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NEUROIMAGING FOR CEREBRAL PALSY: A REVIEW
By

Steven James Korzeniewski

A THESIS
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
MASTER OF SCIENCE
DEPARTMENT OF EPIDEMIOLOGY

2006

Abstract
NEUROIMAGING FOR CEREBRAL PALSY: A REVIEW
By

Steven James Korzeniewski

This study provides a systematic review of the literature addressing the role of
neuroimaging for cerebral palsy. Among studies of multiple subtypes of cerebral palsy
and hemiplegia, 78% and 87% of the subjects respectively exhibited an image
abnormality on average; studies of spastic, ataxic, or athetotic subtypes, reported image
abnormalities on average in 86% of their subjects. Studies of hemiplegia reported more
combined white and grey matter damage compared to studies of other cerebral palsy
subtypes. Studies of spastic, ataxic, or athetotic cerebral palsy reported more white
matter damage compared to studies of other subtypes. Across all studies, white matter
damage was the most common finding, reported in nearly 40% of all subjects. Pure grey
matter damage was the least common finding, reported on average in only 6% of
subjects. Overall, the timing of cerebral palsy etiology was estimated to be prenatal,
perinatal, and postnatal in 32%, 44%, and 6% of subjects with cerebral palsy.
Neuroimaging provides important information about cerebral palsy related to the
pathology and etiology of the disorder; however, its use in the diagnosis of the disorder

remains questionable.

ACKNOWLEDGEMENTS

Special thanks go to my primary advisor, Dr. Nigel Paneth, for his dedication to my
development as an epidemiologist. His support and guidance have truly changed my life.
I hope that in the future I will provide service to a young trainee that is as competent and
compassionate as that which I have received from Dr. Paneth. In a life of self-reliance,
Dr. Paneth has shown me the true meaning of the word ‘mentor.’ His efforts are utterly
appreciated. Thanks also go to my thesis committee members, Dr. Mark DeLano and Dr.
Mike Brown, for their input, support, and willingness to accommodate my hectic

schedule over the past few years.

iii

TABLE OF CONTENTS

LIST OF TABLES ............................................................................ vi
LIST OF FIGURES ........................................................................... vii
LIST OF ABREVIATIONS ................................................................. viii
CHAPTER 1
INTRODUCTION ........................................................................... 1
Aims ................................................................................... 1
Definition of cerebral palsy ......................................................... 1
Classification of cerebral palsy .................................................... l
Difficulties in cerebral palsy classification ....................................... 2
Clinical manifestations of cerebral palsy ......................................... 2
Descriptive epidemiology of cerebral palsy ...................................... 2
Population prevalence of cerebral palsy ................................. 2
Prevalence of cerebral palsy subtypes .................................... 3
Gender and ethnicity ........................................................ 5
Gestational age distribution of cerebral palsy ........................... 5
Causes and risk factors of cerebral palsy ................................. 5
Birthweight .................................................................. 6
Neuroimaging for cerebral palsy ................................................... 7
CHAPTER 2
METHODOLOGY ........................................................................... 9
Literature review strategy ........................................................... 9
Selection and classification of studies ............................................. 9
Analytic Strategy ..................................................................... 10
CHAPTER 3
RESULTS ..................................................................................... 12
Selected Studies ..................................................................... 12
Types of Abnormal Neuroimaging Findings .................................... 13
Malformations .............................................................. l 3
Grey Matter Damage ...................................................... 14
White Matter Damage ..................................................... 14
White and Grey Matter Damage ......................................... 15
Ventriculomegaly, Atrophy, and
Cerebrospinal Space Fluid Abnormalities .............................. 15
Overall frequency of abnormalities imaged in studies pf subjects
with multiple forms of cerebral palsy ............................................. 16
Overall frequency of abnormalities imaged in studies of subjects
with hemiplegic cerebral palsy ................................................... 19

iv

Overall frequency of abnormalities imaged in studies of subjects

with spastic, ataxic, and athetotic cerebral palsy ................................ 21
Summary of Overall Image Findings ............................................. 26
Timing of Brain Insults ............................................................. 27

CHAPTER 4

CONCLUSIONS .............................................................................. 29
Implications for Research ........................................................... 29
Emerging Imaging Techniques ..................................................... 31
Implications for Clinical Practice .................................................. 34
Summary ............................................................................... 35

BIBLIOGRAPHY ............................................................................. 37

LIST OF TABLES

Table l: Cerebral palsy prevalence per thousand live births

(unless specified otherwise) in population-based registry studies ...................... 4
Table 2: Male Female Sex Ratio ............................................................ 5
Table 3: Classification of Abnormal Neuroanatomy .................................... 11
Table 4: Studies of subjects with multiple forms of cerebral palsy ..................... 18
Table 5: Studies of subjects with hemiplegic cerebral palsy ............................ 20

Table 6: Studies of subjects with Spastic, Ataxic, or Athetotic Cerebral Palsy ...... 23

Table 7: Estimated Timing of Etiology .................................................... 26

vi

LIST OF FIGURES

Figure 1: Map of brainstem white matter tractography ................................. 30

Figure 2: Diffusion Weighted Imaging ................................................... 31

vii

LIST OF ABBREVIATIONS

CP- Cerebral Palsy

CSF- Cerebrospinal fluid

PVL- Periventricular leukomalacia

viii

CHAPTER 1
INTRODUCTION
Aims:
The aims of this review are to assess the role of neuroimaging in attributing
cerebral palsy (CP) etiology, to make recommendations about what could be done in
future studies to more fully support this attribution, and to briefly discuss the role of

neuroimaging in the diagnosis of the disorder.

Definition of Cerebral Palsy:

According to the most recent (2004) international conference on its classification,
cerebral palsy (CP) is defined as a group of developmental disorders of movement and
posture causing activity limitation or disability that are attributed to disturbances
occurring in the fetal or infant brain and may be accompanied by a seizure disorder or by

disturbance of sensation, cognition, communications and/or behavior.l

Classification of Cerebral Palsy:

CP has been difficult to both define and classify since first being described by
William Little and Sigmund Freud during the latter half of the 19th century. 2“
Historically, the disorder has been classified either by topography of signs, as indicated
by the terms monoplegic, diplegic, and quadriplegic indicating the number of limbs
affected, or by type of motor manifestations including hypotonic, ataxic, spastic,

dystonic, and dyskinetic.5

Difficulties in Cerebral Palsy Classification:

As Grant and Barkovich (1997) explain, a classification scheme based on the type
and distribution of motor symptomatology while suitable for planning rehabilitation
provides little information regarding the etiology, pathology, and timing of insults. 6 The
primary difficulty with such classification is that many different etiologies occurring at
different developmental stages can result in the same clinical type of CP; alternatively a
similar etiology may produce variable outcomes. Thus, clinical classifications may not

provide insight into the etiology of CP.

Clinical Manifestations of Cerebral Palsy:

Children with CP are the single largest group of children in the population having
major disabilities7; CP is commonly associated with epilepsy, mental retardation, and
visual disabilityg’9 One in five children with CP born prematurely has severe intellectual
deficits.'0 The Northern Ireland Cerebral Palsy Register (2001) reports just over a quarter
(29%) of cases are unable to walk (with/without aids), and one-fifth (22%) have no useful
hand/arm function; almost half (49%) of the cases had at least one other impairment

(intellectual, sensory impairment or active seizures) in assoc1ation With their CP.l

Descriptive Epidemiology of Cerebral Palsy:

Population Prevalence of Cerebral Palsy

Registry and population based studies of CP converge on a prevalence estimate of
around 2 per 1,000 school aged children.12 (Table l) The incidence of CP has remained

relatively stable around the world over the past 30 years ranging between I and 3 per

1,000 live births.12 (figure 1) The most recent study of CP trend in the United States
based on one year survivors ranged between 1.7-2.1/ 1,000 between 1977-1991;‘3
however, this years report, covering years 1996-2000, utilizes the number of 8 year olds

in the area as the denominator population and provides a significantly higher estimate of

3.6/1,000.”

Prevalence of Cerebral Palsy Subtypes

The prevalence of CP subtypes may vary geographically. Himmelman et al. report
that spastic hemiplegia, diplegia and tetraplegia account for 38%, 35% and 6%,
respectively, while dyskinetic CP and ataxia account for 15%, and 6% respectively. Thus,
in the Western Swedish population study hemiplegia is the most common subtype.34
According to Parkes et al.’s analysis of the Northern Ireland Cerebral Palsy Register data
from 1981—93 which included 784 cases of CP, the most common (55%) CP subtype was
bilateral spastic cerebral palsy.” Sciberras and Spencer conducted a population based
study of CP in Malta from 1981 to 1990 (including postnatally acquired CP) and reported
the most common subtype of CP is tetraplegia (52%), followed by diplegia (17%) and
hemiplegia (1 1%). Pharaoh et al. conducted a study of CP trends in England, excluding
cases of postnatal origin, during the same time period (1984) as Sciberras and Spencer
and reported hemiplegia was the most common (40%) subtype, followed by tetraplegia

(27%) and Diplegia (24%).‘5

Table 1: CP prevalence per thousand live births (unless specified otherwise) in

population-based registry studies12

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Western Australia

 

 

 

 

 

Population
. N of Denominator
Location Author, year Period cases (live births CP prevalence
covered per thousand
of CP unless
indicated)
UK - Mersey Pharoah 1987" 1966-1977 685 453,146 1.51
UK - Scotland & 7829600
. . Pharoah 199816 1984-1989 1649 neonatal 2.10
5 English counties -
SUI'VIVOI‘S
UK — Avon MacGillivray 199577 1969-1988 489 236,920 2.06
486,666
g)" ‘ NM“? East Williams 1998" 1980-1986 584 neonatal 1.2
ames region .
Slll'VlVOI‘S
UK — Birmingham Griffiths 1967” 1950-1959 302 186,125 1.62
308,488
UK ’ N°"h'Eas‘ Colver 200020 1964-1993 584 neonatal 1.89
England .
Slll'VIVOI‘S
172,376
Netherlands ‘ Wichers 2001“ 1977-1988 127 survivors to 0.74
Gelderland e six
3"an ‘. Topp 20012123 1979-1990 908 342,198 2.66
astem region
Norway - 24
Vestvold Meberg 1995 1970-1989 110 45,976 2.4
Sweden — Hagberg ”‘33 &
Gothenberg region Himmelmann, 200534 1954-1998 1824 935’367 1'95
Sweden — 35
. Nordmark 2001 1990-1993 167 65,514 2.2
Southern region
"3'? ‘ “”53“ Bottos 19993‘5 1965-1989 610 334,598 1.82
3101)
Slovenia Kavic 199837 1981-1990 768 258,585 3.0
Ireland - Counties 33
“Cork & Ken? Cussen 1978 1966-1975 254 98,648 2.57
Northern Ireland - Parks, 2001" 1981-1993 982 445,464 2.20
Iceland- Eastern Gudmundsson 1967
Health Board area 39 1953-1962 102 46,036 2.28
US ‘ M°"°P°"“"‘ Bhasin 2006" 1996-2000 268 80’8” five' 3.32
Atlanta year olds
US — Metropolitan Year in-Allsopp, 1975-1977;
Atlanta 1992§°, 1981-1991; 8‘5 43 L760 1'89
US ’ M°"°P°"“‘“ Winter 2002“ 1985-1987 206 102,000 2.0
Atlanta
242,293
Japan - Shiga Suzuki 2002‘2 1977-1991 325 survivors to 1.34
age six
MSW” ‘ Stanley, 1982 1956-1975 903 377,824 2.39

 

 

Gender & Ethnicity

Males are slightly more likely than females to be diagnosed with CP;'5’34‘43'46
(Table 2) however, the disorder generally does not vary significantly by race.47 Winter et
al.’s (2002) population based study of the Metro-Atlanta area revealed over a 16 year

period birthweight/race specific rates of CP were similar between whites and blacks. '3

Table 2: MaleFemale Sex Ratio48

 

 

 

 

 

 

 

 

 

 

Years of Birth Location M/F Ratio Reference

1958 UK 1.9:1 Edomnd, 1989
l956-1967 ' Western Australia 1.5:1 Stanley et al., 1984
1959-1966 USA 1.6:] Nelson, 1985
1966-77 Mersey, UK 1.4:] Pharoah, 1987
1968-75 Western Australia 1.2:1 Stanley et al., 1984
1970 UK 1.3:] Edomnd, 1989
1975-90 Sweden 0.9:1 Hagberg, 1993
1987-90 Sweden 1.1:1 Hagberg, 1996

 

 

 

 

 

Gestational Age Distribution of Cerebral Palsy

Himmelman et al.’s most recent Swedish population based study of 162 children
with CP (excluding those of postnatal origin) reported 10% were born at less than 28
weeks gestational age (GA), 14% were born between 28-31 weeks GA, 19% were born
between 32-36 weeks GA, and the majority (57%) were born at term.34 At the lowest

gestational ages where survival now occurs the risk of CP is 5%-15%.49

Causes & Risk Factors of Cerebral Palsy

The causes of CP remain largely unknown. Until recently, birth asphyxia, first
proposed as a central etiologic factor by Little in 1862 based on a study of 47 affected
children, was the leading etiologic hypothesis.2 Nelson and Ellenberg provided powerful
evidence against the asphyxia hypothesis in the National Collaborative Perinatal Project,
a seven year follow up study of more than 50,000 children born from 1959-66; in their
study, measures reflective of birth asphyxia (fetal bradycardia, low Apgar score, delayed
time to first breath, etc.) when combined with pre-labor characteristics accounted for only
a Slightly higher proportion of CP than was accounted for when the analysis was limited
to characteristics identified before labor. 50 Blair and Stanley (1988) reported similar
evidence based on a case-control study involving 183 children with spastic CP and 549
matched controls from Western Australia; the authors reported that only 8% of spastic CP
was possibly attributable to intrapartum asphyxia.“ Badawi et al. also found similar
results in their Western Australian population based case-control study of neonatal
encephalopathy, which mediates the relationship between asphyxia and cerebral palsy;
isolated pure intraparturn hypoxia accounted for only 4% of moderate to severe newborn
encephalopathy in their study. ”’53 Although the asphyxia hypothesis is often considered,
especially when birth injury litigation is proposed,54 researchers have directed their
efforts towards new lines of thought regarding the etiology of CP including the role of

pregnancy or perinatal infections, 55'” 6° inflammatory responses, “’62 thrombophillias

61,63-67 68-70

and genetic components primarily in full term infants; and hypothyroxinemia,

and hypocapnia primarily in preterm infants.”73

Birthweight

According to data from the Surveillance of Cerebral Palsy in Europe (SCPE),
which includes information on over 6,000 children with CP from 13 geographically
defined populations from 1980 to 1990, the risk of CP is 70 times greater in children
weighing less than 1500g compared to those weighing 2500g or more at birth. '0
Neuroimaging for Cerebral Palsy

In the hope of learning more about the etiology and pathology of CP, some
researchers have suggested a potentially important role for neuroimaging in its
classification and diagnosis.6‘74‘75 Neuroimaging supplements an earlier understanding of
CP neuroanatomy gained from autopsy studies of the 19508. 76 The original
neuroimaging studies were conducted during the late 19708 and early 19805. Koch et al.
claim to have conducted the original CT study Specifically focusing on CP in 1980;
however, Ito et al. (1979) published a CT study examining 110 subjects with CP one year
earlier‘in Japan-’7’78 The first MRI study of subjects with CP having a sample size greater
than 15 was conducted in 1988.79

Traditionally, imaging has been conducted only for those children with severe
encephalopathic indications; for instance, infants who received extremely low Apgar
scores, or those who were born prior to 32 weeks GA.so Recently (2003-2004), the
American Academy of Neurology published two practice parameters advocating for the
first time the routine neuroimaging of children with suspected cerebral palsy or global
developmental delay of unknown origin. “’82

Considerable controversy surrounds Ashwal et al.’s (2004) recommendations on

imaging in CP diagnosis, especially in regard to the evidence supporting it, or lack

thereof. In correspondence following the 2004 Ashwal et al. publication, Mink and
Jenkins stated “the current literature is not adequate to develop Practice Parameters in
this area83”; and Whelan attacked the sampling techniques used in most of the CP
neuroimaging studies presented by Ashwal et al. (2004), characterizing them as “studies

”84 These criticisms stem from the

of selected, not representative, groups of people.
clinical question intended to be addressed by the practice parameter: does the evidence
indicate that neuroimaging supports the process of diagnosing the child with CP? This
review will briefly discuss the evidence surrounding the role of imaging in the diagnosis
of CP; however, the primary focus is to address an equally, if not more, interesting
question: does imaging aid in attributing CP etiology, and what could be done in future
studies to more fully support this attribution.

To address this question, the current study provides a review of the literature,
extending the work of Ashwal et al. (2004) to include a more elaborate discussion of the

current techniques, evidence, potential benefits, and future directions of neuroimaging in

CP with Specific consideration placed on etiologic research.

CHAPTER 2
METHODOLOGY

Literature Review Strategy

The systematic review methodology used in this study is based on the work of
Egger, Smith, and Altman (2001).85 Literature searches for relevant articles published
from 1960-2006 were conducted with the Science Citation Index (SCI) and MEDLINE
(OCLC firstsearch) electronic indexes using the following key-words: “Cerebral Palsy,
Magnetic Resonance Imaging, MRI, computed axial tomography, CT scan, Single photon
emission tomography, SPECT, diffusion weighted imaging, functional MRI, and
diffusion tensor imaging.” Experts in neuroimaging in cerebral palsy were contacted to

identify any gray (unpublished) literature.

Selection & Classification of studies

One reviewer (SK) selected studies based on the following criteria. The a priori
exclusion criteria were: sample sizes less than 15; study did not report the proportion of
abnormal scans; and if the abstract was not published in English. All admissible studies
were classified via sampling scheme as either population-based or clinic-based (both
referral and non-referral). Information extracted from each study included: author, year,
sample size, type of CP studied, imaging modality, proportion with an abnormal scan,

proportion with brain malformations, imaging results, and sampling technique.

Analytic Strategy

The studies are analyzed both quantitatively, examining imaging findings, and
qualitatively, examining authors’ conclusions. Image findings for each study were
abstracted into an excel database; either individual findings or authors’ categorization of
those findings (when matching the current study’s classification paradigm) are E
categorized into 5 groups based on correspondence with experts in the fields of
neuroscience, pediatrics, and epidemiology including Dr. Mark Delano and Dr. Nigel
Paneth. (Table 3)

Our classifications are based on anatomical findings which are not mutually
exclusive; thus, the total percentages may sum to greater than 100% if the study authors
reported more than a dominant finding. In the event that authors reported multiple
findings per category without providing details by subject the greatest proportion per
category is reported in our study; i.e., if an author were to report 12% of subjects had
white matter hyperintensities and 86% had sings of periventricular leukomalacia without
indicating whether these findings were in separate subjects, we would report the
proportion of white matter damage to be 86%. Thus, it is possible that the sum of the
proportions of abnonnalities within each category could also be lower than the reported
total proportion of abnormalities if we had to default to the greatest proportion reported
per category because the findings were not denominated by the number of subjects.

Rather than attributing a quality score to each study, the results are assessed both
across all studies and according to sampling methodology; class I, II, and III correspond

to population-based, clinic-based, and missing sampling information respectively. This

10

strategy is based on the assumption that population based studies may provide higher

quality findings than smaller clinic based studies.

Table 3: Classification of Abnormal Neuroanatomy

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Classification Neuroanatomical Finding
Schizencephaly :11; egalenceph Microcephaly
Malformations Heterotopia Polymicrogyria Lissencephaly
Macrogyrus Cortical dyspflasia Abnormal sgital structure
Microcephaly Pachygyria Lobar holoprosencephaly
Gray Matter injuries to the basal thalarnic D' . .
. . . iencephalic leSions
Damage ganglia abnormalities
cortical defects
Periventricular White matter
white matter infarct
abnormalities.
Periventricular White matter Tl . .
leukamalacia abnormality ning 0f the corpus callosum
White Matter Periventricular White .matter Agenesis/disgenesis of the
D atrophy- reduction corpus-callosum
amage
Decreased density Corpus callosum
& periventricular Decreased density of the
of the centrum . .
. white matter cerebral hemisphere
semiovale .
abnormalil
White matter Myelin . . .
hyperintensity abnormality Juxtaventricular hypodenstties
Cortical/subcp r tical Optic radiation involvement
Greay 81: White les1ons or cavmes
Infarcts Porencephalies/porecncephalic cysts
Matter Damage . .
Encephalomalacia Multicystic Parasagital injury
encephalomalacia
Bilateral/ unilateral . . .
enlarged ventricles Ventriculomegaly Posterior fossa abnormality
Ventricle dilatation CSF space Posterior horns ventricular
Ventriculomegaly, abnormality abnormality
gtrOphy, or CSF Ocapital horn Culpocephaly Pons involvement
pace enlargement
Abnormalities Hydrocephalus Subdural effusion Atrophy
Bilateral/Unilateral Ventriculomegaly Posterior Fossa abnormality
enlarged ventricles
Small hemisphere Hemiatrophy
Cerebellum parasagital lesion Vermian cerebellar hypoplasia
, involvement-
Miscellaneous . . . .
findings Cystic IeSion Treatable leasmns Neurofibromatosm
Calcification / high

 

density area-

 

calcification

 

High density area

 

11

 

CHAPTER 3
RESULTS

Selected Studies

A total of 769 titles/abstracts were identified via SCI, and 1,536 title/abstracts via
MEDLINE. For the SCI search, bibliographies were investigated electronically, and
references citing the selected material were also reviewed. A total of 41 CT and MRI
studies were selected for this review.

Computed Tomography (CT) imaging consists of utilizing x-ray technology and
computer-applied algorithms to create high resolution images of brain anatomy via a map
of the local x-ray absorption coefficient.86 MRI uses the magnetic properties of protons,
known as nuclear magnetic resonance, to produce gray-scale images of the brain.86
Protons, mostly in water and fat molecules, tend to align with a uniform static magnetic
field within the MRI machine; when a pulsed magnetic field is applied perpendicular to
the direction of the static field it changes the alignment of those protons which then emit
a signal used to construct images.‘5 Variation in the strength, timing, and duration of the

magnetic pulses are used to produce different tissue contrasts; T1 -weighted, proton

o o . 8
dens1ty, and TQ-weighted spin echo sequences are the most commonly used sequences.6

 

‘ For ”a review of the physics involved in MRI and the various imaging sequences
available please see: Edelmann RR, Hesselink JR, Zlatkin M (eds) (1996): MRI: Clinical
magnetic resonance imaging. 2nd edition. Philadelphia: WB Saunders.

l2

Types of A bnormalities Neuroimaging Findings

Malformations:

The most recent (2004) international conference on CP definition and
classification has decided to include brain malformations in the CP category if they
produce the clinical motor findings characteristic of the disorder.87 Traditionally, the
inclusion of malformations under the diagnostic rubric of CP has been controversial,
since brain malformation syndromes such as neural tube defects are not usually classified
as CP even in the presence of motor disability. However, malformations are of emerging
importance in the understanding of CP etiology.

Interruptions during the critical stages of development of any individual part of
the brain will result in a malformation.6 Brain malformations causing CP are usually the
result of the interruption of migrating neurons during the process of grouping local and
distant synaptic connections into cylindrical columns and layers to form the cortex.6
Migration disorders commonly found in CP are indicated by imaging results depicting
varying levels of abnormal gyral and sulcal development including: lissencephaly,
heterotopia, polymicrogyria (cortical dysplasia), schizencephaly (agenetic porencephaly),
and hemimegalencephaly.78’1”"98 Holoprosencephaly, a condition characterized by the
failure of the cerebrum to both divide laterally into distinct cerebral hemispheres and to
divide transversely into a diencephalon and telencephalon, is also found in subjects with
CP. Malformations are more common among term (>37 wks GA) than pre-term born
subjects with CP; this coincides with the fact that malformations are more common in

hemiplegia which also occurs more frequently in term born children.75’88’94‘99

13

Grey matter damage
Grey matter damage reported in subjects with CP, other than malformations,
include injuries to the basal ganglia, cortical defects, thalarnic abnormalities, and

diencephalic lesions.8893’94’9‘5'99'103

White matter damage

White matter abnormalities are particularly frequent in children with CP born
premature. 91,94,104-107 75 '108 ‘09 “0 102"“ Damage to the white matter, often termed
periventricular leukomalacia (PVL),l ” is diagnosed in patients who have
ventriculomegaly with irregular outlines of the trigone and body of the lateral ventricle, a
reduced quantity of periventricular white matter, deep prominent cerebral sulci, and
periventricular signal abnormalities of low intensity on T1-weighted images and high
intensity on T2-weighted images.1 '2" ‘3 Contrary to conventional thinking, PVL is not
uncommon among full term infants.75’98’99’”4°”6 Kwong’s (2004) study of 122 subjects
with spastic CP reported 1/3 of term infants exhibited signs of paraventricular white
matter damagemz Krageloh-Mann et al. found PVL in 53% of term children with no
clinical evidence of perinatal/neonatal antecedents.l '7 Steinlin et al. reported of the 10
subjects in their study with PVL, only 2 were born prior to 38 weeks GA.93

Interruptions in callosal development are also found in the white matter of
subjects with CP.99 These interruptions result in either the complete absence of the
corpus callosum or in it being partially formed (hypogenetic). Generally, when the

corpus callosum is hypogenetic the genu is commonly present while the spleniurn and

rostrum are frequently small or absent.118 Sometimes, in cases of CP, hypogenetic

14

callosal anomalies are found in conjunction with holoprosencephaly, a birth defect
characterized by the failure of the prosencephalon (forebrain of the embryo) to develop.75

Myelin abnormalities are also quite common in CP.

White and Grey matter damage

Several abnormalities are not specific to either white or grey matter and are thus
classified as their own category. Infarcts, unless otherwise specified, are commonly found
in both white and grey matter surrounding the middle cerebral artery among subjects with
CP, most commonly among hemiplegics.77’93’97" '6" 19"” 88'89‘mo'122’m Cortical cavities
also surrounding the middle cerebral artery have been reported in subjects with CP,
again, particularly among hemiplegics.m’125 Encephaloclastic porencephalies and
encephalomalacia are also common in CP. 108,123,126 Encephaloclastic porencephalies are
well defined cavities in the white and/or grey matter that are surrounded by minimal glial
reaction.127 Encephalomalacia refers to cerebral necrosis, either uni-focal or multi-focal,

and is differentiated from porencephalies by the presence of astrogliosis.‘28

Ventriculomegaly, Atrophy, and Cerebrospinal Space Fluid Abnormalities

Ventriculomegaly common to subjects with CP includes enlarged, dilated, or
reduced ventricles (unilateral or bilateral), abnormalities of the atria and ventricular or
occipital horns (culpocephaly), and posterior fossa abnormalities. Hydrocephalus and
subdural effusion are also aspects of ventriculomegaly found in subjects with CP.
Hydrocephalus is a condition of excess fluid in the brain. Subdural effusion is a

collection of fluid beneath the outer membrane covering the brain. Cerebral atrophy, a

15

common finding among subjects with CP, is characterized by diffuse sulcal widening of
the cerebrum with symmetrical ventricular dilatation without periventricular Signal
abnormalities occurs.75’98’1'9’129’130 Cerebrospinal fluid (CSF) space abnormalities involve
damage or abnormal signals occurring in the meninges, a layer surrounding the brain
which protects it from trauma and infection and encloses the CSF.

Overall fimency of abnormalities imaged in sags oisybiects with multiple forms of
cerebral palsy

On average, among studies of multiple forms of CP (n=20), 78% of subjects
exhibited image abnormalities. (Table 4) As indicated in table 4, white matter damage,
ventriculomegaly, CSF Space abnormalities, and atrophy are the most common findings
in this group. Pure grey matter damage was the rarest image finding, reported in only
5.5% of these subjects. On average, malformations were reported in nearly one of 10
subjects with multiple forms of CP.

Only Sugimotto et al.’s (1995) study found image abnormalities in all of their
subjects.13 I Schenkrootlieb et al. (1994) reported the smallest proportion of subjects with
image abnormalities, 55%.1 '4 The single population-based study of subjects With multiple
forms of cerebral palsy conducted by Himmelmann et al. (2005) reported a higher
frequency of abnormalities and malformations compared to the clinic-based
investigations. Himmelmann et al. (2005) also report significantly less ventricular, CSF
space, and atrophy abnormalities compared to the average of all of the studies combined.
However, this finding may be due to the fact that they reported a dominant
neuroanatommical finding and the majority of other studies (17/20) reported multiple

findings.

16

MRI studies of subjects with multiple forms of cerebral palsy reported
Significantly more overall abnormalities, malformations, and white matter damage,
compared to investigations using CT (86% vs. 70%). CT studies of multiple forms of
cerebral palsy were more likely to report ventricular, CSF space, and atrophy
abnormalities as well as combined white and grey matter damage compared to MRI

investigations.

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18

Overall freqyency of abnormalities imaged in studies ofsubiects with hemiplegic
cerebral palsy

Studies of hemiplegic cerebral palsy (n=10) reported that on average 86.7% of
their subjects exhibited an image abnormality. (Table 5) Population-based studies of
hemiplegia reported more malformations and white matter damage, while clinic-based
studies reported more ventricular, CSF space, and atrophy abnormalities and combined
gray and white matter damage. The single MRI study of hemiplegic subjects reported
more grey matter abnormalities compared to investigations using CT. Humphreys et al.
(2000) reported the largest proportion of abnormalities among hemilegics, 100%.
Wiklund et al.’s (1991) study of full term born children with hemiplegia reported the
smallest proportion of image abnormalities, 74%.

Compared to studies of multiple forms of cerebral palsy, those focusing on
hemiplegia reported considerably more overall abnormalities (86.7% vs. 78.1%). Studies
of hemiplegia also reported a different distribution of anatomical findings compared to
studies of multiple CP subtypes. Among hemiplegics, combined grey and white matter
abnormalities were more common (31.1% vs. 13.5%) and ventricular, atrophy, or CSF
space damage was less common (25.8% vs. 38%). Unlike subjects with multiple forms
of cerebral palsy, hemiplegic subjects had more combined grey and white matter damage
than singular white matter damage (31.1% vs. 23.5%). These findings are consistent with
hypothesized etiologies of hemiplegia suggesting that the disorder stems in large part
from infarcts occurring around the middle cerebral artery rather than insults to the

periventricular white matter.

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20

Overall frequency of abnormalities imaged in studies of subjects with spastic, ataxic, and
athetotic forms of cerebral palsy

Studies of spastic (diplegia, quadriplegia, tetraplegia), ataxic, and athetotic
cerebral palsy (n=11) reported image abnormalities on average in 86% of their subjects.
(Table 6) Three studies in this group reported image abnormalities in all of their

. 104,107,132
subjects;

only Yacochi et al.’s (1991) study of athetotic cerebral palsy reported a
proportion of subjects with image abnormalities below 70%.101 Population-based study
findings did not vary significantly from those of clinic-based investigations; the most
significant difference was the frequency of ventriculomegaly, CSF space abnormalities,
and atrophy findings as well as combined grey and white matter damage fi'equencies.
The single population based study providing information on the distribution of image
characteristics reported no ventriculomegaly, CSF space abnormalities, or atrophy
findings; although, this may be due to the fact that Krageloh-Mann et al. (1995) reported
dominant rather than multiple findings.‘ ‘7 Yokochi et al.’s (1991) study of athetotic CP
reported significantly more grey matter abnormalities and less white matter abnormalities
than other studies in this group. "H

The primary contrast in findings from this group of subjects, compared to studies
of hemiplegia or multiple subtypes, is the proportion of pure white matter damage found.
On average, 66.9% of these subjects exhibited pure white matter damage, as opposed to
23.5% in hemiplegic subjects, and 28.2% in subjects with multiple forms of cerebral
palsy. This finding is consistent with the hypothesized relationship between white matter

damage and more significant motor disabilities characteristic of spastic, ataxic, and

athetotic clinical subtypes of cerebral palsy. However, the results may be influenced by

21

the imaging modality used in this group of studies; the majority used MRI as opposed to

CT (9/11) which is better able to image white matter abnormalities.

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23

Summary of Overall Image Findings

On average, across all studies (n=4l), 17.6% of subjects did not exhibit an image
abnormality. Thus, normal neuroanatomy is also a common finding among subjects with
CP. This may possibly be the result of microscopic cerebral damage unable to be imaged
by CT or MRI. For instance, Piovesana et al. demonstrated in their study of 175 children
with hemiplegic CP that some children with normal CT scans actually had small areas of
PVL either in isolation or in association with periventricular hemorrhagic porencephaly
by comparing MRI and CT results for 57 cases.98 Niemann et al. also reported similar
results in their study of 102 subjects with hemiplegic CP; of those with a normal CT scan,
6 showed signs of white matter damage (hyperintensities in T2-weighted images) on MRI
imagesm Therefore, although normal neuroimages are not uncommon, this does not
rule out the presence of a neuroanatomical abnormality.

White matter damage is the most common neuroanatomical finding among all
studies included in this review, occurring in 36.9% of all subjects (n=3,074). However,
this proportion is likely an underestimate considering some studies report a dominant
finding and do not provide information about other image abnormalities, and some do not
provide information by subject. Thus, it is expected that the proportion of subjects with
CP having white matter image abnormalities is above 50%. Pure grey matter damage,
found on average in 6% of subjects in this review, is the least common image finding;
although, again, this is likely an under-estimate due to the variation in reporting dominant

or multiple findings by subject.

24

Timing of brain insults

N euroimaging also contributes to the assessment of brain insult timing primarily
by providing information concerning either neuronal migration or glial reaction. The
process of neuronal migration is thought to be complete by the 20th week of gestation;133
therefore, migration disorders are thought to be indicative of insults occurring during the
first half of pregnancy. The timing of brain insults are also assessed via the brains ability
to mount a glial response.6 This ability is thought to begin somewhere around the 2nd to
3rd trimester; its absence, commonly concomitant with malformations, indicates an insult
occurring around the first half of gestation. When a glial response is present, the degree,
best seen on MRI, is used to assess the timing of the insult.

Thirteen MRI and CT studies estimated the timing of brain insults contributing to
CP.(Table 7) Overall, these studies report that insults deriving CP occur during the
prenatal, perinatal, and postnatal periods in 32%, 44%, and 6% of subjects respectively.
On average, the timing of insult was unable to be estimated in 18% of the subjects. Two
studies included a ‘pre/perinatal’ timing category; for comparability with other studies,
this category was considered perinatal.”130 Population-based studies, on average,
attributed etiology to prenatal, perinatal, and postnatal insults in 20%, 38%, and 6% of
their subjects respectively (29% were unclassifiable). Among clinic-based studies,
etiology was attributed to prenatal, perinatal, and postnatal insults in 36%, 48%, and 4%
while in 13% of the subjects, timing was unclassifiable. On average, studies of
hemiplegia reported less prenatal and more postnatal insults compared to studies of
multiple CP subtypes. Studies of spastic cerebral palsy reported insult timing estimates

similar to studies of multiple CP subtypes.

25

Table 7: Estimated Timingof Etiolgy

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Author Year Class CP CT Prenatal Perinatal Postnatal Unclassifiable
type MRI

Himmelmann 2005 I Multiple Both 14 51 0 35
Krageloh-M 1995 I Spastic MRI 27 39 5 29
Miller 1988 I Ataxic CT 29 28 3 8
Wiklund 1991 I Hemi CT 16 35 26 28
Wiklund 1991 I Hemi CT 14 39 0 46
Candy 1993 II Multiple MR] 67 15 9 9
Chen 1981 11 Multiple CT 53 47 0 O
Cioni 1999 II Multiple MRI 23 59 O 18
Claeys 1983 II Hemi CT 44 37 0 19
Cohen 1981 II Hemi CT 1 1 74 1 5 0
Fedrizzi 1996 II Spastic MRI 18 57 O 32
Hou 2004 III Multiple MRI 33 54 13 0
Park 1998 III Spastic CT 59 30 l 1 0

Mean 32 44 6 18

 

 

 

 

 

26

 

CHAPTER 4
CONCLUSIONS

Implications for Research and Potential for [mgrovement

The application of neuroimaging to CP is in its nascency and the interpretation of
imaging results is rapidly changing. Recently, a plethora of research has indicted the
brain continues to change structure through the lifespan which may influence how
abnormal neuroanatomy common to CF is defined or interpreted. The first large-scale
morphologic neuroimaging studies of children, conducted by Geidd and colleagues and
Rice and colleagues, found large variability in structural volumes across the age span,
even when correcting for total cerebral volumem"38 Durston et al. (2001) summarized
findings of twenty-five MRI studies of the developing brain and reported that while brain
size does not increase significantly after age 5, the white matter, grey matter, basal
ganglia, amygdala, and hippocampus alter with age.139 Sex differences in brain
maturation have also been revealed.13 4’1“ Recently, Reiss et al. investigated sex-
associated effects of preterm birth on cerebral gray matter and white matter volumes;
only males with preterm birth had significantly reduced white matter compared with term
males (p=.021), whereas female groups had equal white matter volumesl‘“ Also, girls
born preterm exhibited stronger correlations between neuro-anatomical variables and
both neonatal risk factors and cognitive outcome compared to boys. Thus, our
understanding of the natural history of brain development and sex associated differences

is advancing and should be considered when defining abnormal neuroanatomy common

to CP.

27

If neuroimaging is to advance the understanding of CP the interpretation of results
should also depart from etiologic based interpretations and move towards a purely
anatomical description. Many researchers have attributed brain damage indicated by CT
or MRI to either hypoxia or ischemia with little explanation of their epistemology. For
instance, Sugimoto et al., Nieman et al., Krageloh-Mann et a1, and more attribute PVL
specifically to hypoxia-ischemia]16"21’13"142 ”3 Most explanations rest on the speculation
that the watershed zone of the premature infant is most susceptible to a decrease in blood
pressure thought to cause periventricular damage.144

For instance, leading neuroradiologist AJ. Barkovich, author of Pediatric
Neuroimaging, speculates that up to the end of the second trimester of gestation the
paraventricular white matter is extremely vulnerable to hypoxic insults due to decreased
oxygen exchange and limited vasodilatory capacity of the cerebral blood vessels of the
premature infant.1 '8 Krageloh-Mann uses the same rationale speculating that term infants
have less hypoxic events due to more stable cardiorespiratory control.94 However, the
speculation of variance in oxygen demands between the premature and term infant is not
enough to support a causal inference between hypoxia-ischemia and PVL. The relatively
common finding of PVL among full term infants contradicts Barkovich and Krageloh—
Mann’s speculations. Thus, use of etiologic terms to describe image findings likely
distorts their importance. An example of such distortion is that Truwit et al. (1992)
attributed global atrophy specifically to hypoxia,110 yet Candy et al. reported that all of
their subjects having global atrophy exhibited normal APGAR scores at birth and
exhibited no signs of hypoxia;88 thus, the use of etiologic terminology distorts the

relevance and meaning of imaging findings.

28

Consistent language and interpretation would also further the understanding of
CP. Image findings vary significantly across studies and many lack information
important to understanding etiology. More than 120 findings were reported in the
literature and authors rarely described their findings in a manner similar to others. Such
variability makes it difficult to compare studies and inhibits the overall understanding of
the findings. Many findings also lacked sufficient anatomical description; often, atrophy
was not specified to the grey or white matter, the location of cavities was not specified,
and specific anomalies were not elaborated.

Studies also vary by the assertion of principal findings; some assert a principal
finding and utilize mutually exclusive categorization while others report multiple findings
per image. Thus, comparison of abnormalities across studies is extremely difficult.
Consistent classification and reporting of brain abnormalities and thorough descriptions
would allow similarities across studies to become evident providing an opportunity to
learn more about the abnormal neuroanatomy and pathology of CP. Perhaps patterns
would emerge that could be used to further investigate possible etiologic agents

associated with those patterns.

Emerging Imaging Techniques:

The understanding of CP may also be further advanced by the application of
emerging imaging modalities including, diffusion tensor and diffusion weighted imaging,
magnetic resonance spectroscopy, fimctional MRI, and fast spin echo imaging. Diffusion

tensor imaging (DTI), a nuclear magnetic resonance modality, uses the variability in

29

water diffusion in different directions to map white matter pathways based on structural
tissue organization. ”5 (figure 1)

Figure 1: Map of brainstem white matter tracto_ra . h ”6

  

Considering white matter damage, particularly PVL, is common in CP, the advanced
ability of DTI to image white matter could lead to increased understanding. DTI is the
only non-invasive method for mapping white matter fiber tract trajectories in the human
brain.‘47

While DTI maps fiber tracts, Diffusion weighted imaging (DWI) uses the
diffusion of water molecules occurring normally in the central nervous system to map the
entire brain; past applications include the identification of ischemic injury in both
children and adults.86‘l48’149 DWI has been shown to reveal abnormalities in the cerebral
white matter of the preterm brain that are not demonstrated on conventional MRI.'50‘154
DWI, however, is less sensitive than conventional MRI in detecting grey matter
damage.155 lBydder and Rutherford suggest DWI is the most important advance in

imaging during the last decade.156

30

147

Figure 2: Diffusion Weighted lmaging

     

'90 .r “ - . it?“

6 year old boy with cerebral palsy resulting from periventricular leukomalacia who presented with
asymmetric spastic diplegia affecting lefi side more than right.

A-D. Color maps of brainstem white matter tracts show decreases in size of corticopontospinal tracts in
affected boy (arrowheads, C and D). Furthermore, right cortieoponospinal tract is more involved than left
in affected boy, which correlates with his neurologic examination. A

Magnetic resonance spectroscopy involves suppressing water signals with a
software modification of existing MRI hardware to view metabolites present in lower
concentrations within tissue as spectra.86 Particular metabolites are thought to be markers
of pathogenic processes; i.e., according to Hunter, and Wang, choline is a marker for
demyelination and inflammation, and glutamate is elevated in ischemia.‘57 Mapping these
metabolites may provide further insight into the etiology and pathology of CP.

Functional MRI utilizes the paramagnetic effect of deoxyhemoglobin to study
brain organization and the biochemistry of functional pathways in movement without
radiation or contrast.”158 FMRI could be used to evaluate brain organization and
biochemistry in both movement and speech which are commonly affected in persons with

CP.

31

Modifications of MRI also include those aimed towards reducing or eliminating
motion artifact; such as, periodically rotated overlapping parallel lines with enhanced
reconstruction (PROPELLER) and single-shot fast spin echo (SS-FSE) imaging.
Traditionally, the reduction of motion artifact has been achieved via sedation. Chloral
hydrate is used to sedate infants and young children, intravenous Nembutal is used for
older children, and some undergo general anesthesia during imaging;86 however, many
parents consider the risk of sedation too great and opt to forgo the procedure if their child
can not remain still during the process. Some researchers have been able to image young
children while they slept, or have used audio or visual cues to train children to remain
still during imaging;159 although computer assisted motion correction provides a means of
assessing individuals who either fail to respond to such training or are unable to remain
still due to cognitive limitations. While SS-FSE speeds the imaging process,
PROPELLER intrinsically compensates for translational or rotational head motion during

signal acquisition through a unique mode of data collection.'60

Implicati0n_s for Clinical Practice

Available literature does not clearly support the American Academy of
Neurology’s strong recommendation of neuroimaging during the CP diagnostic process
because the disorder is primarily defined via non-progressive motor symptomatology
commonly assessed via physical examination and clinical history. While neuroimaging
provides anatomical description, this description is not currently used to define the
disorder and is therefore of limited use in the process of diagnosis. However, the most

recent definition of Cerebral Palsy does advocate the use of radiologic and anatomic

32

findings to classify the disorder;1 although uniform classification schemes based on these
findings have yet to be detailed.
The primary contribution of neuroimaging to CF diagnosis is to rule out

1 Such disorders are rare and are indicated via

progressive or genetic disorders.16
neuroimaging when evidence of deterioration or episodes of metabolic decompensation
are found. However, progressive disorders are often revealed via analysis of clinical
history, thus bringing the importance of neuroimaging in relation to diagnosis into
question. It is preferred that diagnostic tools be tested prospectively in representative
populations for predictive power compared to a current standard in order to assess added
benefit. Neuroimaging for CP has yet to be assessed in this way. Similarly, no
prospective study has evaluated the efficacy of neuroimaging in identifying metabolic
disorders masquerading as CP, which again is thought to rarely occur.

Nevertheless, neuroimaging remains important to the evolution of CP
understanding. However, this importance is primarily because of the relation of imaging
to etiology. The principal contributions of neuroimaging to the realm of CP etiologic
research are to be found in its potential to advance the understanding of abnormal
neuroanatomy underlying the clinical diagnosis of CP, and to estimate the timing of brain
insults in some cases.

Summacy
Regardless of the imaging modality selected, researchers should place
considerable thought on study design and sampling methodology to further the

understanding of CP. To date, only 5/41 CT or MRI studies imaging subjects affected by

CP having a sample size greater than 15 were population based; most studies, by contrast,

33

involved a sample of patients attending a referral based clinic and are by definition
thought not to represent the general population. Thus, systematic sampling with attention
to external validity is recommended to further the understanding of CP.

Neuroimaging has provided considerable insight into the neuroanatomy
underlying the clinical diagnosis of CP; however, its contribution to diagnosis is not
strongly supported by evidence and remains to be fully understood. If the anatomical
description of insults common to CF were used to define or classify the disorder,
heightened understanding of etiology might become evident. Through sound application
of epidemiological methods, utilization of emerging imaging modalities, and use of
anatomical rather than etiological descriptions of findings, fiu'ther insight into CP

etiology is likely.

34

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