Hemodynamic and Metabolic Correlates of Perinatal White Matter Injury Severity

Abstract

Background and PurposeAlthough the spectrum of perinatal white matter injury (WMI) in preterm infants is shifting from cystic encephalomalacia to milder forms of WMI, the factors that contribute to this changing spectrum are unclear. We hypothesized that the variability in WMI quantified by immunohistochemical markers of inflammation could be correlated with the severity of impaired blood oxygen, glucose and lactate.MethodsWe employed a preterm fetal sheep model of in utero moderate hypoxemia and global severe but not complete cerebral ischemia that reproduces the spectrum of human WMI. Since there is small but measurable residual brain blood flow during occlusion, we sought to determine if the metabolic state of the residual arterial blood was associated with severity of WMI. Near the conclusion of hypoxia-ischemia, we recorded cephalic arterial blood pressure, blood oxygen, glucose and lactate levels. To define the spectrum of WMI, an ordinal WMI rating scale was compared against an unbiased quantitative image analysis protocol that provided continuous histo-pathological outcome measures for astrogliosis and microgliosis derived from the entire white matter. ResultsA spectrum of WMI was observed that ranged from diffuse non-necrotic lesions to more severe injury that comprised discrete foci of microscopic or macroscopic necrosis. Residual arterial pressure, oxygen content and blood glucose displayed a significant inverse association with WMI and lactate concentrations were directly related. Elevated glucose levels were the most significantly associated with less severe WMI.ConclusionsOur results suggest that under conditions of hypoxemia and severe cephalic hypotension, WMI severity measured using unbiased immunohistochemical measurements correlated with several physiologic parameters, including glucose, which may be a useful marker of fetal response to hypoxia or provide protection against energy failure and more severe WMI.

White matter injury in the preterm infant: pathology and mechanisms

“…Ischemia thus appeared to be necessary but not sufficient to generate necrotic or diffuse WMI. In preterm fetal sheep, the severity of WMI was significantly associated with the magnitude of hypotension, hypoxemia and hypoglycemia [152]. Collectively, these findings suggest that the propensity for more severe WMI is related to a combination of vascular anatomic immaturity, disturbances in cerebrovascular autoregulation and a variety of metabolic factors that may predispose to more severe energy failure in regions of focal white matter necrosis.…”

Empirical estimation of the normative blood pressure in infants <28 weeks gestation using a massive data approach

“…Determining the target blood pressure range in very preterm infants (<28 weeks gestation) has been the subject of debate for several decades. Hypotension has been previously linked to the development of intraventricular hemorrhage ( 1 , 2 ) and white matter injury ( 3 ). Description of a normative set of blood pressure values in very preterm infants is confounded by varied methodology, heterogeneous patient populations used in prior studies, substantial changes in strategies for hemodynamic support and monitoring methodology, and survival rates among preterm infants since Versmold et al published the first normative data set in 1981.…”

Unbiased Stereological Analysis of Reactive Astrogliosis to Estimate Age-Associated Cerebral White Matter Injury

“…By contrast, although conventional neuropathological review of paraffin-embedded tissue sections is widely employed by neuropathologists for diagnostic purposes, this approach lacked the sensitivity to distinguish control from VBI cases. In experimental models of preterm WMI, we found that pathology scores have markedly reduced sensitivity when WMI is in the mild to moderate severity range and more closely resemble controls (24). The fact that we detected group differences using optical fractionator, spaceballs, and process thickness measurements (but not with other methodologies) supports the utility of high-magnification and 3-dimensional stereological approaches to quantify the burden of astrogliosis across an unidentified cohort of cases with variable agerelated vascular injury and low AD burden.…”

“…We employed an ordinal rating scale to estimate the burden of reactive astrogliosis in the white matter using a protocol modified from Riddle et al, wherein astrogliosis was scored by a blinded neuropathologist (CDK) as follows: 0 (none); 1 (focal, < 25% of tissue involved); 2 (patchy, 25%-75% of tissue involved); and 3 (diffuse !75% of tissue involved) ( Fig. 2D) (24).…”

“…To define the spectrum of WMI in VBI versus No VBI cases, we adapted an ordinal rating scale to estimate the burden of astrogliosis based upon neuropathological review of GFAP-immunostained, paraffin-embedded tissue sections (24). Using this scale, we observed a broad spectrum of astro-cyte reactivity across the cohort of No VBI cases.…”