Current Literature

In Clinical Science

Combined Treatment of ‘Vigabatrin and Corticoids’ for

Infantile Spasms: A Superiority Complex or Truly Superior
to Corticoids Monotherapy?

Safety and Effectiveness of Hormonal Treatment Versus Hormonal Treatment With Vigabatrin for Infantile
Spasms (ICISS): A Randomised, Multicentre, Open-Label Trial.
Finbar J. K. O’Callaghan, Stuart W. Edwards, Fabienne D. Alber, Eleanor Hancock, Anthony L. .Johnson, Colin R. Kennedy,
Marcus Likeman, Andrew L. Lux, Mark Mackay, Andrew A. Mallick, Richard W. Newton, Melinda Nolan, Ronit Pressler,
Dietz Rating, Bernhard Schmitt, Christopher M. Verity, John P. Osborne; for the participating investigators. Lancet Neurol
2017;16:33–42.
BACKGROUND: Infantile spasms constitutes a severe infantile epilepsy syndrome that is difficult to treat and has a high
morbidity. Hormonal therapies or vigabatrin are the most commonly used treatments. We aimed to assess whether
combining the treatments would be more effective than hormonal therapy alone. METHODS: In this multicentre,
open-label randomised trial, 102 hospitals (Australia [three], Germany [11], New Zealand [two], Switzerland [three], and
the UK [83]) enrolled infants who had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) EEG no
more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal
therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1)
of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hor-
monal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but inves-
tigators assessing electro-clinical outcome were masked to treatment allocation. Minimum doses were prednisolone 10
mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without vigabatrin
100 mg/kg per day. The primary outcome was cessation of spasms, which was defined as no witnessed spasms on and
between day 14 and day 42 from trial entry, as recorded by parents and carers in a seizure diary. Analysis was by inten-
tion to treat. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), num-
ber 54363174, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2006-000788-
27. FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly
assigned to hormonal therapy with vigabatrin (186) or hormonal therapy alone (191). All 377 infants were assessed for
the primary outcome. Between days 14 and 42 inclusive no spasms were witnessed in 133 (72%) of 186 patients on
hormonal therapy with vigabatrin compared with 108 (57%) of 191 patients on hormonal therapy alone (difference
15·0%, 95% CI 5·1-24·9, p=0·002). Serious adverse reactions necessitating hospitalisation occurred in 33 infants (16 on
hormonal therapy alone and 17 on hormonal therapy with vigabatrin). The most common serious adverse reaction
was infection occurring in five infants on hormonal therapy alone and four on hormonal therapy with vigabatrin. There
were no deaths attributable to treatment. INTERPRETATION: Hormonal therapy with vigabatrin is significantly more
effective at stopping infantile spasms than hormonal therapy alone. The 4 week period of spasm cessation required to
achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be
confirmed at the 18 month follow-up.

Commentary monitoring response to treatment, and measuring long-term

Infantile spasms (IS) is an epileptic encephalopathy that
poses challenges for early diagnosis and effective treatment,
Epilepsy Currents, Vol. 17, No. 6 (November/December) 2017 pp. 355–357
© American Epilepsy Society
outcomes. IS varies in clinical presentation; can have atypical
EEG findings besides hypsarrhythmia; and lacks diagnostic,
treatment, and follow-up guidelines. One consensus exists
on the urgency to induce remission defined as cessation of
spasms and hypsarrhythmia (1). O’Callaghan et al. of the Inter-
national Collaborative Infantile Spasms Study (ICISS) must be
applauded. This multinational randomized study of 102 centers

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Combined Vigabatrin and Corticoids versus Corticoids Monotherapy for Infantile Spasms
(83 in the United Kingdom) represents the largest IS trial (n =
377) thus far, and compared corticoids (oral prednisolone or
intramuscular tetracosactide depot, n = 191) monotherapy
with combined (vigabatrin + oral prednisolone or vigabatrin
+ intramuscular tetracosactide, n = 186) therapy. Investiga-
tors used simple exclusion criteria and a clinically weighted
42-day (treatment begins day 0) protocol. Neither patients nor
clinicians could be masked to treatment allocation due to the
trial design. In addition, the trial allowed choice of corticoids
by parents, and this skewed the number of infants on the oral
prednisolone, being 2 to 3 times the number on the intramus-
cular tetracosactide in each arm. Primary outcome was clinical:
‘cessation of spasms during 14 to 42 days’. A key component of
EEG in defining the primary outcome was lacking. IS outcomes
are best evaluated by clinical assessments and video-EEG
(VEEG). A multihour or overnight VEEG that records multiple
awake and sleep stages and transitions and identifies any ictal
events is ideal (1-3). Measuring response from a seizure diary
without confirmation with the VEEG, as used in this trial, can
miss subtle spasms or variants of spasms, mislabel an ictal EEG
cluster as an ‘isolated spasm’ or ‘no spasm’ (subclinical) due to
electroclinical dissociation, and may label nonepileptic head
nods as spasms. This is more likely in infants with severe brain
diseases, hypotonia from disease or treatment, and partial
responders. Investigators attempted to study the electroclini-
cal response as a secondary outcome by combining a blinded
review of EEG done between days 14 and 21. However, EEG
protocol at the trial entry and on treatment was unclear, and
how the EEG duration, recording of awake–sleep stages and
transitions, and capturing of ictal events impacted the trial is
unknown. At trial entry, 55 patients were not treatment naïve
and were on concurrent antiepileptic treatment (unspeci-
fied) of ‘other seizure types’. The ratio of screened to enrolled
patients was 50%, which is not uncommon in such trials.
However, there was no documentation of reasons for excluding
50% of screened patients. In theory, a selection bias in enroll-
ment cannot be excluded.
The primary outcome measure showed a difference be-
tween groups, with 72% spasm cessation in the combined ver-
sus 57% in corticoids group. The response rate in the corticoids
monotherapy group was lower than previously reported and
generally accepted. A previous trial by the same investigators
reported a much higher responder rate of 73% from corticoids
monotherapy, but the study was under powered and mea-
sured outcome of 48-hours spasm cessation (4). As a secondary
outcome, when EEG was added to determine electroclinical
response, response rates dropped to 66% in combined versus
55% in corticoids groups. Responder rates dropped steeply in
the combined (72%–66%) but modestly in the corticoids (57%–
55%) groups, which is intriguing and emphasizes difficulties in
labeling IS remission on the basis of parental reports that can
be optimistic. On days 13 to 14, 89% in combined and 69% in
corticoids group had cessation of spasms (P < 0.001) but 57
(19%, 33 combined and 24 corticoids group) relapsed by day
42. The trial allowed local investigators to increase doses on
any day between days 7 and 14 for nonresponders/early re-
lapsers but then assessed primary outcome beginning day 14.
If some patients had treatment escalation just before or on day
14, they may not have had enough time to reach the steady
356
pharmacological state on the higher dose of the long acting/
depot drugs and could have been classified as nonresponders
for the primary outcome. The trial suggested that the chance
of achieving an electroclinical response with oral prednisolone
was less than with intramuscular tetracosactide, but due to the
trial design, this result should be interpreted with caution. Past
studies have reported similar findings, however, the evidence
remains insufficient (5).
IS studies have shown that short-term remission, occur-
rence of relapse, and long-term epilepsy and cognitive out-
come strongly depend on the etiology. Systematic documenta-
tion of refined etiology is lacking in the trial despite all centers
being in developed countries. Investigators simply separated
the subjects into those with or without risk factors of develop-
ment impairment by using clinical ‘risk factors of development
impairment’ as a surrogate marker. Of the 58% of the cohort
who had an etiologic diagnosis, most were in the severe brain
disease group. It is no surprise that children at ‘high risk of
developmental impairment’ showed poor primary outcome
and electroclinical response rates compared with the ‘low-risk’
group in both treatment arms.
The trial noted that greater than 2 months of delay in initia-
tion of treatment was associated with lower rate of cessation
of spasms, emphasizing the need to urgently recognize and
treat IS. The authors do not report significant differences in
the adverse events in the two groups. However, in Table 5,
O’Callaghan et al. show sedation in 24% (4 significant) in the
combined compared with 2% in corticoids group. Sedation
may reflect vigabatrin side effect or exaggerated pharma-
codynamic/pharmacokinetic interaction of vigabatrin with
corticoids and/or other antiepileptic drugs (unspecified) and
should be a caution especially in children with severe brain
disease, hypotonia, multiple organ-system involvement, and
risk of aspiration or infection.
Investigators plan to follow the cohort and report 18
months outcome, which will be of even greater value to know
relapse rates, emergence of other catastrophic epilepsies,
and cognitive development in combined versus corticoids
group. There is a suggestion from a previous monotherapy
trial that children with cryptogenic IS (low risk for develop-
mental disabilities) who were allocated to corticoids had a
better neurodevelopmental outcome at 14 months and 4 years
(6, 7) compared to those who received vigabatrin. Whether
corticoids and vigabatrin combination therapy used in the
cryptogenic group would offer even further improvement in
long-term outcomes compared to corticoids monotherapy has
not been determined, but would be an interesting question
to have answered to further strengthen arguments for early
combination therapy in the cryptogenic group.
This ICISS trial highlights aggressive and early treatment of
IS. Combined therapy may offer advantages in infants who are
relatively healthy and lack ingredients of severe brain disease
but it must be done with close monitoring for side effects,
objectively documenting response via VEEG, and assessing ben-
efits and risks at periodic intervals. In infants with severe brain
disease, serial therapy may still be a better alternative due to risk
of side effects, guarded prognosis for developmental outcome
over the long term, and cost. In IS due to an epileptogenic brain
MRI lesion highly associated with intractability and amenable
 Combined Vigabatrin and Corticoids versus Corticoids Monotherapy for Infantile Spasms
to surgical resection, benefits and risks of combined trials, and
other treatments should be carefully weighed against delaying
surgery. Further trials with rigorous assessment of electroclini-
cal outcomes as well as systematic capture of etiology need be
done to establish if combined therapy as a standard of treat-
ment for all IS or a subset of IS can be accepted.
by Ajay Gupta, MD
References
1. Pellock JM, Hrachovy R, Shinnar S, Baram TZ, Bettis D, Dlugos DJ,
Gaillard WD, Gibson PA, Holmes GL, Nordl DR, O’Dell C, Shields WD,
Trevathan E, Wheless JW. Infantile spasms: a U.S. consensus report.
Epilepsia 2010;51:2175–2189.
2. Lux AL, Osborne JP. A proposal for case definitions and outcome mea-
sures in studies of infantile spasms and West syndrome: consensus
statement of the West Delphi group. Epilepsia 2004;45:1416–4128.
3. Hrachovy RA, Frost JD Jr. Infantile epileptic encephalopathy with
hypsarrhythmia (infantile spasms/West syndrome). J Clin Neurophysiol
2003;20:408–425.
4. Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton
RW, O’Callaghan FJ, Verity CM, Osborne JP. The United Kingdom
Infantile Spasms Study comparing vigabatrin with prednisolone or
tetracosactide at 14 days: a multicentre, randomised controlled trial.
Lancet 2004;364:1773–1778.
5. Go CY, Mackay MT, Weiss SK, Stephens D, Adams-Webber T, Ashwal
S, Snead OC III; for the Child Neurology Society; for the American
Academy of Neurology. Evidence-based guideline update: medical
treatment of infantile spasms. Report of the Guideline Develop-
ment Subcommittee of the American Academy of Neurology and
the Practice Committee of the Child Neurology Society. Neurology
2012;78:1974–1980.
6. Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton
RW, O’Callaghan FJ, Verity CM, Osborne JP; for the United Kingdom
Infantile Spasms Study. The United Kingdom Infantile Spasms Study
(UKISS) comparing hormone treatment with vigabatrin on devel-
opmental and epilepsy outcomes to age 14 months: a multicentre
randomised trial. Lancet Neurol 2005;4:712–717.
7. Darke K, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Lux AL,
Newton RW, O’Callaghan FJ, Verity CM, Osborne JP; for the trial steer-
ing committee on behalf of participating investigators. Developmen-
tal and epilepsy outcomes at age 4 years in the UKISS trial comparing
hormonal treatments to vigabatrin for infantile spasms: a multi-centre
randomised trial. Arch Dis Child 2010;95:382–386.
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