Advances in Understanding Cerebral Palsy Syndromes After Prematurity Lubov Romantseva and Michael E Msall Neoreviews 2006;7;e575 DOI:

10.1542/neo.7-11-e575

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/7/11/e575

Neoreviews is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since . Neoreviews is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN: .

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

Advances in Understanding Cerebral Palsy Syndromes After Prematurity

Lubov Romantseva, MD,* Michael E. Msall, MD*

Article

development

Objectives

After completing this article, readers should be able to:

Author Disclosure Drs Romantseva and Msall did not disclose any nancial relationships relevant to this article.

1. List neonatal morbidities that have been associated with the development of cerebral palsy (CP). 2. Describe the ultrasonographic ndings that are suggestive of CP. 3. Compare and contrast the use of ultrasonography and magnetic resonance imaging in detecting lesions associated with CP. 4. Review strategies to adapt the infant neurologic examination to detection of CP. 5. Explain how the International Classication of Functioning can be used to examine risk and resiliency factors with respect to outcome. 6. Describe the severity of most cases of CP.

Introduction

During the past 25 years, major advances in maternal-fetal medicine, neonatology, and translational developmental biology have resulted in survival rates exceeding 90% among infants born at weights between 1,000 and 1,499 g, 80% for infants born at weights between 751 and 999 g, and 60% for infants born weighing 500 to 750 g. (1) These birthweight categories approximately reect appropriate weights for 28 to 32 weeks, 26 to 27 weeks, and 23 to 25 weeks gestation, respectively. Although survival has improved among these very and extremely preterm infants, prevention of adverse neurodevelopmental outcomes in early childhood among such high-risk survivors as well as other neonatal cohorts receiving new technologies remains a major challenge. (2) The most common early recognized neurodevelopmental impairment is cerebral palsy (CP), and the overall prevalence of this disorder has not decreased over the past 25 years. However, with recent discoveries in brain structure and function, immunology, nutrition, early childhood learning, and developmental plasticity, the future holds promise. The purpose of this review is to describe risk factors for CP in preterm infants, focusing predominantly on extremely low-birthweight (ELBW) and very low-birthweight infants, but also highlighting gaps in the current knowledge of outcomes among moderately low-birthweight infants. Recent data from multicenter studies emphasize the complex pathways to the CP syndromes in infants born very and extremely preterm. We use as a framework the International Classication of Functioning (ICF) model, which describes a childs health and well-being via four components: 1) body structures, 2) body functions, 3) activities, and 4) participation. (3) We illustrate the ICF model for children who have diplegic, hemiplegic, triplegic, and quadriplegic CP after prematurity. We also illustrate the value of early motor milestones, sequential neurodevelopmental evaluation at key ages, and a classication system at age 2 years to optimize habilitative strategies in the preschool years. It is critically important to understand causal pathways, the spectrum of developmental functioning, and family supports to devise prevention strategies for future vulnerable populations of preterm infants receiving new technologies. Current epidemiology evidence suggests that approximately 1 in 3 children who have CP were born at either 28 to 31 weeks or 32 to 36 weeks gestational age. (4)(5)(6)(7)(8)(9) In the United States, with its currently scarce CP resources, groups considered at low-risk for neonatal follow-up surveillance contribute a large number of cases of CP. From a population impact, understanding pathways of the CP syndromes in
*University of Chicago Pritzker School of Medicine, Comer Childrens and LaRabida Childrens Hospitals, Section of Developmental and Behavioral Pediatrics, Kennedy Center, and Institute of Molecular Pediatrics, Chicago Ill. NeoReviews Vol.7 No.11 November 2006 e575

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

development

cerebral palsy

term and moderate preterm infants of 32 to 36 weeks gestation, term and preterm pregnancies affected by intrauterine growth restriction (IUGR), and pregnancies involving multiple births is critical to efforts at reducing the prevalence of CP. (10) (11)(12)(13)(14)(15) More than 750,000 children and adults in the United States are affected by one of the CP syndromes, with the lifetime cost estimated at $1,000,000 per individual and $1.2 billion in direct medical costs for children born in 2000. (16) In this respect, disproportionate attention to both severe perinatal hypoxemic-ischemic encephalopathy in term infants and extreme prematurity led to the erroneous perception that these two risk groups of children accounted for the majority of cases of CP.

Neonatal Morbidities and Risk for CP

Although a multitude of risk factors for CP in the prenatal, perinatal, and postnatal course of the preterm baby have been proposed, this review focuses on several variables shown to be signicant predictors of future CP in multicenter studies. Five risk factors are especially important: 1) parenchymal brain injury (dened as intraventricular hemorrhage [IVH] grade 3 or 4), ventriculomegaly, or cystic periventricular leukomalacia (PVL); 2) postnatal sepsis, necrotizing enterocolitis (NEC), or meningitis; 3) chronic lung disease (CLD) (dened as supplemental oxygen at 36 weeks gestation); 4) severe retinopathy of prematurity (ROP) (stage 4 or 5); and 5) multiple gestation. Schmidt and colleagues (17) examined parenchymal brain injury, CLD, and severe ROP in 910 infants who weighed less than 1,000 g at birth and were enrolled in a study of prophylactic indomethacin to prevent IVH. Among survivors to 18 months of age, 1 in 7 had CP and 1 in 4 had cognitive disability. Notably, rates of CP increased to 36% for those who had parenchymal brain injury. Additionally, 24% of children who had severe ROP and 17% of those who had CLD had CP. Among the children who were free of these three comorbidities, the rate of death or neurodevelopmental impairment at 18 months was 18%. (This occurred in a setting of mortality between 1.2% and 3%.) In contrast, the rates of death or neurodevelopmental disability were 88% if all three of the comorbidities were present, with a risk of mortality of approximately 10%. More than threequarters (78%) of the children who had parenchymal brain injury or severe ROP had neurodevelopmental disability. Several recent reports have examined the impact of infection such as sepsis, meningitis, or NEC on neurodevelopmental outcomes of survivors of very preterm birth.
e576 NeoReviews Vol.7 No.11 November 2006

Stoll and colleagues (18) retrospectively studied the role of postnatal infection on outcomes of survivors whose birthweights were between 401 and 1,000 g and who were born between 1993 and 2001 in the National Institute of Child Health and Human Development (NICHD) Neonatal Network. Three primary risk groups were identied: 1) infants who were infection-free during their hospital stay (n2,161); 2) infants who had clinical infections requiring antibiotics for at least 5 days or sepsis (n3,460); and 3) infants who had NEC or meningitis (n472). Some 65% of survivors had postnatal infections, the overwhelming majority of which were late-onset (72 h after birth). In the infection-free group, 1 in 12 children had one of the CP syndromes. In contrast, approximately 1 in 5 infants who had sepsis, NEC, or meningitis developed CP. In addition to the higher rate of CP, these investigators reported greater rates of cognitive disability (dened as a Bayley II mental developmental index [MDI] of 70 at 18 months of age). Cognitive disability occurred in approximately 1 in 5 infants who were infection-free and in 1 in 3 to 2 in 5 of those who had infection. Notably, the relationship between infection status and neurodevelopmental disability held after adjusting for CLD and ultrasonographically detected parenchymal brain injury, two of Schmidts major determinants of adverse outcomes in extremely preterm cohorts. (17)(19) These ndings are underscored by another study of ELBW survivors who did and did not have NEC from the same NICHD Neonatal Network group. (20) The investigators compared rates of neurodevelopmental disability in infants who had required medical or surgical management of NEC and those who did not have NEC. They found that 24% of children who had surgically managed NEC developed CP, and 37% of those children had cognitive disabilities. Thus, the impact of NEC reaches beyond the gastrointestinal system, affecting both neuromotor and cognitive outcomes. Recently, severe ROP (grade 4 or 5) has emerged as another potential predictor of early childhood disability. In the multicenter Cryosurgery for Retinopathy of Prematurity Study, (21) children who reached threshold ROP but had favorable visual status at 5.5 years had a rate of motor functional disability of 5%, reecting ongoing challenges in basic upright mobility. Self-care functional disability was present in 25% of children, reecting challenges in feeding, dressing, and grooming. In contrast, children who had threshold ROP and an unfavorable visual status at 5.5 years had rates of self-care functional disability of 77% and motor functional disability of 43%. For reference, the children who had no or minimal ROP

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

development

cerebral palsy

had rates of motor and self-care functional disabilities of less than 10%. These data suggest that severe ROP is an important marker for the severity of neuromotor and self-care adaptive disability at kindergarten entry. Advancing reproductive technologies have been associated with a marked increase in the birth and survival of twins, triplets, and higher order multiples. Historically, the higher rate of CP in multiple births was noted initially by Sigmund Freud in the 1800s. In the modern era, the concept was conrmed by several studies in which twins contributed 5% to 10% of CP cases, even though twins accounted for only 1.6% of all live births. (22) The disproportionately large number of twins in CP cohorts was conrmed by a multicenter registry that showed a fourfold higher rate of CP among twins compared with single births. (23) In singleton pregnancy, the risk for CP is 2 in 1,000; in one of twins, the risk is 20 in 1,000; in one of triplets, the risk is 100 in 1,000; and in one of quadruplets, the risk is 500 in 1,000. The risk of CP is related to gestational age, birthweight, IUGR, zygosity, and survival of a cotwin or cotriplet.

Advances in Understanding CP via Neuroimaging

raphy. Ultrasonography missed 1 in 11 of those who had CP and 1 in 4 of children who had cognitive disability. In examining cystic PVL as the ultrasonographic lesion often linked to preterm CP, Hamrick and colleagues (27) found that although cystic PVL was highly predictive of future CP, the severity of outcome varied. However, cystic PVL and a related lesion of periventricular hemorrhagic infarction (PVHI) accounted for only 32% (9/28) of CP cases and 13% (12/90) of cognitive disability. In contrast, Rogers and colleagues (28) found that cystic PVL occurred in 3% of ELBW survivors and that size and location of cysts predicted the severity of disability. Children who had bilateral and large cysts had high rates of quadriplegic CP and severe cognitive disability. Interestingly, although the rate of ultrasonographically detected cystic PVL decreased between the years of 1992 and 2002, the rate of CP for the same cohort and time period did not. Based on these ndings, researchers have concluded that brain abnormalities other than cystic PVL and PVHI (that presumably are untedectable by cranial ultrasonography) are likely to be responsible for a signicant portion of preterm CP cases. (29)(30)

In many centers, ultrasonography remains the mainstay of intracranial imaging for preterm newborns because it is an efcient bedside imaging tool with minimal disturbance to the fragile baby. Ultrasonography is most useful for detecting space lesions, such as hydrocephalus, hemorrhage, or PVL. However, timing of the examination is critical; cystic PVL often cannot be visualized until 32 to 34 weeks postmenstrual age (PMA). De Vries and colleagues (24) demonstrated the value of sequential ultrasonographic imaging for all infants up to 32 weeks PMA and showed a sensitivity of 95%, a specicity of 99%, and a positive predictive value of 48% for CP at age 2 years. Similarly, Vohr and colleagues (25) found that among children who had CP in the 1995 to 1998 NICHD Neonatal Network cohort, PVL was documented in 51% of those who had quadriplegia, 24% of those who had hemiplegia, and 19% of those who had diplegia. Additionally, they documented grade 3/4 IVH among 67% of those who had hemiplegia, 48% of those who had quadtiplegia, and 35% of those who had diplegia. Approximately 1 in 2 of ELBW survivors who had CP did not have ultrasonographically detected grade 3/4 IVH, PVL, or ventriculomegaly. In another study, Laptook and associates (26) followed the outcomes of children at ages 18 to 24 months who were born weighing less than 1,000 g and had normal ndings on cranial ultrasonog-

Magnetic Resonance Imaging (MRI) and New Techniques

In addition to cranial ultrasonography, brain MRI is an increasingly popular imaging technique that offers greater detail of white matter and areas not easily accessed by ultrasonography. Several investigators have sought to compare the sensitivity and specicity of brain ultrasonography with that of brain MRI in preterm infants. A recent review (31) demonstrated that the heterogeneity of the studies add to the difculty in rigorous comparisons because they vary in denition/gradation of abnormal ndings, study samples, image timing, and outcome measures. However, several common themes have emerged. First, ultrasonography and MRI complement each other because they appear best suited to detect different types of lesions in the preterm brain. The are both noninvasive and can be used at different critical developmental stages. Ultrasonography has very good sensitivity for cystic and large hemorrhagic lesions, and MRI is much better at detecting white matter and other subtle changes (such as punctate parenchymal hemorrhages) that may be missed on ultrasonography. (32)(33) This is relevant because the incidence of focal lesions such as cystic PVL and PVHI has declined in recent years, with noncystic white matter abnormalities such as ventriculomegaly, white matter atrophy, and diffuse excessive highNeoReviews Vol.7 No.11 November 2006 e577

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

development

cerebral palsy

signal intensity among the most commonly reported preterm brain injuries. (31) Second, serial ultrasonography improves the modalitys sensitivity and specicity, as supported by studies correlating serial ultrasonography and histopathology for germinal matrix hemorrage/IVH lesions. (34) DeVries and colleagues (24) showed that even with weekly ultrasonographic scanning, 46% of hypoechoic white matter lesions were not detected until after 28 days after birth, and 14% were not identied until 40 weeks PMA. Third, at this time, it remains unclear whether serial ultrasonography can approach the sensitivity and specicity of MRI. The available comparative studies have a wide range of values, but three studies deserve specic comment. Devries and associates (24) reported that serial ultrasonography had a sensitivity of 76% to 86% and a specicity of 95% to 99% for infants more than 32 weeks gestational age. Mirmiran and colleagues (35) compared cranial MRI at near term (36 to 40 weeks PMA) with serial cranial ultrasonography in infants who weighed less than 1,250 g and were less than 30 weeks gestation. MRI was 86% sensitive and 89% specic for detecting CP at 2.5 years. In comparison, ultrasonography was 43% sensitive and 82% specic for detecting CP. Woodward and colleagues (36) reported similar numbers for sensitivity and specicity in a prospective investigation of 167 infants born at 30 weeks gestational age or younger who were followed with serial cranial ultrasonography and brain MRI at term age equivalent, comparing the rate of imaging-detected abnormalities with the neurodevelopmental outcome at 2 years corrected age. They found that moderate-to-severe white matter MRI abnormalities predicted CP with a sensitivity of 65%. Thus, it is critically important to recognize both the value and responsibility of including an MRI exam at 36 weeks PMA for the high-risk cohort of preterm infants. Needless to say, the study must be performed safely, avoiding sedation whenever possible. More importantly, however, is the need to provide affected families access to early intervention and specialist services. Finally, professionals must understand that with this test, as with almost any other, there will be a small percentage of missed cases, which must be acknowledged during the interpretation of results to families and colleagues. Brain MRI also brings an expanding array of new techniques and protocols for imaging the preterm brain, providing more detailed visualization of white matter. (37)(38) Currently, T1- and T2-weighted images are the part of the standard preterm imaging protocol. Because neonatal brains have greater water content than adult brains, MR pulse sequences must be adequately adjusted,
e578 NeoReviews Vol.7 No.11 November 2006

and T1- and T2-weighted fast spin echo are considered optimal. Other techniques, such as diffusion-weighted imaging/diffusion tensor imaging (DTI), may detect white matter damage before it is demonstrated on conventional MRI. (39) DTI and ber tractography were employed to image two patients known to have CP in a recent report by Lee and colleagues. (40) Although these techniques currently remain in a largely experimental realm, they offer much promise in advancing understanding of CP at the neural ber tract level.

Advances in the Early Detection of CP

Despite a growing understanding of the risk factors and pathways to CP, the methods of detecting CP in a high-risk population need to be much improved; no existing imaging strategy has 95% sensitivity and specicity. Early detection of CP-related lesions is critical to timely diagnosis, which is directly related to accessing habilitative and family support services. Palmer (41) points out two major challenges in the early detection of CP. First, the clinical manifestations of CP evolve and declare themselves over time as the child develops and either attains or struggles to reach appropriate milestones. Although the structural impairment of the developing brain has occurred in one of several possible developmental epochs, ranging from preconception to rst trimester, second trimester, third trimester, perinatal, neonatal, and early childhood, the consequences cannot be fully appreciated until the child has gone through several major stages of central nervous system (CNS) development that underlie motor, manipulative, and communicative skills. In other words, children can be free from signs of dysfunction at early age but grow into a functional challenge with increasing age because of age-related increase in the complexity of neural functions. (42) This concept is illustrated by the landmark articles from the National Collaborative Perinatal Project (NCPP). (43) In comparing the results of the infant neurologic examination to the outcome at 7 years of age, only 23% of children who had diagnosed CP at 7 years had abnormal examination ndings as newborns. (44) Further, the predictive ability of a 4-monthold examination was only slightly better. Finally, approximately 50% of the children diagnosed as having CP at age 1 year lost that diagnosis by age 7 years but were found to have challenges in communicative, cognitive, academic, and neurobehavioral competencies. Second, Palmer (41) suggests that the classic neurologic examination, when applied to the infant, is better suited to catalog all the existing impairments rather than to detect the particular impairments that are likely to

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

development

cerebral palsy

result in functional limitations in the future. Early detection of such functionally relevant impairments is critical because it drives intervention and family supports that optimize positioning, handling, feeding, and the development of skills in self-mobility, manipulation, and communication. Several different strategies have been investigated to adapt the infant neurologic examination to the task of early detection of CP. Some authors have added the assessment of primitive reexes and postural responses to the standard neurologic examination, with resultant moderate improvement in sensitivity and specicity for the early detection of CP. (45)(46) This approach emphasizes persistent primitive reexes, especially the asymmetric tonic neck reex, tonic labyrinthine supine reex, and positive support reex. Zafeiriou and colleagues (47) used seven specic postural reactions (PRs), in addition to the neurologic examination, as a screening tool for predicting future CP in a high-risk cohort of neonatal intensive care unit survivors. They followed 204 preterm and term infants with serial augmented neurologic examinations during infancy and subsequently at 3 years of age. At 3 years of age, patients were divided into three groups: those who had CP, those who had cognitive disability, and those who had neither problem. Of the children later diagnosed with CP, 86% had at least ve abnormal PRs at 1 month of age compared with no children having more than four abnormal PRs and 99% having only three abnormal PRs in the unaffected group. Thus, this method of augmenting neurologic examination with assessment of seven specic PRs appears promising and capable of predicting CP at a very young age. Study limitations, including small numbers of patients and a single examiner, require that these results be reconrmed by other investigators. Another strategy makes use of operationally dened motor milestones and calculates a motor quotient to predict CP at an early age. (48)(49)(50) For example, a motor quotient of less than 0.5 at 8 months of age predicts delayed age of walking (24 months) with a sensitivity of 87% and specicity of 89%. (41) However, this method loses its utility in children younger than 6 months of age. This can be attributed to the importance of a child reaching a CNS level of maturity and myelination equivalent to a 6-month-old child or CNS motor development progressing to a level that allows observation of trunk control, sitting balance, and hand function. A third advance in the early detection of CP was discovered by Ferrari and colleagues, (51) who found that observing the spontaneous general movements (GMs) of infants as young as 2 to 4 months of age

correlated well with future development of CP. A specic type of abnormal spontaneous GM, termed cramped synchronized GM, predicted CP diagnosis at age 2 to 3 years with a sensitivity of 100% and specicity of 93%. In addition, the technique predicted the severity of motor delay, with the earlier onset of abnormal movement correlating to greater functional limitation. To our knowledge, this technique represents the earliest method of CP prediction with such good sensitivity and specicity. However, the sample size is small, and additional research is warranted.

Using the ICF Framework

The ICF framework is a useful tool to attempt to understand factors of risk and resiliency with respect to outcomes. We have chosen four scenarios for the ICF model (Table 1). In the ICF model, body structures are anatomic parts of the body, such as organs and limbs, as well as structures of the nervous, sensory, and musculoskeletal systems. (3) Body functions are the physiologic functions of body systems, including psychological functions, such as attending, remembering, and thinking. Activities are tasks and include learning, communicating, walking, feeding, dressing, toileting, and playing. Participation means involvement in community life, such as relationships, child care, and preschool education. The ICF model also accounts for contextual factors in a childs life, including environmental and personal factors. Environmental factors, such as policy, social, and physical facilitators and barriers, encompass positive and negative attitudes of others, legal protections, and discriminatory practices. Personal factors include age, sex, interests, and sense of self-efcacy. Much dynamic change in posture and voluntary motor control occurs in the rst postnatal year. (52) These changes include rostral to caudal pattern of myelination; establishment of visual tracking, reaching, and eye-hand manipulation; and dynamic mobility underlying rolling, maintaining sitting position, crawling, pulling to stand, cruising, and walking. All of these key functional activities are included in the ICF model. Historically, CP was dened as a disorder of movement and posture due to a lesion or dysfunction in the developing brain and included a topography of dysfunction based on the number of affected limbs. The topography includes monoplegia (one lower extremity), hemiplegia (one side of body, arm more than leg), diplegia (bilateral lower extremity involvement), triplegia (combination of diplegia and hemiplegia), and quadriplegia or tetraplegia (four-limb involvement). In the ICF model,
NeoReviews Vol.7 No.11 November 2006 e579

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

development

cerebral palsy

Quadriplegia, microcephaly, seizures, recurrent pneumonias, gastrostomy tube, tracheostomy Unable to roll, unable to maintain sitting balance, does not say any words, cannot hold covered cup Attends infant massage group, unable to nd child care

Family lives on third oor, adapted stroller denied

2-year-old

Likes to be rocked, requires 2 AM feeding

these distinctions reect challenges in body function. Table 2 illustrates a topography with functional descriptors that can be combined with the gross motor function measure, oral motor, and communicative skills in the rst 3 postnatal years. (53) More recently, an expert panel dened CP as a group of (developmental) disorders of movement and posture that cause activity limitations and are attributed to nonprogressive disturbances that occurred in the developing fetal or infant brain. (54) The motor disorders of CP often are accompanied by disturbances of sensation, cognition, communication, perception, or behavior or by a seizure disorder. The expert panel also included anatomic and radiologic ndings as well as considerations of causation and timing as key components of the classication system. Thus, the stage has been set for a more detailed understanding of pathways involved in the syndromes of CP.

Says mom, dad, attains blocks with L hand, likes Simon Attends Easter Seals child care, at regional center for children with special health-care needs, can see orthopedics physical therapy and obtain equipment Screams when frightened, drools, wont let go of other peoples hair

In prone position, unable to extend and bear weight on R arm; supported sitting

Triplegia, partial seizures, on pureed diet

30-month-old

ICF Model and Children Who Have Cerebral Palsy

Lessons From Past Studies of Preterm Cohorts

Important information about the natural history of motor outcomes in children who have CP has accumulated over the past 4 decades. Crothers and Paine (55) demonstrated that hemiplegia and sitting balance in the rst 2 years after birth were key predictors of walking in children who had CP. Campos de Paz and colleagues (56) demonstrated that attaining head righting by 9 months, sitting balance at 24 months, and crawling by 30 months predicted ambulation in children who had CP. Almost all children who had spastic diplegia attained ambulation, and most children who had spastic quadriplegia did not walk. In the Vancouver study of 492 neonates weighing less than 2,000 g born between 1959 and 1964, Dunn followed 80% to age 6.5 years. (57) Of the original cohort, 27% weighed less than 1,500 g. CP was present in 8.1% and distributed as 48% with diplegia, 22% with hemiplegia, 11% with quadriplegia, 15% with monoplegia, and 4% with ataxia. Of the 85% who walked, 100% of those who had hemiplegia and monoplegia walked, 85% of those who had diplegia walked, and 33% of those who had quadriplegia walked. Watt and colleagues (58) examined 737 neonatal intensive care survivors, of whom 74 (10%) were diagnosed with CP. The mean gestational age was 32.9 weeks (SD3.9). At age 8 years, ambulation status was as follows: 57% were independent, 7%

Combat crawls, stands on toes when pulls to stand, cannot cruise, says 5 words Mother loses part-time job because of inability to secure child care Church accepts child into toddler group

Diplegia, strabismus, cystic periventricular leukomalacia

18-month-old

Body function and structure

e580 NeoReviews Vol.7 No.11 November 2006

Table 1.

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

Personal factors

Environmental factors

Participation

Activities

Mother does not know any parent in similar circumstances, early intervention only provides limited physical therapy and occupational therapy, limited access to child care Sleeps through night

No pincer grasp on R, cannot transfer object from L hand to R, cannot cruise from L to R

L porencephalic cyst, R hand contracture, R hemiplia

1-year-old

Attends early intervention play group

Sleeps through night

development

cerebral palsy

than 1,000 g. (60) The same group examined outcomes for 1,016 infants at the threshold of viability. (61) These infants had Type of Cerebral Palsy Classication/Description birthweights of less than 750 g, One-sided Mild: Difculty with performing pincer task on gestational ages of less than 24 Hemiplegia an involved side. completed weeks, and 1-minute Moderate: Intermittently sted, unable to Apgar scores of 3 or less. Some manipulate objects in hand. 75.8% died, and among the surviSevere: Fisted, unable to use hand to assist, vors, 30% had one of the CP synunable to transfer from good hand to the more affected hand. dromes, and almost 1 in 2 had Leg-dominated Mild: Tall kneeling, spasticity at ankle. cognitive developmental disabilDiplegia Moderate: Walks with crouched gait, difculty ity. climbing stairs, spasticity at heels and Bax and colleagues (62) reankles. cently reported a multicenter colSevere: Scissoring, spasticity at hip, unable to stand. laboration that examined clinical Three-limb-dominated Mild: One upper extremity with pincer, easily correlates of CP in a population Triplegia lifts arm over head and extends reach and sample and compared clinical grasp. ndings with information availModerate: Upper extremity with ability to use able on MRI. A cross-sectional rst and third digits. Severe: Raking with best upper extremity. population of children who had Four-limb-dominated Mild: Pulls off socks, self-mobility in prone CP born between 1996 and 1999 Quadriplegia position, sits with hands free. were assembled from eight major Moderate: Assisted sitting, some rolling, European centers. Most imporhandles pureed textures. tantly, 431 children who had CP Severe: Inability to sit or roll both ways, difculty with using hands to feed self, syndromes were assessed clinically difculty with chewing. using a structured history and a systematic neurodevelopmental evaluation that included topograwere independent with aides, and 36% were nonambulaphy (diplegia, hemiplegia, quadriplegia), physiology tory. Topography at age 8 years was distributed as 24% (spasticity, dyskinesia, dystonia, ataxia), and neurologic with hemiplegia, 42% with diplegia, 28% with quadriplecomorbidities involving vision, hearing, and epilepsy. gia, and 5% with movement disorders. In this cohort, all Cranial MRI was undertaken in 351 children at age 18 children who had hemiplegia walked, 90% of children months or later, and the images were reviewed systematwho had diplegia walked, 25% of those who had moveically by a single evaluator using a consensus protocol. ment disorders walked, and none of the children who The study cohort appropriately captured most of the had quadriplegia walked. Of the children who sat before CP syndromes occurring in early childhood (ie, 2 to 5 y). age 2 years, 98% became ambulatory. Almost 1 in 3 children had the diplegic pattern, 1 in 4 had hemiplegia, and 1 in 5 had quadriplegia. Recent Multicenter CP Studies In terms of prenatal risk, approximately 1 in 5 mothers In 2000, Stanley and colleagues (59) proposed that (20%) who had an affected child had a urinary tract etiologic research on single factors should be refocused infection compared with 2.9% in a regional obstetric to include a more comprehensive framework of causal database. More than 50% of the children who had CP pathways to understand the complexity of children who were of term gestation, and 1 in 3 affected children were have CP syndromes. One population at known risk for born by emergency caesarean section. Some 12% of CP is very preterm or extremely preterm infants, espechildren who had CP were from a multiple pregnancy cially at the limit of viability. Recent data from the compared with 1.5% expected. Almost 1 in 5 children 14-center NICHD Neonatal Network showed rates of were small for gestational age (birthweight 10th perCP of 19% in survivors of 22 to 26 weeks gestation and centile). More than 40% of the children who were born at birthweight of less than 1,000 g and 12% for children term spent more than 5 days in the special care unit and who survived 27 to 32 weeks gestation and weighed less were regarded as signicantly ill. Approximately 1 in 3
Table 2.
NeoReviews Vol.7 No.11 November 2006 e581

Topography of Cerebral Palsy at 18 to 24 months

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

development

cerebral palsy

children who had CP were born at either 28 to 31 weeks or 32 to 36 weeks gestational age. Notable, only 10.9% of the children who had CP were born at less than 28 weeks gestation. Recurrent seizures occurred in 28% of infants, hearing impairment in 7.2%, and visual impairment in 33%, characterized by strabismus, restricted elds, and refractive errors. Another major lesson from this study is that most cases of CP are not severe. (25)(53) Approximately 3 in 5 of the children who had CP had hemiplegia or diplegia. This topography has an excellent prognosis for ambulation and, based on the number of limbs involved, can be considered as representing less severe disability. In this group of preschoolers, 89% of those who had hemiplegia were walking, as were 63% of those who had diplegia. (62) Fewer than 1 in 5 of the children who had CP had quadriplegia, and only 9% of those could walk. Most of the children who had quadriplegia had sitting challenges, manipulative challenges, and communicative difculties. (63)(64)(65) Because children who have quadriplegia often have comorbidities of dysphagia, seizures, and recurrent pneumonia, medical students and residents experience such affected children during their periods of hospital training as typical and consider the model of outcomes for CP to be one of severe multiple neurodevelopmental functional challenges and medical frailty. In absolute terms, however, children who have severe manifestations represent only a small minority of all individuals who have CP. Nonetheless, it is this oftenhospitalized minority of all children who have CP that accounts for the greatest share of health and supportive services. Neuroimaging data from the Bax study (62) was most informative. White matter abnormalities were present in 43% of the children, including 71% of children who had diplegia, 34% of children who had hemiplegia, and 35% of children who had quadriplegia. This nding highlights the critical importance of understanding biomarkers and pathways in preterm infants born before 34 weeks gestation as well as some term infants who have experienced problems that suggest vulnerability during their third trimester of intrauterine life. (66)(67)

care unit. However, there is growing concern about the high rates of CP and neurodevelopmental disabilities among these children, especially in those born at 24 to 26 weeks gestation. This cohort represents approximately 10% of all CP cases. A recent epidemiologic review (8) found that with increasing rates of prematurity and multiple gestations, survivors who have CP are increasing in absolute numbers. Their survival translates into a greater prevalence of CP and its comorbidities in the pediatric population. Systematic evaluation of health, developmental, functional, and educational outcomes is required to advance understanding of CP, as is assessment of both healthrelated quality of life and measures of participation. (65) (68)(69)(70)(71) Better understanding of the pathways to CP and existing barriers to dening the disability of CP should allow clinicians to promote the necessary family supports, habilitative resources, and comprehensive medical care. ACKNOWLEDGEMENTS. This work was supported in part by Research Grant 2004-06 13560B from The Childrens Guild of Buffalo entitled Development and Normalization of a Functional Assessment Tool for Children Birth to 36 Months; and U01 HD037614 DHHS/ NICHD Family & Child Well-Being Network entitled Child Disability and the Family. Susan Troyke Plesha, MA, OTR, provided invaluable feedback, and Sporty Watson and Bucky Holmberg taught the importance of follow-up over time. The authors wish to acknowledge the contributions of the University of Chicago Comer and LaRabida Childrens Hospitals rehabilitation teams for their tireless efforts to improve the early identication and parent-professional partnership on behalf of children who have CP. Dr. Romantseva is a Steve AN Goldstein Research Fellow in the University of Chicago Department of Pediatrics.

References

1. Lemons JA, Bauer CR, Oh W, et al. Very low birth weight

Conclusion

Just as maternal corticosteroids, comtinuous positive airway pressure, and surfactant replacement have changed the natural history of respiratory distress syndrome and its sequelae, advances in ventilatory support, regionalization of neonatal care, and extracorporeal membrane oxygenation have led to greater survival of sicker and more preterm infants in the neonatal intensive
e582 NeoReviews Vol.7 No.11 November 2006

outcomes of the National Institute of Child Health and Human Development Neonatal Research Network, January 1995 through December 1996. NICHD Neonatal Research Network. Pediatrics. 2001;107:e1. Available at: http://pediatrics.aappublications.org/ cgi/content/full/107/1/e1 2. Marlow N. Neurocognitive outcome after very preterm birth. Arch Dis Child Fetal Neonatal Ed. 2004;89:F224 F228 3. World Health Organization. International Classication of Functioning Disability and Health. Geneva, Switzerland: World Health Organization; 2001 4. Nelson KB, Ellenberg JH. Apgar scores as predictors of chronic neurologic disability. Pediatrics. 1981;68:36 44

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

development

cerebral palsy

5. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. I.

Univariate analysis of risks. Am J Dis Child. 1985;139:10311038 6. Jacobsson B, Hagberg G. Antenatal risk factors for cerebral palsy. Best Pract Res Clin Obstet Gynaecol. 2004;18:425 436 7. Blair E, Watson L. Epidemiology of cerebral palsy. Semin Fetal Neonatal Med. 2006;11:117125 8. Himmelmann K, Hagberg G, Beckung E, Hagberg B, Uvebrant P. The changing panorama of cerebral palsy in Sweden. IX. Prevalence and origin in the birth-year period 19951998. Acta Paediatr. 2005;94:287294 9. OShea TM. Cerebral palsy in very preterm infants: new epidemiological insights. Ment Retard Dev Disabil Res Rev. 2002;8: 135145 10. Croen LA, Grether JK, Curry CJ, Nelson KB. Congenital abnormalities among children with cerebral palsy: more evidence for prenatal antecedents. J Pediatr. 2001;138:804 810 11. Dite GS, Bell R, Reddihough DS, Bessell C, Brennecke S, Sheedy M. Antenatal and perinatal antecedents of moderate and severe spastic cerebral palsy. Aust N Z J Obstet Gynaecol. 1998;38: 377383 12. Folkerth RD. Periventricular leukomalacia: overview and recent ndings. Pediatr Dev Pathol. 2006;9:313 13. McQuillen PS, Ferriero DM. Selective vulnerability in the developing central nervous system. Pediatr Neurol. 2004;30: 227235 14. Topp M, Huusom LD, Langhoff-Roos J, Delhumeau C, Hutton JL, Dolk H. Multiple birth and cerebral palsy in Europe: a multicenter study. Acta Obstet Gynecol Scand. 2004;83:548 553 15. Hoyert DL, Mathews TJ, Menacker F, Strobino DM, Guyer B. Annual summary of vital statistics: 2004. Pediatrics. 2006;117: 168 183 16. Centers for Disease Control and Prevention (CDC). Economic costs associated with mental retardation, cerebral palsy, hearing loss, and visual impairment-United States, 2003. MMWR Morb Mortal Wkly Rep. 2004;53:5759 17. Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whiteld MF, Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators. Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely lowbirth-weight infants at 18 months: results from the trial of indomethacin prophylaxis in preterms. JAMA. 2003;289:1124 1129 18. Stoll BJ, Hansen NI, Adams-Chapman I, et al, National Institute of Child Health and Human Development Neonatal Research. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA. 2004; 292:23572365 19. Ment L, Vohr B, Allan W. Outcome of children in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics. 2000;105:485 491 20. Hintz SR, Kendrick DE, Stoll BJ, et al. Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis. Pediatrics. 2005;115:696 703 21. Msall M, Phelps DL, DiGaudio KM, et al. Severity of neonatal retinopathy of prematurity is predictive of neurodevelopmental functional outcome at age 5.5 years. Pediatrics. 2000;106:998 1005 22. Laplaza FJ, Root L, Tassanawipas A, Cervera P. Cerebral palsy in twins. Dev Med Child Neurol. 1992;34:10531063 23. Pharoah PO. Risk of cerebral palsy in multiple pregnancies. Clin Perinatol. 2006;33:301313 24. De Vries LS, Van Haastert IL, Rademaker KJ, Koopman C,

Groenendaal F. Ultrasound abnormalities preceding cerebral palsy in high-risk preterm infants. J Pediatr. 2004;144:815 820 25. Vohr BR, Msall ME, Wilson D, Wright LL, McDonald S, Poole WK. Spectrum of gross motor function in extremely low birth weight children with cerebral palsy at 18 months of age. Pediatrics. 2005;116:123129 26. Laptook AR, OShea TM, Shankaran S, Bhaskar B, NICHD Neonatal Network. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics. 2005;115:673 680 27. Hamrick SE, Miller SP, Leonard C, et al. Trends in severe brain injury and neurodevelopmental outcome in premature newborn infants: the role of cystic periventricular leukomalacia. J Pediatr. 2004;145:593599 28. Rogers B, Msall M, Owens T, Guernsey K, Brody A, Buck G, Hudak M. Cystic periventricular leukomalacia and type of cerebral palsy in preterm infants. J Pediatr. 1994;125:S1S8 29. Murata Y, Itakura A, Matsuzawa K, Okumura A, Wakai K, Mizutani S. Possible antenatal and perinatal related factors in development of cystic periventricular leukomalacia. Brain Dev. 2005;27: 1721 30. Neil JJ, Inder TE. Imaging perinatal brain injury in premature infants. Semin Perinatol. 2004;28:433 443 31. OShea TM, Counsell SJ, Bartels DB, Dammann O. Magnetic resonance and ultrasound brain imaging in preterm infants. Early Hum Dev. 2005;81:263271 32. Debillon T, NGuyen S, Muet A, Quere MP, Moussaly F, Roze JC. Limitations of ultrasonography for diagnosing white matter damage in preterm infants. Arch Dis Child. 2003; 88:275279 33. Miller SP, Cozzio CC, Goldstein RB, et al. Comparing the diagnosis of white matter injury in premature newborns with serial MR imaging and transfontanel ultrasonography ndings. Am J Neuroradiol. 2003;24:16611669 34. Paneth N, Rudelli R, Kazam E, Monte W. Germinal matrix and intraventricular bleeding: location, extent, ultrasound imaging. In: Brain Damage in the Preterm Infant. London, United Kingdom: Cambridge University Press; 1994:7198 35. Mirmiran M, Barnes PD, Keller K, et al. Neonatal brain magnetic resonance imaging before discharge is better than serial cranial ultrasound in predicting cerebral palsy in very low birth weight preterm infants. Pediatrics. 2004;114:992998 36. Woodward LJ, Anderson PJ, Austin NC, Howard K, Inder TE. Neonatal MRI to predict neurodevelopmental outcomes in preterm infants. N Engl J Med. 2006;355:685 694. 37. Accardo J, Kammann H, Hoon AH, Jr. Neuroimaging in cerebral palsy. J Pediatr. 2004;145(2 suppl):S19 S27 38. Hoon AH Jr. Neuroimaging in cerebral palsy: patterns of brain dysgenesis and injury. J Child Neurol. 2005;20:936 939 39. Inder T, Huppi PS, Zientara GP, et al. Early detection of periventricular leukomalacia by diffusion-weighted magnetic resonance imaging techniques. J Pediatr. 1999;134:631 634 40. Lee SK, Kim DI, Kim J, et al. Diffusion-tensor MR imaging and ber tractography: a new method of describing aberrant ber connections in developmental CNS anomalies. Radiographics. 2005;25:53 65 41. Palmer FB. Strategies for the early diagnosis of cerebral palsy. J Pediatr. 2004;145(2 suppl):S8 S11 42. Hadders-Algra M. General movements: a window for early identication of children at high risk for developmental disorders. J Pediatr. 2004;145(2 suppl):S12S18 43. Freeman JM, National Institute of Child Health and Human
NeoReviews Vol.7 No.11 November 2006 e583

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

development

cerebral palsy

Development (U.S.), National Institute of Neurological and Communicative Disorders and Stroke. Prenatal and Perinatal Factors Associated With Brain Disorders. Bethesda, Md: National Institute of Child Health and Human Development, National Institute of Neurological and Communicative Disorders and Stroke, United States Department of Health and Human Services, Public Health Service, National Institutes of Health; 1985 44. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy. Multivariate analysis of risk. N Engl J Med. 1986;315:81 86 45. Capute AJ, Palmer FB, Shapiro BK, Wachtel RC, Ross A, Accardo PJ. Primitive reex prole: a quantitation of primitive reexes in infancy. Dev Med Child Neurol. 1984;26:375383 46. Blasco PA. Primitive reexes: their contribution to the early detection of cerebral palsy. Clin Pediatr (Phila). 1994;33:388 397 47. Zafeiriou DI, Tsikoulas IG, Kremenopoulos GM, Kontopoulos EE. Using postural reactions as a screening test to identify high-risk infants for cerebral palsy: a prospective study. Brain Dev. 1998; 20:307311 48. Capute AJ, Shapiro BK. The motor quotient: a method for the early detection of motor delay. Am J Dis Child. 1985:139:940 942 49. Capute AJ, Blehl RF. Functional developmental evaluation: prerequisite to habilitation. Pediatr Clin North Am. 1973;20:326 50. Capute AJ, Accardo PJ. The infant neurodevelopmental assessment: a clinical interpretive manual for CAT-CLAMS in the rst two years of life. Curr Probl Pediatr. 1996;26:238 257, 279 306 51. Ferrari F, Cioni G, Einspieler C, et al. Cramped synchronized general movements in preterm infants as an early marker for cerebral palsy. Arch Pediatr Adolesc Med. 2002;156:460 467 52. Campbell S. The childs development of functional movement. In: Physical Therapy for Children. Philadelphia: WB Saunders Co; 1994:337 53. Msall ME. The panorama of cerebral palsy after very and extremely preterm birth: evidence and challenges. Clin Perinatol. 2006;33:269 284 54. Bax M, Goldstein M, Rosenbaum P, et al. Proposed denition and classication of cerebral palsy, April 2005. Dev Med Child Neurol. 2005;47:571576 55. Crothers B, Paine RJ. The Natural History of Cerebral Palsy. London, United Kingdom: MacKeith Press; 1988 56. Campos da Paz A, Burnett SM, Braga LW. Walking prognosis in cerebral palsy: a 22-year retrospective analysis. Dev Med Child Neurol. 1994;36:130 134

57. Dunn HG. Sequelae of Low Birthweight: The Vancouver Study.

ambulation of neonatal intensive care survivors with cerebral palsy. Dev Med Child Neurol. 1989;31:766 773 59. Stanley F, Blair E, Alberman E. Cerebral Palsies: Epidemiology and Causal Pathways. Clinics in Developmental Medicine. No. 151. London, United Kingdom: Mac Keith Press; 2000 60. Vohr BR, Wright LL, Poole WK, McDonald SA. Neurodevelopmental outcomes of extremely low birth weight infants 32 weeks gestation between 1993 and 1998. Pediatrics. 2005; 116:635 643 61. Shankaran S, Johnson Y, Langer JC, et al. Outcome of extremely-low-birth-weight infants at highest risk: gestational age or 24 weeks, birth weight or 750 g, and 1-minute Apgar or 3. Am J Obstet Gynecol. 2004;191:1084 1091 62. Bax M, Tydeman C, Flodmark O. The Multicenter European Cerebral Palsy Study: an overview of the clinical and MI ndings of 431 children. JAMA. 2006. In press 63. Shapiro BK. Cerebral palsy: a reconceptualization of the spectrum. J Pediatr. 2004;145(2 suppl):S3S7 64. Rogers B. Feeding method and health outcomes of children with cerebral palsy. J Pediatr. 2004;145(2 suppl):S28 S32 65. Liptak GS, Accardo PJ. Health and social outcomes of children with cerebral palsy. J Pediatr. 2004;145(2 suppl):S36 S41 66. Back SA, Rivkees SA. Emerging concepts in periventricular white matter injury. Semin Perinatol. 2004;28:405 414 67. Dammann O, Leviton A. Inammatory brain damage in preterm newborns dry numbers, wet lab, and causal inferences. Early Hum Dev. 2004;79:115 68. Msall ME, Tremont MR. Measuring functional outcomes after prematurity: Developmental impact of very low birth weight and extremely low birth weight status on childhood disability. Ment Retard Dev Disabil Res Rev. 2002;8:258 272 69. Marlow N, Wolke D, Bracewell MA, Samara M, EPICure Study Group. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med. 2005;352: 9 19 70. Ment L, Vohr B, Allan W. Outcome of children in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics. 2000;105:485 491 71. Rogers B. Feeding method and health outcomes of children with cerebral palsy. J Pediatr. 2004;145(2 suppl):S28 S32

58. Watt JM, Robertson CM, Grace MG. Early prognosis for

London, United Kingdom: MacKeith Press; 1986

e584 NeoReviews Vol.7 No.11 November 2006

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

development

cerebral palsy

NeoReviews Quiz
3. Several risk factors during prenatal, perinatal, and postnatal development have been proposed as predictors of cerebral palsy in preterm infants. Of the following, the highest rate of cerebral palsy among preterm infants is associated with: A. B. C. D. E. Bronchopulmonary dysplasia. Necrotizing enterocolitis requiring surgery. Parenchymal brain injury. Sepsis or meningitis. Severe retinopathy of prematurity.

4. You are examining a preterm infant, whose birthweight was 790 g and estimated gestational age at birth was 24 weeks, in the follow-up clinic at 4 months of postmenstrual age. The parents inquire about the probability of the development of cerebral palsy in their child. Of the following, the EARLIEST method for prediction of cerebral palsy with high sensitivity and specicity is the assessment of: A. B. C. D. E. Motor milestones. Muscle tone. Postural responses. Primitive reexes. Spontaneous general movements.

5. Historically, the description of cerebral palsy has included topography based on the number of affected limbs. Of the following, the most common topography among preterm survivors with cerebral palsy is: A. B. C. D. E. Diplegia. Hemiplegia. Monoplegia. Quadriplegia. Triplegia.

NeoReviews Vol.7 No.11 November 2006 e585

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012

Advances in Understanding Cerebral Palsy Syndromes After Prematurity Lubov Romantseva and Michael E Msall Neoreviews 2006;7;e575 DOI: 10.1542/neo.7-11-e575

Updated Information & Services References

including high resolution figures, can be found at: http://neoreviews.aappublications.org/content/7/11/e575 This article cites 63 articles, 17 of which you can access for free at: http://neoreviews.aappublications.org/content/7/11/e575#BIBL This article, along with others on similar topics, appears in the following collection(s): Fetus and Newborn Infant http://neoreviews.aappublications.org/cgi/collection/fetus_newb orn_infant Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml Information about ordering reprints can be found online: /site/misc/reprints.xhtml

Subspecialty Collections

Permissions & Licensing

Reprints

Downloaded from http://neoreviews.aappublications.org/ at UNIV OF CHICAGO on July 10, 2012