Case report

Brain injuries in
early foetal life:
consequences for
brain development
J Mancini* MD;
V Lethel MD;
C Hugonenq MD;
B Chabrol MD, Department of Paediatric Neurology,
Paediatric University Hospital, La Timone, Marseille, France.
*Correspondence to first author at address above.

Learning disability and cerebral palsy are often related to
factors present before birth. We report three patients (two
with schizencephaly, one with unilateral cerebellar agenesis)
in whom the timing of an insult to the foetus was known. In
the first case, the mother had a trauma at 16 weeks of
pregnancy and schizencephaly was discovered in the male
infant associated with a left hemiplegia. In the second child,
amniocentesis performed at 16 weeks into pregnancy may
have been responsible for the same cortical anomaly. In the
third case, sequential foetal echographies clearly
demonstrated that an apparent unilateral cerebellar agenesis
was related to an haemorrhagic event secondary to cerebellar
trauma that occurred at 19 weeks of pregnancy. It is
suggested that these brain malformations are related to an
ischemic mechanism or a traumatic event in foetal life.

Until recently, foetal brain damage was often attributed to
intrapartum events but accumulated evidence suggests that
learning disability* and cerebral palsy are often related to
factors present before birth. In some cases, because of
medicolegal implications, dating brain injury should be of
interest. We recorded three patients in whom the timing of a
damaging stimulus to the foetus was known. Collecting
information about such cases will serve to understand better
underlying pathological mechanisms.
Case reports
PATIENT 1

At 16 weeks of pregnancy the mother of this boy was knocked
down by a car. She was operated on for multiple consequent
fractures. Then she was treated with heparin until delivery
because of lower limb thrombophlebitis. Two foetal ultrasounds were normal. Foetal movements were present. There
was no polyhydramnios. The boy was born without any problem at 36 weeks. The perinatal period was uneventful. Left
congenital hemiplegia was diagnosed when the boy was 18
months old. Brain CT and MRI clearly showed a right-closed
schizencephaly from the gyrus supramarginalis to the Rolandic
area (Fig. 1). An arachnoid cyst was noted in the frontoinsular
area. Outcome was good. Psychomotor acquisitions progressed at normal time. The boy was 12 years old at the time of
follow-up. A slight left hemiplegia persisted with hemiatrophy
especially on the leg. There was no epilepsy. Intellectual function was normal with good academic achievement.
PATIENT 2

The mother’s pregnancy at age 39 years was normal except
that she underwent amniocentesis due to her age at 16
weeks. The puncture was difficult and, according to the
mother, ‘the needle struck against something’. Karyotype of
the child was normal as were later sonograms. Delivery
occurred at 40 weeks’ without any special event. There was
no specific mark on the scalp skin at birth. At 8 months of age
this girl was hospitalized because of West syndrome. On
*UK usage. US usage: mental retardation.

52

Developmental Medicine & Child Neurology 2001, 43: 52–55

Downloaded from https://www.cambridge.org/core. University of Massachusetts Amherst, on 01 Jun 2018 at 20:20:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0012162201000081

examination, a left-sided hemiparesis was noted. CT was performed at 10 months of age and showed large ventricular
cavities with irregular walls. One month later, brain MRI
showed closed schizencephaly at the level of the right insula
(Fig. 2). At the time of follow-up this patient was 13 years old.
She had a moderate right-sided hemiplegia. Seizures occured
less than once every 3 months. She has moderate learning
disability (IQ=75).
PATIENT 3

In this patient, timing of brain injury during pregnancy is
accurately documented. At 17 weeks the mother underwent
a direct abdominal trauma: she was violently kicked by her
son who was lying near her. A foetal ultrasound was performed 3 days after this episode and showed a hyper
echogenic structure in the posterior fossa that seemed to be
vermian (Fig. 3) and was first considered to be a tumour.
However, its evolution indicated a haemorrhagic event with
a two component (hypo–hyper) echogenic aspect 2 weeks
later. Foetal ultrasound 2 months after the trauma showed
disappearance of these images and suggested that a left
hypoplastic cerebellum had developed. A left cystic structure
in the cerebellum was diagnosed with ultrasound 3 and 4
months later. Delivery was normal and at term. Psychomotor
development was normal. At 3 years of age, there was only a
slight tremor; intellectual function and language were normal. Brain MRI was performed at 28 months of age and
showed cerebellar left hemisphere necrosis with mild atrophy of the brain stem especially of the right cerebellar
pedunculus (Fig. 4).

Discussion
With MRI, brain cortical malformations are more easily diagnosed and some pathogenic aspects have begun to be elucidated. Cortical malformations should not be thought to
result invariably from migration disorders. A genetic process
is responsible for some cortical malformations such as
lissencephalies type II, some lissencephalies type I, and band
heterotopias (Des Portes et al. 1998) or even posterior agyria–pachygyria (Ferrie et al. 1995), and schizencephaly (Brunelli
et al. 1996). However, in most cases cortical malformations are
due to prenatal insults occurring during neuronal migration,
between 12 and 20 weeks. Some recent animal models have
served to explain pathological processes during pregnancy,

Figure 2: Patient 2. MRI of schizencephaly at level of right
insula.

Figure 1: Patient 1. CT of right closed schizencephaly from
gyrus supramarginalis to Rolandic area.

Figure 3: Patient 3. Prenatal ultrasound imaging of
hyperechogenic structure in posterior fossa: post-traumatic
haemorrhage.

Case Report
Downloaded from https://www.cambridge.org/core. University of Massachusetts Amherst, on 01 Jun 2018 at 20:20:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0012162201000081

53

using of ibotenate, a glutamatergic agonist. Using this substance during pregnancy in mice and hamsters has shown
different types of brain lesions according to the timing of
drug administration (Marret et al. 1995).
A causal relation between brain injury and cerebral abnormalities is obvious in patients 1 and 3 and possibly in patient
2. Whether the puncture during amniocentesis was responsible for the schizencephaly in patient 2 is difficult to determine. Usually, when amniocentesis is performed, the foetus
is able to move far from the needle. Nevertheless some cases
of brain injury due to amniocentesis (porencephaly), have
been reported (Eller and Kuller 1995). In patient 1, the date
of the mother’s trauma fits well with the type of cortical malformation diagnosed some years later in her child. The term
schizencephaly was first used by Yakovlev and Wadsworth to
define a developmental defect as ‘symmetric clefts in cerebral
mantle during neuronal migration’ (1946a, p 116). There are
two theories concerning the pathogenesis of schizencephaly.
The first, proposed by Yakovlev and Wadsworth, suggests a
localized failure of induction of neural migration from the
neural cells lining the primitive ventricle. Such a pathogenesis could be likely for patients reported as heterozygous for
germline mutations in the homeobox gene EMX 2 (Brunelli et
al. 1996). The second theory is that an early destructive lesion
involving a segment of the hemisphere can lead to schizencephaly; this mechanism is clearly documented in patient 1, in
whom direct consequences of maternal trauma on the foetal
brain could be responsible for a localized ischemic event.
Alternately, heparin therapy could also have been involved.
Schizencephaly with in utero warfarin exposure has been
reported by Pati and Helmbrecht (1994). Nevertheless these

authors suggested that schizencephaly results from vascular
accident and haemorrhage and not as a direct effect of warfarin
on CNS morphogenesis. Schizencephaly is a regional disturbance of cerebral cortex formation. This process can occur
when the cerebral mantle is thin enough to be destroyed.
Clefts bordered by micropolygyria would result from a malacic
process initiated between the 12th and 20th foetal weeks
(Landrieu and Lacroix 1994). Ultrasound could not have diagnosed such an anomaly during pregnancy in our cases because
they were type 1 schizencephalies (with closed lips and without any cystic component; Komarnisky et al. 1990).
In patient 3, a brain MRI performed at 2 years of age displayed a cerebellar left-hemisphere necrosis that mimicked
unilateral cerebellar agenesis. A clearly documented follow-up showed that this unilateral agenesis was not a true
malformation. The consequences of abdominal trauma
were visualized on successive ultrasound examinations.
Cerebellar trauma induced localized haemorrhagic infarction at 17 weeks of pregnancy; a subsequent necrosis led to
a cystic lesion 6 weeks later. The same type of cerebellar
lesion was reported in preterm children by Mercuri and colleagues (1997); these authors suggested a perinatal haemorrhagic/ischemic anoxic injury. In our case we believe it
was a haemorrhagic/ischemic injury secondary to a trauma.
In this study, the brain malformations identified in these
children are believed to have happened in foetal life, in association with an ischemic (or an haemorrhagic/ischemic) event
either secondary to a maternal or foetal trauma. These brain
injuries were related to events in the early midtrimester while
most of the existing literature concerns later events (Murdoch
Eaton et al. 1991, Cohen and Roesman 1994, Baethman et al.
1996). Owing to their early occurrence, we suggest that the
injuries in these patients caused anomalies that mimicked
congenital brain malformations.
Accepted for publication 27th January 2000.
Acknowledgement
The authors wish to thank Professor P Evrard for his valuable
suggestions.

Figure 4: Patient 3. MRI of unilateral cerebellar post
necrotic agenesis.

54

References
Baethmann M, Kahn T, Lenard HG, Voit T. (1996) Fetal CNS damage
after exposure to maternal trauma during pregnancy. Acta
Paediatrica 85: 1331–8.
Brunelli S, Faiella A, Capra V, Nigro V, Simeone A, Cama A,
Boncinellei E. (1996) Germline mutations in the homeobox gene
EMX2 in patients with severe schizencephaly. Nature Genetics
12: 94–6.
Cohen M, Roessman U. ( 1994) In utero brain damage: relationship
of gestational age to pathological consequences. Developmental
Medicine & Child Neurology 36: 263–70
Des PortesV, Pinard JM, Billuart P, Vinet MC, Koulakoff A, Carrié A,
Gelot A, Dupuis E, Motte J, Berwald Netter Y, Catala M, Kahn A,
Bedjord C, Chelly J. (1998) A novel CNS gene required for
neuronal migration and involved in X-linked subcortical laminar
heterotopia and lissencephaly syndrome. Cell 92: 51–61.
Eller KM, Kuller JA. (1995) Porencephaly secondary to fetal trauma
during amniocentesis. Obstetriccs and Gynecology 85: 865–7.
Ferrie CD, Jackson GD, Giannakodimos S, Panayiotopoulos CP.
(1995) Posterior agyria-pachygyria with polymicrogyria: evidence
for an inherited neuronal migration disorder. Neurology
45: 150–3.
Komarnisky CA, Cyr DA, Mack LA, Weinberger E. (1990) Prenatal
diagnosis of schizencephaly. Journal of Ultrasound Medicine
9: 305–7.
Landrieu P, Lacroix C. (1994) Schizencephaly, consequence of a
developmental vasculopathy? Clinical Neuropathology 13: 192–6.

Developmental Medicine & Child Neurology 2001, 43: 52–55

Downloaded from https://www.cambridge.org/core. University of Massachusetts Amherst, on 01 Jun 2018 at 20:20:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0012162201000081

Marret S, Mukendi R, Gadisseux JF, Gressens P, Evrard P. (1995)
Effect of ibotenate on brain development: an excototoxic mouse
model of microgyria and posthypoxic like lesions. Journal of
Neuropathology and Experimental Neurology 54: 358–70.
Mercuri E, He J, Curati WL, Dubowitz L, Cowan FM, Bydder GM.
(1997) Cerebellar infarction and atrophy in infants with a history
of premature birth. Pediatric Radiology 27: 139–43.
Murdoch Eaton D, Ahmed Y, Dubowitz L. (1991) Maternal trauma
and cerebral lesions in preterm infants. Case Reports. British
Journal of Obstetrics and Gynecology 98: 1292–4.
Pati S, Helmbrecht GD.(1994) Congenital schizencephaly
associated with in utero warfarin exposure. Reproductive
Toxicology 8: 115–20.
Yakovlev Pl, Wadsworth RC. (1946a) Schizencephalies: a study of the
congenital clefts in the cerebral mantle. I: Clefts with fused lips.
Journal of Neuropathology and Experimental Neurology
5: 116–30.
— — (1946b) Maternal trauma and cerebellar lesions in preterm
infants. II: Clefts with hydrocephalus and lips separated. Journal
of Neuropathology and Experimental Neurology 5: 169–206.

Notices
25th Annual Conference of the Michigan Association for
Infant Mental Health. Hand in Hand: Multi-disciplinary
Approaches to Supporting Relationships and Early
Development
Michigan, USA, May 20–22, 2001
This conference will focus on the relationships between parents and infants, families and providers, and the community
systems needed to support the healthy growth and development of young children. Topics include cross-systems models
for enhancing caregiving and child development; innovative
programs and policies addressing infant, toddler, and family
needs; fathers and their role as nurturers; family and professional partnerships; interdisciplinary communication in
coordinating services; and creative solutions to institutional
barriers. Tel: +1 734 764 4276, Fax: +1 734 764 1557. E-mail:
ptully@umich.edu

5th International Congress on Cerebral Palsy
Bled, Slovenia, June 7–10, 2001
The International Child Neurology Association (ICNA) second announcement and call for abstracts (submission date
January 15, 2001). For further information see Web site:
www2.mf.uni-lj.si/~cp2001/index.html

6th International Conference of Baltic Child Neurology
Association
Kaunas, Lithuania, June 13–16, 2001
For further information, please contact, Dr Nerija Vaiciene/
Dr Milda Endziniene, Department of Neurology, Kaunas
University of Medicine, Eiveniu 2, LT–3007 Kaunas, Lithuania.
Tel/Fax: (370-7) 330 423. E-mail nerija.vaiciene@takas.lt.
Web site: www.info.kma.lt/BCNA.

Society for Research into Hydrocephalus and Spina Bifida
Uppsala, Sweden, June 27–30, 2001
Special session ‘Monitoring of intracranial pressure at all
ages’. Abstract forms (deadline February 16, 2001) and further details available from Ms CA Sobkowiak FCSP. Tel: +44
1325 465 033. Fax: +44 1325 465 033.
E-mail: maureensrhsb@btinternet.com

4th Congress of the European Paediatric Neurology Society
Baden-Baden, Germany. September 13–16, 2001
Dr F Hanefeld, President of the European Paediatric Neurology
Society cordially invites you to participate in the forthcoming
congress in Germany. For further information, please contact, AKM Congress Service GmbH, Obere Schanzstrasse 18,
D-79576 Weil am Rhein, Germany. Tel: (+49) 7621 98 330.
Fax: (+49) 7621 78 714. E-mail: akmweil@akmcongress.com.
Web site: www.akm.ch/epns2001.

Case Report
Downloaded from https://www.cambridge.org/core. University of Massachusetts Amherst, on 01 Jun 2018 at 20:20:49, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0012162201000081

55