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

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Article

development

Advances in Understanding
Cerebral Palsy Syndromes After
Prematurity
Lubov 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 cerebral
palsy (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, 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 reflect 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 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 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 classification 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.
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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 significant predictors of future CP in
multicenter studies. Five risk factors are especially important: 1) parenchymal brain injury (defined 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) (defined 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.

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 identified: 1) infants who were infection-free during their hospital stay (n!2,161); 2) infants who had
clinical infections requiring antibiotics for at least 5 days
or sepsis (n!3,460); and 3) infants who had NEC or
meningitis (n!472). 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 (defined 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 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 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%, reflecting ongoing
challenges in basic upright mobility. Self-care functional
disability was present in 25% of children, reflecting 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

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development

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 confirmed 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 confirmed 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

In many centers, ultrasonography remains the mainstay

of intracranial imaging for preterm newborns because it
is an efficient 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 specificity 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 findings on cranial ultrasonog-

cerebral palsy

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 findings,
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 significant portion of preterm CP cases.
(29)(30)

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 specificity 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 difficulty in rigorous
comparisons because they vary in definition/gradation of
abnormal findings, 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
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cerebral palsy

signal intensity among the most commonly reported

preterm brain injuries. (31)
Second, serial ultrasonography improves the modalitys sensitivity and specificity, 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 identified until 40 weeks PMA.
Third, at this time, it remains unclear whether serial
ultrasonography can approach the sensitivity and specificity of MRI. The available comparative studies have a
wide range of values, but three studies deserve specific
comment. Devries and associates (24) reported that serial ultrasonography had a sensitivity of 76% to 86% and
a specificity 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% specific for detecting CP
at 2.5 years. In comparison, ultrasonography was 43%
sensitive and 82% specific for detecting CP. Woodward
and colleagues (36) reported similar numbers for sensitivity and specificity 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,

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 fiber 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 fiber 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 specificity. 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 first 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 findings 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

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development

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
reflexes and postural responses to the standard neurologic examination, with resultant moderate improvement in sensitivity and specificity for the early detection
of CP. (45)(46) This approach emphasizes persistent
primitive reflexes, especially the asymmetric tonic neck
reflex, tonic labyrinthine supine reflex, and positive support reflex. Zafeiriou and colleagues (47) used seven
specific 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 five 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 specific 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 reconfirmed
by other investigators.
Another strategy makes use of operationally defined
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 specificity 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

cerebral palsy

correlated well with future development of CP. A specific

type of abnormal spontaneous GM, termed cramped
synchronized GM, predicted CP diagnosis at age 2 to 3
years with a sensitivity of 100% and specificity 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 specificity. 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-efficacy.
Much dynamic change in posture and voluntary motor control occurs in the first 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 defined 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,
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Likes to be rocked, requires

2 AM feeding

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
Environmental
factors

Personal factors

Attends early intervention play

group
Participation

Sleeps through night

Family lives on third floor,

adapted stroller denied

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

No pincer grasp on R, cannot

transfer object from L hand to
R, cannot cruise from L to R
Activities

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

Triplegia, partial seizures, on

pureed diet

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 find child care
L porencephalic cyst, R hand
contracture, R hemiplia

Diplegia, strabismus, cystic

periventricular
leukomalacia

30-month-old
1-year-old

18-month-old

2-year-old

In prone position, unable to

extend and bear weight on R
arm; supported sitting

cerebral palsy

Body function and

structure

Table 1.

ICF Model and Children Who Have Cerebral Palsy

development

these distinctions reflect 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 first 3 postnatal years. (53)
More recently, an expert panel defined 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 findings as well as considerations of causation and timing as key components of the classification system. Thus, the stage has been set for a
more detailed understanding of pathways involved
in the syndromes of CP.

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 first 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 (SD!3.9). At age 8 years, ambulation
status was as follows: 57% were independent, 7%

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development

cerebral palsy

Topography of Cerebral Palsy at 18 to

24 months

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
Classification/Description
birthweights of less than 750 g,
One-sided
Mild: Difficulty with performing pincer task on
gestational ages of less than 24
Hemiplegia
an involved side.
completed weeks, and 1-minute
Moderate: Intermittently fisted, 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, difficulty
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.
findings with information availModerate: Upper extremity with ability to use
able on MRI. A cross-sectional
first 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,
difficulty with using hands to feed self,
syndromes were assessed clinically
difficulty 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 significantly ill. Approximately 1 in 3
Table 2.

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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
fields, 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 difficulties.
(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 finding 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)

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

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 defining 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 identification
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.

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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 specificity is the assessment of:
A.
B.
C.
D.
E.

Motor milestones.
Muscle tone.
Postural responses.
Primitive reflexes.
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

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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

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