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Management of Encephalopathy of Prematurity
KEY POINTS
- 1.
Encephalopathy of prematurity reflects white and gray matter injury combined with neuronal-axonal abnormalities impacting preterm infants.
- 2.
Key risk factors include hypotension and the need for inotropes, hypoxia, and inflammation.
- 3.
Evaluation of high-risk infants in the neonatal intensive care unit (NICU) includes use of neuroimaging and neurobehavioral assessments such as the General Movements Assessment.
- 4.
Management starts prior to birth and continues throughout the NICU stay and is geared toward prevention and treatment of risk factors.
- 5.
After NICU discharge, management is geared toward use of developmental surveillance, parental support, and physical and occupational therapy.
Introduction
Encephalopathy of prematurity is the result of altered brain development and brain injury after preterm birth. The term “encephalopathy of prematurity” describes a phenomenon that results from a variety of different pathophysiologic factors that occur either alone or in combination. These affect the development and maturation of white and gray matter, both of which undergo crucial development during the third trimester. Infants at highest risk are very low birth weight infants (<1500 g) and to a greater extent extremely low birth weight infants (<1000 g). Periventricular leukomalacia (PVL) combined with neuronal-axonal injury is the hallmark of encephalopathy of prematurity. , These findings can be seen either in isolation or in conjunction with other forms of preterm brain injury, such as periventricular-intraventricular hemorrhage, intraparenchymal hemorrhage, or cerebellar injury.
White matter involvement can be focal or diffuse, both involving damage to the preoligodendrocytes and disruption of developmental myelination. Consequences of this white matter injury include motor deficits such as cerebral palsy, affecting about 5% to 10% of very low birth weight infants and much more commonly visual, cognitive, and neurobehavioral abnormalities including autism, which can be seen in up to 25% to 50% of patients. Although white matter injury most commonly affects infants born prior to 32 weeks’ gestation, similar injury patterns have been associated with intrauterine chronic hypoxic states including placental insufficiency and cyanotic heart disease.
As implied by the name, encephalopathy of prematurity affects mainly preterm infants. The overall rate of prematurity, defined as birth before 37 weeks of gestation, is 10.6% worldwide; of those, 15.4% are born before 32 weeks’ gestation. In the United States, the rate of preterm birth decreased from 12.5% in 2004 to a low of 9.57% in 2014 but has since increased to 10.0% in 2018, with a stable rate of birth before 32 weeks of 2.75%.
The incidence of cystic PVL has decreased overtime, but diffuse white matter injury remains prevalent and is now the most common manifestation of encephalopathy of prematurity. The incidence of any degree of white matter injury has been reported in some studies to be as high as 72%. Abnormal neurodevelopmental outcome is strongly correlated to the degree of white matter injury, in particular moderate to severe white matter injury.
Pathophysiology
White Matter Injury
Periventricular leukomalacia is the hallmark of encephalopathy of prematurity, defined by the pathologic characteristics of focal necrosis in the periventricular area combined with diffuse reactive gliosis and activation of microglia cells in the surrounding white matter. Large areas of necrosis (>1 mm) may evolve over weeks into macroscopic cysts, termed cystic PVL. This occurs in less than 5% of preterm infants in the current era. Diffuse PVL is characterized by small focal necrotic areas measuring ≤1mm, surrounded by reactive astrocytosis and microgliosis. These smaller or microscopic areas of necrosis, caused by injury to immature oligodendrocytes, evolve into glial scars. Punctate white matter lesions and diffuse white matter injury represent the most common imaging manifestations of white matter injury. Both patterns result in damage to the preoligodendrocytes and thus result in impaired maturation of preoligodendrocytes and dysfunctional oligodendrocytes. Oligodendrocytes derive from neuroglial stem cells, which differentiate sequentially into oligodendrocyte precursors and premyelinating oligodendrocytes before becoming mature myelinating oligodendrocytes. As a result, hypomyelination can be observed. Myelin surrounds the axons and facilitates signal transmission and developmental migration. Abnormal myelination can result in axonal damage and modification of the white matter tracts. Oligodendrocytes also play an important role in axonal development, and impaired function of the mature oligodendrocyte has been associated with abnormal axonal development. ,
Neuronal-Axonal Injury
White matter injury has historically been described as an appearance of cysts alongside the ventricles, termed cystic PVL, occurring approximately 10 days to 2 weeks after an insult. These cysts may disappear over the following weeks, replaced with glial tissue, which can be detected on later brain magnetic resonance imaging (MRI) as diffuse white matter lesions, now the most common form of preterm brain injury ( Fig. 48.1 ). Several risk factors have been associated with a higher risk of PVL, including hypoxia-ischemia, prolonged hypercapnia, inflammatory states, and transient impairment of cerebrovascular autoregulation.
A combination of neuronal and axonal injury is commonly found in conjunction with PVL. White matter injury can generate abnormalities in the gray matter as a result of terminal axonal injury. Axonal guidance is required for developing and migrating neurons to reach their target destination. Interruption of such guides results in abnormal migration, most commonly seen as reduction of neurons and pyramidal cells in cortical layer V.
One of the underlying pathophysiologic mechanisms of preterm brain injury is related to impaired cerebrovascular autoregulation and the resulting pressure passive state. Cerebrovascular autoregulation refers to the ability to maintain a stable cerebral blood flow independent of systemic blood pressure. This mechanism, however, is not fully developed in preterm infants and may result in a pressure-passive state where systemic blood flow correlates linearly with cerebral blood flow ( Fig. 48.2 ). This is particularly common in the most critically ill patients. The pressure-passive state can be observed in nearly all preterm neonates for some period of time, and the duration of time spent in a pressure-passive state correlates with an increased risk for brain injury. Near infrared spectroscopy in combination with blood pressure monitoring can be used to evaluate cerebral blood flow and thereby identify the infants at highest risk. Predisposing factors for a pressure passive state include extreme prematurity, hypocarbia (P co 2 <30 mm Hg), and hypercarbia (P co 2 >55 mm Hg). Three injury types have been described in the setting of impaired cerebral autoregulation: focal cystic necrosis, incidence ≤5%; focal microscopic necrosis, incidence 15% to 20%; and diffuse nonnecrotic injury, incidence ≥50%.
Gray Matter Injury
The gray matter component of encephalopathy of prematurity is characterized by neuronal loss combined with reactive gliosis. Synaptic connections formed during brain development are also altered by preterm birth, resulting in altered functional connectivity that persists through adolescence and is a significant risk factor of neurodevelopmental impairment.
The patterns of injury are heterogeneous and reflect different types of injury. The disruption of normal cortical development can result in a delay in cortical folding of >2 weeks and volume loss. , Gray matter lesions are most commonly found in the subcortical area and cerebellum. Fig. 48.2 illustrates the interactions that result in encephalopathy of prematurity. A summary of the mechanisms implicated in the pathogenesis of encephalopathy of prematurity is shown in Fig. 48.3 .
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