Encephalopathy of Prematurity: Pathophysiology

Periventricular Vascular Anatomical and Physiological Factors

The development of the vasculature that supplies the preterm human cerebral white matter is significant for arterial end and border zones. Initial studies focused on the hypothesis that more severe focal necrotic white matter lesions coincide with regions of greater ischemia generated within these arterial end zones . (The earlier concept that the deep periventricular region also contained arterial border zones involving so-called ventriculofugal arteries is not supported by later studies as reviewed by Gilles and co-workers. ) The periventricular arterial end zones originate from vessels penetrating the cerebral wall from the pial surface. These long penetrating arteries are derived from the middle cerebral artery, and, to a lesser extent, the anterior or posterior cerebral artery, and they terminate in the deep periventricular white matter ( Fig. 19.3 ). The end zones that result are essentially distal fields in the periventricular white matter that are hypothesized to be more susceptible to a fall in perfusion pressure and CBF.

The penetrating cerebral arteries can be further divided into the long penetrators that terminate deep in periventricular white matter and the short penetrators that extend only into subcortical white matter (see Fig. 19.3 ). At 24 to 28 weeks of gestation, the long penetrators have relatively few side branches and infrequent intraparenchymal anastomoses with each other and with the short penetrators, which also are relatively sparse. Thus end zones and border zones may exist at this time in the cerebral white matter relatively distant from the periventricular region. From 32 weeks to term, maturation of the short penetrators and the anastomoses between the long and short penetrators occurs and may promote CBF to be more similar to the term infant.

The susceptibility to hypoperfusion may also be influenced by the rate at which the vascular supply matures in the white matter. The last 16 weeks of human gestation is a period of active maturation of the periventricular vasculature. Indeed, this development could be used as an index of cerebrovascular maturity. Detailed analysis of the development of the vascular supply to the periventricular preterm white matter defined an avascular area at the common site of WMI. This avascular area may represent an area of vascular immaturity or an area of particular predilection to significant vascular necrosis that occurred in association with more severe WMI ( Fig. 19.4 ).

Consistent with the immaturity of the vascular supply of the preterm brain are human and experimental studies that have demonstrated the significantly lower basal blood flow to preterm cerebral white matter . Low basal white matter flow was suggested initially by xenon clearance studies that documented mean global CBF values in ventilated human premature infants of only ~10 to 12 mL/100 g/min. Subsequent xenon studies confirmed these very low mean global values (see Chapter 13 ). Importantly, studies of regional CBF by positron emission tomography confirmed the low global values and further documented that surviving preterm infants with normal or nearly normal neurological outcome had basal flow that ranged from only 1.6 to 3.0 mL/100 g per minute. These very low values in white matter were approximately 25% of those in cortical gray matter, a regional difference confirmed in a study using single photon emission tomography. These basal flow values of less than 5.0 mL/100 g per minute are markedly less than the threshold value for viability in adult human brain of 10 mL/100 g per minute ( normal CBF in the adult is ≈50 mL/100 g per minute). The very low values of volemic flow in cerebral white matter in the human premature infant suggest a minimal margin of safety for blood flow to cerebral white matter in such infants and suggests that the susceptibility of the preterm infant to WMI is related to a heightened propensity for ischemia .

Cerebral Ischemia, Impaired Cerebrovascular Autoregulation, and Pressure-Passive Cerebral Circulation

An apparent impairment of cerebrovascular regulation in sick premature infants may render cerebral white matter more vulnerable to injury from ischemia (see Box 19.1 ). Clinically stable premature infants seem less likely to exhibit this apparent lack of cerebrovascular autoregulation. Early radioactive xenon clearance studies showed that certain premature infants, mechanically ventilated and often clinically unstable, appeared to exhibit pressure-passive cerebral circulation ( Fig. 19.5 ). This fundamental observation has been confirmed by less invasive methods multiple times. Thus, in such sick premature infants with a pressure-passive cerebral circulation, it would be expected that when blood pressure falls, as occurs commonly in such infants, so would CBF, with consequent cerebral ischemia. With intact cerebrovascular autoregulation, CBF is not pressure passive but rather remains constant over a wide range of blood pressure because of arteriolar dilation with decreases in blood pressure and arteriolar constriction with increases in blood pressure (see the curve for the mature child in Fig. 19.6 ). The propensity to a pressure-passive abnormality in premature infants may relate in part to an absent muscularis around penetrating cerebral arteries and arterioles in the third trimester in the human brain. The maturation of neurovascular coupling involves the integration of multiple factors that locally regulate smooth muscle cell contractility, such as neuronal glutamatergic signaling and neuronal and glial release of vasoactive agents.

The proportion of infants with a pressure-passive cerebral circulation and the duration of the abnormality appear to be substantial (see Chapter 13 ). In a serial study of 32 mechanically ventilated premature infants from the first hours of life, near-infrared spectroscopy (NIRS) was used to demonstrate a pressure-passive cerebral circulation in 53% (see Chapter 16 ). The nadirs of blood pressure often are not markedly low and thus could be readily overlooked with routine monitoring. Importantly, nearly all the cases of WMI (and severe intraventricular hemorrhage [IVH]) were in the pressure-passive group.

In a later, more detailed study of a larger number of infants ( N = 90), pressure-passive periods were identified in 95% of the infants, and the overall mean proportion of the pressure-passive time was 20%. Some infants had a pressure-passive circulation more than 50% of the time. The likelihood of a pressure-passive state increased with decreasing gestational age and periods of hypotension. Several recent studies showed that premature infants who developed an IVH also displayed impaired cerebral autoregulation, which was accompanied by reduced cerebral oxygenation and impaired cerebrovascular reactivity to hypoxemia.

Although the numbers were small, these studies suggest that (1) infants with impaired cerebrovascular autoregulation and a pressure-passive cerebral circulation could be identified by NIRS before the occurrence of WMI, (2) the circulatory abnormality was related to the occurrence of such injury, and (3) if the pressure-passive state could be corrected, the WMI could be prevented. A limitation of these studies is a lack of regional estimates of white matter flow. NIRS is limited to measurements of CBF at the cortical surface that may not reflect white matter flow during a suspected ischemic event. It would be particularly informative to measure temporal changes in white matter flow under basal conditions, as well as during ischemia and reperfusion, as is feasible experimentally (see later). Although at early stages of investigation, it may be feasible in the future to predict infants at risk for pressure passivity by employing specific clinical parameters (e.g., heart rate or blood pressure) or mathematical models to estimate CBF.

Factors That Predispose to a Pressure-Passive Circulation

A number of metabolic abnormalities that influence vascular reactivity are likely to promote the pressure-passive state (see Chapter 16 ). Both hypocarbia (P co ₂ < 30 mm Hg) and hypercarbia (P co ₂ > 55 mm Hg) can significantly perturb CBF. Hypocarbia may promote hypotension and an increased risk for IVH and WMI through disturbances in CBF. A pronounced reduction in more severe cystic WMI appeared to be related to a decrease in days of mechanical ventilation, possibly related to reduced hypocarbic alkalosis, which can promote hypotension. Early studies identified that hypocarbia is a potential risk factor for more severe WMI. Analysis of the cumulative exposure to hypocarbia demonstrated an increased risk for more severe WMI that was confirmed in a large study of nearly 800 infants studied in the first 7 days of life and found to exhibit a strong association with WMI identified as echolucencies on cranial ultrasonography ( Fig. 19.7 ). Infants with the highest quartile of cumulative exposure to hypocarbia had a more than fivefold increased risk of WMI compared with infants in the lowest quartile. The contribution of hypercarbia to WMI is less well defined. Although trials of permissive hypercapnia found no evidence of cystic WMI by cranial ultrasound evaluation, abnormal white matter microstructure was identified when extremely low birth weight (ELBW) infants were evaluated at term by diffusion tensor magnetic resonance imaging (MRI).

A role for hypoxemia in disrupting maturation of cerebral autoregulation is supported by observations that hypoxia can disrupt vascular smooth muscle maturation and contractility. The capacity for cerebral oxygen extraction also appears to be developmentally regulated and diminished in less mature preterm infants (23 to 25 weeks) relative to older infants (26 to 28 weeks). Hypoxemia appears to be less deleterious than hypoxia-ischemia to directly promote WMI, whereas isolated mild hypoxemia is sufficient to promote gray matter neuronal dysmaturation independently of ischemia (see later). Transient hypoxemia caused inconsistent WMI in the midgestation of near-term sheep, whereas WMI was more severe when significant hypotension caused apparent ischemia.

Additional potential reasons for a pressure-passive cerebral circulation include the mechanical trauma of labor or vaginal delivery to the easily deformed cranium of the premature infant. A combination of these factors or other factors (e.g., cytokine-mediated vascular effects) could be operative. Finally, even in the presence of intact cerebrovascular autoregulation , marked cerebral vasoconstriction or severe systemic hypotension could lead to sufficiently impaired CBF to vascular end zones and border zones to result in cerebral WMI. This explanation may account for the demonstrated relationships between marked hypocarbia or hypotension and WMI.

Factors That Influence the Timing and Distribution of White Matter Injury

A complex interplay of factors appears to define the enhanced propensity of the preterm human white matter to injury. As discussed earlier, these include an immature vascular supply and disturbances in cerebrovascular autoregulation that can particularly render CBF pressure passive in the setting of critical illness. Central unresolved questions are the factors that define the distribution of WMI and the developmental window of heightened vulnerability. Moreover, is a greater magnitude of ischemia necessary and sufficient to render certain regions more susceptible to more severe necrotic WMI? Often, but not exclusively, the focal necrotic lesions that affect all cellular elements localize to deep cerebral white matter in a periventricular distribution. These lesions frequently coincide with more superficial diffuse cerebral WMI that principally targets oligodendroglial precursor cells (pre-OLs). Is selective pre-OL death and the relative sparing of other cellular elements perhaps related to less severe ischemia sustained by diffuse WMI?

Multiple studies in preterm fetal sheep have confirmed that, as observed in humans, the cerebral white matter has an intrinsically lower basal CBF than other gray matter regions and also displays a pressure passive circulation relative to term and adult animals. Back and coworkers achieved spatially resolved quantitative measurements of fetal CBF in utero that were coregistered with histologically defined analyses of WMI. Flow in periventricular white matter was 60% to 70% lower than that observed in cerebral cortex. However, under conditions of moderately severe global cerebral ischemia, the nadir of ischemic CBF was similar in multiple cerebral gray matter regions relative to the white matter. After 30 minutes of ischemia, both cortical and white matter flows decreased proportionally to about 10% to 15% of basal flows. Later studies confirmed these observations and found that there were no pathologically significant measurable gradients of flow between fetal cerebral cortex and deep cerebral white matter during either ischemia or reperfusion. Moreover, histologically confirmed WMI did not localize to regions susceptible to greater ischemia, nor did less vulnerable regions of white matter have greater blood flow during ischemia. These findings supported that ischemia is necessary but not sufficient to generate WMI ( Box 19.2 ). Even under conditions of moderately severe uniform ischemia, some regions of white matter were relatively spared, whereas other neighboring regions sustained significantly more cell death.

This paradox was addressed in preterm fetal sheep, where in regions that sustained similar ischemic CBF, the distribution of WMI was explained by the distribution of one particular cell type, the pre-OL (see Chapter 16, Chapter 18 ). In developing white matter, human pre-OLs are markedly more susceptible to hypoxia-ischemia and oxidative stress than other neural cell types. In regions that contained more differentiated oligodendrocytes, the susceptibility to WMI was significantly reduced. The timing of appearance of pre-OLs during white matter development also significantly influences the magnitude and distribution of WMI. Preterm fetal rabbits display a window in preterm white matter development (embryonic day 25) when the white matter is mostly populated by early oligodendrocyte progenitors that are less mature than pre-OLs. These early progenitors give rise to pre-OLs and are much more resistant to hypoxia-ischemia than are the pre-OLs. Importantly, these early progenitors rapidly respond to injury by mounting a robust proliferative response that initiates repair of WMI by regenerating pre-OLs (see later). Consistent with these observations, the rabbit E22 white matter was highly resistant to pronounced cerebral ischemia in contrast to the E25 white matter when pre-OLs are diffusely present. Hence, both the timing of appearance and the distribution of pre-OLs define the location of susceptible regions of white matter under conditions of moderately severe ischemia .

It is also clinically important to identify the factors that define the pathogenesis of more severe WMI. The duration of cerebral ischemia is a critical factor that defines the burden of white matter necrosis. In preterm fetal sheep, graded WMI is generated that is related to the duration of ischemia. As discussed earlier, it is also likely that the magnitude of a number of systemic factors (e.g., hypotension) and metabolic factors (e.g., hypoxemia, hypocapnia, hypoglycemia, lactic acidosis) interact to determine the severity of ischemic WMI. Given how low basal CBF is in human preterm white matter, regional blood flow and metabolism may be equivalently low and matched for metabolic requirements. Ischemia may be relatively well tolerated unless there is pronounced energy failure that shifts the balance toward focal or more diffuse necrotic cell death. Hence, ischemia appears to be necessary but not sufficient to cause WMI, and cellular maturational and metabolic factors likely influence the severity of the WMI response .

It is also currently unclear if recurrent hypoxia-ischemia predisposes to more severe WMI. In preterm-equivalent neonatal rats, a pronounced increase in cell death was observed in chronic WMI after recurrent hypoxia-ischemia. However, in preterm fetal sheep that develop WMI that more closely resembles human recurrent hypoxia-ischemia did not trigger more pronounced WMI. Perhaps recurrent hypoxia-ischemia may confer protection against more severe WMI through an ischemic tolerance-like mechanism. This is an important direction for future study.