Intrauterine Growth in Children with Cerebral Palsy
Uvebrant P, Hagberg G
Department of Pediatrics II, University of Goteborg, Sweden.
The risk of cerebral palsy in connection with intrauterine growth
retardation has been analyzed in a case-control study. The case series
comprised 519 children with cerebral palsy born in 1967-1982 in the west
health-care region of Sweden and the control series 445 children born during
the same years in the same region. The risk of cerebral palsy in
small-for-gestational-age infants was significantly increased in term and
moderately preterm infants. The highest proportion among infants with
cerebral palsy born at term was found in tetraplegia, followed by diplegia
and dyskinetic cerebral palsy. It was concluded that small for gestational
age on the one hand reflects early prenatal brain damage, and on the other
mediates prenatal risk factors compatible with fetal deprivation of supply
and also potentates adverse effects of birth asphyxia and neonatal hypoxia.
#2
Cerebral palsy.
Eicher PS, Batshaw ML
Department of Pediatrics, Children's Hospital of Philadelphia, Pennsylvania.
Over the last century, our understanding of cerebral palsy has broadened.
For example, we now know that it results more commonly from prenatal
abnormalities than from perinatal difficulties. Yet, in most cases we are
still no closer to understanding the operant mechanism of injury or how the
injury results in the expressed motor disorder. Hopefully, the strides being
made in neurodevelopmental physiology and neurotransmitter communication
will help elucidate the mechanism of injury in cerebral palsy and thereby
lead to methods of prevention. Meanwhile, comprehensive clinical evaluation
and treatment and periodic reassessment will help tailor strategies to the
individual needs of the child. This should enable the child with cerebral
palsy to optimize his or her function in society.
#3
Am J Perinatol 1994 Nov;11(6):377-81
Prevalence of prematurely, low birthweight, and asphyxia as perinatal risk
factors in a current population of children with cerebral palsy.
Naulty CM, Long LB, Pettett G
Department of Pediatrics, Walter Reed Army Medical Center, Washington, DC.
To test the hypothesis that increasing survival of infants at highest risk
for long-term neurological sequelae has strengthened the associations
between perinatal events and subsequent cerebral palsy (CP), we compared the
prevalence rates for prematurity, low birthweight, congenital malformations,
and perinatal asphyxia from a current population of children with CP with
those reported nearly 30 years ago by the National Collaborative Perinatal
Project (NCPP, 1959-1966) of the National Institute of Neurologic and
Communicative Disorders and Stroke. Although we saw no differences in the
proportion of children who were born prematurely, we did find a significant
shift in the birthweight and gestational age distribution, with a nearly
threefold greater prevalence of births less than 1501 g in our population
(31.1% and 95% confidence interval [CI] of 20.6 to 41.7% Vs 9.1% and 95% CI
of 5.0 to 13.2%). Nearly half (43.5%) of these very low birthweight infants
had evidence of brain injury (intraventricular hemorrhage), a diagnosis not
commonly recognized in the NCPP. On the other hand, birth asphyxia and
congenital malformations occurred no more frequently in our population than
that reported earlier. Furthermore, the majority (60%) of full-term infants
who develop CP continue to be the products of normal pregnancies and have no
perinatal events that may have caused their neurological impairment. The
increasing prevalence of births less than 1501 g among children with CP may
well reflect the improving survival of very small infants over the last 30
years.
PMID: 7857425, UI: 95160821
#4
Article in French]
Cerebral palsy and perinatal asphyxia in full term newborn infants
Rumeau-Rouquette C, Breart
Unite de Recherches Epidemiologiques sur la Sante des Femmes et des Enfants,
INSERM U-149, Paris.
Despite improvement in perinatal care, the prevalence of cerebral palsy has
not decreased in France, Sweden, the United Kingdom or Australia. Based on a
review of recent publications, the course of cerebral palsy can be partially
explained by the increase in risk among very low birthweight and very
pre-term infants whose survival is now better. Until recently, many
publications have supported the hypothesis that asphyxia at birth was the
major cause of cerebral palsy. However, these results have been widely
questioned; the role of asphyxia remained unclear. In 1993 and 1994, several
publications showed that there is a significant relationship between
asphyxia and cerebral palsy, but that the role of asphyxia was overestimated
in the past. The role of maternal and antenatal risk factors must also be
taken into account. The prevention of cerebral palsy must be undertaken very
early in pregnancy.
Breart G, Rumeau-Rouquette C
Inserm unite 149, Paris, France.
Actual data on the frequency of cerebral palsy (CP) and "infirmite motrice
cerebrale" (IMC), and their relationship with perinatal asphyxia and
perinatal managements, are presented. In France, the frequency of IMC at 9
years of age, approximates 1 per thousand, for the 1972, 1976, 1981
generations. Three surveys, two English and one Australian, show an
association between perinatal asphyxia and CP. However computation of
percent attributable risk indicates that asphyxia can explain only one case
of CP out of six among term neonates. These surveys show also that 10% of CP
only could be prevented by improving perinatal managements. This, in
addition to other factors such as the increase in survival of very preterm
babies, explains the absence of a significant reduction of CP frequency
despite improvements in the perinatal care.
Davis DW
Department of Pediatrics, University of Louisville, KY 40292, USA.
Cerebral palsy (CP) is a nonprogressive disorder of motor function. Although
it has been recognized for more than a century, much remains unknown
regarding its etiology. It has been estimated that 17 to 60 percent of the
cases of CP have no known perinatal or neonatal complications. Undocumented
antenatal events may cause brain damage or increase the infant's
vulnerability to future events. The prevalence of CP has remained relatively
constant; however, its incidence in the preterm population has increased
with the improving survival of the very low birth weight infant.
#7
Early Hum Dev 1997 Apr 25;48(1-2):81-91
Antenatal and delivery risk factors simultaneously associated with neonatal
death and cerebral palsy in preterm infants.
Spinillo A, Capuzzo E, Orcesi S, Stronati M, Di Mario M, Fazzi E
Department of Obstetrics and Gynecology, IRCCS Policlinico San Matteo,
Pavia, Italy.
To evaluate the simultaneous effects of antenatal and delivery risk factors
on neonatal death and cerebral palsy in preterm infants, we conducted a
cohort study of 363 singleton pregnancies delivered between 24 and 33 weeks
gestation. Neurodevelopmental outcome of the infants was evaluated at 2
years of corrected age. Risk factors associated with death or cerebral palsy
were analysed by politomous logistic regression. Overall, the mortality rate
was 14.6% (53/363) and the prevalence of cerebral palsy among surviving
infants was 12.3% (38/310). Decreasing gestation and meconium-stained
amniotic fluid were the only antenatal factors associated with increased
odds for both death and cerebral palsy. The effect magnitude and the
predictive value of gestational age were greater for death than for cerebral
palsy. After adjustment for confounders, prolonged (> or = 48 h) rupture of
membranes (odds ratio 2.98, 95% confidence interval 1.12-7.96) and male sex
of the infant (odds ratio 3.01, 95% confidence interval 1.32-6.71) were
significantly associated only with cerebral palsy. We conclude that neonatal
death and cerebral palsy share few common antenatal risk factors. The
characteristics of antenatal risk factors for cerebral palsy suggest that
bacterial infestation of the amniotic cavity may be implicated in the
etiology of the cerebral impairment.
#8
Prenatal events and the risk of cerebral palsy in very low birth weight
infants.
O'Shea TM, Klinepeter KL, Dillard RG
Department of Pediatrics, Bowman Gray School of Medicine, Wake Forest
University, Winston-Salem, NC 27103, USA.
The purpose of this study was to analyze associations between prenatal
factors and cerebral palsy in a geographically based cohort of very low
birth weight infants. Cases (n = 80) and controls had birth weights of
500-1,500 g and were born in 1978-1989, to a resident of one of 17 counties
in northwest North Carolina. Medical records were reviewed for data about
prenatal and neonatal factors. Associations were analyzed separately for
three clinical forms of spastic cerebral palsy (hemiplegia, diplegia, and
quadriplegia) and for cerebral palsy with and without antecedent major
cranial ultrasound abnormalities. The following factors were associated most
strongly with an increased risk of cerebral palsy: multiple gestation,
chorioamnionitis, maternal antibiotics, antepartum vaginal bleeding, and
labor lasting less than 4 hours. Preeclampsia and delivery without labor
were associated with a decreased risk. Evidence of confounding was found for
each of these associations, except for those with chorioamnionitis and labor
lasting less than 4 hours. The association with chorioamnionitis was
stronger for diplegia (compared with hemiplegia and quadriplegia) and for
cerebral palsy without major cranial ultrasound abnormalities. Associations
with antepartum vaginal bleeding (increased risk) and preeclampsia
(decreased risk) were stronger for cerebral palsy occurring with major
cranial ultrasound abnormality.
#9
Aust N Z J Obstet Gynaecol 1998 Nov;38(4):377-83
Antenatal and perinatal antecedents of moderate and severe spastic cerebral palsy.
Dite GS, Bell R, Reddihough DS, Bessell C, Brennecke S, Sheedy M
Department of Child Development and Rehabilitation, Royal Children's
Hospital, Melbourne, Victoria, Australia.
Routinely collected perinatal morbidity data were abstracted for 204 cases
of moderate and severe spastic cerebral palsy and 816 matched controls.
Separate analyses were conducted for cases with birth-weight > or = 2,500 g
and birth-weight < 2,500 g. The presence of a congenital abnormality was an
important risk factor for cerebral palsy in both groups and further analyses
were conducted after dividing the groups according to presence or absence of
a congenital abnormality. In the < 2,500 g group, resuscitation needed was
clearly identified as a risk factor for cerebral palsy in the group with no
congenital abnormalities (adjusted OR=3.4; 95% CI=1.6-7.5) while in the
group with congenital abnormalities, none of the risk factors were clearly
associated with an increased risk of cerebral palsy. Among the cases with
birth-weight > or = 2,500 g, intrauterine hypoxia/birth asphyxia was clearly
associated with an increased risk of cerebral palsy (adjusted OR=18.1; 95%
CI=1.8-186) in the group with no congenital abnormalities while in the group
with congenital abnormalities, none of the factors were clearly associated
with an increased risk of cerebral palsy.
#10
Antecedents of cerebral palsy. I. Univariate analysis of risks.
Nelson KB, Ellenberg JH
A large prospective study investigated prenatal and perinatal antecedents of
chronic motor dysfunction (cerebral palsy [CP]), evaluating approximately
400 characteristics of the mothers, pregnancies, or deliveries. In addition
to confirming some, but not all, of the classic risk factors for CP, this
study observed relatively large increases in the CP rate in association with
maternal mental retardation, seizure disorders, hyperthyroidism, or with the
administration of thyroid hormone and estrogen in pregnancy. Some risk
factors were predictive of CP only insofar as they were associated with low
birth weight or low Apgar scores. Among factors not significantly related to
CP rate were maternal age, parity, socioeconomic status, smoking history,
maternal diabetes, first trimester vaginal bleeding, kidney or bladder
infection, moderate hypertension, long cord, use of anesthetic agents, or
use of oxytoxics for initiation or augmentation of labor. Duration of labor,
whether precipitate or prolonged, was not a risk factor for CP.
PMID: 4036890, UI:
#11
Antecedents of cerebral palsy. Multivariate analysis of risk.
Nelson KB, Ellenberg JH
We examined prenatal and perinatal factors predicting cerebral palsy, using
multivariate analysis to investigate which factors were most important and
the proportion of cases for which they accounted. Maternal mental
retardation, birth weight below 2001 g, and fetal malformation were among
the leading predictors. Breech presentation was also a predictor, but breech
delivery was not. A third of the children with cerebral palsy who had breech
presentations had a major noncerebral malformation. Among 189 children with
cerebral palsy, 40 (21 percent) had at least one of three clinical markers
suggestive of asphyxia; only 17 of these 40 children (9 percent of all
cases) lacked major congenital malformation or other intrinsic defects that
might have contributed to an unfavorable outcome. When all the principal
risk factors present by the time labor began were considered, the 5 percent
of the population at highest estimated risk was seen to have contributed 34
percent of the cases. When all the risk factors present during the period
beginning before pregnancy and extending through the nursery stay were
included, the 5 percent at highest risk was seen to have contributed 37
percent of the cases. Thus, the inclusion of information about the events of
birth and the neonatal period accounted for a proportion of cerebral palsy
only slightly higher than that accounted for when consideration was limited
to characteristics identified before labor began.
#12
Am J Dis Child 1987 Dec;141(12):1333-5
The asymptomatic newborn and risk of cerebral palsy.
Nelson KB, Ellenberg JH
Neuroepidemiology, Branche, National Institute of Neurological and
Communicative Disorders and Stroke, Bethesda, MD 20892.
We investigated whether infants weighing over 2500 g who had experienced one
or more of 14 late pregnancy or birth complications, but who were free of
certain signs in the nursery period were at increased risk of cerebral palsy
(CP). The signs evaluated were decreased activity after the first day of
life, need for incubator care for three or more days, feeding problems, poor
suck, respiratory difficulty, or neonatal seizures. More than 90% of the
infants weighing over 2500 g had none of these signs. In asymptomatic
infants with one or more birth complications, the rate of CP by 7 years of
age was 2.3/1000; among asymptomatic infants whose births were
uncomplicated, the rate of CP was 2.4/1000. The risk for CP rose with number
of abnormal neonatal signs, and children with sustained neonatal
abnormalities were at higher risk than those whose abnormalities were
transient. Most children with CP did not derive from groups at increased
risk. The full-term infant whose birth was complicated but who was free of
certain abnormal signs in the newborn period was not at increased risk of
CP.
#13
Pediatrics 1988 Aug;82(2):240-9
Intrapartum asphyxia and cerebral palsy.
Freeman JM, Nelson KB
Department of Neurology, Johns Hopkins Medical Institution, Baltimore, Maryland.
Signs of presumed hypoxia/asphyxia of the fetus are not uncommon and can be
detected during labor, in the delivery room, and during the early neonatal
period. Virtually no single sign or symptom has sufficient correlation to
enable prediction of later cerebral palsy with a reasonable degree of
medical certainty. To attribute cerebral palsy to prior asphyxia with
reasonable certainty, there must be evidence that a substantial hypoxic
injury occurred and that a sequence of events ensued which would prove the
clinical impact of that hypoxic insult.
#14
Am J Obstet Gynecol 1998 Aug;179(2):507-13
Potentially asphyxiating conditions and spastic cerebral palsy in infants of
normal birth weight.
Nelson KB, Grether JK
Neuroepidemiology Branch, National Institute of Neurological Disorders and
Stroke, Bethesda, Maryland, USA.
OBJECTIVE: Our purpose was to examine the association of cerebral palsy with
conditions that can interrupt oxygen supply to the fetus as a primary
pathogenetic event. STUDY DESIGN: A population-based case-control study was
performed in four California counties, 1983 through 1985, comparing birth
records of 46 children with disabling spastic cerebral palsy without
recognized prenatal brain lesions and 378 randomly selected control children
weighing > or = 2500 g at birth and surviving to age 3 years. RESULTS: Eight
of 46 children with otherwise unexplained spastic cerebral palsy, all eight
with quadriplegic cerebral palsy, and 15 of 378 controls had births
complicated by tight nuchal cord (odds ratio for quadriplegia 18, 95%
confidence interval 6.2 to 48). Other potentially asphyxiating conditions
were uncommon and none was associated with spastic diplegia or hemiplegia.
Level of care, oxytocin for augmentation of labor, and surgical delivery did
not alter the association of potentially asphyxiating conditions with
spastic quadriplegia. Intrapartum indicators of fetal stress, including
meconium in amniotic fluid and fetal monitoring abnormalities, were common
and did not distinguish children with quadriplegia who had potentially
asphyxiating conditions from controls with such conditions.
CONCLUSION:
Potentially asphyxiating conditions, chiefly tight nuchal cord, were
associated with an appreciable proportion of unexplained spastic
quadriplegia but not with diplegia or hemiplegia. Intrapartum abnormalities
were common both in children with cerebral palsy and controls and did not
distinguish between them.
Comments:
Comment in: Am J Obstet Gynecol 1999 Jan;180(1 Pt 1):251
PMID: 9731861, UI: 98400587
#15
Neurol Clin 1999 May;17(2):283-293
The Neurologically Impaired Child and Alleged Malpractice at Birth.
Nelson KB
Neuroepidemiology Branch, National Institute of Neurological Disorders and
Stroke, Bethesda, Maryland.
[Record supplied by publisher]
Controlled studies, improved epidemiologic and statistical techniques, and
an increase in biological information on mechanisms of fetal and neonatal
brain injury or maldevelopment have led to a better, although still
imperfect, understanding of the cause of developmental disabilities. The
role of asphyxia during the birth process is smaller than was once believed.
Intrauterine exposure to infection, autoimmune and coagulation disorders,
and problems specific to multiple pregnancies are risk factors for cerebral
palsy. Electronic fetal monitoring and other observations during birth are
unsatisfactory management guides, having enormously high rates of
false-positive identification. There is no evidence that caesarean section
can prevent cerebral palsy in term infants.
PMID: 10196409
#15
Dr James MD on Hyperbaric Oxygen therapy and C/P 1999
HYPERBARIC OXYGEN THERAPY FOR CEREBRAL PALSY CHILDREN
Philip James MB ChB, DIH, PhD, FFOM, Wolfson Hyperbaric Medicine
Unit, The University of Dundee, Ninewells Medical School, Dundee DD1
9SY.
To significantly increase the delivery of oxygen delivery to the
tissues requires the use of hyperbaric conditions, that is, pressures
greater than normal sea level atmospheric pressure. When tissue is
damaged the blood supply within the tissue is also damaged and too
little oxygen may be available for recovery to take place. Hyperbaric
medicine is not taught in most medical schools and is often
dismissed by doctors as "alternative" medicine, but it is drugs that
are alternative. Some raise fears about toxicity but in practice
this is not a problem. More is known about oxygen and its dosage
than any pharmaceutical. There is no more important intervention than
to give sufficient oxygen to correct a tissue deficiency but,
unfortunately, oxygen is only given in hospital to restore normal
levels in the blood. The increased pressure has no effect on the
body, although the pressure in the middle ear and sinuses in adults
has to be equalized.
When does the damage occur?
Ultrasonic scanning of the brain has shown that in most children the
events which cause the development of cerebral palsy (CP) occur at the
time of birth, 1 although it may be many months before spasticity
develops.2 Where does the damage occur? The areas affected in CP are
in the middle of the hemispheres of the brain and one side or both
sides may involved. These critical areas, called the internal
capsules, are where the fibres from the controlling nerve cells in the
gray matter of the brain pass down on their way to the spinal cord. In
the spinal cord they interconnect with the nerve cells whose fibres
activate the muscles of the legs and arms.
Why does the damage occur?
Unfortunately, the internal capsules have a poor blood supply, shown by the frequent occurrence of damage to these areas in younger patients
with multiple sclerosis and in strokes in the elderly by Magnetic
Resonance Imaging (MRI). When any event causes lack of oxygen the
blood vessels leak, the tissues become swollen and there may even be
leakage of blood. The increased water content, termed edema, reduces
the transport of oxygen. This applies to any tissue, but especially too
the brain where a sufficient quantity of oxygen is vital both to the
function and, in children, its development.
What causes paralysis and spasticity to develop?
When the controlling nerve cells in the brain
are disconnected from the spinal cord, the signals to the arms and
legs cannot pass and the ability to move is lost. Eventually, because
the nerve cells in the spinal cord are separated from the control of
the brain, they send an excess of signals to the muscles, causing the
uncontrolled contractions known as spasticity. The areas carrying the
nerve fibres to the legs are the closest to the ventricles of the
brain where the blood supply is poorest3 so the legs are the most
commonly affected. The is called diplegia, to indicate that the
problem is in the brain and distinguish it from paraplegia where the
damage is in the spinal cord.
Why is spasticity delayed?
This is a crucial question that is, at present, not adequately
explained or even raised. Children who develop spasticity often appear
to develop normally for several months and then lose function
gradually. Because in many children there is voluntary movement for a
time after birth, the connections must still be intact. Why then are
they lost allowing spasticity to develop? The answer almost certainly
is due to the failure of the coverings of the nerve fibres, known as
myelin sheaths, to develop. This evidence has come from MRI.2 Myelin
sheaths envelop the nerve fibres like a Swiss roll in order to
increase the speed of impulse transmission. Myelination normally
begins about a month before birth and progresses to completion by the
age of two. If there is tissue swelling in the mid-brain the delicate
cells that form myelin die and the nerve fibres, left exposed, slowly
deteriorate with the ultimate development of spasticity.
What may be possible?
Loss of function in the brain can be either due to tissue swelling,
which is reversible, or tissue destruction, which is not. The
recoverable areas can now be identified by a technique called SPECT
imaging. The initials stand for Single Photon Emission Computed
Tomography. It can demonstrate blood flow which is linked to
metabolism of the brain which is, of course, directly related to
oxygen availability. By giving oxygen at the high dosages possible
under hyperbaric conditions, areas which are not ''dead but sleeping''
can be identified. This phenomenon has been discussed for many years
in stroke patients and authorities have even stated that the critical
parameter is not blood flow it is oxygen delivery.4 Under normal
circumstances, blood flow and oxygen delivery are inextricably
coupled, but the use of hyperbaric conditions can change this
situation. Tissue edema and swelling may persist in, for example,
joints, for many years and SPECT imaging has now revealed that this is
true in the brain.5 Suggesting that more oxygen, that is additional
oxygen supplied under hyperbaric conditions may be of value generates
further questions:
What does hyperbaric mean?
It means a pressure greater than normal sea-level atmospheric
pressure. Atmospheric pressure at sea-level varies with the weather
and on a high pressure day more oxygen is available to the body. Aches
and pains may be worse on a low pressure day because of the reduction
of oxygen pressure. A hyperbaric chamber allows much more oxygen to be
dissolved in the blood. An indication of the power of this technique
is that at twice atmospheric pressure breathing pure oxygen the work
of the heart is reduced by 20%. So much can be dissolved in the
plasma that life is possible for a short time without red blood cells.
The research behind the development of hyperbaric oxygen therapy has
been undertaken by doctors involved in aviation, space exploration and
diving. This critical information is not yet taught in our Medical
Schools, despite many thousands of published articles including
controlled studies in many conditions.
How can cerebral palsy children be helped?
Clearly the appropriate time to use of oxygen is at the start of a
disease process, not after a delay of months or years. Nevertheless, a
course of oxygen therapy sessions at increased pressure has been shown
to resolve tissue swelling after the lapse of years. It works by
constricting blood vessels and interrupting the vicious cycle where
oxygen lack leads to tissue swelling, which then leads to further
oxygen deficiency. Although formal studies have yet to be undertaken
in children with cerebral palsy there is every reason to believe that
exactly the same effect that is seen in stroke patients can occur.
Also in children the brain is still developing and therefore the prospects for improvement are very much greater than in adults.
Recovery of brain damage in children resulting from cardiac surgery has been documented using X ray scanning.6
Will oxygen therapy cure cerebral palsy?
Hyperbaric oxygen therapy is not a miracle cure for children with
cerebral palsy, it is simply a way of ensuring the most complete
recovery possible. It should be used with exercise programs, because
lack of use in muscles and joints leads to changes that can only be
reversed by exercise.
Why are there no formal studies?
Unfortunately most of the medical research in the UK is funded by the drug industry and the costs involved are enormous. As the use of oxygen cannot be patented,
there is no way that the cost of trials could be recouped and no
finance is available for the promotion of the therapy. Because of the
great advances made in the use of drugs a climate has been created in
which doctors are conditioned to expect a drug-based solution to every
disease. Oxygen has been available in Medicine for over a hundred
years so it is difficult to accept that it is not being used properly,
but over 500 chambers are now operating in the USA and Japan, 1500 in
Russia and a similar number in China. As is so often the case much of
the original research was undertaken and published in the UK. In many
diseases the cost of investigations is often a great deal more than
the cost of providing hyperbaric oxygen therapy. MRI and SPECT imaging
may allow the benefit to be demonstrated, but they are not in any way
therapeutic. There is no better assessor of a child suffering from
cerebral palsy than a parent or carer involved in day-to-day hands on
care.
Are there dangers ?
The only risk with hyperbaric conditions properly supervised is to
the ear drum, just as when aircraft - which are hyperbaric chambers -
descend. There are limits to oxygen delivery, for example, the very
high pressures used in diving can cause convulsions, but the Chinese
have shown that epilepsy is actually treated by hyperbaric oxygen
therapy at lower pressures. There is no evidence of either eye or lung
toxicity at 1.5-1.75 atm abs.
References
- Pape KE, Wiggleworth JS. Haemorrhage, ischaemia and the perinatal brain. Clinics in developmental medicine. Nos. 69/70 William Heinemann Medical Books, London, 1979.
- Dubowitz LMS, Bydder GM, Mushin J. Developmental sequence of periventricular leukomalacia. Arch Dis Child 1985;60:349-55.
- Takashima S, Tanaka K. Development of cerebrovascular architecture and its relationship to periventricular leukomalacia. Arch Neurol 1978;35:11-16.
- Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia; the ischemic penumbra. Stroke 1981;12:723-25.
- Neubauer RA, Gottlieb SF, Kagan RL. Enhancing idling neurones. Lancet 1990;336:542.
- Muraoka R, Yokota M, Aoshima M, et al. Subclinical changes in brain morphology following cardiac operations as reflected by computed tomographic scans of the brain. J Thorac Cardiovasc Surg 981;81:364-69.
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