Neuromaturation is a dynamic process in which the central nervous system (CNS) is formed by a continuous interaction between the programmed genetic processes encoded within the genome and then the intrauterine environment, followed by the extrauterine environment. The successive turning on and then turning off of specific genes propel development forward, whereas surrounding cells, temperature, nutrients, and unknown environmental factors influence cell division, differentiation, function, connections, and migration. At 16 days from conception, the neural plate, which contains the cells that form the brain, is formed. A neural groove then forms and then begins to close to become the neural tube by 3 to 4 weeks from conception. At one end of the neural tube, embryonic brain vesicles form and begin to differentiate into the forebrain, midbrain, and hindbrain (i.e., the prosencephalon, mesencephalon, and rhombencephalon, respectively) (Capone, 1996). By the end of the 6th week, the basic subdivisions of the adult brain have formed. Neurons and their glial support cells actively divide during the first trimester, with the peak period of proliferation between the 2nd and 4th months of gestation. Neuronal migration is the mass movement of neurons from where they were formed to an ultimate destination in a specified layer of the brain and occurs between the 3rd and 5th months of gestation.
Fetal movement begins shortly after the brain begins to differentiate and can be detected by prenatal ultrasound as early as 8 to 10 weeks from conception. Fetal and infant activity and sensory input shape the development of the CNS. The fetus moves in response to cutaneous stimulation by 9 to 11 weeks and demonstrates the earliest signs of primitive reflexes (i.e., rooting and grasping) (Hooker, 1952; Hooker and Hare, 1954; Humphrey, 1964). Neurons continue to differentiate, and axons grow out and connect to dendrites to form synapses from the 6 month of gestation to at least 3 years from term. A complex and extensive network of neuronal circuits form; and they are shaped by patterns of electrical activity promoted by sensory input, movement, and responses to the environment. Fetal movements and responses are necessary for the normal development of the limbs and the CNS. Ongoing activity, learning, and sensory input determine which circuits are reinforced, whereas unused circuits are pruned. Myelination covers the neuron with a lipid sheath and reduces conduction times. The myelination process begins as early as 6 months gestation in some regions of the CNS and continues throughout childhood.
Incomplete formation of the CNS makes neonates vulnerable to CNS injury, especially if the infant was born preterm. Injury to the CNS can occur during pregnancy, labor, delivery, the transition to extrauterine life, or a subsequent illness or exposure. Many etiologies of preterm delivery (e.g., infection and maternal illness) contribute to fetal CNS injury. Concerns about the ability of the extremely preterm infants to tolerate the contractions of labor and the trauma of vaginal delivery have raised the question as to whether delivery by cesarean section is neuropro-tective (Grant and Glazener, 2001). Trials to evaluate this question have suffered from recruitment problems, and there is not sufficient evidence of improved infant outcomes to balance the increased morbidity for mothers. Infants born preterm also have more difficulties with the transition from placental support to extrauterine life and the many vascular changes that occur.
In preterm infants, the white matter around the ventricles and highly vascular germinal matrix eminence are especially vulnerable to injury (de Vries and Groenendaal, 2002; Gleason and Back, 2005; Madan and Good, 2005). They have difficulties with autoregulation of cerebral blood flow (i.e., maintaining adequate cerebral blood flow, despite changes in blood pressure). Ischemia, hypoxia, and inflammation contribute to CNS injury in the preterm infant, but the relative importance of these factors remains controversial. The most common signs of CNS injury in preterm infants are IVH, intraparenchymal hemorrhage (IPH; bleeding within the substance of the brain), and white matter injury (including periventricular leukomalacia [PVL]). Neuroimag-ing studies, including ultrasound, computerized tomography, and magnetic resonance imaging (MRI), provide ways to visualize brain injury in infants. Ultrasound has the advantage of being cheaper and easily available (i.e., it can be performed at the bedside), but MRI is increasingly being used for better visualization of the brain parenchyma.
Germinal Matrix Injury, IVH, and IPH
IVH generally begins with bleeding into the germinal matrix just below the lateral ventricles (i.e., a subependymal or germinal matrix hemorrhage). During the late second and early third trimesters, the subependymal germinal matrix supports the development of cortical neuronal and glial cell precursors, which migrate to the cortical layers. The germinal matrix is highly vascularized, with a rich capillary network and a relatively poor supportive matrix. Blood filling the lateral ventricles may dilate the ventricles. The incidence and severity of IVH increases with decreasing gestational age and birth weight. Factors that contribute to IVH include hypotension, hypertension, fluctuating blood pressures, poor autoregulation of cerebral blood flow, disturbances in coagulation, hyperosmolarity, and injury to the vascular endothelium by oxygen free radicals. In 10 to 15 percent of infants a germinal matrix hemorrhage will obstruct venous return and lead to venous infarction of brain tissue (called IPH) (de Vries and Groenendaal, 2002).
Severe IVH can lead to ventricular dilation and posthemorrhagic hydrocephalus if there is an obstruction to the flow of cerebrospinal fluid, with increased intracranial pressure. Intermittent spinal taps or ventricular taps (i.e., drawing off of the cerebrospinal fluid with a needle) can relieve this pressure. This should be done primarily if the infant is symptomatic, as studies have demonstrated no benefits to regular taps of asymptomatic infants (Whitelaw, 2001). Once the blood is mostly cleared from the ventricles, a ventriculoperitoneal (VP) shunt can be surgically placed to drain the cerebrospinal fluid into the abdominal cavity where it is absorbed. De Vries and Groenendaal (2002) found that a third of preterm infants with large IVH required a VP shunt. Neither diuretics nor streptokinase (a clot buster) reduces the need for a shunt, nor do they improve outcomes (and a borderline increase in motor impairment was detected at 1 year of age after the use of diuretics) (Whitelaw, 2001; Whitelaw et al., 2001).
Infants with subependymal or germinal matrix hemorrhage or IVH without ventricular dilation have a good prognosis; but those with IVH with ventricular dilation, posthemorrhagic hy-drocephalus or IPH are at an increased risk of neurodevelopmental disability (deVries and Groenendaal, 2002). As many as 11 percent of infants with birth weights of less than 1,500 grams have IVH with ventricular dilation or IPH (Lee et al., 2000; Lemons et al., 2001). The prevalence of neurodevelopmental disabilities in preterm infants with severe IVH and ventricular dilation or posthemorrhagic hydrocephalus ranges from 20 to 75 percent (de Vries et al., 2002; Fernell et al., 1994). Although early studies showed a high incidence of neurodevelopmental disabilities with IPH among preterm infants, recent studies have shown that the prevalence of disability varies with the size and the location of the hemorrhage (de Vries and Groenendaal, 2002; de Vries et al; 2002; Guzzetta et al., 1986). A study of infants born between 1979 and 1989 with gestational ages of less than 33 weeks found that the probabilities of a major disability at age 8 years were 5 percent for infants with a normal ultrasound, germinal matrix hemorrhage, or small IVH without ventricular dilation and 41 percent for infants with ventricular dilation, hydrocepha-lus, or cerebral atrophy (Stewart and Pezzani-Goldsmith, 1994).
Antenatal betamethasone (a corticosteroid) reduces the incidence of IVH in preterm infants, but many other treatments have been less successful (Crowley, 1996; NIH, 1994). There is not enough evidence to support the antenatal use of either phenobarbital or vitamin K to prevent IVH, and phenobarbital-sedated mothers (Crowther and Henderson-Smart, 2003; Shankaran et al., 2002). Postnatal phenobarbital did not significantly improve the incidences of IVH, severe IVH, posthemorrhagic ventricular dilation, severe neurodevelopmental disability, or death; and there was a trend toward a longer duration of ventilation (Whitelaw, 2001). A meta-analysis of five trials of prolonged neuromuscular paralysis with pancuronium treatment in preterm infants with asynchronous breathing concluded that although pancuronium did help decrease the incidences of IVH and pneumothorax, concerns about its safety and long-term pulmonary and neurological effects precluded recommendation of its routine use (Cools and Offringa, 2005). Intramuscular doses of vitamin E may have reduced the incidence of IVH in preterm infants, but they were also associated with an increased incidence of sepsis (and high doses may increase the risk of IVH) (Brion et al., 2003). The prophylactic use of indomethacin in the first hours and days after delivery reduced the incidence and severity of IVH, especially in preterm boys, but the use of indomethacin results in many side effects (e.g., renal complications, NEC, and gut perforation) and it has little sustained effect on neurodevelopmental outcomes (although it might improve the verbal abilities of boys) (Fowlie and Davis, 2002; McGuire and Fowlie, 2002; Ment et al., 2004; Schmidt et al., 2004). As with other complications of prematurity, the prevention of preterm birth would be the most effective way to prevent IVH and IPH.
White Matter Injury and Periventricular Leukomalacia
Injury to the periventricular white matter is a sign of CNS injury and is a complication of preterm birth. Its pathogenesis is currently the subject of extensive study (Damman et al., 2002; Wu and Colford, 2000) (see Chapter 6). White matter injury includes a spectrum of CNS injuries, from focal cystic necrotic lesions (also called PVL) to ventricular dilation with irregular ventricular edges or cerebral atrophy (as a result of the resorption of injured brain tissue) and extensive and bilateral white matter lesions. A complex interplay of etiologic factors predisposes the preterm infant's white matter to injury, but the gray matter may be injured as well. Poor blood flow to regions of the brain because of obstruction, low blood pressure or an immature vascular system, poor autoregulation of cerebral blood flow, hypoxia, the vulnerability of preoli-godendrocytes (i.e., supporting cells), excitatory neurotransmitters (e.g., glutamate), and harmful inflammatory substances (e.g., cytokines and free radicals) carried by the blood can all contribute brain injury. A meta-analysis found significant relationships between white matter injury and clinical chorioamnionitis, PVL, and cerebral palsy in preterm infants (Wu and Colford, 2000).
Imaging of white matter injury is more difficult than imaging of IVH or IPH (deVries and Groenendaal, 2002). Ultrasounds should be repeated at 3 to 4 weeks after birth and at 34 to 36 weeks of postmenstrual age to detect signs of white matter injury, which evolve over time. The first sign may be an uneven density of the white matter that resolves (transient echogenicity) or that evolves into cystic lesions. Cystic lesions can collapse, so the timing and the quality of the ultrasound examinations are crucial for the detection of white matter injury. MRI is helpful for the detection of patchy or nonhomogeneous echogenicity.
Children with cystic PVL have a high risk of neurodevelopmental disabilities, and the more extensive that it is, the higher the risk that the children have (e.g., the risk is 100 percent with extensive bilateral cystic PVL) (Holling and Leviton, 1999; Rogers et al., 1994; van den Hout et al., 2000). These children are also at high risk for the development of cerebral palsy, which tends to be more severe with extensive PVL; cognitive impairments; and cortical-visual impairments with visual-perceptual problems. Children with more focal or unilateral cystic PVL also have a high incidence of cerebral palsy (up to 74 percent), but it tends to be a milder motor impairment (Pierrat et al., 2001). Approximately 10 percent of children with periventricular echodensities develop cerebral palsy, generally in the form of mild spastic diplegia. MRI studies of infants born at term and older children have detected reduced regional cortical volumes (especially in sensorimotor regions and in both white and gray matter) that correlate with cognitive or neuromotor impairments (Inder et al., 2005; Peterson et al., 2000).
There have been a paucity of studies of strategies for the prevention of white matter injury and the amelioration of the effects of white matter injury. The effects of neuroprotective medications for IVH (e.g., indomethacin) on white matter injury are not clear, especially as the definitions of IVH are changing to include not just PVL but also irregular ventricular dilation and cortical atrophy. Some intriguing studies of insufficient naturally occurring developmentally regulated neuroprotective substances (e.g., hydrocortisone, thyroxine, and erythroietin) have suggested that they are associated with increased rates of mortality, BPD/CLD, and possibly, negative neurodevelopmental outcomes (Kok et al., 2001; Osborn, 2002; O'Shea, 2002; Scott and Watterberg 1995; Sola et al., 2005; van Wassenaer et al., 2002; Waterberg et al., 1999). Many avenues are available for study and exploration, and research into the causes of preterm brain injury and neuroprotective strategies and the NICU interventions that can be undertaken to improve the neurodevelopmental outcomes of preterm infants is very much needed.
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