Cerebral Palsy.romantseva

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DOI: 10.1542/neo.7-11-e5752006;7;e575Neoreviews

Lubov Romantseva and Michael E MsallAdvances in Understanding Cerebral Palsy Syndromes After Prematurity

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Advancesin UnderstandingCerebral Palsy Syndromes AfterPrematurityLubov Romantseva, MD,*

Michael E. Msall, MD*

Author Disclosure

Drs Romantseva and

Msall did not disclose

any financial

relationships relevant

to this article.

Objectives After completing this article, readers should be able to:

1. List neonatal morbidities that have been associated with the development of cerebralpalsy (CP).

2. Describe the ultrasonographic findings 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 Classification 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, andtranslational 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 weightsbetween 751 and 999 g, and 60% for infants born weighing 500 to 750 g. (1) These

birthweight categories approximately reflect appropriate weights for 28 to 32 weeks, 26 to27 weeks, and 23 to 25 weeks gestation, respectively. Although survival has improved

among these very and extremely preterm infants, prevention of adverse neurodevelopmen-tal 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 commonearly recognized neurodevelopmental impairment is cerebral palsy (CP), and the overallprevalence of this disorder has not decreased over the past 25 years. However, with recent

discoveries in brain structure and function, immunology, nutrition, early childhoodlearning, and developmental plasticity, the future holds promise.

The purpose of this review is to describe risk factors for CP in preterm infants, focusingpredominantly on extremely low-birthweight (ELBW) and very low-birthweight infants,

but also highlighting gaps in the current knowledge of outcomes among moderatelylow-birthweight infants. Recent data from multicenter studies emphasize the complexpathways to the CP syndromes in infants born very and extremely preterm.

We use as a framework the International Classification 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 forchildren who have diplegic, hemiplegic, triplegic, and quadriplegic CP after prematurity.

We also illustrate the value of early motor milestones, sequential neurodevelopmentalevaluation at key ages, and a classification system at age 2 years to optimize habilitativestrategies in the preschool years. It is critically important to understand causal pathways,

the spectrum of developmental functioning, and family supports to devise preventionstrategies for future vulnerable populations of preterm infants receiving new technologies.

Current epidemiology evidence suggests that approximately 1 in 3 children who haveCP 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, groupsconsidered 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



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term and moderate preterm infants of 32 to 36 weeks

gestation, term and preterm pregnancies affected by in-trauterine growth restriction (IUGR), and pregnancies

involving multiple births is critical to efforts at reducingthe prevalence of CP. (10) (11)(12)(13)(14)(15) More

than 750,000 children andadults in the UnitedStates areaffected by one of the CP syndromes, with the lifetimecost 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 interm infants and extreme prematurity led to the errone-

ous perception that these two risk groups of childrenaccounted for the majority of cases of CP.

Neonatal Morbidities and Risk for CP

Although a multitude of risk factors for CP in the prena-tal, perinatal, and postnatal course of the preterm babyhave been proposed, this review focuses on several vari-

ables shown to be significant predictors of future CP inmulticenter studies. Five risk factors are especially impor-tant: 1) parenchymal brain injury (defined as intraven-

tricular hemorrhage [IVH] grade 3 or 4), ventriculo-megaly, or cystic periventricular leukomalacia (PVL);

2) postnatal sepsis, necrotizing enterocolitis (NEC), ormeningitis; 3) chronic lung disease (CLD) (defined as

supplemental oxygen at 36 weeks gestation); 4) severeretinopathy of prematurity (ROP) (stage 4 or 5); and

5) multiple gestation.

Schmidt and colleagues (17) examined parenchymalbrain injury, CLD, and severe ROP in 910 infants who

weighed less than 1,000 g at birth and were enrolled in astudy of prophylactic indomethacin to prevent IVH.

Among survivors to 18 months of age, 1 in 7 had CP and1 in 4 had cognitive disability. Notably, rates of CP

increased to 36% for those who had parenchymal braininjury. Additionally, 24% of children who had severeROP 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 ofmortality between 1.2% and 3%.) In contrast, the rates of

death or neurodevelopmental disability were 88% if allthree of the comorbidities were present, with a risk ofmortality of approximately 10%. More than three-

quarters (78%) of the children who had parenchymalbrain injury or severe ROP had neurodevelopmental

disability.Several recent reports have examined the impact of

infection such as sepsis, meningitis, or NEC on neurode-velopmental outcomes of survivors of very preterm birth.

Stoll and colleagues (18) retrospectively studied the roleof postnatal infection on outcomes of survivors whosebirthweights were between 401 and 1,000 g and who

were born between 1993 and 2001 in the NationalInstitute of Child Health and Human Development

(NICHD) Neonatal Network. Three primary risk groupswere identified: 1) infants who were infection-free dur-

ing their hospital stay (n2,161); 2) infants who hadclinical infections requiring antibiotics for at least 5 daysor sepsis (n3,460); and 3) infants who had NEC or

meningitis (n472). Some 65% of survivors had postna-tal infections, the overwhelming majority of which were

late-onset (72 h after birth). In the infection-freegroup, 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 greaterrates of cognitive disability (defined as a Bayley II mentaldevelopmental index [MDI] of 70 at 18 months of

age). Cognitive disability occurred in approximately 1 in5 infants who were infection-free and in 1 in 3 to 2 in 5

of those who had infection. Notably, the relationshipbetween infection status and neurodevelopmental dis-

ability held after adjusting for CLD and ultrasonographi-cally detected parenchymal brain injury, two ofSchmidts major determinants of adverse outcomes in

extremely preterm cohorts. (17)(19)These findings are underscored by another study of

ELBW survivors who did and did not have NEC from the

same NICHD Neonatal Network group. (20) The inves-tigators compared rates of neurodevelopmental disabilityin infants who had required medical or surgical manage-ment of NEC and those who did not have NEC. They

found that 24% of children who had surgically managedNEC developed CP, and 37% of those children had

cognitive disabilities. Thus, the impact of NEC reachesbeyond the gastrointestinal system, affecting both neu-

romotor 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 Pre-maturity Study, (21) children who reached threshold

ROP but had favorable visual status at 5.5 years had a rateof motor functional disability of 5%, reflecting ongoing

challenges in basic upright mobility. Self-care functionaldisability was present in 25% of children, reflecting chal-

lenges in feeding, dressing, and grooming. In contrast,children who had threshold ROP and an unfavorablevisual 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

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had rates of motor and self-care functional disabilities of

less than 10%. These data suggest that severe ROP is animportant marker for the severity of neuromotor and

self-care adaptive disability at kindergarten entry.Advancing reproductive technologies have been asso-

ciated with a marked increase in the birth and survival oftwins, 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, theconcept was confirmed by several studies in which twins

contributed 5% to 10% of CP cases, even though twinsaccounted for only 1.6% of all live births. (22) The

disproportionately large number of twins in CP cohortswas confirmed by a multicenter registry that showed a

fourfold higher rate of CP among twins compared withsingle 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; inone of triplets, the risk is 100 in 1,000; and in one ofquadruplets, 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 viaNeuroimagingIn many centers, ultrasonography remains the mainstay

of intracranial imaging for preterm newborns because itis an efficient bedside imaging tool with minimal distur-

bance to the fragile baby. Ultrasonography is most useful

for detecting space lesions, such as hydrocephalus, hem-orrhage, or PVL. However, timing of the examination is

critical; cystic PVL often cannot be visualized until 32 to34 weeks postmenstrual age (PMA). De Vries and col-

leagues (24) demonstrated the value of sequential ultra-sonographic imaging for all infants up to 32 weeks PMA

and showed a sensitivity of 95%, a specificity of 99%, anda 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 NICHDNeonatal Network cohort, PVL was documented in 51%

of those who had quadriplegia, 24% of those who hadhemiplegia, and 19% of those who had diplegia. Addi-

tionally, they documented grade 3/4 IVH among 67%of those who had hemiplegia, 48% of those who hadquadtiplegia, and 35% of those who had diplegia. Ap-

proximately 1 in 2 of ELBW survivors who had CP didnot have ultrasonographically detected grade 3/4 IVH,

PVL, or ventriculomegaly. In another study, Laptookand associates (26) followed the outcomes of children at

ages 18 to 24 months who were born weighing less than1,000 g and had normal findings on cranial ultrasonog-

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 le-

sion often linked to preterm CP, Hamrick and colleagues(27) found that although cystic PVL was highly predic-

tive of future CP, the severity of outcome varied. How-ever, 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 dis-ability. In contrast, Rogers and colleagues (28) found

that cystic PVL occurred in 3% of ELBW survivors andthat size and location of cysts predicted the severity of

disability. Children who had bilateral and large cysts hadhigh rates of quadriplegic CP and severe cognitive dis-

ability. Interestingly, although the rate of ultrasono-graphically detected cystic PVL decreased between the

years of 1992 and 2002, the rate of CP for the samecohort and time period did not. Based on these findings,researchers have concluded that brain abnormalities

other than cystic PVL and PVHI (that presumably areuntedectable by cranial ultrasonography) are likely to be

responsible for a significant portion of preterm CP cases.(29)(30)

Magnetic Resonance Imaging (MRI) and NewTechniquesIn addition to cranial ultrasonography, brain MRI is anincreasingly popular imaging technique that offers

greater detail of white matter and areas not easily ac-

cessed by ultrasonography. Several investigators havesought to compare the sensitivity and specificity of brain

ultrasonography with that of brain MRI in preterm in-fants. A recent review (31) demonstrated that the heter-

ogeneity of the studies add to the difficulty in rigorouscomparisons because they vary in definition/gradation of

abnormal findings, study samples, image timing, andoutcome measures. However, several common themeshave emerged.

First, ultrasonography and MRI complement eachother because they appear best suited to detect different

types of lesions in the preterm brain. The are bothnoninvasive and can be used at different critical develop-

mental stages. Ultrasonography has very good sensitivityfor cystic and large hemorrhagic lesions, and MRI ismuch 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 ascystic PVL and PVHI has declined in recent years, with

noncystic white matter abnormalities such as ventriculo-megaly, white matter atrophy, and diffuse excessive high-




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signal intensity among the most commonly reported

preterm brain injuries. (31)Second, serial ultrasonography improves the modali-

tys sensitivity and specificity, as supported by studiescorrelating serial ultrasonography and histopathology for

germinal matrix hemorrage/IVH lesions. (34) DeVriesand colleagues (24) showed that even with weekly ultra-sonographic scanning, 46% of hypoechoic white matter

lesions were not detected until after 28 days after birth,and 14% were not identified until 40 weeks PMA.

Third, at this time, it remains unclear whether serialultrasonography can approach the sensitivity and speci-

ficity of MRI. The available comparative studies have awide range of values, but three studies deserve specific

comment. Devries and associates (24) reported that se-rial ultrasonography had a sensitivity of 76% to 86% and

a specificity of 95% to 99% for infants more than 32 weeksgestational age. Mirmiran and colleagues (35) comparedcranial MRI at near term (36 to 40 weeks PMA) with

serial cranial ultrasonography in infants who weighed lessthan 1,250 g and were less than 30 weeks gestation.

MRI was 86% sensitive and 89% specific for detecting CPat 2.5 years. In comparison, ultrasonography was 43%sensitive and 82% specific for detecting CP. Woodward

and colleagues (36) reported similar numbers for sensi-tivity and specificity in a prospective investigation of 167

infants born at 30 weeks gestational age or younger whowere followed with serial cranial ultrasonography and

brain MRI at term age equivalent, comparing the rate of

imaging-detected abnormalities with the neurodevelop-mental outcome at 2 years corrected age. They found

that moderate-to-severe white matter MRI abnormalitiespredicted CP with a sensitivity of 65%.

Thus, it is critically important to recognize both thevalue and responsibility of including an MRI exam at

36 weeks PMA for the high-risk cohort of preterm in-fants. Needless to say, the study must be performedsafely, avoiding sedation whenever possible. More im-

portantly, however, is the need to provide affected fam-ilies 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 theinterpretation of results to families and colleagues.

Brain MRI also brings an expanding array of newtechniques and protocols for imaging the preterm brain,providing more detailed visualization of white matter.

(37)(38) Currently, T1- and T2-weighted images are thepart of the standard preterm imaging protocol. Because

neonatal brains have greater water content than adultbrains, MR pulse sequences must be adequately adjusted,

and T1- and T2-weighted fast spin echo are consideredoptimal. Other techniques, such as diffusion-weightedimaging/diffusion tensor imaging (DTI), may detect

white matter damage before it is demonstrated on con-ventional MRI. (39) DTI and fiber tractography were

employed to image two patients known to have CP in arecent report by Lee and colleagues. (40) Although these

techniques currently remain in a largely experimentalrealm, they offer much promise in advancing under-standing of CP at the neural fiber tract level.

Advances in the Early Detection of CPDespite a growing understanding of the risk factors andpathways to CP, the methods of detecting CP in ahigh-risk population need to be much improved; no

existing imaging strategy has 95% sensitivity and specific-

ity. Early detection of CP-related lesions is critical totimely diagnosis, which is directly related to accessinghabilitative and family support services.

Palmer (41) points out two major challenges in theearly detection of CP. First, the clinical manifestations of

CP evolve and declare themselves over time as the childdevelops and either attains or struggles to reach appro-priate milestones. Although the structural impairment of

the developing brain has occurred in one of severalpossible developmental epochs, ranging from precon-

ception to first trimester, second trimester, third trimes-ter, perinatal, neonatal, and early childhood, the conse-

quences cannot be fully appreciated until the child has

gone through several major stages of central nervoussystem (CNS) development that underlie motor, manip-

ulative, and communicative skills. In other words, chil-dren can befreefrom signs of dysfunction at early age but

grow into a functional challenge with increasing agebecause of age-related increase in the complexity of

neural functions. (42) This concept is illustrated by thelandmark articles from the National Collaborative Peri-natal Project (NCPP). (43) In comparing the results of

the infant neurologic examination to the outcome at 7years of age, only 23% of children who had diagnosed CP

at 7 years had abnormal examination findings as new-borns. (44) Further, the predictive ability of a 4-month-

old examination was only slightly better. Finally, approx-imately 50% of the children diagnosed as having CP atage 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 neuro-logic examination, when applied to the infant, is better

suited to catalog all the existing impairments rather thanto detect the particular impairments that are likely to




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result in functional limitations in the future. Early detec-

tion of such functionally relevant impairments is criticalbecause it drives intervention and family supports that

optimize positioning, handling, feeding, and the devel-opment of skills in self-mobility, manipulation, and com-

munication. Several different strategies have been inves-tigated to adapt the infant neurologic examination to thetask of early detection of CP.

Some authors have added the assessment of primitivereflexes and postural responses to the standard neuro-

logic examination, with resultant moderate improve-ment in sensitivity and specificity for the early detection

of CP. (45)(46) This approach emphasizes persistentprimitive reflexes, especially the asymmetric tonic neck

reflex, tonic labyrinthine supine reflex, and positive sup-port reflex. Zafeiriou and colleagues (47) used seven

specific postural reactions (PRs), in addition to the neu-rologic examination, as a screening tool for predictingfuture CP in a high-risk cohort of neonatal intensive care

unit survivors. They followed 204 preterm and terminfants with serial augmented neurologic examinations

during infancy and subsequently at 3 years of age. At 3years 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 laterdiagnosed with CP, 86% had at least five abnormal PRs at

1 month of age compared with no children having morethan four abnormal PRs and 99% having only three

abnormal PRs in the unaffected group. Thus, this

method of augmenting neurologic examination withassessment of seven specific PRs appears promising and

capable of predicting CP at a very young age. Studylimitations, including small numbers of patients and a

single examiner, require that these results be reconfirmedby other investigators.

Another strategy makes use of operationally definedmotor milestones and calculates a motor quotient topredict CP at an early age. (48)(49)(50) For example, a

motor quotient of less than 0.5 at 8 months of agepredicts delayed age of walking (24 months) with a

sensitivity of 87% and specificity of 89%. (41) However,this method loses its utility in children younger than 6

months of age. This can be attributed to the importanceof a child reaching a CNS level of maturity and myelina-

tion equivalent to a 6-month-old child or CNS motordevelopment progressing to a level that allows observa-tion of trunk control, sitting balance, and hand function.

A third advance in the early detection of CP wasdiscovered 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 specifictype of abnormal spontaneous GM, termed crampedsynchronized GM, predicted CP diagnosis at age 2 to 3

years with a sensitivity of 100% and specificity of 93%. Inaddition, the technique predicted the severity of motor

delay, with the earlier onset of abnormal movementcorrelating to greater functional limitation. To our

knowledge, this technique represents the earliest methodof CP prediction with such good sensitivity and specific-ity. However, the sample size is small, and additional

research is warranted.

Using the ICF FrameworkThe ICF framework is a useful tool to attempt to under-stand factors of risk and resiliency with respect to out-

comes. 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 struc-

tures of the nervous, sensory, and musculoskeletal sys-tems. (3) Body functions are the physiologic functions of

body systems, including psychological functions, such asattending, remembering, and thinking. Activities aretasks and include learning, communicating, walking,

feeding, dressing, toileting, and playing. Participationmeans involvement in community life, such as relation-

ships, child care, and preschool education. The ICFmodel also accounts for contextual factors in a childs life,

including environmental and personal factors. Environ-

mental factors, such as policy, social, and physical facili-tators and barriers, encompass positive and negative atti-

tudes of others, legal protections, and discriminatorypractices. Personal factors include age, sex, interests, and

sense of self-efficacy.Much dynamic change in posture and voluntary mo-

tor control occurs in the first postnatal year. (52) Thesechanges 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 activi-ties are included in the ICF model.

Historically, CP was defined as a disorder of move-ment and posture due to a lesion or dysfunction in thedeveloping brain and included a topography of dysfunc-

tion based on the number of affected limbs. The topog-raphy includes monoplegia (one lower extremity), hemi-

plegia (one side of body, arm more than leg), diplegia(bilateral lower extremity involvement), triplegia (com-

bination of diplegia and hemiplegia), and quadriplegia ortetraplegia (four-limb involvement). In the ICF model,




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these distinctions reflect challenges in body func-

tion. Table 2 illustrates a topography with functionaldescriptors that can be combined with the gross

motor function measure, oral motor, and commu-nicative skills in the first 3 postnatal years. (53)

More recently, an expert panel defined CP as agroup of (developmental) disorders of movementand posture that cause activity limitations and are

attributed to nonprogressive disturbances that oc-curred in the developing fetal or infant brain. (54)

The motor disorders of CP often are accompaniedby disturbances of sensation, cognition, communi-

cation, perception, or behavior or by a seizure dis-order. The expert panel also included anatomic and

radiologic findings as well as considerations of cau-sation and timing as key components of the classifi-

cation system. Thus, the stage has been set for amore detailed understanding of pathways involvedin the syndromes of CP.

Lessons From Past Studies of PretermCohortsImportant information about the natural history ofmotor outcomes in children who have CP has accu-

mulated over the past 4 decades. Crothers and Paine(55) demonstrated that hemiplegia and sitting bal-

ance in the first 2 years after birth were key predic-tors of walking in children who had CP. Campos de

Paz and colleagues (56) demonstrated that attaining

head righting by 9 months, sitting balance at 24months, and crawling by 30 months predicted am-

bulation in children who hadCP. Almost all childrenwho had spastic diplegia attained ambulation, and

most children who had spastic quadriplegia did notwalk.

In the Vancouver study of 492 neonates weigh-ing 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. CPwas present in 8.1% and distributed as 48% with

diplegia, 22% with hemiplegia, 11% with quadriple-gia, 15% with monoplegia, and 4% with ataxia. Of

the 85% who walked, 100% of those who had hemi-plegia and monoplegia walked, 85% of those whohad diplegia walked, and 33% of those who had

quadriplegia walked.Watt and colleagues (58) examined 737 neonatal

intensive care survivors, of whom 74 (10%) werediagnosed with CP. The mean gestational age was

32.9 weeks (SD3.9). At age 8 years, ambulationstatus was as follows: 57% were independent, 7%T

able

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were independent with aides, and 36% were nonambula-tory. Topography at age 8 years was distributed as 24%

with hemiplegia, 42% with diplegia, 28% with quadriple-gia, and 5% with movement disorders. In this cohort, all

children who had hemiplegia walked, 90% of childrenwho had diplegia walked, 25% of those who had move-

ment disorders walked, and none of the children whohad quadriplegia walked. Of the children who sat beforeage 2 years, 98% became ambulatory.

Recent Multicenter CP StudiesIn 2000, Stanley and colleagues (59) proposed thatetiologic research on single factors should be refocused

to include a more comprehensive framework of causalpathways to understand the complexity of children whohave CP syndromes. One population at known risk for

CP is very preterm or extremely preterm infants, espe-cially at the limit of viability. Recent data from the

14-center NICHD Neonatal Network showed rates ofCP of 19% in survivors of 22 to 26 weeks gestation and

birthweight of less than 1,000 g and 12% for childrenwho survived 27 to 32 weeks gestation and weighed less

than 1,000 g. (60) The same

group examined outcomes for1,016 infants at the threshold of

viability. (61) These infants hadbirthweights of less than 750 g,

gestational ages of less than 24completed weeks, and 1-minuteApgar scores of 3 or less. Some

75.8% died, and among the survi-vors, 30% had one of the CP syn-

dromes, and almost 1 in 2 hadcognitive developmental disabil-

ity.Bax and colleagues (62) re-

cently reported a multicenter col-laboration that examined clinical

correlates of CP in a populationsample and compared clinicalfindings with information avail-

able on MRI. A cross-sectionalpopulation of children who had

CP born between 1996 and 1999were assembled from eight majorEuropean centers. Most impor-

tantly, 431 children who had CPsyndromes were assessed clinically

using a structured history and asystematic neurodevelopmental

evaluation that included topogra-

phy (diplegia, hemiplegia, quadriplegia), physiology(spasticity, dyskinesia, dystonia, ataxia), and neurologic

comorbidities involving vision, hearing, and epilepsy.Cranial MRI was undertaken in 351 children at age 18

months or later, and the images were reviewed systemat-ically by a single evaluator using a consensus protocol.

The study cohort appropriately captured most of theCP syndromes occurring in early childhood (ie, 2 to 5 y).

Almost 1 in 3 children had the diplegic pattern, 1 in 4had hemiplegia, and 1 in 5 had quadriplegia.

In terms of prenatal risk, approximately 1 in 5 mothers

(20%) who had an affected child had a urinary tractinfection compared with 2.9% in a regional obstetric

database. More than 50% of the children who had CPwere of term gestation, and 1 in 3 affected children were

born by emergency caesarean section. Some 12% ofchildren who had CP were from a multiple pregnancycompared with 1.5% expected. Almost 1 in 5 children

were small for gestational age (birthweight 10th per-centile). More than 40% of the children who were born at

term spent more than 5 days in the special care unit andwere regarded as significantly ill. Approximately 1 in 3

Table 2.Topography of Cerebral Palsy at 18 to24 months

Type of Cerebral Palsy Classification/Description

One-sidedHemiplegia

Mild: Difficulty with performing pincer task onan involved side.

Moderate: Intermittently fisted, unable tomanipulate objects in hand.

Severe: Fisted, unable to use hand to assist,unable to transfer from good hand to themore affected hand.

Leg-dominatedDiplegia

Mild: Tall kneeling, spasticity at ankle.Moderate: Walks with crouched gait, difficulty

climbing stairs, spasticity at heels andankles.

Severe: Scissoring, spasticity at hip, unable tostand.

Three-limb-dominatedTriplegia Mild: One upper extremity with pincer, easilylifts arm over head and extends reach andgrasp.

Moderate: Upper extremity with ability to usefirst and third digits.

Severe: Raking with best upper extremity.Four-limb-dominated

QuadriplegiaMild: Pulls off socks, self-mobility in prone

position, sits with hands free.Moderate: Assisted sitting, some rolling,

handles pureed textures.Severe: Inability to sit or roll both ways,

difficulty with using hands to feed self,difficulty with chewing.




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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 impair-

ment in 33%, characterized by strabismus, restrictedfields, and refractive errors.

Another major lesson from this study is that most

cases of CP are not severe. (25)(53) Approximately 3 in5 of the children who had CP had hemiplegia or diplegia.

This topography has an excellent prognosis for ambula-tion and, based on the number of limbs involved, can be

considered as representing less severe disability. In thisgroup 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 ofthe children who had quadriplegia had sitting challenges,manipulative challenges, and communicative difficulties.

(63)(64)(65) Because children who have quadriplegiaoften have comorbidities of dysphagia, seizures, and

recurrent pneumonia, medical students and residentsexperience such affected children during their periods ofhospital training as typical and consider the model of

outcomes for CP to be one of severe multiple neurode-velopmental functional challenges and medical frailty. In

absolute terms, however, children who have severe man-ifestations represent only a small minority of all individ-

uals who have CP. Nonetheless, it is this often-

hospitalized minority of all children who have CP thataccounts for the greatest share of health and supportive

services.Neuroimaging data from the Bax study (62) was most

informative. White matter abnormalities were present in43% of the children, including 71% of children who had

diplegia, 34% of children who had hemiplegia, and 35%of children who hadquadriplegia. This finding highlightsthe critical importance of understanding biomarkers and

pathways in preterm infants born before 34 weeks ges-tation as well as some term infants who have experienced

problems that suggest vulnerability during their thirdtrimester of intrauterine life. (66)(67)

ConclusionJust as maternal corticosteroids, comtinuous positive

airway pressure, and surfactant replacement havechanged the natural history of respiratory distress syn-

drome and its sequelae, advances in ventilatory support,regionalization of neonatal care, and extracorporeal

membrane oxygenation have led to greater survival ofsicker and more preterm infants in the neonatal intensive

care unit. However, there is growing concern about the

high rates of CP and neurodevelopmental disabilitiesamong these children, especially in those born at 24 to

26 weeks gestation. This cohort represents approxi-mately 10% of all CP cases. A recent epidemiologic

review (8) found that with increasing rates of prematurityand multiple gestations, survivors who have CP are in-creasing in absolute numbers. Their survival translates

into a greater prevalence of CP and its comorbidities inthe pediatric population.

Systematic evaluation of health, developmental, func-tional, and educational outcomes is required to advance

understanding of CP, as is assessment of both health-related quality of life and measures of participation. (65)

(68)(69)(70)(71) Better understanding of the pathwaysto CP and existing barriers to defining the disability of

CP should allow clinicians to promote the necessaryfamily supports, habilitative resources, and comprehen-sive medical care.

ACKNOWLEDGEMENTS. This work was supported in

part by Research Grant 2004-06 13560B from TheChildrens Guild of Buffalo entitled Development andNormalization of a Functional Assessment Tool for Chil-

dren 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 acknowledgethe contributions of the University of Chicago Comerand LaRabida Childrens Hospitals rehabilitation teamsfor their tireless efforts to improve the early identification

and parent-professional partnership on behalf of childrenwho have CP. Dr. Romantseva is a Steve AN Goldstein

Research Fellow in the University of Chicago Depart-ment of Pediatrics.

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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 highestrate of cerebral palsy among preterminfants is associated with:

A. Bronchopulmonary dysplasia.B. Necrotizing enterocolitis requiring surgery.C. Parenchymal brain injury.D. Sepsis or meningitis.E. Severe retinopathy of prematurity.

4. You are examining a preterm infant, whose birthweight was 790 g and estimated gestational age at birthwas 24 weeks, in the follow-up clinic at 4 months of postmenstrual age. The parents inquire about theprobability of the development of cerebral palsy in their child. Of the following, the EARLIEST method forprediction of cerebral palsy with high sensitivity and specificity is the assessment of:

A. Motor milestones.

B. Muscle tone.C. Postural responses.D. Primitive reflexes.E. Spontaneous general movements.

5. Historically, the description of cerebral palsy has included topography based on the number of affectedlimbs. Of the following, the mostcommon topography among preterm survivors with cerebral palsy is:

A. Diplegia.B. Hemiplegia.C. Monoplegia.D. Quadriplegia.E. Triplegia.




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DOI: 10.1542/neo.7-11-e5752006;7;e575Neoreviews

Lubov Romantseva and Michael E MsallAdvances in Understanding Cerebral Palsy Syndromes After Prematurity

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