1. health and fitness
2. disease

PREDICTION OF
NEUROSENSORY DISABILITY
IN VERY LOW BIRTH WEIGHT
PRETERM INFANTS
Structural and functional brain imaging and hearing screening
at term age and follow-up of infants to a corrected age of 18
months
M A RIT A
VAL KA MA
Department of Paediatrics,
University of Oulu
Department of Diagnostic Radiology,
University of Oulu
Department of Clinical Neurophysiology,
University of Oulu
OULU 2001
MARITA VALKAMA
PREDICTION OF NEUROSENSORY
DISABILITY IN VERY LOW BIRTH
WEIGHT PRETERM INFANTS
Structural and functional brain imaging and hearing
screening at term age and follow-up of infants to a
corrected age of 18 months
Academic Dissertation to be presented with the assent of
the Faculty of Medicine, University of Oulu, for public
discussion in the Auditorium of the Department of
Paediatrics, on March 23rd, 2001, at 12 noon.
O U L U N YL I O PI STO, O U L U 2 0 0 1
Copyright © 2001
University of Oulu, 2001
Manuscript received 22 February 2001
Manuscript accepted 6 March 2001
Communicated by
Docent Anna-Liisa Järvenpää
Docent Erkki Svedström
ISBN 951-42-5915-7(URL: http://herkules.oulu.fi/isbn9514259157/)
ALSO AVAILABLE IN PRINTED FORMAT
ISBN 951-42-5914-9
ISSN 0355-3221(URL: http://herkules.oulu.fi/issn03553221/)
OULU UNIVERSITY PRESS
OULU 2001
Valkama, Marita, Prediction of neurosensory disability in very low birth weight
preterm infants
Department of Paediatrics, University of Oulu, P.O.Box 5000, FIN-90014 University of Oulu,
Finland, Department of Diagnostic Radiology, University of Oulu, P.O.Box 5000, FIN-90014
University of Oulu, Finland, Department of Clinical Neurophysiology, University of Oulu, P.O.Box
5000, FIN-90014 University of Oulu, Finland
2001
Oulu, Finland
(Manuscript received 22 February 2001)
Abstract
The objectives were to study ultrasound (US), magnetic resonance imaging (MRI), single photon
emission tomography (SPET) and brainstem auditory evoked potentials (BAEP) as structural and
functional imaging methods for the prediction of later neuromotor outcome and to assess the reliability of auditory brainstem responses (ABR), transient evoked otoacoustic emissions (TEOAE) and
free-field auditory behavioural responses (FF) for the prediction of permanent hearing loss.
The series comprised 51 surviving very low birth weight preterm infants born at <34 gestational
weeks with a birth weight <1500 grams, taking 52 full-term infants as controls with respect to hearing
screening and 21 with respect to brainstem function. The imaging examinations and hearing screening were performed at term age and follow-up continued to a corrected age of 18 months for the evaluation of neurodevelopment and hearing. MRI images were analysed with regard to the degree of
myelination, parenchymal lesions, ventricular-brain ratios and widths of the extracerebral spaces,
and the predictive value of the findings for later neuromotor development was assessed by comparison with US. In the SPET examinations (on 34 infants) relative regional perfusion levels and hemispheric asymmetries were evaluated in slices. The predictive value of perfusion defects in SPET was
similarly assessed relative to US abnormalities. Brainstem size was measured by MRI, and brainstem
function evaluated by BAEP, and results being used to predict neurosensory disability. Hearing was
screened by means of TEOAE, ABR and FF, and the results used to predict permanent hearing loss.
Parenchymal lesions in MRI predicted cerebral palsy (CP) with a sensitivity of 82% and a specificity
of 97%, the corresponding figures for US being 58% and 100%. Delayed myelination, ventricularbrain ratios and widths of the extracerebral spaces failed to predict CP. The sensitivity of perfusion
defects in SPET for predicting CP was 82% and the specificity 70%, and correspondingly US attained
a sensitivity of 73% and a specificity of 83%. The best brainstem dimensions for predicting neurosensory disability reached at sensitivity of 23-31% and a specificity of 97-100%. The best predictors
in BAEP gave the sensitivity of 93% with a specificity of 57-59%. Bilateral failure in TEOAE predicted hearing loss with a sensitivity of 50% and with a specificity of 84%, and that in ABR with a
sensitivity of 100% and a specificity of 98%. The FF examination showed a sensitivity of 50% and a
specificity of 98%.
In conclusion, out of the brain imaging methods used here MRI was the best for predicting abnormal neuromotor outcome. Brainstem dimensions in MRI appear to predict neurosensory disability
poorly, however, whereas BAEP shows a better prediction value, but is limited by a low specificity.
ABR seems to be the best hearing screening method because it includes retrocochlear involvements
in preterm infants.
Keywords: hearing loss, cerebral palsy, magnetic resonance imaging, single photon emission tomography
To my family
Acknowledgements
The work for this dissertation was carried out at the Department of Paediatrics,
University of Oulu, in collaboration with the Departments of Diagnostic Radiology,
Clinical Neurophysiology, Clinical Chemistry and Otorhinolaryngology over the years
1993–2001.
I wish to express my respect for Professor Mikko Hallman, M.D., Head of the
Department of Paediatrics, and the sympathetic and supportive attitude that he has shown
towards this work. His prominent and notable reputation in the field of neonatal research
has always stimulated and encouraged me to exceed all expectations. I also express my
gratitude to Professor Matti Uhari, M.D., for offering me possibilities to study a wide
range of statistical matters and to obtain the computer support that I needed for these
achievements. I similarly wish to express my grateful thanks to Emeritus Professor Kauko
Kouvalainen, M.D., former Head of the Department of Paediatrics, for his support at the
beginning of this project and his confidence in its eventual completion.
My deepest gratitude and respect go to Docent Maila Koivisto, M.D., former Head of
the Division of Neonatology and my supervisor in neonatology during these years. She
was always ready to contribute towards achieving this goal and never lost her belief in
me. Equally, I express my sincere gratitude and appreciation to Docent Leena Vainionpää,
M.D., my supervisor in paediatric neurology. She also guided me with optimism in the
field of scientific thinking and writing. Many new frontiers in this work have been opened
up through discussions with these mentors.
I am indebted to Docent Anna-Liisa Järvenpää, M.D., and Docent Erkki Svedström,
M.D., for their constructive criticism and humane attitude in discussions on the final
construction of this work, and I am grateful to Malcolm Hicks, M.A., who skilfully
revised the English language to convert the original manuscripts and the present work
into successful instruments of science.
I offer my warmest thanks to Docent Peter Lanning, M.D., Docent Eija Pääkkö, M.D.,
Eero Ilkko, M.D., and Liisa Kerttula, M.D., at the Department of Diagnostic Radiology,
for their kind and smooth collaboration over the analyses of ultrasound and magnetic
resonance images. I also acknowledge the contributions of Docent Aapo Ahonen, M.D.,
specialist in nuclear medicine, and Pentti Torniainen, physicist at the Division of Nuclear
Medicine in the Department of Clinical Chemistry, who made me familiar with the
possibilities for studying brain perfusion. I am sincerely grateful to Docent Uolevi
Tolonen, M.D., at the Department of Clinical Neurophysiology for his fruitful
contribution to this series of papers. I was lucky to have such a kind, experienced and
helpful person as co-operator. I am under a deep obligation to Docent Kyösti Laitakari,
M.D., at the Department of Otorhinolaryngology, and to Mirja Väyrynen, M.D., at the
Division of Phoniatrics, for the work that they did in the screening of hearing. Their
friendly way of teaching this difficult subject proficiently to clinical physicians was
admirable.
I am very grateful to the preterm infants and their families, who made this work
possible. I also wish to thank all the competent staff at the co-operating departments for
taking care of the infants and performing the examinations. I am also grateful for the help
I have recieved from my fellow research workers. I would like to express my special
thanks to Mrs. Marjatta Paloheimo for her help and advice in office matters, and to Mrs.
Maija Veikkola for her collaboration in the library. I have been encouraged by the
achievements of other colleagues in the Department of Paediatrics, and I am happy to
have been able to keep in touch with the clinical colleagues.
I appreciate the frequent supportive conversations I have had with Tuula Kaukola,
M.D., my room-mate, and research colleague, and with Marja-Leena Pokela, M.D., and
Timo Saarela, M.D., physicians currently working at the Division of Neonatology. I have
had many occasions for inspiring chats whenever I have met with Docent Outi Tammela,
M.D., and Riitta Marttila, M.D., my colleagues in Tampere and Seinäjoki, respectively.
I have leaned greatly on my family during all these years. My mother has always
supported me whatever I have done, and my brother and sisters have been eagerly waiting
for the big moment. My dear husband, Juhani, has been patiently longing for it finally to
come to an end. While waiting for this, he has provided a winter week on the fells and a
summer week on the beach every year to relief my stress. Our lovely children Olli, Jussi
and Heidi have taken this project as a part of their everyday life. Their attitudes have
strengthened me to keep on writing eagerly. I admire childrens' ability to show how a
simple explanation is a complete one. They never stopped waiting to have another real
medical doctor in the family. I dedicate this work to my dear family.
This research was supported financially by the Maud Kuistila Memorial Foundation,
Helsinki, Finland, the Alma and K.A. Snellman Foundation, Oulu, Finland, the
Foundation for Paediatric Research in Finland, Oulu, Finland, and the Oulu University
Support Foundation, Finland.
Oulu, February 2001
Abbreviations
ABR
AGA
BAEP
BOA
BW
CBF
CI
CP
CRIB
CT
DQ
DB
EEG
ELBW
FF
GQ
GA
(k)Hz
LBW
MRI
(n)HL
NICU
OR
PHI
PVL
ROI
ROP
SEH
SD
SGA
SPET
auditory brainstem responses
appropriate for gestational age
brainstem auditory evoked potentials
behavioural observation audiometry
birth weight
cerebral blood flow
confidence interval
cerebral palsy
critical risk index for babies
computed tomography
developmental quotient
decibel
electroencephalography
extremely low birth weight
free-field auditory examination
general developmental quotient
gestational age
(kilo)hertz
low birth weight
magnetic resonance imaging
(normal) hearing level
neonatal intensive care unit
odds ratio
periventricular haemorrhagic infarction
periventricular leukomalacia
region of interest
retinopathy of preterm
subependymal haemorrhage
standard deviation
small for gestational age
single photon emission tomography
SQ
Tc-99m HMPAO
Tc-99m ECD
TEOAE
US
VLBW
VM
WML
sub-quotient
technetium-99-m hexamethyl propylene amine oxime
technetium-99-m ethylcysteinate dimer
transient evoked otoacoustic emissions
ultrasound
very low birth weight
ventriculomegaly
white matter loss
List of original papers
This thesis is based on the following articles, which are referred to in the text by their
Roman numerals:
I
Valkama AM, Pääkkö ELE, Vainionpää LK, Lanning FP, Ilkko EA & Koivisto ME
(2000) Magnetic resonance imaging at term and neuromotor outcome in preterm
infants. Acta Paediatr 89:348–355.
II
Valkama AM, Ahonen A, Vainionpää L, Torniainen P & Koivisto M (2001) Brain
single photon emission computed tomography at term age for predicting cerebral
palsy after preterm birth. Biol Neonate 79:27–33.
III
Valkama AM, Tolonen EU, Kerttula LI, Pääkkö ELE, Vainionpää LK & Koivisto
ME Brainstem size and function at term age in relation to later neurosensory disability in high risk preterm infants. Revised version submitted to Acta Paediatr.
IV
Valkama AM, Laitakari KT, Tolonen EU, Väyrynen MRH, Vainionpää LK &
Koivisto ME (2000) Prediction of permanent hearing loss in high-risk preterm
infants at term age. Eur J Pediatr 159:459–464.
Contents
Abstract
Acknowledgements
Abbreviations
List of original papers
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 Review of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2 Prevalence of neurosensory disability
in preterm infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3 Pathophysiology of brain damage in preterm infants . . . . . . . . . . . . . . . . . . . . .
2.3.1 Maturational aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.2 Haemorrhages and periventricular haemorrhagic infarction . . . . . . . . . . .
2.3.3 Periventricular leukomalacia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4 Prediction of the outcome for preterm infants by
neonatal brain imaging methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.1 Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.2 Magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.3 Single photon emission tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5 Neonatal brainstem auditory evoked potentials
in preterm infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6 Neonatal screening of hearing in preterm infants . . . . . . . . . . . . . . . . . . . . . . . .
2.6.1 Auditory brainstem responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.2 Transient evoked otoacoustic emissions . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.3 Free-field auditory examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7 Neonatal neurological assessment and follow-up
of preterm infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3 Aims of the research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4 Subjects and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1 Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1 Neonatal brain imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1.1 Ultrasound at term age (I, II) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1.2 Magnetic resonance imaging (I, III) . . . . . . . . . . . . . . . . . . . . . . .
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4.2.1.3 Single photon emission tomography (II) . . . . . . . . . . . . . . . . . . . .
4.2.2 Brainstem auditory evoked potentials (III, IV) . . . . . . . . . . . . . . . . . . . . .
4.2.3 Neonatal screening of hearing (IV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.4 Developmental follow-up and neurosensory outcome . . . . . . . . . . . . . . . .
4.2.5 Statistical methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1 Neurodevelopmental outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.1 Cerebral palsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.2 Developmental outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2 Abnormalities in imaging examinations at term age
and later neuromotor outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.1 Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.2 Magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.3 Single photon emission tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3 Brainstem auditory evoked potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4 Screening of hearing at term age and permanent hearing loss . . . . . . . . . . . . . .
5.4.1 Screening of hearing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.2 Hearing loss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5 Prediction of neurosensory outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.1 Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.2.1 Neurodevelopmental follow-up and outcome . . . . . . . . . . . . . . . . . . . . . .
6.3 Abnormalities in imaging examinations at term age and
later neuromotor outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.1 Ultrasound . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.2 Magnetic resonance imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.3.3 Single photon emission tomography . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.4 Brainstem auditory evoked potentials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.5 Screening of hearing and permanent hearing loss . . . . . . . . . . . . . . . . . . . . . . . .
6.6 Clinical implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1 Introduction
Prematurity is one of the greatest unsolved problems in perinatology and it comprises two
thirds of neonatal mortality (1). Although improved educational and socioeconomic level,
modern perinatal technology, advances in knowledge, increases in obstetric and neonatal
personnel and both concomitance and co-operation with other specialties have reduced
mortality rates in preterm infants, morbidity rates are still high (2–5).
Prematurity covers a wide range of gestational ages and birth weights (3, 6, 7). The
neonatal mortality of very low birth weight infants (VLBW, birth weight less than 1500
grams) in industrialized countries had fallen over the last thirty years from 50 to 15–20%
by the early 1990s, and that of extremely low birth weight infants (ELBW, birth weight
less than 1000 grams) from 80 to 30–40% (5, 8–14). The incidence of survivors with
major complications, either severe intracerebral haemorrhage or chronic lung disease, has
remained stable or increased (4, 5, 7). While the birth age of surviving preterm infants has
become progressively lower in terms of gestational weeks, it has come to be expected that
the more mature infants will manage better in life without any disability after neonatal
care (8). The higher numbers of VLBW infants who have survived have also been shown
to have increased the prevalence of cerebral palsy (CP), and has been even more true of
ELBW infants (15–17).
Neurosensory disabilities have been regarded in the course of times as the most
important measure of the long-term outcome among preterm infants, the main examples
of these being CP of any type, blindness, deafness and mental retardation (6, 10, 18). The
prevalence of CP in surviving VLBW infants has been reported to be 7–35%, and that of
hearing loss 2–17% (11, 19–21). Functional and neuropsychological assessments which
focus on speech and language, visual-spatial abilities, attention and behaviour disorders
and daily living skills in later life have been highlighted more recently (10, 22), and nonhandicapped VLBW infants have been shown to possess clumsy gross and fine motor
skills and to encounter a wide range of difficulties at preschool and school age when
followed up to adolescence (22–25).
Early identification of brain damage can help in targeting intensive follow-up and
rehabilitation adequately, but as neurological examinations alone have not proved reliable
enough in predicting the outcome for preterm infants, new methods have been sought
(26). The use of computed tomography (CT) has been restricted by the high radiation
16
exposure involved and the method has largely been replaced by grey scale and real-time
ultrasound (US) and magnetic resonance imaging (MRI) (27). US imaging is the most
widely used method for the prognostic assessments of brain damage. Of the functional
methods available electroencephalography (EEG) and evoked responses have been used
as diagnostic tools, but the newer functional methods of brain perfusion such as positron
emission tomography (PET) and single photon emission tomography (SPET) require the
use of isotopes and therefore involve a moderate degree of radiation exposure (27–29).
The main objectives here were to study US, MRI, SPET and brainstem auditory
evoked potentials (BAEP) as structural and functional imaging methods for the prediction
of the later neuromotor outcome, and to assess the reliability of auditory brainstem
responses (ABR), transient evoked otoacoustic emissions (TEOAE) and free-field
auditory behavioural responses (FF) for the prediction of permanent hearing loss at term
age in VLBW preterm infants.
2 Review of the literature
2.1 Definitions
An infant weighting less than 2500 grams was initially defined as a preterm infant by
Ylppö (30). Definitions for a preterm infant and the first weight of the newborn after birth
according to the International Classification of Diseases (ICD) are presented in Table 1
(31, 32).
Table 1. Definitions for a preterm infant and the first weight of the newborn after birth
according to the International Classification of Diseases (31, 32).
Infant
Definition
A preterm
An infant born before 37 completed gestational weeks
(259 days of gestation)
A very preterm
An infant born before 32 completed gestational weeks
(between 154 and 224 days of gestation)
An extremely preterm
An infant born before 28 completed gestational weeks
(between 154 and 196 days of gestation)
Low birth weight=LBW
The first weight < 2500 grams
Very low birth weight=VLBW
The first weight < 1500 grams
Extremely low birth weight=ELBW
The first weight < 1000 grams
Small for gestational age (SGA) means having a birth weight two or more standard
deviations (SD) or 10 percentiles below the mean value for the infant’s gestational age.
According to the WHO International Classification of Impairments, Disabilities and
Handicaps; an impairment is any loss or abnormality of psychological, physiological or
anatomical structure or function, a disability is any restriction or lack (resulting from an
impairment) of ability to perform an activity in the manner or within the range considered
normal for a human being, and a handicap is a disadvantage for a given individual
resulting from an impairment or disability that limits or prevents the fulfilment of a role
that is normal for the individual (depending on age, sex and social and cultural factors)
(32, 33). Although this WHO classification is difficult to modify for use with children,
18
there are functional losses that are likely to limit the individual severely in some field in
later life and can thus be designated as disabilities. Severe motor and sensory disabilities
can certainly be evaluated during the first two years of life (32). Neurosensory disabilities
most often include four major domains: CP, deafness, blindness and mental retardation/
developmental delay (18).
Cerebral palsy is defined as ‘a non-progressive permanent impairment of voluntary
movement or posture presumed to be due to damage to the developing brain before,
during or shortly after birth’ (32, 33), and it entails clinical signs including delayed motor
development, deviant muscle tone and strength, abnormality in postural reactions
(righting, protection and equilibrium) and inappropriate persistence of primitive reflexes
beyond the normal age. Spastic CP is defined as spasticity of the extremities with flexor
hypertonicity and increased tendon reflexes and characteristic posturing. In its
distribution of topographic involvement, spastic tetraplegia consist of severe spastic
paresis of the four limbs with disability in the upper extremities being of the same degree
or more pronounced than that in the lower ones. Spastic diplegia implies spastic paresis
of the lower extremities with variable but lesser involvement of the upper limbs, and
spastic hemiplegia spastic paresis of the arm and leg on one side. An ataxic component
means ataxic traits, especially dyssynergia and intention tremor in the limbs, and the
dyskinetic group comprises syndromes of choreo-athetosis and the more disabling
dystonic forms. (34, 35) In terms of severity, motor disability may be described as
functionally mild if the child has consistent physical findings but no limitation on
ordinary activities, being able to walk independently, moderate if there are definite
difficulties in daily activities and the child is often dependent on assistive devices to move
independently, and severe if there are moderate to great limitations in activity and the
child mostly needs a wheelchair for mobility (36).
According to the ICD, profound, severe or moderate retardation is considered to be
present if the child has a developmental quotient (DQ = developmental age/chronological
age x 100) of less than 50, and mild when it is 50–69. The ICD does not categorize
borderline and definite normal cases (32). There are various global scoring systems which
can be used to assess an infant’s developmental, cognitive and intellectual progress for
follow up purposes (10). The boundary scores on different scales below which the child
has a developmental delay causing major or severe disability have been 70–85 (7, 37, 38).
The WHO defines hearing impairment according to the better ear hearing level
averaged at frequencies of 0.5, 1, 2 and 4 kHz (BEHL0.5–4 kHz), in which context
sensorineural deafness is defined as a hearing loss of 40 desibels (dB) or more at any
frequency in the range of 0.5–4 kHz in the better ear (with or without associated
conductive loss) (32, 39). The hearing impairment may be classified in terms of BEHL as
mild (26–40 dB), moderate (41–60 dB), severe (61–80 dB) or profound (>80 dB) (39).
2.2 Prevalence of neurosensory disability
in preterm infants
Volpe (40) estimated that 5–15 % of surviving VLBW infants in the USA later have CP
and an additional 25–50% have abnormalities that disturb their daily life and schooling.
19
In a meta-analysis reviewing reports from industrialized countries, the proportion of
surviving VLBW infants with an intact outcome was shown to have increased from 25 to
50% over the thirty years up to the late 1980s (8). According to another meta-analysis by
Escobar et al. (18), the disability rate for VLBW preterm survivors from 1960 to 1985
varied from 21 to 34%. The improvement in the survival of ELBW infants has
progressively compromised the most critical disability group, steering it towards the
tiniest and most preterm cases, while the heavier infants have fared better (8, 9, 38, 41).
More than 90% of all preterm infants with a BW of 1000–1499 g in the early 1990s were
reported to have normal motor abilities and more than 80% to have a normal cognitive
outcome, whereas about 50% of ELBW preterm infants were found to be normal (16, 38,
42, 43). Even lower rates of 20% for severe neurosensory disability (CP, mental
retardation, blindness and / or deafness) have nevertheless been reported among ELBW
infants during the 1980s and 1990s (44, 45).
CP is the most commonly reported major neurological disorder identified in ELBW
and VLBW children during the first two years of life (10). According to the meta-analysis
of VLBW survivors between 1960 and 1985, the prevalence of CP ranged from 5 to 9%
(18). The prevalence of CP in surviving VLBW preterm infants in Europe has been 5–
35% in the 1990s, and 7–17% in ELBW preterm infants (9, 12, 15, 21, 46, 47). Rates of
CP published in the USA have been 7% in VLBW infants and 10–17% in ELBW infants
(11, 16, 38). Two reviews of infants born at gestational ages of less than 26 weeks
between 1977 and 1997 have found CP in 12% of such infants, while 12–15% of preterm
infants born before 34 gestational weeks in the early 1990s developed CP (7, 48, 49).
Nine percent of VLBW infants born in the early 1990s were found to have DQ≤80 (2
SD below the mean) at a corrected age of 6 months, while at the age of one year 22% of
VLBW infants in the mid-1990s were assessed as having major neurodevelopmental
impairment (DQ<85) (50, 51).
Infants with a BW of 1000–1500 g had severe hearing disability in 2% of cases and
severe visual disability in 6% in the late 1980s, whereas 10% of ELBW infants had severe
hearing disability and 16% severe visual disability (41). Overall, the prevalence of
hearing loss in VLBW infants has been 2–17% in recent decades (19, 20, 41). More
recently deafness was found in 9–11% of surviving ELBW infants in the 1990s and
blindness in 1% (16, 38). A half of the ELBW infants with hearing loss were also
reported to have CP (52). Later, at the age of 5 years, sensorineural, conductive or
unspecified hearing loss was found in 15–30% out of series of very preterm infants (53,
54).
2.3 Pathophysiology of brain damage in preterm infants
Brain damage in preterm infants may result from a series of events rather than from one
specific insult (55). Maturational characteristics with a failing adaptation capacity may
predispose the brain to harmful events during both intrauterine and extrauterine life (56,
57).
20
2.3.1 Maturational aspects
Structural and functional immaturity of the organs responsible for ventilation and the
circulation in a preterm infant is the basic reason leading to a lack of an acceptable
cerebral blood flow and arterial oxygen delivery in the brain under unfavourable clinical
conditions. Immature vascular structures, certain developmental characteristics in the
cerebral circulation, intrinsic cell vulnerability and various toxic mechanisms overlap and
contribute to a predisposition to cerebral damage (56, 58–61).
The germinal matrix tissue where the neuroblasts originate between 10 and 20 weeks
of gestation and the glioblasts originate in the third trimester, is located adjacent to the
lateral ventricles, with the greatest abundance tissue lying between the ventricles and the
caudate nucleus in the telencephalon (27). The tissue extends originally around and
beside the horns of the lateral ventricles in the periventricular areas and diminishes
gradually with advancing gestation, mostly disappearing by the 36th gestational weeks
(56, 62). This germinal matrix tissue is a loose network that is abundant in tiny, fragile,
thin-walled vessels that serve as straight passageways for blood originating from the
anterior and middle cerebral and anterior choroidal arterial supplies, and it is separated
from a lateral ventricle by only one layer of ependyma (56, 63). Drainage of the germinal
matrix takes place through the terminal vein, into the internal cerebral vein and then
through the great vein of Galen into the straight sinus, in the same way as the venous
blood draining from the white matter and the choroids plexus. The vessels between the
arteries and veins in the inner germinal matrix are not easily distinguished as arterioles,
venules or capillaries, and this microvascular network presents a weak vascular border
zone. The most critical area is a vascular border zone between the striate and thalamic end
arteries, where the decreased oxygen and increased carbon dioxide partial pressures lead
to vasodilatation, causing hyperperfusion and sometimes subsequently hypoperfusion
depending on the persistence of hypoxia, because of impaired cerebral autoregulation.
Fluctuations in cerebral blood flow (CBF) can lead to rupture of these fragile vessels,
causing haemorrhages especially in sick preterm infants with coagulopathy. As neuronal
cell migration to the cortex is completed by the 24th gestational weeks, haemorrhages in
the germinal matrix may destroy the migrating glial precursor cells and partly nullify
subsequent brain development (27).
The white matter includes critical areas for ischaemic injury, i.e. the ‘distal fields’ or
‘watershed areas’, or more precisely the arterial terminal end zones and border zones
(27). Of the penetrating cerebral arteries, the long penetrators branching from the
leptomeningeal artery terminate in the deep white matter (i.e. the vascular end zones) at
24–28 gestational weeks and have only infrequent anastomoses with the short penetrators
(i.e. the vascular border zones), which extend only to the subcortical white matter (i.e. the
vascular end zones) (57). There are only a few interconnections of the long penetrators in
the intermediate white matter (i.e. the vascular border zone) (57). Vessel density in the
deep white matter has been shown immunohistochemically to be high at 16–24
gestational weeks in the mean foetal period, and then transiently low at 28–36 gestational
weeks followed by an increase after 39 gestational weeks (58, 64). This agrees with the
finding that the CBF to the white matter has been measured as being extremely low
around the 30th gestational weeks (65). Although there is also small degree of
physiological oscillation or variability in CBF velocity in healthy preterm infants,
21
cerebral vascular autoregulation is needed to maintain the required constant CBF during
any change in cerebral perfusion pressure (=mean arterial pressure minus intracranial
pressure) (66, 67). The most common clinical situations in which secondary loss of CBF
autoregulation may occur are events such as hypotension, acidosis, septic shock,
hypocarbia, patent ductus arteriosus, recurrent apnoea and bradycardia (27, 59). The lost
autoregulation may render preterm infants susceptible to both to haemorrhagic and
ischaemic events in the most vulnerable vascular end and border zone areas, which
thereby serve as determinants of a poor neurological outcome (40, 60).
The vessel density in the cerebral cortex (grey matter) and subcortical white matter
has been found to be low at 16–28 weeks of gestation, followed by an increase after 36
weeks (64). The CBF to the cortex increases in the first days of life and further with
advancing gestational age in very preterm infants after birth (68, 69).
The number of vessels in the basilar pons of the brainstem has been shown to increase
at 28–32 gestational weeks more than that in the tegmentum of pons, which is in
agreement with progress of myelination (64, 70). Because of the active metabolism and
corresponding abundant blood flow in the brainstem, it is highly vulnerable to adverse
events at 26–32 gestational weeks, when the neurons are still immature (27, 64).
The intrinsic vulnerability of cells plays a major role in the generation of brain
damage. Oligodendrocyte precursors or early differentiating oligodendroglia have found
to be the most vulnerable target cells at the premyelinating stage, because of their
enhanced glucose and energy requirements for lipid synthesis, and they are also rich in
iron-binding proteins during the maturation process (40). After hypoxic-ischaemic insult
during the reperfusion period, more cell damage is caused by the release of oxygen
radicals, the synthesis of nitric oxide, inflammatory reactions and an imbalance between
the excitatory and inhibitory neurotransmitter systems, and also by apoptosis (40).
Cytokines connected with inflammations are the latest adverse clinical features to be
associated with brain damage, as indicators of maternal infection and a foetal
inflammatory response have been seen to precede white matter abnormalities (71, 72).
The expression of a wide variety of cytokines, e.g. tumour necrosis factor and interleukins
has been found to relate white matter damage (73). Perinatal infections have been found
in VLBW preterm infants with later CP (74).
Myelination, i.e. myelin deposition, is the main pattern for CNS maturation, beginning
in the peripheral nervous system, with the motor roots first, followed by the sensory roots,
and progressing from the spinal cord in a caudocranial direction, so that it appears in
some major sensory systems, including the inferior colliculus, and in some major motor
systems, including the corticospinal tracts in the midbrain and pons, before term age (27,
75). Through the posterior limb of the internal capsule, myelination reaches the
hemispheric white matter, from where it proceeds from the central sulcus towards the
poles. Myelination advances from deep areas to superficial ones and from posterior areas
in an anterior direction (75–77). Reached myelination stages (M1-4) visualised in MR
images lags behind some weeks when compared with histological timetables (75). Stages
M1-M2 on MR images are described in Table 2.
22
Table 2. A timetable of normal progress of myelination in MRI (76, 78).
Myelination
stage
Post-conceptional
age (weeks)
Presence of myelin
M1
Before 37
Myelin in the brainstem, the vermis and the cerebellar hemispheres
M2
At 37–38
Myelin in the posterior limb of the internal capsule and the lenticular
nucleus and thalamus
M3
At 39–40
Myelin in the central corona radiata and the caudate nucleus
M4
At 40–42
Myelin in the centrum semiovale
2.3.2 Haemorrhages and periventricular haemorrhagic infarction
Papile et al. (79) provided the first classification of germinal matrix and intraventricular
haemorrhages (GMH-IVH) based on the results of CT images of the brain in an
unselected sample of VLBW infants (Table 3).
Table 3. Classification of haemorrhages in VLBW infants, according to Papile et al. (79).
Grade
Extension of haemorrhage
I
Subependymal haemorrhage (SEH)
II
Intraventricular haemorrhage (IVH)
III
Intraventricular haemorrhage with ventricular dilatation (IVH+VD)
IV
Intraventricular haemorrhage with ventricular dilatation and parenchymal extension
This classification is still in use, although the grades of haemorrhages are now
described in a cumulative sense (80). The classification used by Volpe (27) is based on
the severity of GMH-IVH in US in preterm infants, and treats the grades as separate
entities (Table 4).
Table 4. Grading of the severity of germinal matrix-intraventricular haemorrhages from
US scan, adapted from Volpe (27).
Grade
Extension of haemorrhage
I
Germinal matrix haemorrhage with minimal or no intraventricular haemorrhage
(<10% of ventricular area in parasagittal view)
II
Intraventricular haemorrhage
(10–50% of ventricular area in parasagittal view)
III
Intraventricular haemorrhage
(>50% of ventricular area in parasagittal view; usually distends lateral ventricle)
Separate
notion
Periventricular echodensity
(location and extent)
The most common single pathological involvement in the brain of the preterm infants
is GMH-IVH (56). A grade I haemorrhage, originating from the germinal matrix, will not
have any harmful consequences, as it originates in an area that disappears and will not
23
normally extend to the white matter (27). In addition to the dominant region for
subependymal haemorrhages (SEHs) in the caudothalamic zone, haemorrhages may more
rarely occupy occipital and temporal locations (56). As intraventricular haemorrhages, of
grade II, originating from the germinal matrix or the choroid plexus, do not reach the
white matter areas, either, these have no neurological sequelae. Grade III IVH entails
ventricular dilatation, however, and as a consequence of the vulnerability of the
developing brain, adverse cognitive and motor development has been found in preterm
infants with posthaemorrhagic ventriculomegaly (VM) (81). A mortality rate of
approximately 20% has been observed when the haemorrhage fills the ventricles, and
over half of the survivors may exhibit VM (27). Progressive VM is caused by
disturbances in cerebrospinal fluid flow or absorption, causing hydrocephalus. The
occurrence of IVH with VM has frequently been found to increase the incidence of white
matter damage (82, 83). Neonatal mortality may be related more to additional ischaemic
lesions than to the severity of haemorrhage per se (84).
Haemorrhage in the germinal matrix can be complicated by ventricular haemorrhage
extension and intraparenchymal haemorrhage (Papile’s grade IV). This may also promote
venous congestion with periventricular haemorrhagic infarction (PHI) through ischaemia
in the medullary vein area, with its most noteworthy involvement in the white matter just
near the ventricular angle (57). This destroys some of the white matter, leaving a pore or
an area of thinning. The typical fan-shaped topographic appearance of the apex area of
the trigone reaches the descending corticospinal tract motor fibres (27). This lesion
normally occurs only on one side and causes spastic hemiplegia, but a larger one can
causes spastic tetraplegia and intellectual deficit (57, 85).
A focal infarct in the main branch of the middle cerebral artery can sometimes occur in
preterm infants, and even more often smaller infarcts with the involvement of a cortical
branch or one or more lenticulostriate branches. Infarction in the main branch of middle
cerebral artery may cause hemiplegia, while infarction in a cortical branch will have
milder consequences and infarction in the lenticulostriate branches will have an outcome
varying from normal motor functions to athetoid CP or global delay according to the
attachments to the motor tracts (86). Thalamic lesions in premature infants have been
seen to lead to disturbances in tone persisting throughout infancy (87). Intracerebellar
haemorrhages of primary origin in the cerebellar germinal matrix zones or secondary to
traumatic delivery have been seen in 14–28% of autopsy cases involving VLBW preterm
infants (56). Sometimes IVH may extend to the subarachnoid spaces, but in traumatic
deliveries solitary subarachnoidal haemorrhages are also observed in preterm infants, as
seen at autopsy (27, 56).
2.3.3 Periventricular leukomalacia
The most obvious of the primary white matter lesions is periventricular leukomalacia
(PVL), which has been typical of the pathological descriptions of necrosis in the white
matter (88). Leukomalacia can be classified according to the distribution of ischaemic
necrosis in the cerebral pathology, into focal, widespread, diffuse and multifocal (89).
Focal periventricular necrosis predominates in the occipital radiation at the trigone area
24
and in the white matter around the foramen of Monroe, leaving myelin loss through cystic
changes, and focal ventricular dilatation, most often in the trigone as sequelae (27). As
PVL may be distributed focally in the deep white matter of the terminal and border zones,
dorsally and laterally to the external angle of the lateral ventricles, particularly involving
the centrum semiovale (frontal horn and body) and the optic (trigone and occipital horn)
and acoustic (temporal horn) radiations, widespread necrosis appears more widely in the
deep white matter, while diffuse necrosis also includes the subcortical white matter and
the multicystic form additionally involves the grey matter (89). Diffuse leukomalacia is
more common in smaller preterm infants, and it leaves a thinned parenchyma with more
prominent VM (27). PVL is more frequently bilateral than haemorrhagic infarction and
its long-term sequelae correspond to the anatomical location and extent of the injury (40,
56). Solely anterior cystic PVL is usually associated with a normal outcome (71). One
classic long-term consequence of PVL is motor disability, usually spastic diplegia or
tetraplegia, with greater involvement of the lower limbs because of damage to the
corticospinal tracts passing through the internal capsule, the centrum semiovale and the
corona radiata (27, 56). Extensive white matter loss (WML) with involvement of the
optic and acoustic radiations has been observed to cause not only severe neurological
sequelae but also severe cerebral visual impairment and deafness (90, 91). Periventricular
white matter injury may moreover lead to a reduction in cerebral cortical grey matter
development, bearing an anatomical correlation with later intellectual deficits (92).
The originally histological diagnosis of PVL is commonly applied nowadays to both
echodense and echolucent abnormalities in US images of the cerebral white matter (93).
The changing appearance of PVL as it develops means that time is needed before it
becomes conclusively assessable in its cystic form during neonatal period. These PVL
changes, classified by de Vries et al. (29), are shown in Table 5.
Table 5. Classification of periventricular leukomalacia, according to de Vries (29).
Grade
Definition
I
Transient periventricular echodensities persisting for 7 days or longer
II
Periventricular echodensities evolving into small localized frontoparietal cystic lesions
III
Periventricular densities, evolving into extensive periventricular cystic lesions
IV
Densities extending into the deep white matter evolving into extensive cystic lesions
Brainstem lesions in preterm infants have mostly been seen in autopsies following
with IVH or PVL and in connection with cortical, cerebellar and basal ganglion lesions
(56, 84). The tegmentum of pons, nuclei and the subiculum of the hippocampus are
preferred regions for hypoxic-ischaemic injury, chiefly pontosubicular necrosis, which
has been seen more commonly in preterm than term infants (27, 84). Microscopic
examinations have shown not only a great number of karyorrhectic neuronal cells in the
pons and subiculum, but also possible injuries to the inferior olivary nucleus, cerebellum,
basal ganglia, thalamus and cerebral cortex, particularly in the most immature preterm
infants (84, 94, 95). Only minimal glial reactions have been seen in cases of neuronal
karyorrhexis (95).
25
2.4 Prediction of the outcome for preterm infants by
neonatal brain imaging methods
Although the anatomical and physiological maturation processes in the brain are
interdependent, they are different entities, and their development and disturbances have to
be measured by different techniques. Of the morphological imaging methods, CT was the
first just before grey scale and real-time US to be taken into clinical use, and it has
nowadays been largely replaced by MRI, while among the functional methods mention
should be made of EEG, evoked responses, SPET, PET and magnetic resonance
spectroscopy (27, 96–98). The methods to be considered below are US, MRI, SPET and
BAEP.
2.4.1 Ultrasound
US is the most frequently used method for assessing intracranial abnormalities in
neonatal period (27, 99). It is less expensive, fast and easily transportable to the bedside.
The standard coronal and parasagittal images are obtained through the anterior fontanelle
and modern scanners with transducers of 5–10 MHz offer high resolution (99). One
disadvantage of US is the restricted field of view, which may prohibit the observation of
peripheral involvements and also mean that the brainstem and cerebellum are not outlined
sharply (100). Visual descriptions of US findings such as echodensities, echolucencies,
loss of parenchyma and dilatation of ventricles can be interpreted to a diagnosis of
haemorrhage, PVL, VM or other minor defects (27, 79, 99).
Predictive value of abnormalities in US. A half of the surviving VLBW infants in the
1980s and 1990s have been reported to have evidence of haemorrhages in their US
images during neonatal period (99, 101). The traces suggest that some bleeding can be
judged to have taken place before birth (102, 103). Earlier it was estimated that 90% of
GMH-IVHs become visible in the first three days of life, but it has been reported recently
that only 65% of haemorrhages in VLBW infants are seen in US during the first week of
life (27, 99). About 50% of haemorrhages affected the germinal matrix, 35% filling less
than 50% of ventricles and the other 15% being more severe forms (99). US has shown a
sensitivity of 60–100% and a specificity of 40–100% in detecting post mortem
identifiable GMH-IVHs in VLBW preterm infants (56). GMH-IVHs just after the birth
have recently been reported to associate with significant motor developmental delay and
CP in 15% of VLBW infants and with delayed mental developmental in 39% (104, 105).
Isolated germinal matrix or choroid plexus cysts, whether or not consequent upon
haemorrhages, have sometimes been seen just after birth (99, 106). Thalamic echoes have
been imaged, either as isolated phenomena or in association with haemorrhages, in infants
less than 34 gestational weeks at birth and in VLBW infants (99, 103). Cerebellar
haemorrhages are sometimes observed at autopsy, but seldom in US, because of technical
restrictions (27, 107). Haemorrhages in neonatal US had a sensitivity of around 60% and
a specificity of around 85% in the prediction of disabling CP in preterm infants (108).
Traces of haemorrhages in discharge US images of VLBW infants have been able to
26
predict an adverse outcome with a sensitivity of almost 70% and a specificity of around
50% (101).
PHI is unilateral and often associated with ipsilateral IVH. It can best be determined
by means of serial US examinations, as the haemorrhagic appearance of a PHI can vary
from a striking echogenic lesion to a single large porencephalic cyst (27, 56, 85). If PHI
(or IVH with parenchymal involvement) appears around the trigone, it is almost always
followed by mild, moderate or severe hemiplegia (109). Focal arterial infarcts may be
associated with IVH or PVL (86). Cysts visible in US on the second day of life have been
interpreted as pointing to an infarct with antenatal onset (103). Infarction of the middle
cerebral artery causes increased echogenicity in the region supplied by the affected artery
followed by cystic degeneration after 2–4 weeks, but involvements of the cortical anterior
branches may be difficult to detect even with serial US unless cysts develop, similarly
small infarctions in the lenticulostriate branches until very late cysts or hyperechogenicity
appear in the thalamus or basal ganglia (86). Hemiplegia may be the consequence of an
infarction in areas of the brain supplied by the entire middle cerebral artery, in the
complete set of cortical branches of that artery, in its anterior or posterior trunk, in its
lenticulostriate branches or in the anterior choroidal artery (86, 110).
Cystic PVL was found in 5–8% of surviving VLBW infants in the 1980s and 1990s
and prolonged flare in 15–30% (99, 101, 111). The average proportion of CP was 60% in
infants with persistent flares or cystic PVL in their US image, according to a review of
reports published between 1980 and 1990, the most severe CP forms having arisen from
cystic PVL in the external angle of the lateral ventricles (56).
Almost 20% of preterm infants with persistent foetal periventricular echodensities
have been observed to develop cystic PVL involvement after 10 days to 7 weeks (112),
although many reports consider PVL to have had an antenatal onset when the cysts have
already been visible in the first US after birth or during the first two weeks (55, 102, 103,
113). Cysts often seem to appear during the first or the second weeks after echodensities
in the initial US, but in cases of normal scans cystic PVL has tended to evolve during the
3rd to 7th weeks of life (90, 99, 111, 114). Although these echolucent cysts usually
disappear within 3 months, they may leave enlarged ventricles, and very early onset PVL
may reflect intrauterine problems and leads to severe disability more often than later
onset PVL. Even transient periventricular echodensities have been observed to associate
with significant motor developmental delay in a few of VLBW infants with that finding
and to delayed mental developmental in one quarter of cases (104).
The ventricular dimensions at term age are wider in VLBW infants than in full-term
infants (115). The diagnosis of VM is mostly based on exact measurements, but the
boundary of the VM in US at term age has varied in width, being abnormal at the midbody of the lateral ventricles in a oblique coronal scan or having a ventricular index (midbody ventricular width divided by hemispheric width) that is abnormal, i.e. more than
0.32–0.39 (81, 115–119). A mean value of 0.51 (95 % CL 0.40–0.60) has been quoted for
the corresponding ventricular-brain ratio at the trigone (atrium) level (116). Apart from
reduced amount of parenchymal tissue, a diagnosis of hydrocephalus with a ventricular
index of over 0.40 requires clinical signs of increased brain pressure with a bulging
anterior fontanelle, widened spreads of the sutures in the bony skull and rapid growth in
head circumference (115, 120). Ventricular dilatation is associated with the severest IVH
grades and with PVL, and not only the lateral ventricles may be dilated but also the third
27
and the fourth ventricles (27, 117). Infants with VM at term age are usually extremely
preterm and have significant low birth weight (81, 83, 99). Where the margins of the
walls of the ventricles most often remain regular after IVH and hydrocephalus caused by
impairment of cerebrospinal fluid (CSF) absorption, dilatation may occur relatively
slowly after PVL, with ragged or irregular ventricular walls in US (117, 119). The most
characteristic enlargement after PVL nevertheless exists in the occipital horns of the
lateral ventricles (40, 121). As only ventricular enlargement is noted, almost a half of
VLBW infants with VM have progressed to CP later (56). It has been observed recently
that preterm infants with VM have spastic tetraplegia, diplegia or hemiplegia significantly
more often than infants with normal ventricles in US, and significantly more often have
an IQ less than 70 (81). The subarachnoidal spaces are relatively large in preterm infants,
but although this feature has been noticed as a sequel to some form of involvement, these
spaces have not normally been used for prediction purposes (27).
Linear hyperechogenicity within the basal ganglia and thalamus may sometimes
appear in preterm infants as a mark of more diffuse brain lesion and cause
neurodevelopmental delay and, in particularly cognitive and behavioural problems (122).
Unilateral thalamic lesions varying in appearance have mainly been connected with
disturbances in tone persisting throughout infancy (87).
2.4.2 Magnetic resonance imaging
MRI has provided help in detailing neonatal brain abnormalities over the last twenty
years. MRI of the brain provides higher contrast resolution than do US and CT, and it
avoids the problems of radiation exposure, restricted views and bony artefacts (123, 124).
The main disadvantages limiting the use of the method for neonatal purposes include
difficulties with availability, expense, transportation to imaging rooms and sedation.
Prenatal and neonatal MRI studies are performed with magnetic field strengths of a 0.15
to 2.35 Tesla (T) (76, 92, 121, 125–128).
Maturational aspects are reflected in imaging properties. As the water content of the
brain is greater in infants than in adults, the signal intensities of the grey and white matter
at term age are the reverse of those seen in adults, that of the white matter being lower
than that of the grey matter in T1-weighted images and higher than that of the grey matter
in T2-weighted images (129, 130). White and grey matter differentiation has been found
to indicate very low white matter intensity before 37 post-conceptional weeks and high
intensity after term age (76, 97). In addition to the white and grey matter differentiation
and myelination, attention has also been paid to other maturation features such as sulcal
and gyral development in cortical folding and volumetric changes in the white and grey
matter and CSF (92, 126, 131–133).
Development and ageing of the brainstem has been assessed by MRI, and
morphometric measurements have also been performed on the images (123, 134–136). As
a part of the midbrain structure, the brainstem demonstrates the presence of myelin from
the 23rd week of gestation onwards and the mature myelin stage is reached in MRI before
term age (75, 124, 137–139). The most frequently used morphometric parameters have
28
been the area and dimensions of the pons, which has been shown to grow exponentially in
early childhood (123, 124, 135, 136).
Predictive value of abnormalities in MRI. Diagnostic abnormalities in conventional
MRI may be deduced from excessively high or low signal intensities in white and grey
matter differentiation and patterns of myelination that deviate from normal age-related
contrast changes, lack of signal intensity in structural entities due to brain material loss, or
exceptional morphometric measurements (76, 125, 126, 133, 139, 140). Brain lesions in
preterm infants have been depicted reliably by MRI in terms of volume and topography
when referenced to autopsy abnormalities, but more subtle histological abnormalities
such as increased glial cells or apoptosis could not be detected on conventional MRI (140,
141). Neonatal MRI has most often been used to confirm findings in neonatal US or as a
point of comparison for them, and later MRI has been used to verify abnormalities with
regard to clinical findings (142–147). In survived preterm infants neonatal brain MRI has
played an increasing role in prediction of neurodevelopmental outcome (87, 145, 147,
148).
Traces of germinal matrix or parenchymal haemorrhages are observed as weak
abnormal signal intensities during an acute stage of less than three days followed by a
higher intensity in T1-weighted images and a lower intensity in T2-weighted images in
the late subacute stage, lasting two weeks. Traces of small haemorrhages have been seen
to fade away after that. Some may persist very late, for a chronic stage of several weeks
with high intensities in both T1-weighted and T2-weighted images, with even
haemosiderin and structural changes acting as reminders of neonatal haemorrhage for
months afterwards. Subependymal and parenchymal haemorrhages remain visible for
longer because of haemosiderin deposits and the development of porencephalic cysts,
some of them being continuous with the ventricular system. Clots following IVHs have
been seen to give a high signal in T1-weighted images and a low signal in T2-weighted
images at first. Later signals reverse in two weeks and these features may persist for
weeks, outlining the walls of the lateral ventricles. (125, 145, 149–151) Extensive IVHs
in foetal MRI, especially with associated parenchymal lesions, have usually led to
intrauterine or postnatal death or caused hydrocephalus and poor development, but
haemosiderin deposits without parenchymal destruction in neonatal MRI have not
predicted an unfavourable outcome (128, 145). The correlation of IVH in neonatal MRI
with the results of neuropathological examination has been excellent (140, 141).
PHI including parenchymal cysts around the trigone area in MRI at post-conceptional
term age in preterm infants, and later haemosiderin deposits and parenchymal volume
loss at the site seen in follow-up MRI images have been found to lead to contralateral
spastic hemiplegia (85, 145). In cases of focal arterial infarctions suspected on the basis
of neonatal US, the findings have been confirmed by MRI during the neonatal period or
in infancy (86, 152). Deep infarctions in the area of the middle cerebral artery and smaller
infarcts in a cortical branch or one or more lenticulostriate branches have been seen in
preterm infants (86, 152). Preterm infants with involvement of the main branch had
usually developed contralateral hemiplegia, but those with involvements of other
branches had more favourable outcome (86).
PVL has been reliably estimated in terms of volume and topography by reference to a
definition of the components of the bilateral lesion at autopsy, including cavities,
translucent zones and cellular reaction, although not in cases of diffuse PVL (140, 141).
29
Early neonatal brain MRI, even after a post-conceptional age of 31–34 weeks, has
demonstrated PVL with bilateral periventricular hyperintensities located mainly
posteriorly and laterally to the occipital horns, anteriorly to frontal horns or in the corona
radiata (140, 153, 154). Profound signal intensity changes in MRI, however, in the
periventricular white matter visible at a mean post-conceptional age of 33 weeks and
corresponding flaring in US have been shown to predict disturbances in tone, which in
part have been only transient in follow up, and therefore no level of significance for the
outcome has been defined for these (147). Later, at term age or after some months, PVL
has been reflected in WML, especially in the areas around the trigone and occipital horns,
with VM and irregularities in the ventricular walls (91, 92, 145, 154). When PVL had
been found by neonatal US, MRI was able to show its degree, and in other respects, too,
very good agreement has been reached (155). Late MRI used with a series of LBW
infants at the age of 1 year or more in the 1980s showed the degree of periventricular
hyperintensity in the white matter to correlate very well with the severity of functional
handicap (156). Severe PVL findings have been the main abnormal features found in
childhood MRI after very preterm birth followed by motor disability, especially spastic
diplegia (91, 143, 144). Reduction of the myelinated white matter in PVL has been
confirmed to relate to a marked reduction in the cerebral cortical grey matter (92).
Ischaemic lesions, whether non-haemorrhagic or haemorrhagic, have also been observed
in the deep grey matter (i.e. the basal ganglia and thalamus) on MRI in preterm infants
(154). Lesions in the deep grey matter areas have been shown to lead to developmental
abnormalities in tone and motor functions (87, 150). Thalamic lesions with PVL have
caused the most severe motor and mental disabilities (157).
Myelination stages are described by the extent of myelination reflected by high
intensities in T1-weighted images and / or low intensities in T2-weighted images. Some
authors have not found prematurity per se to cause delayed myelination in conventional
MRI around term age, but others have found a delay by more modern imaging methods
(97, 158). It has been emphasized that IVH does not delay myelination, although PVL has
been seen to be followed by delayed myelination mostly after the neonatal period (148,
153, 159). Preterm infants with myelination stage M2 in MRI at a corrected age of one
month have had a significantly poorer neurodevelopmental outcome at the age of one
year than those who have reached stage M3 or M4 (148). Marked myelination delay,
however, has been seen more frequently at a few months of age in MRI in infants with
disability following white matter injury (124, 142, 159, 160).
Ventricular size is described by the ventricular-brain ratio, which can be calculated by
relating the ventricular diameter at the level of the frontal horn angles or midbody of the
lateral ventricles to the diameter of the brain at the same level (126). Ratios over 0.35
have been defined as abnormal, and ratios of 0.40 as indicative of diminished
parenchymal tissue (126). Moderate to severe VM in MRI is regarded as a strong sign of
white matter injury in preterm infants (126). All preterm infants with CP in a small cohort
were shown by MRI at the age of 1 year to have dilated occipital horns, and this dilatation
was obvious also in 25% of the infants with a normal outcome (142). Measurements of
CSF volume and extracerebral spaces at term age are greater in preterm infants, even
without PVL, than in full-term ones, and the widths of the interhemispheric fissure and
extracerebral spaces along the cortical convexities have been found to vary between 0 and
3 mm in MRI (92, 126, 133). Other of the extracerebral spaces have been described as
30
abnormally wide or large if they are over 3–4 mm, but these figures were not correlated
with outcome (126, 133).
Abnormalities of the brainstem have been found in foetal MRI examinations, although
insufficient information on the size of the foetal brainstem can be gathered by this means
(139). It has been difficult to localise lesions in small structures such as the brainstem by
neonatal MRI, although some necrosis and infarctions have been seen, but less marked
necrosis or increased glial cells have only been seen in histological examinations in
preterm infants (141). Children with spastic hemiplegia after preterm birth and
hemispheric infarction in neonatal US have been imaged by MRI after some months to
years and found to have measurable shrinkage of the ipsilateral brainstem structures
(152). Some other measurements of the brainstem have been reported including some
infants (123, 135, 136). After severe asphyxia in addition to abnormal intensity of the
thalamus and putamen, one preterm infant proved in a term age MRI to have atrophy of
the brainstem, an observation that was in agreement with the neuropathological findings
(161). Parenchymal lesions in surviving preterm infants, especially PHI and other focal
deep infarcts, can cause brainstem lesion detectable on late MRI as a result of Wallerian
degeneration (152).
2.4.3 Single photon emission tomography
SPET has been used as a functional cerebral imaging method for studying brain
maturation and perfusion changes in neonates (65, 68, 162, 163). Although it is a feasible
method for in vivo measurements of regional CBF distribution, repeated examinations are
restricted because of radiation exposure. The method requires a radiopharmaceutical
tracer that will cross the blood-brain barrier and be retained in the brain tissue in
proportion to the regional blood flow. Tracers such as iodine-123 iodoamphetamine (123
I-IMP), Xenon-133 (133-Xe) and technetium-99-m hexamethyl propylene amine oxime
(Tc-99m HMPAO) have been used with neonates (68, 96, 162, 164, 165). Technetium99m ethylcysteinate dimer (Tc-99m ECD) is newer as a tracer and is not yet widely used
in examinations of newborns, although it has a better brain uptake and greatly increased
clearance from the body by the kidneys than its predecessors (166–168). The tracer
distribution is measured from emitted gamma rays using rotating single, double or
multiple-head gamma cameras (96, 163, 167).
CBF changes are related to the age of the infant (40, 169). Increases are noted even in
extremely preterm infants during the first days of life, representing a normal period of
adaptation of the cerebral circulation (69, 170). Regional CBF of distribution patterns
found by SPET is closely associated with the characteristics of vessel density
development as detected in immunohistochemical studies (64, 65). A distribution map of
blood flow maturation has been determined from infants with a normal outcome (Table 6)
(68, 96).
31
Table 6. Maturational patterns of cerebral blood flow according to brain single photon
emission tomography (68, 96).
Pattern
Age
Regional cerebral blood flow
1
Before term age
Prominent flow activity in the thalamus and in the sensorimotor cortex, low
in the parietal and occipital cortices and very poor in the frontal cortex
2
Term age
Prominent flow activity in the thalamus and sensorimotor cortex, important
activity in the parietal cortex, low in the occipital cortex and very low in the
frontal cortex
3
1 month
Prominent flow activity in the thalamus, sensorimotor and parietal cortices,
important activity in the occipital cortex and low in the frontal cortex
4
2 months
Slightly predominant blood flow in the parietal and occipital cortices, low in
the frontal cortex
5
6 months
Marked cortical flow predominance, but still slighter in the frontal cortex
6
12 months
Important blood flow activity in all cortical areas
Findings in brain SPET have been interpreted by visual approximation or by
semiquantification (68, 96). For comparison of tracer uptake between different cerebral
areas, circular regions of interest (ROIs) at the antero-posterior sagittal level are identified
manually by reference to anatomical structures, including the thalamus, cerebellum and
cortical areas (frontal, sensorimotor, parietal, occipital), and hemispheric right-left
asymmetries are assessed at transversal (transaxial) levels (167, 171).
Predictive value of abnormalities in SPET. Abnormalities in SPET are detected by
hypoperfusion or hyperperfusion of a distribution region in relation to others or globally
in relation to age and by deviations in semiquantitative count ratios (96, 162, 166). By
comparison with other methods available during infancy and childhood, brain SPET has
succeeded in identifying hypoperfusion regions that mainly correspond to the posterior
watershed areas seen in normal CT scans of prematurely born children with CP (172).
Children with CP have been shown by SPET to have unilateral hypoperfusion in the
hemisphere contralateral to hemiplegia, bilateral hypoperfusion of the motor cortex in
moderate diplegia and tetraplegia, and bilateral reduction of perfusion in the
sensorimotor, parietal and frontal regions in severe diplegia or tetraplegia respectively
(173). In cases of children with CP having abnormal CT or MRI findings, brain perfusion
SPET has detected corresponding abnormalities extending further to the cortical and deep
grey matter (174, 175). SPET has occasionally given normal scans in cases of mild CP
(173).
In neonatal cases of haemorrhage SPET approach has pointed to a corresponding area
of low perfusion to that detected in US. Brain SPET has shown involvement to reach the
cortical areas in PHI, and the involvement has not been apparent in neonatal US or MRI
scans. Focal infarctions have been detected in neonates in the form of low perfusion in
the zone of the middle cerebral artery in neonates. In PVL, neonatal SPET has indicated
low cerebral perfusion corresponding to the region shown to be affected in US and MRI,
and low perfusion zones have reached the parietal cortical areas which again has been
larger than could be detected in US or MRI scans. (162)
Hypoperfusion in brain SPET during the first week of life has proved to be predictive
of a major neurological handicap in high-risk neonates, including VLBW, asphyctic or
32
otherwise sick preterm and full-term infants (163, 171). SPET performed at the postconception age of 41–44 weeks has been reported to be even more sensitive than MRI for
predicting major neurological disability in infants born at 32–42 gestational weeks (163).
Others, however, have concluded that brain SPET in the neonatal period could not
provide any additional information for predicting the outcome relative to a diagnosis
based on lesions visible in US or MRI in preterm and term neonates, although the regions
of diminished perfusion defined in SPET extended beyond the apparent limits visible in
US and MRI (162).
2.5 Neonatal brainstem auditory evoked potentials
in preterm infants
BAEP has been used in neonatology to evaluate normal physiological maturation and
integrity of the auditory system, to diagnose brain damage and to provide a prognosis for
the outcome (176–178). The auditory system is the earliest sensory pathway to mature, at
25 gestational weeks, and is already affected by high intensity auditory stimuli in preterm
infants (28, 179, 180). Monaural 2000 stimulations at rates of 10 to 20 / s are normally
required, with intensities of 70 to 80 dBs above the average hearing level of normal
adults (normal hearing level, nHL), to achieve the most reliable responses in neonates
(176, 180). BAEP examinations can detect lesions that may be asymptomatic. One
disadvantage, however, is that the examination is time consuming. The results are
primarily analysed for the presence of the waves I, III and V. Wave I, or latency I (L I), is
based on the transformation of tone-specific responses in the hair cells into impulses
travelling along the auditory nerve, and after passing the cochlear nucleus of the
brainstem, the impulse reaches the superior olivary complex, forming wave III, or latency
III (L III) (181). Wave V, or latency V (L V), is then produced in the inferior colliculus,
and finally the temporal auditory cortex is reached (181). A significant shortening of the
evoked response has been demonstrated with term post-conceptional age (176, 178). The
motor and sensory nerve roots in the brainstem have completed the myelination process
before term age, and healthy preterm infants have normally reached a state of
morphological maturation in BAEP which is equal to that of their full-term counterparts
(70, 75, 176, 178). Inter-peak latency (IPL) I–V, the brainstem central conduction time, is
reported to be about 5 ms for the stable preterm infants, whereas IPL III–V, the pontine
conduction time, is remarkable stable throughout most of life and without sex difference
in children, however, it is recommended that each laboratory should have own normative
data (181).
Predictive value of abnormality in brainstem auditory evoked potentials. Most failures
in 40 and 70 dBnHL ABR screenings at post-conceptional age less than 35 weeks have
resulted from immaturity (182). The effect of stimulus intensity is the greater the more
immature the preterm infant is, and as the intensity is increased the wave latencies in both
preterm and full-term infants decrease, while the amplitude increases (183–185). The
central conduction time, IPL I–V, has frequently been found to become for neonates with
greater duration of extrauterine life (186). Some reports indicate no deviate alternations in
33
the responses of small for gestational age (SGA) preterm infants, but others point to
accelerated conduction in the neonatal period (187).
Brainstem structures appear to be selectively vulnerable to ischaemic perinatal insults,
especially in the superior colliculi, inferior colliculi, facial motor nuclei, vestibular nuclei
and olivary nuclei (94, 161). Such adverse events may affect impulse conduction through
the brainstem, causing abnormalities in BAEP findings (188).
An abnormal BAEP, manifested as an absence or prolongation of latencies or a
diminution of the V/I amplitude ratio, has been associated with adverse neurological
development (188, 189). Transient dysfunction or maturational delay in neonatal BAEP
measurements, including prolongation of the IPL I–V and IPL III–V conduction times,
has been found in high-risk preterm infants with a transient neurological abnormality
(189). A bilateral abnormality in a pre-discharge BAEP examination of a VLBW infant
has been shown to correlate with an adverse outcome in intelligent quotient, language and
academic achievements (177).
Increased IPL III–V and IPL I–V conduction times have been shown to be
significantly prognostic for delayed motor development and abnormal neurological
findings such as CP at one year in high-risk preterm and full-term infants (188).
Abnormal or repeatedly absent BAEPs during the neonatal period have been correlated
closely with the impairment of psychomotor development (181). Abnormal BAEPs in
prematurely born children with spastic CP indicate a poor prognosis and are associated
with a “multihandicap state” (190). The predictive value with respect to hearing loss is
discussed in the following section.
2.6 Neonatal screening of hearing in preterm infants
The first behavioural response of the foetus to a sound stimulus at a high intensity level
of >110 dB (A) and with a low frequency of 250–500 Hz can be observed at around the
20th gestational week, the required intensity level gradually decreasing and the frequency
band broadening towards term age (191).
Two neonatal hearing screening techniques were developed in the 1980s, one based on
ABR and the other on TEOAE (192). Behavioural observation audiometry (BOA), e.g.
FF audiometry, is a psychophysiological measure which has been used to evaluate
peripheral hearing acuity and the neurological development of auditory behaviour in
infants (193). In accordance with the recommendations of the Joint Committee on Infant
Hearing, most screening programmes are targeted at infants with a high-risk of hearing
deficits, including infants with BW <1500 g, birth asphyxia, mechanical ventilation,
hyperbilirubinaemia exceeding the exchange transfusion level, congenital perinatal
infection, syndromes or craniofacial anomalies, bacterial meningitis, ototoxic medication,
or a family history of congenital hearing impairment (194).
34
2.6.1 Auditory brainstem responses
In ABR (BAEP) screening, clicks are presented to the infant’s ear and the resulting
electrical activity generated in the auditory pathway is recorded with the surface
electrodes and averaged (192). The conventional ABR screening procedure is timeconsuming, and a highly trained physician is needed to evaluate the results (195). Modern
automated screeners are quicker (196).
Predictive value of abnormalities in auditory brainstem responses. The pass criterion
for the ABR examination is a replicable wave V component that can be identified
bilaterally at the test intensity required (196).
According to the Joint Committee on Infant Hearing, a screening series including
high-risk infants had a total of 3.3% with a unilateral pathological automated ABR and
2.0% with a bilateral pathological response (197). The best predictive value for neonatal
ABR screening has been found with respect to a severe to profound degree of hearing
impairment observed initially at an intensity of 60 dBnHL, whereas an initial suspicion of
a milder hearing deficit based on lower intensities has more often reverted to normal in
the follow-up (196).
2.6.2 Transient evoked otoacoustic emissions
TEOAEs are produced by an active physiological mechanism in the healthy cochlea, and
can be elicited in response to clicks presented to the ear through a small probe, which
includes a microphone to catch the acoustic energy generated by the cochlea and
transmitted back to the outer ear (192). Emissions are normally found at a 3 dB signal to
noise ratio from 1 to 4 kHz, reflecting cochlear function under 30–40 dBHL (198, 199).
The pass criteria for emissions can be rated visually or automated (197, 199, 200). As the
amplitude and frequency ranges of emissions increase with age with the largest changes
between 37 and 39 gestational weeks, the preferred approach has been to perform
TEOAE screening at discharge or at term post-conceptional weeks (199, 201, 202).
TEOAE screeners have the advantages that they are easily portable and that single-ear
evaluations can be performed, and the method is also quick, objective and non-invasive
(199). The disadvantages are false negative findings if used very early just after birth, and
passes when cochlear function is normal although there is a retrocohlear deficit (203,
204).
Predictive value of abnormalities in TEOAEs. Emissions are not produced in an ear
when there is hearing loss of more than 30 to 40 dB, but unfortunately a small number of
data points, a weak stimulus, low reproducibility, poor probe stability, a whimpering or
crying infant, debris in the external ear canal, or performance of the test at too early a
juncture are other things that may cause absence of a response in addition to a hearing
defect (202, 203, 205). A failure rate of 9% in both ears has been reported for infants in
universal screening, a high failure rate of 13% in one ear or 6 to 16% in both ears
screened for high-risk infants, and a very high failure rate of 46% in one or both ears for
VLBW infants (197, 200, 206, 207). TEOAE screening performed in a neonatal nursery
has been reported to give failure rates of 18–25% for one ear (208). Failure rates in
35
screening before discharge from a NICU have been highest in infants with the lowest
BWs, the oldest chronological age and the longest duration of post-conceptional care
(206, 208). Universal TEOAE screenings of newborn infants, within the Rhode Island
Hearing Assessment Program and elsewhere, have achieved sensitivities of 95–100% and
specificities of 90–95% for the prediction of hearing loss (204, 207). Because of the high
failure rates among preterm and other high-risk infants a sensitivity of 100% with a
specificity of 50% has been reported for such series (206).
2.6.3 Free-field auditory examination
The simplest form of behavioural screening for hearing impairments is observation of the
infants. Full-term infants respond to pure tone stimuli with a mean threshold of 85 dB in
BOA, whereas only one third of preterm infants are reported to respond at 90 dB.
However, neurologically normal preterm infants have reached normal threshold ranges by
the age of 9 months (193).
Predictive value of abnormalities in FF examinations. Failure of an infant to be
aroused or startled or to show auropalpebral reflexes repeatedly after test sounds at any
frequency below 100 dBHL may be considered a mark of failure (209). No specific
predictions have been associated with FF examinations.
2.7 Neonatal neurological assessment and follow-up
of preterm infants
It is a problem simply to carry out a clinical neurological assessment of a sick, labile,
immature preterm infant and to reach conclusions on the basis of this (27, 210). So that
serial examinations may be needed to increase the predictive capacity (27, 211). Various
scoring systems based on diagnostic categories, risk factors, therapeutic requirements,
physiological measurements or combinations of these have been used to predict
morbidity and future development (212).
The clinical risk index for babies (CRIB) score has been developed by the International
Neonatal Network to simplify and refine the prediction of neonatal mortality and
morbidity, and sometimes of the general outcome, in VLBW preterm infants (51, 213).
CRIB includes scores for BW (0 for >1350 g, 1 for 851–1350 g, 4 for 701–850 g and 7
for ≤700 g), GA (0 for >24 weeks and 1 for ≤24 weeks), congenital malformations (0 for
none, 1 for not acutely life-threatening and 3 for acutely life-threatening), maximum base
excess in the first 12 h (0 for > –7.0 mmol/L, 1 for –7.0 to –9.9 mmol/L, 2 for –10.0 to –
14.9 mmol/L and 3 ≤ –15.0 mmol/L), minimum appropriate FIO2 in first 12 h (0 for ≤
0.40, 2 for 0.41–0.60, 3 for 0.61–0.90 and 4 for 0.91–1.00) and maximum appropriate
FIO2 in the first 12 h (0 for < 0.40, 1 for 0.41–0.80, 3 for 0.81–0.90 and 5 for 0.91–1.00).
Major cerebral abnormalities on ultrasound have been found in 5% of surviving VLBW
preterm infants at discharge home with CRIB scores 0–5, 12% of those with scores 6–10
and 20% of those with scores > 11. (213)
36
Term age, a milestone in the progression from foetal life to infancy, implies a transition
in posture and a development in movement from lower subcortical control to upper
corticospinal control as maturation of the neuromotor pathways proceeds (210). The
major features to be considered in a motor examination consist of passive muscle tone,
the posture of the limbs, active motility and muscle power, tendon reflexes and the plantar
response (27, 214). Detailed advices on the conducting of neonatal neurological
examinations on full-term infants have been offered for a much longer period than on
preterm infants (214, 215). However, practical and satisfactory methods based on
cumulative experience in the assessment of preterm infants have been modified during the
last decade (214). The tests should be carried out in a sequence that is aimed at causing
minimal disturbance to the state of the infant, by observing and testing items in the
supine, prone and upright positions (214, 215).
Preterm infants have been observed to present transient abnormal neurological signs
with regard to posture, gross motor abilities, fine motor abilities, equilibrium,
coordination, muscle tone or reflexes within the first 2 years (216–218). Common motor
milestones, including the abilities to roll from prone to supine and from supine to prone,
to sit with and without support, to creep, to assume a sitting position, to crawl, to pull to a
standing position, to cruise and to walk, are used for early detection of motor delay or as
part of a more comprehensive development testing methods (219, 220). A normal
neuromotor assessment after six months of age has been found highly predictive of
subsequent normal motor outcome (218). The persistence and extent of a clinical
abnormality in posture, muscle tone and strength, motor abilities or reflexes, or a severe
delay in skills during the follow-up should be interpreted as pointing to a notable motor
disability such as CP (221). Motor delay may also be a sign of delay in some other area of
development, which may arouse concern (220). It has been observed that if a preterm
infant has a major impairment that implies a neurosensory disability (CP, blindness,
deafness, epilepsy or DQ<70) at 1 year of age, this will also exist in the early school years
(37, 222).
Development scales measure intelligence and assess broadly degree of abilities in
subgroups of motor, hearing and speech, personal-social, hand and eye and performance
abilities (219, 223). The normal general DQ on Griffiths’ scales has been considered to be
80 or more with borderline scores of 70–79. During the early months of life a healthy
infant may be transiently far ahead of the average in one subgroup and lower than the
age-related level in another subgroup, depending on the apparent attention paid to these in
the environment. Relatively high or low levels of skills in some area will produce
different developmental profiles, which can show where a weakness or mental disability
lies, or in what direction exceptional progress may be expected. The DQ may be
repeatedly low in preterm infants with severe neuromotor disability, because most of the
subscales demand locomotion ability. A profile for a deaf child may show a deep scaledown in hearing and speech. (219)
3 Aims of the research
The purpose of the present work was to study structural and functional imaging methods
applied at term age for predicting the later neuromotor outcome in very low birth weight
preterm infants and to assess hearing screening methods used at term age in regard to the
prediction of permanent hearing loss. The specific aims were:
1. to study the efficacy of neonatal brain MRI for predicting the later neuromotor
outcome in relation to US in VLBW preterm infants,
2. to study the accuracy of neonatal brain SPET for predicting cerebral palsy in relation
to US in VLBW preterm infants,
3. to measure brainstem size in MRI and brainstem function as shown by BAEP at term
age as means of predicting the later neurosensory outcome in VLBW preterm infants,
and
4. to assess auditory responses by means of ABR, TEOAE and FF behavioural
observation responses as means of predicting permanent hearing loss in VLBW
preterm infants.
4 Subjects and methods
4.1 Subjects
The prospective follow-up series comprised of 51 surviving preterm infants born at less
than 34 gestational weeks with a birth weight below 1500 grams and admitted to the
Neonatal Intensive Care Unit (NICU) from the district primarily served by the Paediatric
Clinic of Oulu University Hospital and of 52 full-term infants born in the Obstetric Clinic
of the same hospital.
VLBW preterm infants (I-IV). The subjects were three pilot infants born during 1993
and 45 consecutive preterm infants born between November 1, 1993 and October 31,
1995, together with three co-born siblings with birth weights of 1645, 1650 and 1800
grams. Of the 65 live-born preterm infants who were treated during the study period and
were eligible for the series, nine died before the research enrolment could be carried out,
four infants were excluded because of serious congenital anomalies and four others
because of parental refusal.
Control full-term infants (III, IV). In order to evaluate the suitability of the screening
methods, 52 full-term healthy newborns were picked out at random from a normal well
baby ward at the Obstetric Clinic of Oulu University Hospital for participation in series
IV, and 21 of these were also included in series III.
The data on the infants in the four series are summarised in Table 7. All the
examinations were approved by the Ethics Committee of Oulu University and conducted
with informed parental consent.
39
Table 7. Clinical characteristics and neonatal morbidity of infants in series I-IV.
Characteristics and morbidity
Number of infants
Gestational age (wk), mean (SD)
Preterm
infants
in series
I,III,IV
Preterm
infants
in series
II (a)
Full-term
infants
in series
III (b)
Full-term
infants
in series
IV
51
34
21
52
29.3 (2.2)
28.9 (2.0)
40.0 (1.0)
40.0 (1.0)
Birth weight (g), mean (SD)
1153
(289)
1090
(273)
3801
(476)
3728
(504)
Head circumference (cm), mean (SD)
26.5
(2.5)
25.9
(2.3)
35.6
(1.3)
35.3
(1.2)
16 (31)
11 (32)
Small for gestational age (n, %)
Male/Female (n)
27/24
18/16
9/12
25/27
Singleton (n, %)
32 (63)
29 (85)
21 (100)
52 (100)
Apgar score at 5 min, mean (SD)
7 (1.7)
6 (1.5)
9 (0.5)
9 (0.4)
Respiratory distress syndrome (n, %)
45 (88)
31 (91)
Bronchopulmonary dysplasia (n, %)
10 (20)
8 (24)
Abnormality in cranial ultrasound (n, %)
Haemorrhagia
gr I-II
gr III-IV
Periventricula leukomalacia
10 (20)
4 (8)
2 (4)
5 (15)
3 (9)
4 (12)
Clinical risk index for babies (CRIB), mean (SD)
4 (3)
a
Preterm infants in this group are a part of preterm infants in series I, III and IV.
b
Full-term infants in this group are a part of full-term infants in series IV.
4.2 Methods
4.2.1 Neonatal brain imaging
4.2.1.1 Ultrasound at term age (I, II)
US examination at term age as a reference imaging method was performed by
experienced radiologists according to Siegel (224) by using transducers of 5 or 7.5 MHz
(Toshiba Sonolayer SSA-270), and images were documented on films. The paediatric
radiologist who was not aware of the clinical histories of the preterm infants
systematically evaluated the resulting hard copy images, identifying all traces of IVHs,
PVL and infarctions. IVHs (germinal matrix cysts, porenchephaly or blood clots) were
graded according to Papile et al. (79), and PVL lesions according to de Vries et al. (24),
and the infarctions were also evaluated. IVHs, cystic PVL and infarctions in the brain
tissue were included in the analyses as parenchymal lesions, which were also analysed
without grade I-III haemorrhages.
40
Ventricular dilatation was defined in terms of the ventricular-brain diameter ratio
calculated for the areas of the frontal horn (frontal horn or Evans index), midbody
(midbody index) and trigone (trigone index) on coronal scans. Ratios exceeding 0.35 in
the frontal horn and midbody implied abnormal dilatation, similarly trigone indices
exceeding 0.60 (115, 116, 118).
4.2.1.2 Magnetic resonance imaging (I, III)
MRI was performed using a scanner of 1.0 T (Magneton, Siemens). The examinations
included sagittal and axial T1-weighted (repetition time of 570-600 msec / echo time of
15 msec / 2 excitations) and axial proton density- and T2-weighted turbo spin echo (3500
/ 19, 93 / 1) images with a slice thickness of 4 mm and a field of view of 180 mm with a
160-192x256 matrix. A T1-weighted axial scan could not be obtained for one child. To
prevent movement artefacts without using of sedative medication, the infants were
transported to the imaging room after feeding and were wrapped in swaddling clothes and
provided with earplugs during imaging. If supplementary oxygen was needed, the infants
were monitored with a pulse oximeter. The images were analysed independently by two
radiologists who were unaware of the clinical outcome of the infants, and a consensus
was reached.
Parenchymal traces of haemorrhages (subependymal or intraparenchymal with or
without porencephalia), PVL (periventricular cysts with or without haemorrhage),
infarctions (mainly atrophic lesions with or without haemorrhage) and clear WML were
treated together as parenchymal lesions in the analyses. Parenchymal lesions were also
analysed without SEHs. The T1-weighted axial images were used to assess of the degree
of myelination (M1-M4) according to McArdle et al. (76). The lateral ventricles were
measured using a cursor on the display. Ventricular-brain ratios at the level of the frontal
horn angles (frontal horn index), midbody (midbody index) and trigones (trigone index)
of the lateral ventricles were measured on the T1-weighted axial images, or the T2weighted image in one case (126). Abnormal frontal horn and midbody indices were
defined as values in excess of 0.35 and abnormal trigone indices as being over 0.60, as in
the US examinations (116, 126). The widths of the lateral and posterior parietal
subarachnoid spaces at the level of the centrum semiovale, lateral ventricles, and the
thalamus and the anterior and posterior interhemispheric fissures were measured on T2weighted axial images. Space widths from 0 to 4 mm were considered normal (126).
Every sagittal (Sag) and axial (Ax) brainstem morphometric dimension of an infant
was obtained as a mean of three measurements performed with help of a cursor on the
display as follows (225, 134, 136):
Sagittal (Sag) measurements of the brainstem
Pontine oblique height = Distance from the pulbo-pontine sulcus to the inferior colliculus.
Brainstem height = Distance between a line connecting the superior margin of the atlas to
the clivus and the proximal end of the Sylvian aqueduct.
Sag-Mesencephalon = The anteroposterior mesencephalon diameter between the upper
border of the pons and a point midway between the superior and inferior colliculi.
41
Sag-Pons = The anteroposterior pontine diameter from its anterior surface to the floor of
the fourth ventricle at the midpoint between its upper and lower borders and
perpendicular to its long axis.
Sag-Medulla Oblongata = The anteroposterior diameter of the medulla oblongata
measured perpendicularly to the longitudinal axis just above the posterior kink at the
cervicomedullary junction.
Axial (Ax) measurements of the brainstem
Ax-Mesencephalon = The maximum interpeduncular diameter at the mesencephalon.
Ax-Pons = The pontine diameter at the point where the trigeminal nerves originate from
the brainstem, between two points just posterolateral to their origins.
Ax-Medulla Oblongata = The minimum transverse diameter in the most caudal section of
the medulla oblongata at which the medulla was still visible.
4.2.1.3 Single photon emission tomography (II)
The brain SPET examinations were carried out by the Division of Nuclear Medicine. To
keep the infants calm without any premedication, they were well nourished and an
intravenous injection route was established in the NICU before they were moved to a
quiet imaging room, where they were wrapped in swaddling clothes on a stretcher after
injection of the perfusion tracer agent. Tc-99m ECD (Neurolite, DuPond Pharma, USA)
was used at a dose of 110 MBq as a tracer, the EDE of which was reduced by enhancing
voiding with a dose of 0.5 mg furosemide intravenously or orally. The images were
captured with a single head rotating gamma camera with a slant collimator (Siemens/
Orbiter) or a double head gamma camera equipped with a fan beam collimator (Adac/
Vertex). The single head provided 64 frames of 30 s each and the double head 64 frames
of 35 s. Transaxial (transversal, parallel to the base of the brain) and sagittal slices 2
pixels (one of 4.7 mm) thick were reconstructed and no attenuation correction was
applied.
Visual interpretation: An experienced physician specialized in nuclear medicine who
was unaware of the infants’ clinical data or other imaging results regarding them
inspected all the transaxial and sagittal slices visually. Relative differences in perfusion
between the cortical areas (frontal, sensorimotor, parietal and occipital) and the reference
areas (thalamus and cerebellum) in the craniocaudal or antero-posterior direction of the
middle sagittal slices were considered and asymmetries between the hemispheres were
estimated in transversal slices (96). Semiquantitative evaluations of the regions of interest
(ROI) in the sagittal slices were made in borderline cases (96). The ratios were classified
as abnormal when at least two of them in the same infant lay outside 2 SD for the
published reference values (96, 167).
Semiquantitative assessments for reference values were calculated from the count
densities collected by a physicist from the ROIs in the middle sagittal slices determined
by a physician in nuclear medicine. Reference values were collected from preterm infants
with a normal outcome in the series.
42
4.2.2 Brainstem auditory evoked potentials (III, IV)
Recordings for both ears were performed using a Disa 1500 system (Disa, Denmark).
Rarefaction clicks of 100 µs duration were delivered separately to both ears through
earphones. The stimulus rate was 10 Hz (alternating in the range 7-15 Hz), the intensity
75 dBnHL with contralateral masking (-40 dB) and the time base 20 ms. The low and
high bandpasses were set at 20 and 3000 Hz respectively. Vertex responses to stimulation
of each ear were recorded with cup electrodes and referenced to both the ipsilateral and
contralateral mastoid. Waveform responses to at least 2000 clicks were averaged twice,
and if no reproducible responses were obtained the clicks were increased to 4000 and the
test performed up to four times. The components of L I, III and V were measured, and
IPL I-V and III-V and the amplitude ratio V/I were determined from printed screens by a
clinical neurophysiologist who were unaware of the clinical data.
When a response was absent or was delayed by more than 2 SD, or an amplitude ratio
V/I was below 2 SD of the reference values (for full-term infants), this was considered
abnormal in a preterm infant.
4.2.3 Neonatal screening of hearing (IV)
All the hearing examinations in the preterm and full-term infants were performed after
feeding without premedication. ABR screenings were carried out in separate sessions at
the Department of Clinical Neurophysiology, while the TEOAE and free-field auditory
examinations were carried out at one session in a soundproof examination room at the
Hearing Centre of the Department of Otorhinolaryngology.
ABR. The ABR method as a part of BAEP is explained in Section 4.2.2. Clear,
reproducible responses at least in waves of type V at the test level were taken as a pass
and their absence as a fail (180). An infant was deemed to have failed the test if both ears
failed, and to have passed if either ear passed.
TEOAE. TEOAEs were measured in both ears using an ILO88 otodynamic analyser
system (Otodynamics Ltd, Southampton, UK) with known guidelines for probe design,
signal processing and technical procedures (203). The results were analysed by an
audiologist who did not know anything about the origin of the infants or their clinical
data, and were interpreted as a pass, if emissions were found at a 3 dB signal to noise
ratio in at least one of the 1-2, 2-3 and 3-4 kHz frequency bands, reflecting cochlear
function under 30-40 dBHL (198, 203). A recording with no emissions was graded as a
fail, and bilateral failure resulted a fail in the screening.
FF. BOA in the form of free-field examination was performed by trained
audiophonological staff. The lowest reaction level was assessed from arousal and startling
or from auropalpebral reflexes in the infant’s behaviour elicited by various filtered
environmental sounds. Sounds in ½-octave frequency bands around 1, 2 and 4 kHz were
delivered at intensities of 60 to 100 dBnHL through loudspeakers placed on the sides of
the infant’s head and at ear level. Clear, repeated behavioural reactions to the test sounds
at any frequency band below 100 dBHL were considered to mark a pass (209).
43
4.2.4 Developmental follow-up and neurosensory outcome
The preterm infants underwent neurological and developmental follow-up examinations
performed by a neonatologist every three months up to a corrected age of 18 months, and
hearing was followed up in all the infants by means of a re-tests and evaluations of
hearing and speech development. CP and permanent hearing loss were recorded as
outcomes for prediction purposes.
Neuromotor outcome. Asymmetries, persistence of primitive/infantile reflexes,
dystonia and deviations in motor skills relative to averaged abilities for the corresponding
corrected age levels and relative to the previous performance of the preterm infant were
highlighted in particular according to Illingworth (221). Preterm infants who had a
continuous delayed in their motor development and abnormal muscle tone and motor
function as impairments or disabilities at a corrected age of 18 months were defined as
having CP in the sense of Illingworth (221) and Hagberg et al. (34). CP was further
evaluated as mild, moderate or severe in terms of functional ability and the severity of
ambulatory impairment (36).
Neurodevelopmental outcome. The developmental abilities of the preterm infants were
evaluated in the fields of locomotor, hearing and speech, personal-social, hand and eye,
and performance according to the developmental scales of Griffiths (219). The general
developmental quotient (GQ) calculated at corrected ages of 6 and 18 months, and values
of 80 or more were held to be normal.
Follow-up of hearing. All the preterm infants with bilateral failures in screening at
term age (ABR and TEOAE/FF) were further evaluated at the Hearing Centre and in the
audiophonological ward by repeated audiological methods (TEOAE/FF and ABR under
sedation). It was planned to re-evaluate all the preterm infants at a corrected age of 6
months by means of at least one audiological examination, either TEOAE or FF or both.
The sub-quotient (SQ) for hearing and speech development was calculated at corrected
ages of 6 and 18 months (219).
Diagnosis of permanent hearing loss was based on 1) absence of responses in a 60-105
dBHL ABR examination under sedation, 2) lack of behavioural responses to sounds
during an observation period in the audiophonological ward, and 3) ability of
amplification devices to enhance reactivity to sounds. If speech development continued to
be normal after passing the hearing tests, the infant's hearing was considered normal, or if
a preterm infant had CP and abnormal speech ability, hearing was considered to be
normal, or at least not severely affected, after passing the hearing tests repeatedly and
responding to sounds.
The full-term infants were followed up by conventional methods, including a
distraction test and an assessment of speech and language development at a family health
care centres. Hospital records and a questionnaire administered at the age of 2-3 years
were also used to verify hearing and speech development. Hearing ability was considered
normal when speech production was normal after obtaining a pass in the screenings.
A summary of the imaging methods and the main outcome measures used in these
series is presented in Table 8.
44
Table 8. Summary of the main methods used in the term age examinations and the main
outcome measures employed at a corrected age of 18 months in series I-IV.
Series
Methods used at term age
Outcome at age of 18 months
I
Brain magnetic resonance imaging
Intracranial ultrasound
Cerebral palsy
II
Brain single emission tomography
Intracranial ultrasound
Cerebral palsy
III
Brainstem magnetic resonance imaging
Brainstem auditory evoked responses
Neurosensory disability
IV
Transient evoked otoacoustic emissions
Auditory brainstem responses
Free-field auditory examination
Permanent bilateral hearing loss
4.2.5 Statistical methods
This data were processed using the Statistical Package for the Social Sciences (SPSS
version 7.5). The values of the neonatal brain MRI and SPET examinations for predicting
CP was evaluated by comparison with US, and the brainstem measurements obtained
from the MRI and BAEP (ABR) results were used to predict neurosensory disability
(including CP and hearing loss). The abilities of ABR (BAEP), TEOAE and FF auditory
examinations to predict permanent hearing loss were likewise evaluated.
The t test for two independent samples was used to compare the means for the
subgroups. The chi square test or Fisher’s Exact Test at low frequencies was used for
prediction purposes, and sensitivity, specificity, odds ratio (OR) with 95% confidence
interval (95 % CI) and significance (p < 0.05) were calculated for each test.
5 Results
5.1 Neurodevelopmental outcome
Neurological and developmental follow-up examinations and recordings of hearing
ability were performed on 49 out of the 51 preterm infants at a mean (SD) corrected age
of 18.6 (1.0) months in order to assess the prediction of neurosensory outcome. One
infant had moved away from the district, but the infant was not excluded and some data
was extracted from the patient records for evaluation. Another died of a severe chronic
lung disease with complications at the corrected age of 9 months.
5.1.1 Cerebral palsy
CP was observed in 12 out of the 51 preterm infants (24%), and in 11 out of the 48
consecutive ones (23%). There were ten infants with CP among the 35 AGA infants and
two among the 16 SGA infants. Eight of the 12 infants with CP had diplegia (six spastic,
one dystonic and one athetotic), while three had tetraplegia (two spastic and one
dystonic), and one had spastic hemiplegia. Five infants had severe CP, three moderate CP
and four mild CP. The gestational age of the infants with later CP at birth was less than 29
weeks, the mean (SD) value being 27.2 (1.4) weeks. This was significantly less than the
mean of 29.9 (1.9) weeks recorded for the infants with a normal motor outcome (p<0.01,
independent samples t test). Likewise, the mean (SD) birth weight of 965 (219) g for the
infants with CP was significantly lower than that of 1210 (283) g for the infants without
CP. A half of the CP cases were ELBW infants. None of the full-term infants had
developed severe neuromotor disabilities.
5.1.2 Developmental outcome
The mean (SD) GQ at the corrected age of 18 months for the 49 preterm infants tested by
means of Griffiths’ developmental scales was 103 (22). Five infants with a GQ less than
46
80 had CP, and the infants with and without CP had a mean (SD) GQ of 73 (27) and 112
(9), respectively.
Six out of the 51 infants had a SQ for hearing and speech of less than 80, their mean
(SD) SQ value at a corrected age of 6 months being 59 (27). Four of these infants had
hearing loss, and the other two had CP. Two of the infants with hearing loss did not attend
for the developmental scoring at the corrected age of 18 months, but the remaining four
received a mean (SD) SQ of 54 (28). The infants without profound hearing loss had a
mean (SD) SQ of 112 (18) at a corrected age of 6 months and 109 (17) at 18 months.
5.2 Abnormalities in imaging examinations at term age
and later neuromotor outcome
5.2.1 Ultrasound
Term age US examinations were performed at a mean (SD) post-conception age of 38.6
(2.4) weeks. Eleven of the preterm infants (22%) had traces of haemorrhages, seven in
the subependymal area (Grade I), one intraventricularly (Grade III), and three in the
parenchymal area (Grade IV). Two of the latter were PHIs the white matter. One infant
with a parenchymal haemorrhage had additional PVL cysts, one with subependymal
haemorrhage and all three with parenchymal haemorrhages developed CP. Four infants
had PVL (one hyperechogenic and three cystic) and all of them developed CP. Fourteen
of the preterm infants (27%) had a parenchymal lesion, eight of whom had CP: one
tetraplegia, six diplegia and one hemiplegia.
Thirty of the preterm infants (59%) had an abnormal frontal horn index, and one third
of the cases had CP. Twentyone had an abnormality in the midbody index (41%), and
eight of these had CP. All told, sixteen infants (31%) had an abnormal trigone index,
seven of these being CP cases.
5.2.2 Magnetic resonance imaging
Fifty preterm infants underwent a MRI examination at a mean (SD) post-conceptional
age of 39.0 (2.4) weeks. The MRI of one infant with later dystonic tetraplegia failed
because of restlessness and severe respiratory difficulty. Some movement artefacts were
observed in 10 cases, but these did not prevent us from seeing cysts or larger
haemorrhages.
Parenchymal abnormalities. Twelve infants (24%) had haemorrhage as the dominant
finding, nine of these being subependymal, including one with diplegia, while the
remainig three infants had intraparenchymal haemorrhage with porenchephaly and
moderate or severe WML. All three infants developed CP: one hemiplegia, one diplegia,
and one teraplegia. Four infants had bilateral PVL in the typical periventricular area (one
haemorrhagic and three cystic), and all these infants developed diplegia. Two infants had
an infarction, one with bilateral cortical dysplasia after severe intrauterine asphyxia who
47
developed tetraplegia, and the other with a parieto-occipital infarction who does not have
CP. One infant with WML developed athetotic diplegia. All together, nineteen out of the
50 preterm infants (38%) had parenchymal lesions in MRI. Eight infants (16%) had
myelination delay; and three of them had CP.
Ventricular size and extracerebral spaces. Eight preterm infants had an abnormal
frontal horn index, a half of whom had CP, while six had an abnormal midbody index,
again a half of them having CP. Four infants had an abnormal trigone index, including
three cases with CP.
Measurements of the extracerebral spaces gave a mean (SD) anterior interhemispheric
width of 2.0 (0.8) mm and a posterior width of 1.9 (1.9) mm. The mean (SD) width of the
lateral parietal subarachnoid space was 0.5 (0.9) on the right and 0.3 (0.8) mm on the left.
The mean (SD) posterior parietal widths were 5.3 (3.2) on the right and 5.2 (3.2) on the
left.
Brainstem size. The mean brainstem dimensions at term age were almost equal
between the SGA and AGA preterm infants, and only the pontine oblique height was
significantly greater (p= 0.019) and the Sag-Mesencephalon significantly thinner (0.045)
in the SGA infants than in the AGA ones. By comparison with brainstem dimensions, the
SGA preterm infants continued their head circumference growth to term age in the same
manner as the AGA infants achieving a mean (SD) of 33.2 (1.5) versus 34.0 (1.6) cm,
although their weight gain fell behind the mean (SD) for the AGA infants (2234 (377)
versus 2573 (477) g, p=0.016, independent samples t test).
The preterm infants with neurosensory disability had smaller brainstem dimensions
than those with normal outcome. The differences in the Sag-Mesencephalon and both in
the sagittal and axial Pons and Medullo Oblongata diameters were significant, as shown
in Table 9.
Table 9. The mean (SD) dimensions of the brainstem on T1-weighted brain magnetic
resonance imaging (MRI) scan at term age in appropriate for gestational age (AGA) and
small for gestational age (SGA) preterm infants (independent samples t test).
MRI brainstem dimension
AGA preterm
infants (n=35)
mean (SD) mm
SGA preterm
infants (n=15)
mean (SD) mm
95% Confidence
interval for the
difference of means
p-value
20.0 (1.5)
21.1 (0.9)
–1.90– –0.18
0.019
0.310
Sagittal
Pontine oblique height
Brainstem height
33.6 (2.3)
34.3 (2.2)
–2.14–0.69
Mesencephalon
13.3 (0.8)
12.9 (0.6)
0.01–0.90
0.045
Pons
13.8 (0.9)
14.2 (0.8)
–1.93–0.12
0.131
Medulla Oblongata
8.2 (0.9)
8.4 (0.7)
–0.55–0.26
0.480
Axial
Mesencephalon
20.8 (1.8)
21.6 (1.1)
–1.75–0.30
0.162
Pons
16.7 (1.5)
17.2 (0.3)
–1.39–0.29
0.196
Medulla Oblongata
9.6 (0.9)
9.6 (0.8)
–0.46–0.56
0.835
The preterm infants with neurosensory disability had smaller brainstem dimensions
than those with normal outcome. The differences in the Sag-Mesencephalon and both in
48
the sagittal and axial Pons and Medullo Oblongata diameters were significant, as shown
in Table 10.
Table 10. The mean (SD) dimensions of the brainstem on T1-weighted brain magnetic
resonance imaging (MRI) scan at term age in preterm infants according to the
neurosensory outcome (independent samples t test).
MRI brainstem dimension
Preterm infants with
normal outcome
(n=37)
mean (SD) mm
Preterm infants
with disability
(n=13)
mean (SD) mm
95% Confidence
interval for the
difference
of means
p-value
Sagittal
Pontine oblique height
20.6 (1.5)
19.7 (1.2)
–0.010–1.82
0.051
Brainstem height
34.1 (2.3)
32.9 (2.0)
–0.280–2.62
0.112
Mesencephalon
13.3 (0.6)
12.8 (0.9)
0.003–0.93
0.049
Pons
14.2 (0.7)
13.2 (0.8)
0.470–1.44
<0.001
8.4 (0.6)
7.9 (0.6)
0.080–0.89
0.019
Mesencephalon
21.4 (1.4)
20.2 (2.1)
–0.170–2.45
0.084
Pons
17.0 (1.3)
16.2 (1.4)
0.030–1.74
0.043
9.8 (0.7)
9.1 (1.0)
0.170–1.16
0.010
Medulla Oblongata
Axial
Medulla Oblongata
5.2.3 Single photon emission tomography
The SPET examinations were performed at a mean (SD) post-conceptional age of 39.2
(2.0) weeks.
Parenchymal abnormalities. Visual interpretation showed sixteen out of 34 infants
(47%) to have a perfusion defect, nine of whom had CP including all the infants with
moderate or severe CP. Of the 16 infants with normal perfusion scans, two had mild
diplegia.
Cranio-caudal abnormalities in the sagittal slices were found in 13 infants, of whom
eight developed CP. Eleven of these thirteen preterm infants had hypoperfusion in the
sensorimotor cortex or thalamus, seven of them developing CP. Transversal hemispheric
asymmetries were seen in seven cases including four cases of CP.
Semiquantitative results. In order to obtain reference values for the 99Tcm-ECD brain
perfusion SPET at term age, regional semiquantitative values were calculated from the
results for seventeen infants with a normal motor outcome. By comparison with these
values, eight of the infants with CP had from one to five values outside 2 SD.
49
5.3 Brainstem auditory evoked potentials
All 51 preterm infants underwent a BAEP examination on both ears at post-conceptional
term age and 21 full-term infants did so at three days of age. The results were used for
neuromotor and audiological prediction purposes.
The preterm infants had longer mean BAEP peak I and V latencies and I–V and III–V
IPL values than the full-term infants, whereas L I was significantly longer in the AGA
infants than in the SGA infants. Most of the infants with neurosensory disability, except
one with severe CP, had bilaterally absent or delayed responses in BAEP components. Of
the 37 preterm infants with a normal outcome, 15 had abnormality in L I, 12 in L III, 19
in L V, 12 in IPL I–V, 16 in IPL III–V and four in A V/I.
5.4 Screening of hearing at term age and permanent hearing loss
5.4.1 Screening of hearing
ABR. Seven out of the 51 preterm infants had bilateral failures and 3 unilateral failures in
ABR screening. Six of the infants with a bilateral failure had hearing loss. None of the 21
full-term infants failed with this screening modality.
TEOAEs. Nine of the 44 preterm infants failed the TEOAE test in one ear and nine in
both ears. Three of the bilateral failure cases and two cases of unilateral failure later had
permanent hearing loss. One preterm infant who passed the TEOAE test had both CP and
permanent hearing loss. Two of the 52 full-term infants failed the TEOAE test in one ear.
FF examinations. Four of the preterm infants failed the FF examination, but none of
the full-term infants. Three of the former had permanent hearing loss.
The results regarding fails in the ABR, TEOAE and FF examinations are summarised
in Figure 1.
50
40
Infants with unilateral
failure
Infants with bilateral
failure
n=9
30
%
20
10
n=3
n=9
n=7
n=0
0
ABR preterm
ABR full-term TEOAE preterm
n=2
TEOAE fullterm
n=4
FF preterm
n=0
FF full-term
Fig. 1. Failure results for the preterm and full-term infants in ABR, TEOAE and FF
examinations at term post-conceptional age.
50
5.4.2 Hearing loss
Six out of the 51 preterm infants (12 %) had a significant bilateral hearing loss (60–105
dB), and four of these also had CP. One of the infants with hearing loss died before any
hearing appliance could be used, but the daily use of hearing devices was feasible for
another infant without CP at a corrected age of 5 months. Four infants with CP were able
to use hearing appliances after 6, 12, 34 and 39 months of age. The delays were caused
by difficulties in confirming amplification enhancement ability in these otherwise
disabled infants.
The planned audiological follow-up examinations were delayed to a mean (SD) age of
9.9 (4.2) months because of infection and middle ear effusion problems in 34 cases
(67%). Seventeen preterm infants (33%) had tympanostomy tubes inserted in both ears
for glue ear, and six of them underwent adenoidectomy. Five of the preterm infants with
hearing loss had ear ventilation tubes. Re-evaluation did not reveal any further preterm
infants with permanent hearing loss. None of the full-term infants had any significant
hearing loss at the follow-up. Twenty of the infants (38%) had suffered from otitis media,
and four (8%) had undergone adenoidectomy and the insertion of tympanostomy tubes
during the corresponding period of time.
5.5 Prediction of neurosensory outcome
Fourteen of the preterm infants (27%) had at least one neurosensory disability, including
12 with CP, four of whom, together with two infants without CP, had permanent hearing
loss. In terms of intrauterine growth, two of the 16 SGA infants had CP and two others
permanent hearing loss. The mean (SD) birth weights of the infants with and without
neurosensory disability were 942 (211) g and 1232 (274) g, respectively (p=0.01,
independent samples t test), and their mean (SD) gestational ages at birth were 27.5 (1.5)
weeks and 30.0 (2.0) weeks (p<0.01, independent samples t test).
The findings in the MRI and SPET examinations were compared to findings in US
examinations for predicting CP. Numbers of the cases in examinations are summarised in
table 11.
51
Table 11. Numbers (n) of preterm infants with normal and abnormal findings in brain
magnetic resonance imaging (MRI) and single photon emission tomography (SPET)
examinations at term age in relation to findings in ultrasound (US) examinations in
preterm infants with and without cerebral palsy (CP and non-CP) as an outcome at a
corrected age of 18 months.
Groups of infants
with examinations
US (n=51)
MRI (n=50)
Normal
(n=34)
SPET (n=34)
Abnormal
(n=16)
Normal
(n=18)
Abnormal
(n=16)
CP
Non-CP
Normal US without SPET
1
14
0
14
1
0
–
–
–
–
Normal US with SPET
3
17
1
14
1
3
1
12
2
5
4
31
1
28
2
3
1
12
2
5
CP Non-CP CP
Total (n)
Non-CP
CP Non-CP CP Non-CP
Abnormal US without SPET
0
2
0
1
0
1
–
–
–
–
Abnormal US with SPET
8
6
0
4
8
2
1
4
7
2
Total (n)
All (n)
8
8
0
5
8
3
1
4
7
2
12
39
1
33
10
6
2
16
9
7
– = not done
Prediction of CP was most sensitive in the case of parenchymal lesion visible in MRI.
Out of the ventricular-brain ratios, only an abnormal trigone index predicted CP in both
US and MRI examinations. Wide extracerebral spaces or delayed myelination as seen in
MRI did not predict CP. Brain perfusion SPET attained a sensitivity and specificity of the
same magnitude as US for predicting all forms of CP, but its sensitivity in predicting
moderate or severe CP was better (100% vs. 71%, but with a specificity of 67% vs. 74%,
p=0.002 vs. 0.070). The predictive values of the different imaging methods for CP as
recorded in the present series are summarised in Table 12.
52
Table 12. Performance of brain magnetic resonance imaging (MRI) and brain perfusion
single photon emission tomography (SPET) at term age for the prediction of cerebral
palsy as an outcome at a corrected age of 18 months in very low birth weight preterm
infants with reference values for ultrasounds (US).
Imaging method and defects
to be predicted
MRI
Number Sensitivity Specificity
of
(%)
(%)
infants
Odds
ratio
95 %
confidence
interval
p-value
50
Parenchymal lesion
19
100
79
Parenchymal lesion, excluding
subependymal haemorrhages
10
82
97
171.0
13.9–2100.0
<0.001
4
27
97
14.2
1.3–155.2
0.029
14
67
85
11.0
2.5–48.4
0.001
7
58
100
16
58
76
4.5
1.1–17.7
0.031
Abnormal trigone index
Reference US
Parenchymal lesion
Parenchymal lesion, excluding
subependymal haemorrhages
Abnormal trigone index
MRI and/or US
<0.001
51
<0.001
51
Parenchymal lesion in both
11
67
92
24.0
4.5–129.0
<0.001
Parenchymal lesion in one
21
83
72
12.7
2.4–67.6
0.002
SPET
34
Perfusion defect
16
82
70
10.3
1.8–60.4
0.010
Cranio-caudal defect
13
73
78
9.6
1.8–50.3
0.007
Cranio-caudal sensomotor or
thalamic hypoperfusion
11
64
83
8.3
1.6–42.6
0.011
73
83
12.7
2.3–70.0
0.005
Reference US
Parenchymal lesion
34
12
Prediction of neurosensory disability was based on abnormal brainstem dimensions in
MRI and unilateral or bilateral failures in components of BAEP. Brainstem dimensions in
MRI gave poor sensitivity values of 23–31%, but their specificities reached 100%. BAEP
components gained more significant predictive values, with sensitivities of 79–93% and
specificities of 49–91%. The significant predictive values of brainstem dimensions and
BAEP for neurosensory disability are summarised in Table 13.
53
Table 13. Brainstem dimensions in magnetic resonance imaging (MRI) and absence or
abnormal peak and inter-peak latencies and the amplitude ratio V/I in brainstem auditory
evoked potentials (BAEPs) at term age for the prediction of neurosensory disability in very
low birth weight preterm infants at a corrected age of 18 months.
Imaging method and
abnormal parameters
Number of
infants
Brainstem MRI
Sensitivity
(%)
Specificity
(%)
Odds
ratio
95 % confidence
interval
10.8
1.0–115.4
p-value
50
Sagittal dimensions
Mesencephalon
23
97
Pons
31
100
0.049
Mesencephalon
31
100
0.003
Pons
23
100
0.015
Peak latency I
93
59
19.1
2.3–161.6
0.001
Peak latency III
79
68
7.6
1.8–32.6
0.005
Peak latency V
86
49
5.7
1.1–29.0
0.029
Inter-peak latency I–V
79
68
7.6
1.8–32.6
0.005
Inter-peak latency III–V
93
57
17.1
2.0–144.4
0.001
Amplitude ratio V/I
79
89
30.3
5.8–156.7
<0.001
Inter-peak latency III–V
and amplitude ratio V/I
79
91
41.6
7.3–236.5
<0.001
Inter-peak latency III–V
or amplitude ratio V/I
93
57
17.1
2.0–144.4
0.001
0.003
Axial dimensions
BAEP
51
Prediction of permanent hearing loss succeeded best with ABR, which had a
sensitivity of 100%, whereas the TEOAE and FF auditory examinations achieved only a
half of this figure. The predictive values of the various hearing assessments for permanent
hearing loss in the series are summarised in Table 14.
Table 14. Auditory brainstem responses (ABR), transient evoked otoacoustic emissions
(TEOAEs), and free-field auditory examination (FF) at term age for the prediction of
permanent hearing loss in very low birth weight preterm infants at a corrected age of 18
months.
Screening method
ABR
Bilateral fail
TEOAE
Bilateral fail
FF
Number of
infants
Sensitivity
(%)
Specificity
(%)
Odds ratio
95 % confidence
interval
p-value
100
98
50
84
5.3
0.9–33.0
0.089
50
98
42.0
3.3–536.8
0.004
51
7
<0.001
44
9
51
Fail
4
6 Discussion
6.1 Subjects
This research design based on prospective follow-up of a homogeneous population
proved advantageous for the comparison of imaging methods. Although the series was
small in size, the infants were followed up closely and frequently without dropouts. The
subjecting of a more numerous series to such a range of multi-imaging examinations
would have required too much time and expense. The birth weight and gestational age
limits for the subjects were selected in order to include the most vulnerable brain
development period affected by adverse events during perinatal care (226, 227), in
addition, CRIB scores based on data recorded within 12 hours of birth were used as an
index of the performance of perinatal care (213). The fairly low scores recorded for this
series testify to the balanced perinatal care provided.
6.2 Methods
6.2.1 Neurodevelopmental follow-up and outcome
It is very difficult to predict clinically the outcome for VLBW preterm infants, as
episodes of abnormal neurological signs, such as hyperirritability, asymmetries and
central hypotonia appearing during the first year of life mostly improve during the
second, and in any case vary greatly in an individual during a clinical follow-up (216,
218, 220, 228). There are many clinical implications to formulating an ambulation
prognosis for a preterm infant, the basis comprises gross motor milestones, primitive
reflexes, muscle tone and posture. Some of the motor milestones may be delayed due to
prematurity, i.e. VLBW infants have been found to learn to walk significantly older than
full-term infants (median 14 months vs. 12 months) even after correction for prematurity
(229). Also, the quality of the movements made is important. Likewise, primitive reflexes
may persist in cases of brain damage and become exaggerated relative to the normal state,
and postural mechanisms may appear later or fail to appear at all (230). Although severe
55
CP can be diagnosed within the first year of life, its degree can be more reliably
determined at 18 months of age or later, simply because of the general prevalence of
hypertonicity in the VLBW preterm population (35). In order to gain accurate
information to confirm the CP outcome in these infants, repeated follow-up contacts and
observations were arranged so that transitory neurological findings could be passed off
before the corrected age of 18 months.
The developmental follow-up in this series was performed using Griffiths’ scales, in
order to obtain information on general abilities, especially cognitive performance. The
proportion of infants with a general quotient (GQ) less than 80 is the same as found by
others, and the finding of an abnormal GQ in preterm infants with CP also agrees with the
experience of others (228, 231).
6.3 Abnormalities in imaging examinations at term age and
later neuromotor outcome
6.3.1 Ultrasound
We choose the term age US examination as a reference for this series, because the MRI
and SPET examinations were performed at that age and comparisons with US could then
be conveniently assessed. By that time the preterm infants were in a suitable maturational
and clinical condition to be discharged from hospital. In addition to different screening
frequency protocols during neonatal care up to the time of discharge home, the definitions
of outcomes, outcome ages and the characteristics of the populations have led to
variations in the predictive value of US (99, 232). Very early timing of imaging may
produce overestimations or underestimations of prognostically informative changes if the
examinations are not repeated later (56, 99, 233, 234). It has been reported that a half of
all VLBW infants have IVH, periventricular echogenicity, VM or solitary cysts in their
initial cranial scans, but two thirds of these abnormalities are interpreted as normal at
discharge (99). US screening at discharge or at term age has been found to be important
not only for the diagnosis of PVL but also for VM, and this approach has recently been
preferred for prediction purposes by other authors as well (111, 232).
US can most often recognise cystic PVL, infarction and parenchymal haemorrhage,
but some minor findings cannot be seen (235, 236). The sensitivity of intraparenchymal
echo abnormalities or PVL in correlating with the neuropathological diagnosis has
nevertheless varied between 20% and 85% with a specificity in the range 69-100%
according to two reviews concerned with the 1980s’ and 1990s’ (56, 237).
One third of all clinically healthy full-term infants in a postnatal ward are likely to
have some US abnormalities without CP in follow-up, but some infants with white matter
densities have later had low scores on Griffiths’ locomotion subscale (238). A normal
cranial US for a VLBW infants usually means freedom from severe motor disability,
although a 5% risk of major disabilities has been reported (239, 240). The predictive
value achieved by term age cranial US in the present series of VLBW preterm infants
qualified it as a reliable reference method. US in this series reached sensitivity and
56
specificity levels equal to those mentioned in previous reports, where sensitivities of 5070% and specificities of 70-90% have been quoted for the ability of parenchymal lesions
in neonatal US to predict disabling CP in VLBW preterm infants (37, 108, 171, 222, 241).
6.3.2 Magnetic resonance imaging
The signal intensity changes before term age due to the water and myelin content of the
immature brain, as seen in the periventricular white matter in MRI being more disturbing
for prediction purposes then at term age (146). There are only few studies of the ability of
MRI of preterm infants around term age to predict the later outcome (145, 160). Many
previous reports on conventional MRI in preterm infants during neonatal care or at term
age concern selected populations, are hospital-based or include infants with different
gestational ages or aetiologies (75, 78, 140, 145, 150). Some series do not include followup and outcome data (133, 150).
Parenchymal lesions in MRI seemed to have better sensitivity than US for predicting
CP in this series, just as foetal MRI has been shown to be better for detecting
haemorrhagic and ischaemic lesions in cases where prenatal US is incomplete, doubtful
or limited (128, 139). The value of MRI for predicting of outcome was underestimated at
first, when only indications of myelination in MRI were compared with PVL seen in
neonatal US, and other definitive information contained in the images was passed over
(148, 160). Technical progress and repeated neonatal MRIs in selected populations have
nevertheless yielded many useful detailed observations for comparison with neonatal US
changes (147). Although MRI has been found to be more sensitive than US for the early
detection of mild periventricular lesions, one case with later CP in the present series had
only bilateral SEHs at first, whereas a typical PVL with ventricular enlargement and
WML were seen in MRI at the age of six months. Conventional MRI, like US, may not
detect all the subtlest abnormalities such as diffuse white matter injury that can be found
at autopsy (141). As in other reports, infarctions were found in two cases in this series to
be better visualised in MRI than in US (86).
Delayed myelination at term age was not found here to predict CP. As significant
perinatal disturbances and adverse consequences cause death or impairment of
oligodendrocytes, they will reduce myelinogenesis (119). The most susceptible regions
are those under active myelination and therefore they are different in preterm infants from
those in full-term infants (75). Other prospective studies of preterm and full-term infants
have shown that a delay after the age of one month is predictive of a poor outcome, and
that a delay at the corrected age of one year is reflected mainly in white matter loss and
irregular shape of the posterior horns in dilated ventricles, presumably representing end
stage PVL in VLBW children with CP (142, 160). It may be difficult to assess
myelination reliably at a very early stage because the areas to be analysed are obscured by
the pathology in infants with an intraparenchymal lesion. Delayed myelination may be
expected to occur at least transiently during a complicated perinatal course, as this will
involve disturbances in the circulation and nutrition in areas with an active myelination
process (76, 124). Normal myelination has been found at term age in preterm infants with
optimal nutrition (124, 160).
57
Neither ventricular-brain indices nor extracerebral space widths were alone capable of
predicting CP in this series. VM is randomly present after large-scale IVH and PVL, and
volumetric MRI at term age and school age has recently shown cortical volumes to be
significantly smaller and the ventricles significantly larger in prematurelly born children
than in full-term ones (92, 242). The increase in the volume of the normal infant brain
during the two months before term age has been found to be due to an increase in grey
matter, whereas the white matter has remained fairly stable. SGA infants have been
observed to have a smaller increase in grey matter volume than AGA infants (131).
Shrinkage of the brainstem at term age was slight in the surviving preterm infants with
later disability studied here, and the sensitivity of this feature for predicting later
disability was poor. Others have described smaller ipsilateral brainstem areas as being
more significant some months after the insult in preterm children with hemiplegia and
Wallerian degeneration (152). Neuronal karyorrhexis has been found in autopsies of
preterm infants delivered before 29 gestational weeks, not only in the pons, but also in the
cerebral cortex, striate corpus, globus pallidum, thalamus, inferior olivary nucleus, and
cerebellar cortex (95).
6.3.3 Single photon emission tomography
The most prominent perfusion regions at term age, the sensorimotor and occipital cortices
and the thalamic region, are concerned with future neuromotor development (68, 96).
Although much of the neurological disability in preterm infants is damage to the white
matter, lesions in the deep and intermediate white matter may extend up to the subcortical
white matter and also have consequences for the cortical grey matter (92). SPET has
enabled more cortical and subcortical abnormalities to be identified in neonates and
children beyond those apparent in MRI, CT or US (162, 172, 175). In this series, SPET
found one infant with an occipital defect and one with a thalamic defect, and CP in both,
although the US scans were normal.
The sensitivities and specificities of the perfusion defects observed in SPET were
equally as good as those of the parenchymal lesions in US for predicting CP, and in
certain cases the prediction of moderate to severe CP was much better with SPET than
with US. The radiation exposure limits the use of repeated clinical examinations,
however, although the overall exposure to the tracer, the effective dose equivalent (EDE),
is only 0.88 mSv, while the yearly background radiation is 4.00 mSv, and a brain CT
examination may reach values between 0.80 and 5.00 mSv, respectively (243, 244).
As the most prominent perfusion region at term age is the sensorimotor cortical area,
this series predicted CP through sensorimotor and thalamic hypoperfusion defects, which
proved to be sensitive predictors. It has been found that regional cortical volumes, and
predominantly sensorimotor cortical volumes in volumetric MRI, are significantly
smaller in preterm children than in full-term ones at the age of 8 years, and that this is
connected with a poorer cognitive outcome (242). The series should therefore be
followed- up and evaluated further to find cognitive difficulties.
Although semiquantification did not help in the series, semiquantitative values were
compiled for healthy infants and presented. Both structural and functional maturation is
58
very rapid during the first months of life and each age group should have reference
values.
6.4 Brainstem auditory evoked potentials
Healthy preterm infants normally reach a state of morphological maturation in BAEP at
term age which is equal to that of full-term infants, and the use of a high stimulus
intensity can give the best possible response (178). Brainstem structures, including
auditory relay nuclei, appear to be selectively vulnerable to ischaemic perinatal insults,
especially in the superior colliculi, inferior colliculi, facial motor nuclei, vestibular nuclei
and in olivary nuclei (94, 161). Such adverse events may affect impulse conduction
through the brainstem, causing absent or delayed responses or decreased amplitude ratios,
as some of the pathways are destroyed (188). Although BAEP is reported to of limited
value for predicting the neurodevelopmental outcome (245), the present findings suggest
that abnormal BAEP, being a functional abnormality, is of much greater prognostic value,
with the best parameters achieving a sensitivity and specificity of about 90%.
6.5 Screening of hearing and permanent hearing loss
Alongside CP and severe developmental delay, bilateral permanent hearing loss is a
serious complication in preterm infants (31). Hearing is a key to the development of
speech, language and cognition, and therefore early detection of hearing loss is very
important (246, 247). Hearing loss, including conductive, sensorineural or mixed hearing
loss, whether temporary or permanent, partial or complete, has effects on infant and
childhood development, as the critical period for language learning is within the first
three years. Early and repeated testing and the detection of auditory impairments by
neonatal and infant follow-up examinations can help to limit developmental delay
secondary to hearing loss (247). The present series shows that the developmental SQ
level for hearing and speech remains low throughout the follow-up in all infants with
hearing loss regardless of CP. Therefore all infants with low scores should have their
hearing screened. The present series confirmed the argument that preterm infants with CP
frequently have hearing loss (52). Early planning of rehabilitative services is essential, as
hearing loss affects speech perception, may cause a distortion of CNS maturation, and
will finally lead to auditory and language processing difficulties, and thereby to
permanent disability (247).
Many of the preterm infants in this series had infections that included middle ear
effusions before the re-evaluation. To exclude speech and language development delay
due to glue ear, this condition was treated before re-examinations. Others investigators
have also encountered such difficulties with preterm infants more often than with a
general population (248).
Failure rates at term age were clearly higher in the present ABR, TEOAE and FF
examinations than in those performed on full-term infants or reported elsewhere (195,
207). This may be attributable to the fact that the subjects in this series were high-risk
59
preterm infants (<1500 g and <34 gestational weeks at birth), and that one third of them
had an abnormality in cranial US. The usefulness of TEOAE with high-risk preterm
infants seems to be limited. The failure rates in the present TEOAE examinations were
higher than in ABR presumably because of disturbing features of middle ear function or
some other features associated with preterm infants (205). High false-positive rates in
screening with TEOAE have roused concern when examining groups of high-risk
neonates (197, 206, 249). In this series TEOAE failed to identify two infants with hearing
loss in addition to CP, obviously because of retrocochlear damage. Others have also
reported on TEOAEs in infants with normal cochleas and subsequently hearing loss
behind the cochlea (201, 250, 204).
FF examination alone did not seem to be very sensitive in predicting early hearing loss
in preterm infants. This was the primary method of infant auditory screening at the
hospital concerned here before the introduction of TEOAE in 1994. It is a BOA method
that measures the acuity of perception of environmental sounds or pure tones in the whole
auditory pathway and requires a response from both the auditory and motor pathways, but
it involves inter-subject variability in the ratio of hearing thresholds to reaction
thresholds. Preterm infants have higher behaviour thresholds for their reactions to pure
tones than full-term infants, but a catch-up interval of 9 months of age has been noted
(193).
The best predictor of permanent hearing loss in the series was bilateral failure in ABR,
possibly because of its ability to detect both cochlear and brainstem lesions. It should also
be mentioned that four of the six preterm infants with permanent hearing loss in the
present series had CP. A conventional BAEP examination is time-consuming, but the
future automated ABR should prove to be a faster screening method.
6.6 Clinical implications
As long as our efforts to prevent preterm births continue to be unsuccessful, there will be
high-risk preterm infants. To be born too prematurely, and to have been exposed to
inadequately distributed brain perfusion during perinatal and neonatal life are major risks
with regard to CP. We do not know what an infant has suffered, however, or how much
this will contribute to the development of a later disability. Although the plasticity of the
developing nervous system is enormous an uneventful neonatal period cannot guarantee
normality. A structural neonatal clinical neurological examination requires experienced
staff, takes a considerable time and frequently has to be repeated, and in any case the
result depends very much on the condition and age of the infant. Its sensitivity in
predicting the outcome will still be uncertain, and a follow-up will be needed. Concern
over the proportion of preterm survivors with disabilities has led us to study the
possibilities for identifying as early as possible the structural and functional lesions which
cause major difficulties for preterm infants at a later stage and to focus resources on
these.
Any lesion in a living preterm infant that involves the brain parenchyma, including
haemorrhagic lesions, porencephalic cysts and cystic leukomalacia, or intraventiricular
haemorrhage complicated by ventricular dilatation, must be defined as a major cerebral
60
abnormality and can frequently be expected to lead to neuromotor and sensory
disabilities. Lesions in the brainstem and the auditory pathways of surviving preterm
infants are less often assessed.
Although US, MRI and SPET are based on different phenomena and may predict
different entities, these methods were used in an attempt to identify changes in the brain
that might be predictive of the neuromotor outcome. MRI at term age was more sensitive
to parenchymal changes than US. Although the main prediction end point for the US,
MRI and SPET examinations may be the motor outcome, not only white matter damage
should be highlighted. As lesions of the grey matter in cortical areas and the thalamus are
often reflections of white matter loss or infarcts, it seems that perfusion defects in SPET
can achieve a moderate predictive value with regard to motor disability. Similarly,
germinal matrix area abnormalities may be connected with more diffuse, invisible white
matter injury, and the deep grey matter areas (the thalamus and basal ganglia) may be
damaged with functional impairments or disabilities later in childhood, adolescence and
adulthood.
Brainstem lesions in MRI of surviving preterm infants remained of low-significance
although the mean diameters of the brainstem were smaller in the infants with
neurosensory disability than in those with a normal outcome. Thus brainstem MRI cannot
be used as the sole predictor of disabilities. BAEP, being a functional measure, achieved a
much better predictive value.
Out of the tests used for auditory screening in this series, TEOAE was disturbed far
too often when applied to preterm infants and FF identified only a half of the disabled
cases, thus attaining poorer predictive values than ABR. This latter identified all the
preterm infants with permanent hearing loss, possibly due to its ability to detect
retrocochlear damage, which may affect preterm infants more often than full-term ones.
ABR should therefore be recommended for the term age screening of hearing in preterm
infants.
7 Conclusions
1. Parenchymal lesions in brain MRI at term age are very sensitive, and better than in
US, for predicting motor disability in VLBW preterm infants. A brain MRI
examination at term age can therefore be recommended for VLBW preterm infants
whenever available.
2. Brain perfusion SPET at term age predicts CP in VLBW preterm infants with the
same accuracy as US. SPET distinguishes the most severe CP forms very well, but the
clinical use of the method is restricted by the radiation exposure involved.
3. The brainstem dimension changes seen in MRI at term age were so unremarkable that
an abnormal neurosensory outcome cannot be predicted on these grounds alone in
VLBW preterm infants, whereas abnormalities in BAEP predict neurosensory
disability relatively well.
4. The predictive value of ABR at term age was better than that of TEOAE or FF for
identifying cases of permanent hearing loss among VLBW preterm infants. The false
failure rate in TEOAE was high in preterm infants. TEOAE failed to identify hearing
loss in two infants with CP, possibly because a defect may be due to retrocochlear
damage. TEOAE alone is not so applicable to the neonatal screening of hearing in
VLBW preterm infants as in full-term infants.
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