and 72 hours of cooling, while glial fibrillary acidic protein was higher at 24 and 72 hours in babies with adverse outcome compared with those with favorable outcome. Conclusions This preliminary data support further studies to evaluate ubiquitin carboxyl-terminal esterase L1 and glial fibrillary acidic protein as immediate biomarkers of cerebral injury severity in newborns with hypoxic ischemic encephalopathy.

Early predictors of outcome in infants treated with hypothermia for hypoxic–ischaemic encephalopathy

“…In the Chalak et al 50 study of infants treated with hypothermia, GFAP values of more than 0.08pg/ml correctly identified all infants with abnormal outcomes at 20 months. Similarly, Massaro et al 46 found higher UCHL1 levels initially and following 72 hours of cooling, and higher GFAP levels at 24 and 72 hours of age, in infants with adverse outcomes than in those with favourable outcomes.…”

“…46 Early measurements of NSE and S100b may be important biomarkers of brain injury following HIE, but information on long-term outcomes is lacking.…”

Blood biomarkers for evaluation of perinatal encephalopathy: state of the art

“…Serum UCHL1 levels were higher in patients with diffuse injury, in contrast to GFAP levels which were higher in patients with focal mass lesions (Mondello et al, 2011). High levels of UCHL1 have been found in the umbilical cord blood of neonates with HIE associated cortical injury and subsequent movement and cognitive disorders (Massaro et al, 2013;Douglas-Escobar et al, 2014).…”

“…GFAP may also be important in the differential diagnosis of various types of stroke, which is clinically relevant as immediate treatment of stroke depends on whether the stroke is ischemic or hemorrhagic (Guingab-Cagmat et al, 2013). In neonates, serum GFAP levels have been shown to be significantly elevated at the time of birth and during the first week of life in term and near-term infants with HIE that have abnormal brain MRI scans at 1 week of life (Ennen et al, 2011;Massaro et al, 2013;Chalak et al, 2014) and in premature neonates that develop periventricular white matter injury (Stewart et al, 2013). In addition, GFAP may provide insights into the pathobiology of therapeutic hypothermia as significant elevations in GFAP occur after rewarming from therapeutic cooling for HIE in the neonates that later have an abnormal MRI, suggesting that the neonates with severe injury manifest reperfusion injury post-therapuetic cooling (Schiff et al, 2012).…”

Biomarkers of Multiorgan Injury in Neonatal Encephalopathy

“…Early GFAP was higher in very low birth weight infants who were later diagnosed with periventricular white matter injury [19] and was also a marker of pediatric traumatic brain injury [20]. GFAP was higher in infants with HIE who received therapeutic hypothermia and poorer outcome [21]. Ennes et al showed that GFAP is increased in neonates with HIE undergoing therapeutic hypothermia compared with controls and a further GFAP elevation was found in NE neonates with abnormal neuroimaging [22].…”