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protein with a substantial reduction in the number of candidate 0glycosylation sites.
M178
Ischaemic burden following traumatic brain injury: Monitoring
correlates and relevance to outcome.
Coles JP, Fryer TD, Parry DA, Smieleswiksi P, Matthews J,
Donovan T, Day D, Aigbrhio F, Clark JC, Pickard JD, Menon
DK.
Wolfson Brain Imaging Centre and Department of Anaesthesia,
Addenbrooke’sHospital, Cambridge.
It has been difficult to demonstrate significant ischaemia following
traumatic brain injury (TBI). Lndeed, early reductions in cerebral
blood flow (CBF) may represent hypoperfusion coupled to
hypometabolism rather than true ischaemia. This abstract details the
use of 0” positron emission tomography (0’’
PET) in defining the
volume of ischaemic brain, and compares our findings to traditional
clinical monitoring tools and eventual outcome using the Glasgow
Outcome Score (GOS).
We studied 10 patients within 24 hours of severe and moderate TBI
(Glasgow Coma Score (GCS) < 12). 0” PET was undertaken on a
GE Advance system with imaging of CBF, cerebral oxygen
metabolism (CMRO?), cerebral blood volume and oxygen extraction
fraction (OEF). Voxels in OEF images were binned according to
their value, and a frequency histogram of OEF distributions
constructed. Cerebral venous oxygen content (CvOz) is a critical
predictor of infarction in experimental and clinical ischaemia. We
estimated an individualised critical OEF threshold for each subject
based on a CvOz of 3.5 mVdl. The volume of voxels below this
threshold represents the ischaemic brain volume (IBV). PET data
were correlated with global measures of cerebral oxygenation
(jugular bulb oximetry (Sjv02) and arteriojugular oxygen differences
(AJDOz)) and outcome using the GOS.
Compared to control data OEF was higher within 24 hours of injury,
with an increase in IBV (59 & 17 ml vs. 5 ~f:2 ml; p < 0.01, unpaired
‘t’ Test), with individual values as high as 200 ml). Although one
subject displayed an SjvOz of 49%. in general, SjvOz and AJDG did
not reach ischaemic thresholds (mean values 65+11% and 5k1 mVdl
respectively) and were poor markers of cerebral ischaemia. GOS
correlated with IBV (Rho -0.67; p<O.O5, Spearman Rank), but not
global average measures of CBF, CMROz and OEF.
Early cerebral ischaemia is a variable but significant problem
following TBI and is predictive of outcome. Traditional global
monitors are poor predictors of such regional ischaemia.
M179
Linkage Analysis Between Childhood Absence Epilepsy and
Genes Encoding GABAe and GABABReceptors
Robert Robinson‘, Nichole Taske’, Armin Heils*, Thomas
Sander’, Michele Rees’, Mark Gardiner’
‘Royal Free and University College Medical School, London,
UK.
*University fur Epileptologie, Bonn Germany. %university
Hospital CharitC, Berlin Germany.
OBJECTIVE: Evidence suggests that mutations in genes encoding
GABAA receptor subunits or GABAB receptors may underlie
childhood absence epilepsy (CAE). The aim was to test this
hypothesis by linkage analysis in 33 nuclear families each with two
or more individuals with CAE.
METHODS: Families were ascertained from European populations.
Individuals were classified as affected using diagnostic criteria based
on the International League Against Epilepsy classification. Ten
GABAARsubunit genes and two GABABreceptor genes were tested
for linkage using thirteen polymorphic microsatellite markers. Twopoint and multipoint linkage analysis were carried out using
LINKAGE and GENEHUNTER.
RESULTS: Negative LOD scores between 4 . 8 and -18.2 were
obtained for ten markers encompassing the GABAAR subunit genes
GABRB2, GABRA6, GABRAl and GABRG2 (chromosome 5q31.133.2) and GABRBI, GABRA4 and GABRA2 (chromosome 4p13-12),
and the GABAB receptor genes GABBRI (chromosome 6 ~ 2 1 . 3 and
)
CABER2 (chromosome 9q22.1). Positive heterogeneity LOD scores
were obtained for markers GABRB3CA, 155CA2, A55CAI
encompassing the GABAAR subunit genes GABRAS, GABRB3.
GABRG3 (chromosome 15qll-13). The HLOD was 0.68 ( d . 3 2 ) at
the GABRB3 intragenic marker GABRB3CA, and 0.78 ( d . 3 5 ) at
ASSCAI (approximately 20Kb centromeric to GABRG3).
CONCLUSIONS: The positive results, although not statistically
significant, are consistent with a contribution from GABRAS,
GABRB3 or GABRG3 in a subset of patients. Further investigation of
these genes is planned using association analysis with a larger
number of patients. Seven other GABAA receptor subunits and two
GABAB receptors are excluded from a major contribution to the
CAE phenotype.
This work was supported by The Wellcome Trust, The Medical
Research Council and Action Research.
M180
Multiple Deaths due to Homoplasmic Mitochondrial DNA
Mutations.
R. McFarland, K.M. Clark, A.A.M. Morris, RW. Taylor,RN.
Lightowlers, D.M. Turnbull.
Department of Neurology, University of Newcastle-upon-Tyne,
UK.
The mitochondrial genome is a small (16.5kb), closed circle of
double stranded DNA inherited exclusively along the maternal
lineage. This unique extra-nuclear genome is crucial for the synthesis
and assembly of the mitochondrial respiratory chain. Consequently,
mutations in mitochondrial DNA (mtDNA) result in energy defects
and a number of clinically diverse human diseases. An unusual
feature of these diseases is that the mutated mtDNA often coexists
with wild type in the same cell, a situation known as heteroplasmy,
the relative amounts of each then determine the seventy of the
phenotype.
We investigated two families with suspected mitochondrial disease
in whom a heteroplasmic mutation could not be found. In the first
family, six of the index case’s children, by four unrelated partners,
had severe lactic acidaemia and died within hours of birth. Her
surviving child has both clinical and neuro-radiological features of
Leigh’s syndrome. Recently, she gave birth to a female infant whom
despite haemodialysis died at 20 hours. In the second pedigree two
children died of cardiomyopathy in early childhood and the two
survivors
have
hypertrophic
cardiomyopathy.
Extensive
investigation of both of these families has confirmed a mitochondrial
defect with strikingly abnormal histochemical and biochemical
results. Sequencing of the mitochondrial genome of both families has
revealed two homoplasmic (all mtDNA identical) mutations in tRNA
genes (mt-tRNAVal and mt-tRNA1le respectively). Steady state
levels of mt-tRNAVal and mt-tRNA1le in tissue samples were
extremely low. confirming the pathogenicity of these mutations.
Nevertheless, in both families some individuals remain
asymptomatic. While heteroplasmy is conventionally used to explain
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the differences in phenotype between individuals, this cannot be the
case in the families described. Additional epigenetic or nuclear
factors must be important. That two families in a single regional
population should be affected by two different homoplasmic
mutations indicates that such mutations are a significant cause of
mitochondrial disease. Moreover, discovering the mechanisms of
phenotype variation in such mutations is central to our understanding
of mitochondria1 disease in general.
included general medical history, parentally reported sleep and
behaviour questionnaires (Behaviour Screening Questionnaire,
Strengths and Difficulties Questionnaire, Connors Parent
Questionnaire.) The children also kept a sleep diary and were
monitored for a week with Ambulatory Activity Monitors (AM9.
The children also performed continuous performance tasks using a
validated child friendly program on a laptop computer.
Results: Preliminary analysis of the first 15 cases indicates
improvement in both parentally reported and monitored sleep
M181
0.118
0.033
Electrical Impedance Tomography of Neonatal Brain Activity
A T Tidswell,JS Wyatt, RH Bayford and DS Holder
University College Hospital, London
Introduction: Electrical Impedance Tomography (EIT) is a new,
fast and portable neuroimaging technique which produces
tomographic images of the internal impedance of the head from
measurements made through scalp electrodes. Recently EIT has been
used, for the first time, to image evoked brain activity in adults
(Tidswell et al., Neuroimnge, 2001). The images show changes
produced by either changes in regional cerebral blood volume
(rCBV) or cell swelling. In neonates, EIT could be used to image
evoked responses as an index of brain maturation. The purpose of
this work was to determine whether accurate EIT images be obtained
from the neonatal brain.
Method: 3 images per second were obtained with the UCLH 1b EIT
system using 21 Ag/AgCI EEG electrodes. Each image comprised
187 individual impedance measurements from different electrode
combinations: 2 applied a 38kHz, 2mA current and 2 measured the
resultant voltage. Imaging was performed using a block design with
10-15 stimulation periods of 10-25s over 9-12 min. Stimuli were: 1)
Visual - an 8Hz flash using LED goggles (n=4) or 2) Passive motor
- flexiodextension of either wrist at 1.5 Hz (n=7).
Results: Peak increases in raw impedance, for motor and visual
experiments respectively, were 0.43.19b (mean f SE) and
0 . 8 3 . 2 8 , peak decreases were -0.4&0.1% and -l.lf0.4%. Changes
occurred 2.13.4s and 0.5fO.l~after stimulus onset, and returned to
baseline 7.6f0.9~ and 752.0s after motor and visual stimulus
cessation respectively. Images were noisy, but demonstrated stimulus
related impedance changes in the visual cortical area in 3/4 infants
and the contralateral motor cortex area to the hand stimulated in 3fl
infants.
Conclusion: This is the first demonstration that impedance changes
can be imaged in infants during evoked responses. These changes
have a similar time course to those measured with fMRI and are
probably due to increased rCBV in the activated cortex.
Improvements to EIT may enable cotside imaging of the neonatal
brain to monitor normal brain function during intensive care, or
pathological changes due to seizures, intra-ventricular haemorrhage
or cerebral ischaemia.
M182
Sleep and Behavioural Changes after Adenotonsillectomy
HS Heussler, D Bramble
Aims: To investigate the associations of behaviour problems and
sleep difficulties in children undergoing adenotonsillectomy in a
general ENT department.
Methods: This is a case- controlled study of children selected from a
general Ear, Nose and Throat surgical waiting list and undergoing
adenotonsillectomy. Children were aged 4-12 years and were
assessed pre operatively and 6-8 weeks post operatively. Assessment
The highest scores on preoperative assessment were associated with
the greater change, post operatively. Those children with greater
mean activity scores (MI)also had the greater problem behaviours
and greater improvement noted post operatively. Problem behaviours
were infrequent and were reported in children in whom daytime
sleepiness had been a factor pre operatively. Preliminary analysis of
the continuous performance tasks demonstrate improved decision
making, less time to decision and less extra movement when
compared to controls. Completed data will be presented.
Conclusions: Overall positive changes were noticed in both sleep
and behavioural indices. These preliminary results suggest that
behaviour problems and poor sleep with obstruction appear to benefit
from adenotonsillectomy by itself. Improvements in executive skills
may explain some of these changes.
M183
Continuities and Associations of Childhood Developmental
Behaviour Problems
HS Heussler, L Polnay, CL U, C Hollis
Behaviour problems are extremely common and warrant recognition
as a cause of significant morbidity/ disability in childhood.
Aims: To investigate the continuities, associations and predictive
factors associated with a common childhood behaviour problems to
provide guidelines for targeting and early intervention.
Methods: The data from the 1970 British Cohort Study provided
access to the longitudinal data collected on 16,000 live births and
were followed up at 5, 10 and 16 years. Data-sets were compiled for
elimination problems, eating problems, sleeping problems, stomach
upsets and headaches (defined as habit problems). Descriptive
analysis included natural history of the selected problems as well as
clustering. The behaviour difficulties were further investigated
utilising behavioural sub-scores for conduct, emotional, and
hyperactivity disorders derived from the Rutter A and Connors
questionnaires, family and social attributes at study intervals.
Clusters of problems were also analysed.
Results: Although numbers of children with developmental habit
problems decrease with age a significant percentage will continue to
have symptoms and new cases present at 10 and 16 years. The
presentation andor non-resolution is very strongly associated with
social adversity, poor education, maternal malaise, and adverse
parenting attitudes and styles. Discriminant analysis was not able to
identify any particular factor that could predict children with a poor
outcome, however those children with more problems were more
likely to continue to have problems and associations with
behavioural difficulties.
Conclusions: Strong associations of eating, crying and sleeping
problems in the first 6 months suggest that early programming
influence and/or temperamental factors maybe responsible. Major
consequences of these “habit” problems are of strong associations
with poor school attainment, and acquisition of other behaviour