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Developmental and epilepsy outcomes at age 4 years in the UKISS trial

comparing hormonal treatments to vigabatrin for infantile spasms: A multi-
centre randomised trial

Article  in  Archives of Disease in Childhood · May 2010

DOI: 10.1136/adc.2009.160606 · Source: PubMed

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Original article
▶ A list of clinicians
collaborating in UKISS is
published online only. To view
this file please visit the journal
online (http://adc.bmj.com).
1Royal United Hospital Bath NHS
Trust, Combe Park, Bath, UK
2 The School for Health,
University of Bath, Bath, UK
3Child and Family Health
Services, Woking, UK
4 Medical Research Council
Biostatistics Unit, University of
Cambridge, Institute of Public
Health, Cambridge, UK
5MRC Clinical Trials Unit,
London, UK
6Paediatric Neurology, Clinical
Neurosciences, University of
Southampton, Southampton, UK
7Department of Paediatric
Neurology, Frenchay Hospital
and the Bristol Royal Hospital
for Children, Bristol, UK
8Department of Paediatric
Neurology, Royal Manchester
Children’s Hospital,
Manchester, UK
9 Department of Medicine and
Dentistry, University of Bristol,
Bristol, UK
10 Department of Paediatrics,
Addenbrooke’s Hospital,
Cambridge, UK
Correspondence to
Dr Finbar O’Callaghan, Bristol
Royal Hospital for Children,
Upper Maudlin Street,
Bristol BS2 8BJ, UK; finbar.
ocallaghan@bristol.ac.uk
Accepted 22 November 2009
382
Downloaded from http://adc.bmj.com/ on January 4, 2016 - Published by group.bmj.com
Developmental and epilepsy outcomes at age 4 years
in the UKISS trial comparing hormonal treatments
to vigabatrin for infantile spasms: a multi-centre
randomised trial
Katrina Darke,1 Stuart W Edwards,1,2 Eleanor Hancock,2,3 Anthony L Johnson,4,5
Colin R Kennedy,6 Andrew L Lux,2,7 Richard W Newton,8 Finbar J K O’Callaghan,1,2,7,9
Christopher M Verity,10 John P Osborne1,2; the trial steering committee on behalf of
participating investigators
ABSTRACT
Background Infantile spasms is the name given to
a difficult to treat, severe infantile epilepsy with high
morbidity. The United Kingdom Infantile Spasms Study
(UKISS) showed that absence of spasms on days 13
and 14 after randomisation was more common in
infants allocated hormonal treatments than vigabatrin.
At 12–14 months, those with no identified aetiology
allocated hormonal treatment had better development.
However, epilepsy outcome was not affected by
treatment allocated. It is not known if the difference in
development persists as the infants grow.
Methods Infants in UKISS were followed up blind to
treatment allocation by telephone at a mean age of 4
years using the Vineland Adaptive Behaviour Scales
(VABS) and an epilepsy questionnaire.
Findings 9 of 107 enrolled infants had died. 77 were
traced and consented to take part. The median (quartile)
VABS scores were 60 (42, 97) for the 39 allocated
hormonal treatment and 50 (36, 67) for the 38 allocated
vigabatrin (Mann–Whitney U=575; p=0.091; median
difference (95% CI): 8 (−1 to 19)). For those with no
identified aetiology, VABS scores were 96 (52, 102) for
the 21 allocated hormonal treatment and 63 (37, 92) for
the 16 allocated vigabatrin (U=98.5; p=0.033; median
difference (95% CI): 14 (1 to 42)).The proportions in each
treatment group with epilepsy were similar.
Interpretation For all 77 infants, development and
epilepsy outcomes were not significantly different
between the two treatment groups. The better
development seen at 14 months in those with no
identified aetiology allocated hormonal treatment was
seen again at 4 years in this study.
INTRODUCTION
Infantile spasms are a form of epilepsy that pres-
ents in infancy with ictal episodes consisting of
spasms that usually occur in clusters.1 2 The asso-
ciated chaotic and high-voltage interictal EEG pat-
tern is called hypsarrhythmia, although this term
is not always used because it is poorly defi ned and
the EEG can vary with the underlying aetiology
of the spasms and can change as the disorder pro-
gresses. 2 More than half of infants who develop
infantile spasms have an underlying neurologi-
cal disorder, such as periventricular leucomala-
cia, hypoxic ischaemic encephalopathy, Down
What is already known on this topic
▶ In infantile spasms in all aetiological groups,
early seizure control is better following
treatment with prednisolone or tetracosactide
depot than following vigabatrin.
▶ In infantile spasms with no identified
aetiology, development at 14 months
following treatment with prednisolone or
tetracosactide depot is better than following
treatment with vigabatrin.
What this study adds
▶ In infantile spasms with no identified
aetiology, development at 4 years following
treatment with prednisolone or tetracosactide
depot is better than following treatment with
vigabatrin.
syndrome or tuberous sclerosis. 3 Onset of infan-
tile spasms is often associated with developmen-
tal arrest or regression. Many infants will have
severe cognitive and other impairments as well as
other types of seizure in later childhood and adult
life, even those without an identified aetiology for
their spasms. 3
The United Kingdom Infantile Spasms Study
(UKISS) was a pragmatic clinical trial compar-
ing the effects of hormonal treatments (pred-
nisolone or tetracosactide depot) with those
of vigabatrin. We have previously reported on
short-term outcome, namely the absence of
spasms on days 13 and 14 after allocation of
treatment, and found that this was more likely
in infants allocated hormonal treatments than in
those allocated vigabatrin (40/55 (73%) vs 28/52
(54%); difference 19%, 95% CI 1% to 36%;
χ2 =4.1, p=0.043).4
Arch Dis Child 2010;95:382–386. doi:10.1136/adc.2009.160606
 Downloaded from http://adc.bmj.com/ on January 4, 2016 - Published by group.bmj.com
We hypothesised that if one treatment was more success-
ful in controlling the spasms initially, this might result in
improved neurological development on follow-up; no previous
trial of medical treatment for infantile spasms has systemat-
ically measured this outcome. 5 It might also result in better
long-term seizure control. We hypothesised that any such
effects would most likely be seen only in those infants with
no detectable underlying aetiology, since they had no known
reason for poor development other than their spasms. In con-
trast, infants in the proven aetiology group will have many
different causes for their spasms which may have an effect on
development independent of the effect of the epilepsy.
We therefore reported on development in UKISS infants
at the age of 14 months, assessed by the Vineland Adaptive
Behaviour Scales (VABS) composite score.6 There was a sig-
nificant interaction between the effect of treatment allocation
and the presence, or not, of an identified underlying aetiology
for the infantile spasms (test of interaction between treat-
ment and known aetiology: F1,95 =6.78; p=0.011). Specifically,
in infants with no identified aetiology, outcome in those allo-
cated hormonal treatment was significantly better than in
those allocated vigabatrin (mean VABS score (SD) 88.2 (17.3)
(n=24) vs 78.9 (14.3) (n=21); difference 9.3, 95% CI 1.2% to
17.3%; least significant difference test, t 95 =2.28, p=0.025). By
contrast, in infants with proven aetiology, we did not dem-
onstrate a significant difference between the two treatment
groups (mean VABS score (SD) 70.8 (11.1) (n=29) vs 75.9 (11.3)
(n=30); difference 5.1, 95% CI −2.3% to 12.4%; least signifi-
cant difference test, t 95 =1.36, p=0.18).6 It is important to deter-
mine if this difference in development persists as infants grow
older. This further follow-up also provided an opportunity to
assess development blind to treatment allocation.
METHODS
A total of 107 infants were enrolled, with central registration
and random allocation of treatments in Bath; infants aged 2–12
months with infantile spasms were eligible. Study treatments
were hormonal treatment or vigabatrin. Full details of the
design and outcomes up to 14 months have been published.4 6
Ethics approval for this additional follow-up study was
obtained from the UK South and West Multicentre Research
Ethics Committee.
Our original protocol had included follow-up only to devel-
opmental assessment at age 14 months. We had remained in
contact with parents through a regular newsletter inform-
ing them of the progress of the study, so we approached all
parents whose contact details were known and whose child
was known to be alive to invite them to take part in a further
assessment of development (using the VABS7 ) and epilepsy
control (using a questionnaire developed for this purpose,
available from the authors on request). Interviews were con-
ducted by telephone between October 2004 and May 2005 by
a single assessor (KD) who was blind to treatment allocation.
The VABS assesses adaptive behaviour in four domains –
communication, living skills, socialisation and motor func-
tion – from which a composite score is derived. After
adjustment for age at assessment, this yields a standardised
score with a mean (SD) value in the healthy population of 100
(15). It has been extensively validated and has been used in the
UK and USA for developmental studies on children, including
those with infantile spasms.8 9
The structured questionnaire for assessing spasms and
other seizures was piloted on patients in an epilepsy clinic.
Arch Dis Child 2010;95:382–386. doi:10.1136/adc.2009.160606
Original article
Respondents were asked if their child had had any seizures
within the last 4 weeks. If present, they were asked to
describe them to confi rm that the description was compat-
ible with the type of seizure, categorising them as infantile
spasms, blank spells, tonic–clonic (without signs of focal
onset), drop attacks, focal (whether secondarily generalised or
not), myoclonic, tonic and unclassifi able. The name and num-
ber, but not dose, of antiepileptic drugs (AEDs) and the use of
a ketogenic diet on the day of questioning with any history
of epilepsy surgery were recorded. No attempt was made to
obtain an EEG.
Statistical analysis
All analyses were by intention to treat. Visual examination of
the distribution of data showed that the VABS scores were not
normally distributed. Univariate analyses of VABS composite
scores were therefore performed using the Mann–Whitney
test. VABS composite scores were compared between the two
treatment groups and the analyses were then stratified in order
to look at the effect of treatment in the group with proven aeti-
ology and the group with no identified aetiology. Most analy-
ses were performed using the statistical package STATA (v 9)
except that median differences and their 95% CI were calcu-
lated using the CIA software.10
RESULTS
Progress through the trial
Of the 107 infants enrolled, 77 completed the VABS assess-
ments at a mean (SD) age of 4.2 (0.8) years (range 33–76
months), subsequently referred to as 4 years. Of the 30 infants
who did not complete the VABS at 4 years, nine were known to
have died, 14 declined and seven infants were lost to follow-up
(table 1 and figure 1). Of the 77 infants, 39 had proven aetiol-
ogy, 37 had no identified aetiology and the aetiology of one
given vigabatrin had not been fully investigated (no cranial
scan had been performed).
Developmental outcome
VABS composite scores analysed by intention to treat
The VABS composite scores were not normally distributed.
The median (quartiles) VABS scores for the infants were 60 (42,
97) for the 39 allocated hormonal treatment and 50 (36, 67) for
the 38 allocated vigabatrin (Mann–Whitney U=575; p=0.091;
median difference (95% CI): 8 (−1 to 19)). For those with no
identified aetiology, the VABS scores were 96 (52, 102) for the
21 allocated hormonal treatment and 63 (37, 92) for the 16 allo-
cated vigabatrin (U=98.5; p=0.033; median difference (95%
CI): 14 (1 to 42)). The VABS scores for those with proven aeti-
ology were 45 (37, 61) for the 18 allocated hormonal treatment
Table 1 VABS composite scores (median and IQR) at the 4-year assess-
ment by treatment allocation and aetiology
Hormonal treatment Vigabatrin
No No
Treatment All identified Proven identified Proven
allocation infants aetiology aetiology All infants aetiology aetiology
Number 39 21 18 38 16 21
of
infants
Median 60 96 45 50 63 50
VABS
VABS IQR 42–97 52–102 37–61 36–67 37–92 35–65
IQR, interquartile range; VABS, Vineland Adaptive Behaviour Scales.
383
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Original article
Randomised
n=107
55 Allocated hormonal
treatment
(2 discontinued)
55 Primary outcome
at 14 days
55 Local epilepsy assessments at 12
to 14 months#
2 Died, 1 withdrawn*
52 Vineland assessments
at 14 months
2 died,
9 declined,
3 lost to 1 Rejoined*
follow up
39 Assessed at 4 years
Figure 1 Trial profile. *The infant withdrawn was the same one who later rejoined. #This was referred to as the final clinical assessment in the
14-month report.
and 50 (35, 65) for the 21 allocated vigabatrin (U=179.5; p=0.79;
median difference (95% CI): −1 (−11 to 7)).
Loss to follow-up at 4 years
Since there are 26 infants who were evaluated at 14 months
but not at 4 years, we have checked to see whether the loss to
follow-up could have affected our results. The VABS composite
scores for these infants, by aetiology and treatment allocation,
are shown in table 2. Those with no identified aetiology lost
to follow-up at 4 years had worse development at 14 months
in the vigabatrin group than in the hormonal treatment group.
The one infant with aetiology not fully investigated (no cra-
nial scan carried out) would, if included in the analysis as no
identified aetiology, increase the differences reported here. If
included as aetiology proven, no significant change results.
VABS subdomain raw scores
The raw scores (scores of ability before adjusting to an age
norm) of the four subdomains – communication, living skills,
socialisation and motor – were also examined between the
two assessments. At 4 years, 25 infants (14 allocated vigaba-
trin, 10 with no identified aetiology and one not known) had
lower scores in at least one domain: 13 had a fall in one domain
only, 10 in two domains and two in three domains; no infant
had scores that had fallen in all four domains.
384
52 Allocated
vigabatrin
(1 discontinued,
1 received prednisolone)
52 Primary outcome
at 14 days
1 Died
51 Local epilepsy assessments at 12
to 14 months#
2 Died
49 Vineland assessments
at 14 months
2 Died,
5 declined,
4 lost to
follow up
38 Assessed at 4 years
Seizure outcome for all infants at 4 years
Four infants were still receiving vigabatrin at age 4 years
(including one allocated vigabatrin). In the 4 weeks prior to the
4-year assessment, 10 infants, including four with no identified
aetiology, had had infantile spasms (five allocated vigabatrin
and five hormonal treatment). All 10 also had seizures of other
types (table 3). No infant was on a ketogenic diet and none had
had epilepsy surgery. Those with proven aetiology were more
likely to have continuing seizures than those with no identi-
fied aetiology (24/39 (62%) vs 13/37 (35%): χ2 5.3; p=0.021).
DISCUSSION
No difference in developmental outcome was found between
the two treatment groups for all infants, confi rming the pre-
vious similar fi ndings for all infants at 14 months of age.
However, in the subgroup of infants with no identified aetiol-
ogy, those children allocated hormonal treatments had higher
median composite VABS scores than those allocated vigaba-
trin. This difference in median VABS scores is both statisti-
cally significant and large enough to be of clinical importance.
We believe that an improvement of as little as half an SD (7.5)
would be interest to infants and their parents. The differ-
ence we found may be as little as 1 or as much as 42 points on
the VABS composite score. This result confi rms our previous
Arch Dis Child 2010;95:382–386. doi:10.1136/adc.2009.160606
 Downloaded from http://adc.bmj.com/ on January 4, 2016 - Published by group.bmj.com

Original article

Table 2 VABS composite scores at the 14-month assessment by treat- The fall in VABS composite score between the two assess-
ment allocation and aetiology in infants assessed at 14 months but not at ments is in part related to the fact that the minimum attain-
4 years able score at 14 months is 56, whereas at 4 years it has fallen
Hormonal treatment Vigabatrin to 31 and is then better able to identify more profoundly
impaired performance. However, the fall between the two
No No
Reason for identified Proven identified Proven Aetiology assessments in some subdomain raw scores in some infants
no assessment aetiology aetiology aetiology aetiology not fully suggests a loss of skills at a time when new skills should be
at 4 years (n=4) (n=9) (n=6) (n=6) investigated
being acquired since raw scores reflect actual performance and
Died after 50 51, 63 57 are not adjusted for age. Thus a fall in raw score demonstrates
14-month a loss of skills. This developmental regression may have been
assessment
due to epilepsy, the natural history of the underlying condition
Lost to 70, 84, 52, 62, 65, 59, 60, 61, 60, 74,
or even an effect of antiepileptic treatment. The fi nding of an
follow-up* 90, 107 66, 72, 73, 82, 98 85, 94
74, 75 association between treatment allocation and development at
4 years suggests that any protective effect of early control of
VABS, Vineland Adaptive Behaviour Scales.
spasms has not been overwhelmed by subsequent events.
*14 Declined, 6 known to be alive but did not reply and 1 was not traced.
Although absence of spasms on days 13 and 14 was more
Table 3 Seizures and AED use at 4 years by treatment allocation and common with hormonal treatments than with vigabatrin,4
aetiology the proportions spasm-free and seizure-free at 12–14 months
and also at 4 years were similar in each treatment group. This
Hormonal treatment Vigabatrin
probably reflects the fact that infants whose spasms failed to
No No Aetiology respond to the allocated treatment were usually offered the
identified Proven identified Proven not fully
aetiology aetiology aetiology aetiology investigated alternate treatment and that other seizure types were treated
(n=21) (n=18) (n=16) (n=21) (n=1) equally regardless of treatment allocated. The two treatment
Any 4 13 9 11 1 groups were equally likely to be receiving antiepileptic treat-
epilepsy ment at both follow-ups. Those with proven aetiology were
Infantile 2 3 2 3 0 more likely to have continuing epilepsy and to be on AEDs
spasms than those with no identified aetiology.
One other 0 8 5 7 0 The nine deaths reported are consistent with the natu-
seizure ral history of infantile spasms.12 The infants in this trial
type
are still not old enough to be assessed for the visual fi eld
Two or 4 5 3 4 1
more other defect associated with vigabatrin, but data in adults suggest
seizure that after 6 months of treatment, one third will have a sig-
types nificant visual field loss.13 This might also have an adverse
One AED 1 5 4 4 0 effect on neurodevelopment. A recent publication from
Two or 3 8 4 7 1 Finland14 reported that only one of 16 infants treated with
more AEDs vigabatrin for infantile spasms was found to have a visual
AED, antiepileptic drug. field defect at follow-up, suggesting that the risk might be
less than one third. Because those who failed to achieve ces-
sation of spasms on days 13 and 14 often still responded to
similar fi ndings at the 14-month follow-up. The fi ndings at 4 the alternate treatment (data not presented here), we believe
years are more reliable since this assessment was done on older that there is potential both for better control of spasms and
children and was undertaken blind to treatment allocation. The for improved developmental outcome by combining treat-
4-year assessment is limited by the loss of some participants ments, and this also might help those infants with an identi-
to follow-up, but this is unlikely to have led to a false–positive fied aetiology. This is the focus of our current study (http://
conclusion at 4 years since in the group with no identified aeti- www.iciss.org.uk).
ology and lost to follow-up between 14 months and 4 years,
developmental outcome scores were higher at 14 months in Acknowledgements We thank the parents who gave their time and their
those who had been allocated hormonal treatments. The bet- permission for their infants to take part in this further study. We also thank the
ter outcome at 4 years in those allocated hormonal treatments members of the data monitoring and ethics committee who freely gave their
time to review untoward events and the progress of the trial: Philip Milner
may therefore be an underestimate. Our fi ndings at 4 years (Chairman until April, 2002), Mark Gardiner, Christopher Jennison, Christopher
again highlight the known associations between better neu- Martyn (Chairman from April 2002), Jane Schulte and John Wilson. Karen
rodevelopmental scores and both early response to treatment Giles provided IT support and Heather Hill and Patricia Sheppard administrative
and no identified aetiology. Our results are compatible with support. We owe a huge debt of thanks to the clinicians and the EEG
departments who took part.
the theory that early control of spasms does have a persistent
beneficial effect on subsequent development in those with no Patient consent Parental/guardian consent obtained.
identified aetiology. Funding This study was supported by a grant from the Bath Unit for Research
The report of an infant with tuberous sclerosis whose in Paediatrics (BURP) that included support from Cow and Gate and Bishopsgate
Financial Management. FJKO’C was supported by the Wellcome Trust, ALL and EH
detailed development had been followed prospectively and by Cow and Gate and KD and JPO by BURP. The funding source had no role in study
who developed severe developmental delay and autism fol- design, data collection, data analysis, data interpretation or writing of the report.
lowing the onset of infantile spasms at age 21 months, after The work was carried out in Royal United Hospital Bath NHS Trust and the School
prophylactic vigabatrin had been withdrawn, suggests that for Health, the University of Bath.
neurodevelopment is not adversely affected by vigabatrin and Competing interests JPO unsuccessfully approached Aventis for funding of a
adds weight to the suggestion that neurodevelopment may be follow-up study to investigate visual field defects and appeared in a promotional
protected by treatment for infantile spasms.11 video about vigabatrin for Hoechst-Marion-Roussel. ALL received funding from

Arch Dis Child 2010;95:382–386. doi:10.1136/adc.2009.160606 385

 Downloaded from http://adc.bmj.com/ on January 4, 2016 - Published by group.bmj.com
Original article
Hoechst-Marion-Roussel to attend a conference. All other authors have no conflict
of interest.
Ethics approval This study was conducted with the approval of the South West
MREC.
Provenance and peer review Not commissioned; externally peer reviewed.
Contributors KD, SWE and JPO are guarantors of the data. All authors were
involved from protocol design to completion of the paper, had access to the data
and responsibility for the decision to submit for publication. The corresponding
author had full access to all the data in the study and had final responsibility for the
decision to submit for publication.
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Arch Dis Child 2010;95:382–386. doi:10.1136/adc.2009.160606
 Downloaded from http://adc.bmj.com/ on January 4, 2016 - Published by group.bmj.com

Developmental and epilepsy outcomes at age

4 years in the UKISS trial comparing
hormonal treatments to vigabatrin for
infantile spasms: a multi-centre randomised
trial
Katrina Darke, Stuart W Edwards, Eleanor Hancock, Anthony L Johnson,
Colin R Kennedy, Andrew L Lux, Richard W Newton, Finbar J K
O'Callaghan, Christopher M Verity and John P Osborne

Arch Dis Child 2010 95: 382-386

doi: 10.1136/adc.2009.160606

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References This article cites 14 articles, 3 of which you can access for free at:
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Topic Articles on similar topics can be found in the following collections

Collections Epilepsy and seizures (385)
Drugs: CNS (not psychiatric) (476)
Developmental paediatrics (127)
Epidemiologic studies (1747)

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