Etiology
Many factors, both genetic and acquired, have been postulated as causes of cerebral palsy. These include hypoxic-ischemic injury, structural malformations, vascular disorders, intraventricular or subarachnoid hemorrhage, infections, hormonal disorders, toxins, trauma, metabolic disease, prematurity, and hemolytic disease of the newborn. In recent years, several studies have sought to determine the relative contribution of these and other factors to the total incidence of cerebral palsy.
Perinatal Asphyxia
Historically, asphyxia during labor and delivery has been implicated as a major cause of cerebral palsy. In the last decade, a number of large population studies have revealed that asphyxia probably accounts for only a relatively small proportion of cases. The rate is approximately 4 times higher (16.7 versus 4.7) if the Apgar score is 0 to 3 at 10 minutes compared with 5 minutes. It is remarkable that even when the Apgar score was less than or equal to 3 for 15 minutes, the majority of infants did not develop cerebral palsy.When the association of CP with a variety of potentially asphyxiating conditions was examined, only a tight nuchal cord was associated with a statistically significant increase in risk. Thus, these three major studies are all in agreement that birth asphyxia causes fewer than 1 in 5, and probably fewer than 1 in 10, of the cases of cerebralpalsy. Furthermore, the majority of asphyxiated infants do not develop cerebral palsy.
Low Birth Weight and Prematurity
Multiple studies have demonstrated an increased prevalence of cerebral palsy with decreasing birth weight (<1500 g) or decreasing gestation (<37 weeks). The association, however, is not absolute, as only 10% of infants weighing less than 1500 g develop cerebral palsy, and, similarly, only 10 to 28% of children with cerebral palsy weighed less than 1500 g at birth. This relationship depends also upon the type of cerebral palsy, as up to 70% of children with spastic diplegia had low birth weight. It is possible that the cerebral lesion of cerebral palsy might occur antenatally as part of a process that leads also to prematurity or impairment of fetal growth. Alternatively, the cerebral event might occur postnatally, as the brain of a low birth weight or premature infant may be more susceptible to insult.
Congenital Malformations
Congenital malformations occur more frequently in children with cerebral palsy. In the National Collaborative Perinatal Project, 22% of the children with cerebral palsy had a major, noncerebral malformation, as opposed to only 6.8% of the children without cerebral palsy. Thus, more cases of cerebral palsy could be attributed to an underlying maldevelopment of the fetus than could be attributed to perinatal asphyxia. Furthermore, one-third of the children with cerebral palsy and a marker of perinatal asphyxia also had a noncerebral malformation, suggesting that maldevelopment of the fetus may be an underlying factor in producing the clinical picture of asphyxia.
In addition to the noncerebral malformations, a variety of cerebral malformations were also found, although somewhat less commonly than those outside the nervous system. Since the time of the National Collaborative Perinatal Project, advances in technology have furthered the detection of such abnormalities. For example, recent MR studies have found evidence of neuronal migrational disturbance in 30% of full-term infants with CP, further strengthening the relationship between fetal maldevelopment and cerebral palsy.
Infection
Several recent studies have implicated bacterial infection, autoimmune disorders, and coagulation defects in the pathogenesis of CP. Intrauterine exposure to infection is both a cause of premature birth and is associated with an increased risk of CP in both premature and full-term infants. Whereas exposure to any maternal infection increased the risk of CP in full-term infants, those with evidence of placental infection had the highest risk of spastic CP. Infection-exposed infants were more commonly found to have low Apgar scores and meconium aspiration syndrome, whereas those that went on to develop CP also had a higher incidence of hypotension, the need for respiratory support, neonatal seizures, and other signs of encephalopathy than nonexposed infants, suggesting that exposure to infection can mimic hypoxic-ischemic encephalopathy. Interestingly, among those children exposed to infection who later developed CP, spastic quadriplegia was more common than either the diplegic or hemiplegic subtypes. Overall, it is estimated that maternal infection could account for 12% of total spastic CP in children of normal birth weight. Although appreciation of the role of infection in CP is growing, effective therapeutic approaches to this problem have yet to be determined.
Coagulation Factors and Inflammatory Mediators
Elevations of a variety of inflammatory factors have been found in children with CP, including interleukins such as IL-1, -8, -9 (and to a lesser extent IL-6, -11, and -13), tumor necrosis factor-α, RANTES, and interferons. Infection is an obvious, although not exclusive, cause of such elevations. Coagulation factor abnormalities, sometimes autoimmune in nature, have also been implicated in the pathophysiology of CP. Reactive antibodies to lupus anticoagulant, anticardiolipin, antithrombin III; to a translational product of the factor V Leiden mutation; and to proteins C and S have been detected in children with CP. It is postulated that abnormalities in inflammatory pathways, triggered by infections or other factors, could impede brain development in various ways such as by disrupting myelin, interfering with cellular migration, or directly injuring oligodendroglia. Inflammation can lead to coagulation abnormalities that could then lead to thromboembolic events. In this regard, the role of thrombosis in placental vessels is coming to be appreciated as a potential source of emboli. Inflammatory mediators may also be responsible for transient hypothyroxinemia, which has recently been implicated as a possible cause of neurologic problems in preterm infants. These studies suggest that the interplay between infection, inflammation, and coagulation abnormalities may provide a better understanding of the pathophysiology of a large proportion of CP.
Other Antecedents
The National Collaborative Perinatal Project data and other studies associated cerebral palsy with a number of other diverse features. Maternal mental retardation, motor deficits in older siblings, maternal hyperthyroidism, maternal seizures, and a history of two or more prior fetal deaths were all prepregnancy antecedents that suggested maternal, possibly genetic, causes for cerebral palsy. Associated factors that occurred during the pregnancy included severe proteinuria, third-trimester bleeding, hormone use, heart disease, and incompetent cervix. Breech presentation (but not breech delivery), chorionitis, the presence of meconium in the amniotic fluid, and placental complications were the characteristics present during labor and delivery. Even in the aggregate, however, these factors accounted for only a small proportion of the total number of instances of cerebral palsy.
Summary
In summary, although a diverse number of factors have been found in association with cerebral palsy, none of them, alone or in the aggregate, has been shown to account for more than a fraction of the total number of children with cerebral palsy. Although the above studies have increased our understanding of pathophysiological mechanisms at work in cerebral palsy, there remain many cases for which the cause is unknown.
Historically, asphyxia during labor and delivery has been implicated as a major cause of cerebral palsy. In the last decade, a number of large population studies have revealed that asphyxia probably accounts for only a relatively small proportion of cases. The rate is approximately 4 times higher (16.7 versus 4.7) if the Apgar score is 0 to 3 at 10 minutes compared with 5 minutes. It is remarkable that even when the Apgar score was less than or equal to 3 for 15 minutes, the majority of infants did not develop cerebral palsy.When the association of CP with a variety of potentially asphyxiating conditions was examined, only a tight nuchal cord was associated with a statistically significant increase in risk. Thus, these three major studies are all in agreement that birth asphyxia causes fewer than 1 in 5, and probably fewer than 1 in 10, of the cases of cerebralpalsy. Furthermore, the majority of asphyxiated infants do not develop cerebral palsy.
Low Birth Weight and Prematurity
Multiple studies have demonstrated an increased prevalence of cerebral palsy with decreasing birth weight (<1500 g) or decreasing gestation (<37 weeks). The association, however, is not absolute, as only 10% of infants weighing less than 1500 g develop cerebral palsy, and, similarly, only 10 to 28% of children with cerebral palsy weighed less than 1500 g at birth. This relationship depends also upon the type of cerebral palsy, as up to 70% of children with spastic diplegia had low birth weight. It is possible that the cerebral lesion of cerebral palsy might occur antenatally as part of a process that leads also to prematurity or impairment of fetal growth. Alternatively, the cerebral event might occur postnatally, as the brain of a low birth weight or premature infant may be more susceptible to insult.
Congenital Malformations
Congenital malformations occur more frequently in children with cerebral palsy. In the National Collaborative Perinatal Project, 22% of the children with cerebral palsy had a major, noncerebral malformation, as opposed to only 6.8% of the children without cerebral palsy. Thus, more cases of cerebral palsy could be attributed to an underlying maldevelopment of the fetus than could be attributed to perinatal asphyxia. Furthermore, one-third of the children with cerebral palsy and a marker of perinatal asphyxia also had a noncerebral malformation, suggesting that maldevelopment of the fetus may be an underlying factor in producing the clinical picture of asphyxia.
In addition to the noncerebral malformations, a variety of cerebral malformations were also found, although somewhat less commonly than those outside the nervous system. Since the time of the National Collaborative Perinatal Project, advances in technology have furthered the detection of such abnormalities. For example, recent MR studies have found evidence of neuronal migrational disturbance in 30% of full-term infants with CP, further strengthening the relationship between fetal maldevelopment and cerebral palsy.
Infection
Several recent studies have implicated bacterial infection, autoimmune disorders, and coagulation defects in the pathogenesis of CP. Intrauterine exposure to infection is both a cause of premature birth and is associated with an increased risk of CP in both premature and full-term infants. Whereas exposure to any maternal infection increased the risk of CP in full-term infants, those with evidence of placental infection had the highest risk of spastic CP. Infection-exposed infants were more commonly found to have low Apgar scores and meconium aspiration syndrome, whereas those that went on to develop CP also had a higher incidence of hypotension, the need for respiratory support, neonatal seizures, and other signs of encephalopathy than nonexposed infants, suggesting that exposure to infection can mimic hypoxic-ischemic encephalopathy. Interestingly, among those children exposed to infection who later developed CP, spastic quadriplegia was more common than either the diplegic or hemiplegic subtypes. Overall, it is estimated that maternal infection could account for 12% of total spastic CP in children of normal birth weight. Although appreciation of the role of infection in CP is growing, effective therapeutic approaches to this problem have yet to be determined.
Coagulation Factors and Inflammatory Mediators
Elevations of a variety of inflammatory factors have been found in children with CP, including interleukins such as IL-1, -8, -9 (and to a lesser extent IL-6, -11, and -13), tumor necrosis factor-α, RANTES, and interferons. Infection is an obvious, although not exclusive, cause of such elevations. Coagulation factor abnormalities, sometimes autoimmune in nature, have also been implicated in the pathophysiology of CP. Reactive antibodies to lupus anticoagulant, anticardiolipin, antithrombin III; to a translational product of the factor V Leiden mutation; and to proteins C and S have been detected in children with CP. It is postulated that abnormalities in inflammatory pathways, triggered by infections or other factors, could impede brain development in various ways such as by disrupting myelin, interfering with cellular migration, or directly injuring oligodendroglia. Inflammation can lead to coagulation abnormalities that could then lead to thromboembolic events. In this regard, the role of thrombosis in placental vessels is coming to be appreciated as a potential source of emboli. Inflammatory mediators may also be responsible for transient hypothyroxinemia, which has recently been implicated as a possible cause of neurologic problems in preterm infants. These studies suggest that the interplay between infection, inflammation, and coagulation abnormalities may provide a better understanding of the pathophysiology of a large proportion of CP.
Other Antecedents
The National Collaborative Perinatal Project data and other studies associated cerebral palsy with a number of other diverse features. Maternal mental retardation, motor deficits in older siblings, maternal hyperthyroidism, maternal seizures, and a history of two or more prior fetal deaths were all prepregnancy antecedents that suggested maternal, possibly genetic, causes for cerebral palsy. Associated factors that occurred during the pregnancy included severe proteinuria, third-trimester bleeding, hormone use, heart disease, and incompetent cervix. Breech presentation (but not breech delivery), chorionitis, the presence of meconium in the amniotic fluid, and placental complications were the characteristics present during labor and delivery. Even in the aggregate, however, these factors accounted for only a small proportion of the total number of instances of cerebral palsy.
Summary
In summary, although a diverse number of factors have been found in association with cerebral palsy, none of them, alone or in the aggregate, has been shown to account for more than a fraction of the total number of children with cerebral palsy. Although the above studies have increased our understanding of pathophysiological mechanisms at work in cerebral palsy, there remain many cases for which the cause is unknown.
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