A systematic review of noninflammatory cerebrospinal fluid biomarkers for clinical outcome in neonates with perinatal hypoxic brain injury that could be biologically significant

Abstract

Neonatal encephalopathy (NE) that purportedly arises from hypoxia-ischemia is labeled hypoxic-ischemic encephalopathy (HIE). Perinatal asphyxia is a clinical syndrome involving acidosis, a low Apgar score and the need for resuscitation in the delivery room; asphyxia alerts one to the possibility of NE. In the present systematic review, we focused on the noninflammatory biomarkers in cerebrospinal fluid (CSF) that are involved in the development of possible brain injury in asphyxia or HIE. A literature search in PubMed and EMBASE for case-control studies was conducted and 17 studies were found suitable by a priori criteria. Statistical analysis used the Mantel-Haenszel model for dichotomous data. The pooled mean difference and 95% confidence intervals (CIs) were determined. We identified the best biomarkers, based on the estimation approach in evaluating the biological significance, out of hundreds in three categories: cell adhesion and proliferation, oxidants and antioxidants, and cell damage. The following subtotal-population comparisons were made: perinatal asphyxia versus no asphyxia, asphyxia with HIE versus asphyxia without HIE, asphyxia with HIE versus no asphyxia, and term versus preterm HIE newborn with asphyxia. Biological significance of the biomarkers was determined by using a modification of the estimation approach, by ranking the biomarkers according to the difference in the bounds of the CIs. The most promising CSF biomarkers for prognostication especially for the severest HIE include creatine kinase, xanthine oxidase, vascular endothelial growth factor, neuron-specific enolase, superoxide dismutase, and malondialdehyde. Future studies are recommended using such a combined test to prognosticate the most severely affected patients.

Keywords: asphyxia; biomarker; cerebrospinal fluid; hypoxic-ischemic encephalopathy; perinatal.

FIGURE 1

Example of a strong and a doubtful biomarker. (a) The control group (No asphyxia) was compared to a target group (Asphyxia). Data from XO (Batra et al., 1998). Mean ($\overline{X}$) and lower and upper confidence intervals are shown (LCI, UCI). The difference (Δ) between the target LCI and control UCI is calculated and then divided by the control mean and expressed as a percentage(Δ% $\overline{X}$). (b) If the CIs overlapped as shown in the dashed line, then the biomarker was considered as doubtful, as meant for a clinician. Data from NGF (Korhonen et al., 1998). Also, note if the biomarker showed a decrease in the target group, the Δ between the control LCI and target UCI was taken. This Δ was expressed as percentage of the target mean (Δ% $\overline{X}$)

FIGURE 2

Flow chart of analysis process

FIGURE 3

(a) Neuron-specific enolase (NSE) has a moderate score for the subtotal population of hypoxic-ischemic encephalopathy (HIE) with neurobehavioral deficits compared to all others with abnormal Sarnat score after birth, who recovered (brown, score 32) (Hussein et al., 2010). Mean ($\overline{X}$) and LCI, UCI shown. Score is Δ (dashed lines) between the target LCI and control UCI, divided by the control mean, and expressed as a percentage. (b) NSE shows a progression from mild to moderate to severe HIE based on presentation of clinical signs initially (Vasiljevic et al., 2011). Severe HIE had stupor or coma with decerebrate posture, or absent activity, hypotonia, absent reflexes, seizures, nonreactive pupils, abnormal cranial nerve function, and severely abnormal aEEG patterns, NSE score was 144. (c) Creatine kinase (CK) is a strong biomarker (Ray et al., 1998) for death with HIE compared to HIE that recovers with a score of 450 (green) but not for HIE that survives. CK is also a strong biomarker HIE that results in mortality compared to all other perinatal asphyxia, recovered or sick (brown, score 432). (d) Vascular endothelial growth factor (VEGF) score for severe HIE (Vasiljevic et al., 2011) was 205 compared to mild HIE

FIGURE 4

(a) Xanthine oxidase showing a dose response relationship in perinatal asphyxia with increasing values from recovered, to sick (any hypoxic-ischemic encephalopathy [HIE], moderate acidosis, convulsion or bronchopneumonia) to dead (Batra et al., 1998). In brown is any live newborn. XO is a strong biomarker for HIE and death, even when compared with asphyxia which recovered or to any live newborn _‼ (scores 123 and 144, respectively). Mean (X) and LCI, UCI shown. Score is Δ (dashed lines) between the target LCI and control UCI, divided by the control mean, and expressed as a percentage. (b) Malondialdehyde (MDA) in patients with Apgar <3 at 1 min, the subtotal population showing clinical signs of severe HIE by Fenichel classification, namely either stupor, coma, irregular/periodic respirations or ventilated, apnea, convulsions, hypotonia, oculomotor palsies showed a moderate score of 32 compared to a population without any signs of HIE (Kumar et al., 2008)

FIGURE 5

Preterm HIE has much higher creatine kinase brain isoenzyme (CK-BB) than term HIE (Talvik et al., 1995). CK-BB is a weak biomarker for the severity of neurological deficits at 12 months of age if done at 2 days (score 44) but a strong biomarker if done at 5 days of life (score 732)