Drug Profile

For reprint orders, please contact reprints@expert-reviews.com

Vigabatrin monotherapy for

infantile spasms
Expert Rev. Neurother. 12(3), 275–286 (2012)

Eija Gaily
Helsinki University Central Hospital,
Department of Pediatric Neurology,
PO Box 280, 00029 HUS, Helsinki,
Finland
Tel.: +358 50 4270742
Fax: +358 9 47180413
eija.gaily@hus.fi
Infantile spasms syndrome (IS) (also known as West syndrome) is an epileptic encephalopathy
with a heterogeneous etiology. One of the most common specific causes is tuberous sclerosis,
diagnosed in almost 10% of the affected infants. Adrenocorticotropic hormone or steroids
have been the preferred treatments for IS for several decades. Clinical studies have shown that
vigabatrin is superior to placebo in decreasing the frequency of infantile spasms. In tuberous
sclerosis, vigabatrin may be considered the first-line treatment for IS. The mode of action is
increasing concentrations of the inhibitory neurotransmitter GABA in the brain. The use of
vigabatrin is limited by a serious adverse effect, permanent visual field constriction, which may
affect 6–7% of exposed infants. Treatment choices are based on balancing the potential
adverse effects against the risk of catastrophic cognitive and behavioral outcomes caused by
uncontrolled spasms.

Keywords : epilepsy • infantile spasms • vigabatrin • West syndrome

Infantile spasms syndrome (IS) is an epilep-
tic encephalopathy with peak onset at around
6 months of age [1,2] . The term ‘West syndrome’
is practically synonymous with IS  [1] . The esti-
mated incidence is 0.25–0.42 per 1000  live
births per year [3] . Typical seizures are clusters
of epileptic spasms (so-called infantile spasms),
which occur several times daily, especially after
awakening, and last from a few minutes to
15 min, sometimes even longer. Interictal EEG
shows hyps­a rrhythmia, defined as multifocal
high-amplitude spikes and sharp waves with slow
background activity, or multifocal spikes against
a relatively normal background. If spasms are
not controlled by treatment, cognitive outcome
is nearly always poor.
The etiology of IS is symptomatic (related
to a known or unknown brain abnormality) in
approximately 70–80% of children [3–6] . One of
the most common specific causes is tuberous scle-
rosis, which accounts for approximately 10% of
symptomatic etiologies [4,6] . Infants with sympto­
matic etiology may also have other seizure types,
most commonly focal seizures. The terms ‘idio­
pathic’ and ‘cryptogenic’ are often applied as syno-
nyms [1] , although some authors have attempted
to define idiopathic etiology more rigorously,
requiring a hereditary predisposition to epilepsy
and the absence of focal EEG abnormalities after
intravenous diazepam injection [7] .
Treatment response and prognosis of IS are
mainly dependent on etiology. In the sympto-
matic etiology subgroup, 50–60% of infants
become free of spasms with drug therapy, and
fewer than 20% have normal or nearly normal
development [4,8] . In the idiopathic/cryptogenic
subgroup, nearly all infants become spasm-free
and have normal development [4] , provided that
effective treatment was started within 1 month
of spasm onset [9] .
Adrenocorticotropic hormone (ACTH) has
been the preferred treatment for IS for several
decades [2] . Steroids, such as prednisone, pred-
nisolone and hydrocortisone, are used less fre-
quently [2,10] . A ketogenic diet and surgery may
be options for some intractable patients [2] . Data
on the efficacy of antiepileptic drugs other than
vigabatrin for IS are scarce.
Vigabatrin was first reported to be efficacious
in IS in 1990 [11] . It has been used for treatment
of IS in several countries in Europe since the
1990s. Reported adverse effects delayed the
approval of vigabatrin for IS by the US FDA until
2009, when vigabatrin was licensed for treating
IS in children between 1 month and 2 years of
age [12] .
Pharmacology
The chemistry, pharmacology, pharmaco­
kinetics and pharmacodynamics of vigabatrin

www.expert-reviews.com 10.1586/ERN.12.3 © 2012 Expert Reviews Ltd ISSN 1473-7175 275

 Drug Profile Gaily
have been recently reviewed in detail [12,13] ; only a brief summary
is given here.
Vigabatrin is a vinyl-derivative of the inhibitory neuro­
transmitter GABA and causes irreversible inhibition of the
enzyme GABA transaminase. This enzyme is responsible for
the degradation of GABA. The inhibited catabolism results in
elevated GABA concentrations in the brain, leading to seizure
inhibition.
Vigabatrin is well absorbed (more than 95%) after oral admin-
istration. The maximum blood concentration is achieved within
approximately 1 h. Dosage-dependent concentrations of viga-
batrin can be measured in the lumbar cerebrospinal fluid after
6 h. Elimination is mainly via the kidneys as unchanged drug.
There is no protein binding.
Measurements of GABA in the brain in animals have shown
that the concentrations remain high for at least 24–48  h.
Spectroscopic studies in humans have indicated that GABA
concentrations are elevated for at least 24 h after a single dose
of vigabatrin. Therefore, the effects of vigabatrin are prolonged
significantly beyond measurable blood concentrations and depend
on the rate of GABA transaminase resynthesis.
Vigabatrin (Sabrilex ® [manufactured by Patheon France
S.A., distributed in Europe by Sanofi-Aventis Ltd.] or Sabril®
[Lundbeck Inc.]) is available as 500-mg tablets and 500-mg
powder sachets that can be dissolved in liquid. For IS, the rec-
ommended initial dosage is 50 mg/kg/day, which is increased
after 2–3 days to 100 mg/kg/day and, if required, after another
2–3 days to a maximum of 150 mg/kg/day. Dosage needs to be
adjusted in patients with compromised kidney function.
Clinical efficacy
Randomized controlled trials
The randomized controlled trials that have investigated the clini-
cal efficacy of vigabatrin for infantile spasms are summarized in
Table 1.
A French nonblinded study by Chiron et al. only included
infants with tuberous sclerosis  [10] . Twenty two infants
2–17 months of age with IS who had not been previously treated
with ACTH, steroids or vigabatrin were randomized to receive
either vigabatrin or hydrocortisone. Spasm freedom at 1 month
was significantly more common in the vigabatrin than in the
hydrocortisone group.
The study by Vigevano et al. randomized 42 infants
2–9 months of age with new-onset IS to receive either vigabatrin
or ACTH depot 10 IU intramuscularly once daily for 20 days [14] .
Video-EEG was used to confirm diagnosis and spasm cessation.
There was no significant difference in spasm freedom at day 20
between the two groups. When the alternative treatment was
given to infants resistant to the first therapy, two out of five
infants responded to vigabatrin and 11 out of 12 to ACTH, lead-
ing to a significant difference in the total efficacy results: 46 vs
81% in favor of ACTH (p = 0.007). EEG response tended to
appear sooner with ACTH treatment than with vigabatrin. After
3 months, spasm relapses occurred for six patients treated with
ACTH and for one treated with vigabatrin.
276
A multicenter international double-blind study by Appleton
et al. randomized 40 infants (aged 4–20 months) with newly diag-
nosed IS to receive either vigabatrin or placebo [15] . The percent-
age of patients with IS of cryptogenic etiology was 30% in both
groups. Patients with tuberous sclerosis were excluded, as previous
studies had already suggested that vigabatrin may be effective for
that etiology. The mean vigabatrin dosage was 133 mg/kg/day.
Seizure outcome was evaluated at 5 days after starting therapy.
This was followed by an open-label phase during which infants
who were initially started on placebo received vigabatrin. Spasms
were significantly decreased during the first 5 days of therapy in
the group receiving vigabatrin compared with placebo (p = 0.02).
Freedom from spasms was achieved by seven out of 20 infants
in the vigabatrin group and two out of 20 infants in the placebo
group (p = 0.063). Both placebo responders later relapsed with
spasms. During the open-label phase, spasms stopped with viga-
batrin monotherapy for 15 out of 40 infants (38%) in an average
of 8 days. Four children later relapsed.
A US multicenter, single-blind study by Elterman et al. rand-
omized 179 infants who had been diagnosed with IS a maximum
of 3 months previously and who were less than 2 years of age to
receive either a low or a high dosage of vigabatrin [16] . The low
dosage was designed as an active control. The median ages of the
infants at randomization were 6.4 and 6.8 months. Some infants
were receiving other anti-epileptic drugs, but none had been
treated with ACTH, corticosteroids or valproate. The percent-
ages of cryptogenic etiology were similar (31 vs 33%) between
both groups. Patients with tuberous sclerosis were included as
vigabatrin was not yet available for any patients with IS in the
USA. Thirty seven infants were excluded from the study for
various reasons other than adverse effects (mainly missing data)
before evaluation of outcome. The main outcome variable was
the percentage of infants who had been spasm-free for ≥7 days,
provided that spasms had stopped during the first 2 weeks of
therapy. Outcome was confirmed by an 8-h video-EEG. Freedom
from spasms was achieved by 24 out of 67 infants (36%) receiv-
ing the high dosage and by eight out of 75 infants (11%) who
received the low dosage (p < 0.001). There were significantly
more responders among children who had tuberous sclerosis
(13 out of 25) compared with other etiologies (19 out of 117;
p < 0.001). Overall, 16% of responders relapsed during the first
3 months of therapy. The final report of this study 9 years later
included 221 patients and confirmed that spasm freedom was sig-
nificantly more common in the high-dosage than the low-dosage
group (Table 1) [17] .
The most recent and largest randomized controlled study com-
paring vigabatrin and hormonal treatment for IS was the United
Kingdom Infantile Spasms Study (UKISS) by Lux et al. [18] . This
multicenter trial was conducted in 150 hospitals in the UK and
included 107 infants 2–12 months of age with new-onset IS. The
patients were randomized to receive either vigabatrin (divided in two
daily doses), synthetic ACTH (tetracosactide depot) or oral pred-
nisolone. The prednisolone dose was increased to 60 mg/day in three
doses after 1 week if spasms continued. The three treatments were
randomly allocated in the ratio 2:1:1, respectively. Randomization
Expert Rev. Neurother. 12(3), (2012)
 Table 1. Summary of all available randomized controlled studies reporting on the efficacy of vigabatrin for infantile spasms.
Study (year) Study treatment Comparison Patients with Duration Outcome measure Seizure outcome Comment Ref.
mg/kg/day treatment symptomatic of blinded
(patients, n) (patients, n) etiology phase
Chiron et al. VGB 150 (11) Hydrocortisone 100%, all TS 1 month Spasm freedom Spasm free: VGB 100% All HC-resistant [10]

www.expert-reviews.com
(1997) 15 mg/kg/day HC 45%, RR 2.20, infants later
(11) 95% CI 1.15–4.20 became spasm free
with VGB
Vigevano et al. VGB 100–150 (23) ACTH 10 IU/day VGB 70% (TS 13%) 20 days Spasm freedom at Spasm free: VGB 48%, All TS patients [14]
(1997) (19) ACTH 58% (TS 5%) 20 days from therapy ACTH 74%, p = 0.12 became sz-free:
onset, vEEG confirmation 3 with VGB, 1 with
ACTH
Appleton et al. VGB 50–150 (20) Placebo 70% in both 5 days Spasm reduction More reduction of Spasm freedom: [15]
(1999) (20) groups, none with spasms in the VGB p = 0.063
TS group (p = 0.02)
Elterman et al. VGB 100–148 (107) VGB High dosage: 75% 14 days Spasm freedom starting Spasm free: 53% were [16,17]
(2010); Interim 18–36 mg/kg/day (TS 19%), low within 14 days and lasting high dosage 31%, receiving other
results (‘active control’) dosage: 74% >7 days, vEEG low dosage 13%, AEDs for other
published in (114) (TS 16%) confirmation p = 0.0014 seizure types at
2001 onset of VGB
1) Lux et al. VGB 100–150 (52) Tetracosactide† im. VGB 60%, 14 days 1) Spasm freedom for Spasm free: Better cognitive [18,19,20]
(2004); 0.5 mg/every hormonal‡ 55%, 48 h at 13/14 days after 1) VGB 54%, hormonal outcome after
2) Lux et al. other day (30) or none with TS onset of treatment 73% p = 0.04 hormonal therapy
(2005); prednisolone 2) spasm freedom at 2) VGB 76%, hormonal in the group with
3) Darke et al. 40 mg/day (25) 14 months of age, 75% no identified
(2010) 3) seizure freedom at 3) sz free: VGB 45%, etiology
4 years hormonal 56%
†
Synthetic ACTH.
‡
Hormonal includes both tetracosactide and prednisolone.
ACTH: Adrenocorticotrophic hormone; AED: Antiepileptic drug; HC: Hydrocortisone; im.: Intramuscularly; RR: Relative risk; sz: Seizure; TS: Tuberous sclerosis; vEEG: Video-EEG; VGB: Vigabatrin.
Vigabatrin monotherapy for infantile spasms
Drug Profile

277
 Drug Profile Gaily
was stratified based on sex, age and risk factors for developmental
delay. The third stratification criterion probably reflects etiology
relatively well. All 14 infants who were known or suspected to have
tuberous sclerosis were excluded. The diagnosis of IS was based on
clinical presentation and EEG. Hypsarrhythmia was present at the
time of diagnosis in 39 out of 55 infants (71%) in the hormonal and
in 44 out of 52 (85%) infants in the vigabatrin group.
The primary outcome variable was cessation of spasms for at
least 48 h before 14 days had elapsed after treatment initiation.
Analysis was by intention to treat. Spasm freedom was achieved
by 40 out of 55 (73%) infants in the hormonal and 28 out of 52
(54%) infants in the vigabatrin group. Cessation of spasms was
more likely in the hormonal group, the difference being 19%
(95% CI: 1–36; p = 0.043).
As a continuation of the aforementioned study, the same study
group published the results of follow-up assessments at 14 months
[19] and 4 years [20] . Of the children who did not respond to hor-
monal treatment as the first therapy, nine out of 12 (75%) later
became spasm free with vigabatrin, and of those who did not
respond to first-line vigabatrin, 14 out of 19 (74%) achieved spasm
freedom with hormonal treatment. Spasm relapse led to vigabatrin
treatment for 14 children who were first allocated hormonal treat-
ment. Three children relapsed during vigabatrin treatment and
were given hormonal treatment. Vigabatrin was continued until
14 months of age in responders.
At 14  months, the primary outcome variable was neuro­
development assessed with the Vineland Adaptive Behaviour
Scales (VABS) in a telephone interview at 14 months of age on an
intention­-to-treat basis. Seizure outcome and adverse effects at age
12–14 months were the secondary outcomes. Five infants had died
and one was withdrawn before the age of 14 months. There were
no significant differences in developmental scores, severe adverse
effects or rates of seizure freedom between the groups at 14 months.
Seizure freedom was achieved by 28 out of 55 (51%) infants in the
hormonal group and 32 out of 51 (63%) infants in the vigabatrin
group. The mean VABS score was 78.6 in the hormonal treatment
group and 77.5 in the vigabatrin group. However, for infants with
no identified underlying etiology, the mean VABS score was greater
for the hormonal group compared with the vigabatrin group (88.2
vs 78.9; difference: 9.3; 95% CI: 1.2–17.3; p = 0.025).
At 4 years, 77 children from the original cohort had participated
in the study. Nine had died, and 21 children either declined to
continue participating or were lost to follow-up. Data for develop-
mental assessment and seizures were again collected by telephone
interview. There was no significant difference between the median
VABS scores of the hormonal and the vigabatrin groups (60 vs 50),
but again, when the group with no identified etiology was consid-
ered separately, VABS scores were greater for the 21 allocated to
hormonal treatment (median 96) than for the 16 allocated to viga-
batrin (median 63; p = 0.033). There was no significant difference
in the rate of seizure freedom between the groups.
Retrospective studies
The validity of retrospective studies in comparing treatments
is limited in several ways. Often, the groups receiving different
278
drugs are not similar for their prognostic factors, which may
cause significant bias in the results. In addition, evaluation of out-
come may not be consistent and treatment protocols may change
during the period from which data are collected. However, in a
situation where randomized controlled studies on the treatment
of IS are scarce, retrospective studies may provide useful data to
help clinical decision-making.
Population-based noncontrolled data on vigabatrin efficacy
in IS have been obtained [4] . Infants with newly diagnosed IS
were first started on vigabatrin and nonresponders were given
ACTH or valproate as the second drug. All 35 infants with IS
in the Uusimaa region (Finland) diagnosed in November 1993
through November 1997 and seven infants from nearby regions
were included. Etiology for spasms was cryptogenic for ten and
symptomatic for 32 infants. Response was defined as total dis-
appearance of spasms ≥1 month and confirmed by video-EEG.
Eleven infants (26%) responded to vigabatrin: 50% of the cryp-
togenic and 19% of the symptomatic group. Two out of three
infants with tuberous sclerosis responded. The effective dosage
was 50–100 mg/kg/day for all except one infant. Spasm freedom
was observed within 1 week for nine responders. Of vigabatrin
nonresponders, 22 subsequently received ACTH and 11 (50%)
then responded. One infant relapsed after being spasm free with
vigabatrin for 4 months.
During the past 5 years, six retrospective hospital-based studies
have reported on the use of vigabatrin in IS. These studies are
briefly reviewed in the following paragraphs.
Camposano et al. included 68 children who had been treated
with vigabatrin for IS [21] . Forty two children (62%) had tuberous
sclerosis. Control of spasms was achieved by significantly more
children with tuberous sclerosis (73%) than children with IS of
other etiologies (27%).
A multicenter study in Israel identified all children who had
been diagnosed with idiopathic IS in 1985 through 2002 at six
centers and who had at least 5 years of follow-up evaluation  [5] .
The mean age at spasm onset was 5.5 months and the average time
lag to treatment was 25 days. Fourteen infants had been treated
with vigabatrin within 1  month of spasm onset and 14  with
ACTH (eight within 1 month and six later). Response within
the first 2 weeks of therapy was achieved by 78% of vigabatrin­-
treated and 87% of ACTH-treated patients. The mean follow-up
time was 9 years. Normal cognitive outcome was observed for
all children in the early-ACTH group, 67% of the late-ACTH
group and 54% of the vigabatrin group (p = 0.03). Seizure relapses
occurred for 54% of patients in the vigabatrin group, in 33% of
the late-ACTH group and none of the children who received early
ACTH (p < 0.05).
Karvelas et al. studied a population of 80 children diagnosed
with IS between 1990 and 2003  [22] . Two-thirds of the infants
had hypsarrhythmia at presentation. Fifty children (63%) had
symptomatic and 30 had cryptogenic spasm etiologies. First-line
therapy was vigabatrin for 46 infants and ACTH/prednisone for
34 infants. In the cryptogenic group, 82% of infants responded
to vigabatrin and 84% to ACTH/steroids. Of those with
sympto­matic etiology, 52% responded to vigabatrin and 53% to
Expert Rev. Neurother. 12(3), (2012)
 Vigabatrin monotherapy for infantile spasms
ACTH/steroids. Five out of seven infants with tuberous sclerosis
were given vigabatrin and all responded.
A study in Pakistan included 56 patients who presented with
infantile spasms at the Aga Khan University Hospital from
January 2006 to April 2008, and who received either vigabatrin
or ACTH as first-line therapy for spasms [23] . Infants with tuber-
ous sclerosis were excluded from the study. Additional inclusion
criteria were hypsarrythmia or modified hypsarrythmia on EEG,
at least 6 months of follow-up and receipt of any of the two drugs
mentioned above. Symptomatic etiology was observed for 64%
of patients, and 36% were considered cryptogenic or idiopathic.
Vigabatrin was received by 38 patients and ACTH by 18. Choice
of drug depended on availability, cost and ease of administration.
In the event of incomplete response to the first drug, the infant
was switched to the other treatment. Responder rates regarding
the initial therapy were 21 out of 38 (55%) for vigabatrin and
nine out of 18 (50%) for ACTH. Relapses after succesful initial
therapy occurred for 33% of infants who received vigabatrin and
56% of those who received ACTH.
A UK study included 75 children with infantile spasms, and
32% of these had cryptogenic etiology [24] . Fifty four children were
treated with vigabatrin at a maximum dosage of 150 mg/kg/day.
Eighteen children received either prednisolone 2–4 mg/kg/day or
40 mg for 2 weeks, followed by 10-mg reductions every 5 days.
Three were treated with valproate. Response was defined as spasm
freedom for ≥2 weeks. Eleven children (61%) responded to ster-
oids and 23 (42.5%) to vigabatrin. Steroids had significantly bet-
ter response in the cryptogenic group but not in the symptomatic
group. Spasms ceased significantly sooner after steroid therapy
(8 days) than after vigabatrin treatment (16 days).
Adverse effects
Peripheral visual field defect
Vigabatrin was first suspected of causing visual field loss in
patients with epilepsy in 1997 [25] . Soon afterwards, the only rand-
omized-controlled, blinded study on this topic was published [26] .
Fifty patients aged 19–73 years who had been randomized in 1988
through to 1995 to receive either vigabatrin or carbamazepine for
new-onset partial epilepsy were included in the study. At the time
of the study, 32 patients were taking vigabatrin (27 since rand-
omization) and 18 were taking carbamazepine (one changed from
vigabatrin). The duration of medication was 29–119 months.
Visual fields were investigated by Goldmann kinetic perimetry,
and the results were analyzed by two blinded ophthalmologists.
Visual field loss was observed for 13 out of 32 (41%) patients
receiving vigabatrin (aged 22–72  years), and for none of the
patients in the carbamazepine group (number needed to harm:
2; 95% CI: 2–4). Visual field loss was considered to be severe
for three and mild for ten patients. However, none of them had
noticed visual field constriction before participating in the study.
Maguire et al. undertook a systematic review of observational
studies published in 1999–2009 to assess the risk of periph-
eral visual field defect (pVFD) and possible clinical predictors
for vigabatrin-exposed patients with partial epilepsy  [27] . The
authors identified 32 relevant studies of 1678 patients exposed to
www.expert-reviews.com
Drug Profile
vigabatrin and 406 controls. Ten studies included only children
(n = 295), but none who were exposed in infancy. Of vigabatrin-
exposed patients of all ages, 738 (44%) had pVFD compared with
30 (7%) controls. The estimated risk was greater for adults (52%;
95% CI: 46–59) than for children (34%; 95% CI: 25–42). The
relative risk for pVFDs for vigabatrin-exposed patients was 4.0
(95% CI: 2.9–5.5). Increasing cumulative dosage and increasing
age were associated with greater risk of pVFD.
Only two studies have reported visual fields in children who
had been treated with vigabatrin for IS during the first year of life
[28,29] . The first study included 16 children who had been started on
vigabatrin at a mean age of 7.6 months [28] . The median maximum
daily dosage was 137 mg/kg. The duration of therapy varied from
9.3 to 29.8 months (mean: 21 months), and cumulative dosage
ranged from 209 to 1109 g (mean: 655 g). Most children had
cryptogenic etiology for spasms. All had become spasm free either
with vigabatrin treatment monotherapy or combination therapy.
Visual fields were examined by Goldmann kinetic perimetry at
6–12 years of age. Seven children required more than one study
session to obtain conclusive results with improving cooperation.
One child (6%) showed mild pVFD (temporal meridian more
than 50 but less than 70 degrees). He had received vigabatrin for
19 months, with a cumulative dosage of 572 g. The other children
had normal visual fields.
The other study reported visual fields studied by the Goldmann
kinetic perimetry for 15 children started on vigabatrin as treat-
ment for IS at age 2.5–12 months (mean: 6 months)  [29] . The
median daily dosage was 92  mg/kg. The cumulative dosage
ranged from 135 g to >5.9 kg. Two children with tuberous sclero-
sis were treated for 7 and 12 years, respectively. Both had normal
visual fields. For the others (two had symptomatic etiology, two
had cryptogenic and nine had idiopathic), the mean duration of
vigabatrin therapy was 1.7 years (range: 6 months–2.8 years).
Age at examination was >8 years, except for one child, who was
6.5 years old. One child (7%) with idiopathic etiology for spasms
exhibited pVFD after a cumulative dosage of 765 g and treatment
duration of 2.8 years. Another child was tested twice with normal
results in the second study.
Electroretinogram (ERG) studies of infants receiving viga-
batrin have shown abnormal results [30] . The earliest sustained
onset of the vigabatrin-induced ERG abnormality in infants has
been 3.1 months [31] . Abnormal ERG has been associated with
impaired visual function as measured by grating acuity in child­
ren exposed to vigabatrin in infancy [32] . There are no data on
later visual field testing in children with abnormal ERG during
vigabatrin treatment.
No evidence of pVFD was observed for six children with prenatal
exposure to vigabatrin [33,34] .
pVFD does not usually progress in patients who have received
vigabatrin for several years even if they continue on the drug [35,36] .
This suggests that retinal sensitivity to vigabatrin toxicity may be an
idiosyncratic reaction, perhaps genetically determined. The mecha-
nism of pVFD is still unknown, although associations with taurine
deficiency in animals [37] and low basal ornithine–aminotransferase
activity in humans [38] have been observed.
279
 Drug Profile Gaily
A prospective vigabatrin patient registry has been initiated in
August 2009 [39] . All patients who are prescribed vigabatrin in
the USA are enrolled. Visual function is assessed regularly at
every 3 months during therapy, as well as at 3–6 months after
discontinuation. At the first data analysis on 1 February 2011,
1500 patients with IS were included (1234 aged less than 3 years
of age). Follow-up data on visual function are not yet available.
New brain abnormalities detected on MRI
Animal studies have revealed that mice, rats and dogs treated
with high dosages of vigabatrin develop microvacuolation in the
white matter [40] . This is typically localized to the cerebellum,
reticular formation, fornix, hypothalamus and thalamus. The
microvacuoles contain fluid accumulation and separation of
the outer layers of myelin, hence the term intramyelinic edema.
Reactive astrocytosis and microglial activation may also occur.
Animal species differ in susceptibility, and the most sensitive
kind already show typical changes after 4 weeks of treatment.
Microvacuolation increases in severity for the first few months,
then become stable during continued treatment, and completely
disappears after vigabatrin is stopped. MRI is the most sensitive
method for diagnosing intramyelinic edema, but visual-, somato­
sensory- and brainstem-evoked potential also correlate with the
histologic changes in animal studies.
By the year 2000, when the review by Cohen et al. was pub-
lished [40] , no cases of vigabatrin-associated intramyelinic edema
had been reported in humans after autopsy. Patients in clinical
trials with vigabatrin were investigated with evoked potentials
and MRI with negative findings, and it was concluded that these
changes must be very rare in humans. However, infants were not
included in any of the reported trials.
Prompted by an index patient 13 months of age with new
MRI changes during vigabatrin therapy, Pearl et al. undertook a
retro­spective review of MRIs of 22 patients who were scanned at
9 months to 18 years of age while being treated with vigabatrin
for epilepsy [41] . Of the vigabatrin users, seven out of 22 patients
(32%) demonstrated T2-weighted hyperintensive abnormalities
in the basal ganglia, thalamus, brainstem or dentate nucleus,
which had not been present on MRI performed before vigabatrin
onset. The duration of vigabatrin treatment prior to MRI varied
from 1 to 11 months. After vigabatrin discontinuation, these
abnormal­ities disappeared in all patients. All affected patients
had IS, and were also younger at the time of study than unaf-
fected patients (median age of 11 months vs 5 years). None of
the 56 vigabatrin-naive patients with IS exhibited similar MRI
changes.
Wheless et  al. retrospectively studied MRI findings from
93 vigabatrin-exposed infants and 112 infants naive to vigabatrin
but treated with other drugs for IS [42] . Etiology was cryptogenic
for 46% of patients and tuberous sclerosis for 14%. MRI read-
ing was centralized and blinded for clinical data. Reviewers were
instructed to report any hyperintensities on T2-weighted or fluid-
attenuated inversion recovery sequences with or without diffusion
restriction, which were not readily explained by a radio­graphically
well-characterized pathology such as tuberous sclerosis or cortical
280
dysgenesis. The prevalence of these prespecified MRI changes was
significantly increased in vigabatrin-treated infants compared
with vigabatrin-naive children (22 vs 4%). When the analysis
was restricted to children who were scanned both prior to and
during vigabatrin therapy (n = 25), 36% had the typical abnor-
mality pattern. There were no associated clinical symptoms. The
MRI abnormalities resolved for most infants who had follow-up
scans, some of whom continued on vigabatrin. The study also
included older (2–11  years) vigabatrin-exposed patients with
partial epilepsy who did not show similar MRI abnormalities.
Dracopoulos et al. undertook a retrospective analysis of MRI
images of patients treated for IS [43] . Infants with disorders that
could potentially affect the basal ganglia were excluded. Ninety-
five patients treated with vigabatrin and 12 patients non-exposed
to vigabatrin were included in the study. A total of 65% had IS of
cryptogenic etiology, and 22% had tuberous sclerosis. A total of
31% of the vigabatrin­-exposed patients exhibited typical signal
hyperintensity while on the drug. The abnormalities were associ-
ated with diffusion restriction on diffusion-weighted imaging,
which was suggested to be related to intramyelinic edema. Young
age (less than 1 year) and cryptogenic etiology were associated
with a greater frequency of vigabatrin-associated MRI abnormal-
ity. Follow-up scans (most after vigabatrin was stopped) were
available in 66% of the patients who had abnormalities. All but
one resolved. The patients naive to vigabatrin had normal MRI
results.
Figures 1–4 provide the typical MRI changes in a vigabatrin-
treated infant at 7.5 months of age and absence of such abnormal­
ities after vigabatrin discontinuation in the same child, imaged
at 12 months of age.
There is only one pathology report describing white matter
vacuolation and intramyelinic edema after vigabatrin exposure
in a human patient [44] . This infant, with hypoxic–ischemic
brain injury and IS, died at the age of 9 months after receiving
vigabatrin for 3 weeks.
Other adverse effects
In comparison of vigabatrin and placebo, at least one adverse
effect occurred in 60% of vigabatrin-exposed patients and in 30%
of placebo-treated patients during the double-blind phase  [15] .
However, these did not cause withdrawal from the study for any
patient. The most common symptom was drowsiness (40%).
When two dosages of vigabatrin were compared, 48% of the
patients in the high-dosage (>100 mg/kg/day) and 51% of those
in the low-dosage (<36 mg/kg/day) group were reported to have
one or more adverse effects during the blinded phase  [17] . The
most common of those were sedation (17%) and somnolence
(14%), followed by problems with sleep (11%), irritability (10%),
constipation (4%), lethargy (4%), decreased appetite (3%) and
hypotonia (2%).
In children with tuberous sclerosis, vigabatrin was associated
with significantly better tolerability than hydrocortisone  [10] .
Adverse effects were observed in 44% of the children in the
vigabatrin group: drowsiness (17%), hyperexcitability (17%) and
muscular hypertonia or hypotonia (11%).
Expert Rev. Neurother. 12(3), (2012)
 Vigabatrin monotherapy for infantile spasms Drug Profile

Figure 1. MRI showing new bilateral hyperintense changes in globus pallidi in an infant, 32 days after starting vigabatrin
(present dose 150 mg/kg/day) at the age of 7.5 months. (A) T2-weighted image; (B) diffusion tensor image; and (C) resolution of
the changes of vigabatrin at 12 months, 4 months after vigabatrin was stopped, T2-weighted image. Thalamic changes are also seen on
diffusion tensor image.

Vigevano et al. observed adverse effects during the randomized
phase of the study for 13% of vigabatrin-exposed infants and 37%
of those receiving ACTH (nonsignificant difference) [14] . In the
vigabatrin group, drowsiness was present in 9%, irritability in
9% and hypotonia in 9% of the children.
In the UK study, adverse events were reported for 55% of
infants receiving hormonal treatments and for 54% of infants
receiving vigabatrin [18] . The most common symptoms in the
vigabatrin group were drowsiness (27%) and gastrointesti-
nal trouble (21%). Five infants (5%) died before 14 months
of age [19] . One death was caused by Staphylococcus aureus
septicemia and occurred on day 15 of treatment with pred-
nisolone. The remaining four infants died of Leigh’s disease,
aspiration of vomit, broncho­pneumonia and persistent epileptic
encephalopathy (one each).
Conclusion
Randomized controlled studies comparing vigabatrin with pla-
cebo [15] and with an active control of low-dosage vigabatrin [17]
have demonstrated that vigabatrin is efficacious in the treat-
ment of IS. For tuberous sclerosis, vigabatrin seems to be supe-
rior to hormonal therapy [10] . In other etiologies, in the largest
study comparing vigabatrin with ACTH/hormonal therapy,
ACTH/hormonal therapy may have been more efficacious than
vigabatrin in halting infantile spasms at 2 weeks [18] , although
there was no difference in seizure outcome at 14 months between
the groups originally allocated vigabatrin or ACTH/hormonal
treatment. A smaller study with insufficient power also indi-
cated a trend toward ACTH superiority [14] . It should be noted,
however, that the study comparing vigabatrin and placebo only
achieved statistical significance in spasm reduction, possibly due
to short duration of therapy (5 days compared with 14–30 days
in other randomized controlled studies)  [15] . The efficacy end
point in IS should be spasm freedom. The EEG criteria for suc-
cess were met only by two [14,17] of five randomized controlled
studies.
Giving ACTH/hormonal treatment as the first drug for infants
with spasms of cryptogenic etiology seems to lead to a better
developmental outcome at 14 months and 6 years of age com-
pared with infants who were first treated with vigabatrin [19,20] .
This may be explained by earlier cessation of spasms in the
ACTH/hormone group. In the symptomatic subgroup (exclud-
ing tuberous sclerosis), there seems to be no differences in later
seizure outcome or development between ACTH/hormonal
treatment and vigabatrin [19,20] .
Retrospective studies [4,5,21–24] show great variation in response
rates, probably due to the bias caused by different populations,
treatment protocols and definition of response. The results are,
however, in line with randomized controlled studies in suggest-
ing that vigabatrin is efficacious for IS, and infants with tuber-
ous sclerosis benefit most from the drug. Retrospective data
also suggest that cognitive outcomes may be better for the non­
symptomatic etiology group after early ACTH treatment than
vigabatrin therapy.
Peripheral visual field constriction is the most feared adverse
effect of vigabatrin. Only two small studies have examined
visual fields in school-age patients after vigabatrin exposure in
infancy  [28,29] . The results of both studies suggest that the risk
of concentric defects may be lower (perhaps less than 10%) than
patients treated with vigabatrin in later childhood or adulthood
(40–50%) but the data are scarce and further studies are needed.
At present, there are no reliable methods to detect whether or
not visual field defects are developing during ongoing vigabatrin
therapy in infancy.
Recent MRI studies in infants have suggested that approxi-
mately a third of those exposed to vigabatrin exhibit hyper­intensive

www.expert-reviews.com 281
 Drug Profile Gaily

Figure 2. The same MRI studies as in Figure 1 showing hyperintense changes in thalamus on vigabatrin at 7.5 months.
(A) T2-weighted image; (B) diffusion tensor image; and (C) resolution of the changes off vigabatrin at 12 months, T2-weighted image.

abnormalities in the basal ganglia, thalamus, brainstem or den- Expert commentary

tate nucleus on T2-weighted images  [41–43] . These changes are
transient in most infants. They may rarely be accompanied by
muscular dystonia but the majority of the affected children are
asymptomatic. Susceptibility seems to be restricted to infancy,
as older vigabatrin-treated patients do not experience similar
abnormalities.
Of the other adverse effects, the one most commonly related
to vigabatrin treatment in the randomized controlled studies was
drowsiness, reported for 9–40% of the exposed infants, followed
by irritability, changes in muscular tone and gastrointestinal
symptoms.
The available evidence supports the choice of vigabatrin as the
first treatment for infantile spasms caused by tuberous sclero-
sis [10,16] . For infants with cryptogenic (unknown) etiology for
spasms, ACTH/hormonal therapy seems to be the most beneficial
treatment with regard to developmental outcome.
For symptomatic etiologies other than tuberous sclerosis, there
is no evidence based on seizure outcomes or later development to
help clinicians choose between vigabatrin and ACTH/steroids
as first treatment. The choice mainly depends on how the risks
of serious adverse effects are weighed against each other. ACTH
is associated with an increased risk of hypertonia, susceptibility

Figure 3. The same MRI studies as in Figures 1 & 2 showing hyperintense changes in dorsal brain stem on vigabatrin at
7.5 months. (A) T2-weighted image; (B) diffusion tensor image; and (C) resolution of the changes off vigabatrin at 12 months,
T2-weighted image.

282 Expert Rev. Neurother. 12(3), (2012)

 Vigabatrin monotherapy for infantile spasms
Figure 4. The same MRI studies as in Figures 1–3 showing hyperintense changes in nucleus dentatus on vigabatrin at
7.5 months. (A) T2-weighted image; (B) diffusion tensor image; and (C) resolution of the changes off vigabatrin at 12 months,
T2-weighted image.
to severe infections, electrolyte imbalance and adrenocortical
hyporesponsiveness [45–47] , which may rarely be fatal. The risk
of serious consequences can be avoided using minimal effective
ACTH dose and therapy duration, and suitable vigilance [48] . On
the other hand, vigabatrin may cause permanently constricted
peripheral visual fields, although the risk may be relatively small
after exposure in infancy. Taking into account the estimated
developmental potential, degree of functional impairment and
comorbidities, each physician needs to make an individual choice
for each infant.
The recommended dosage of vigabatrin for infantile spasms
is 100–150 mg/kg/day, which is the efficacious dosage based on
randomized controlled studies. If patients do not have a clinical
benefit from vigabatrin within 2–4 weeks of treatment initia-
tion, vigabatrin should be discontinued [2,49] . In responders, the
US consensus report recommends continuation of vigabatrin for
6–9 months [2] . For disease of crypto­genic or hypoxic–ischemic
etiologies, or for Down syndrome, a few months may be sufficient
[50,51] . Longer treatment lasting for several years may be beneficial
for cognitive development in children with tuberous sclerosis [52] .
The potential benefit of reducing the risk of adverse effects with
shorter treatment must be weighed against the risk of relapse and
intractable epileptic encephalopathy with catastrophic cognitive
and behavioral outcomes, especially in patients with tuberous
sclerosis [53,54] .
All patients continuing to receive vigabatrin should undergo
regular visual field examinations for the duration of treatment
[27] . This is a very challenging task in infancy for several reasons;
infantile spasms are frequently associated with visual dysfunction
even in the absence of vigabatrin [55,56] . ERG and optical coher-
ence tomography [57] require anesthesia, and the results may be
difficult to interpret. It is mandatory, however, to get a history
of possible signs of pVFD from the caregivers and assess visual
www.expert-reviews.com
Drug Profile
function as part of the neurologic examination every 3 months [49] ,
including at least once after cessation of therapy. Confrontation
testing of the peripheral visual field is possible with children less
than 2 years of age [49] by bringing an interesting object such as a
toy to the peripheral visual field and noting when the child turns
his/her head or eyes toward the target. If signs of pVFDs are
detected, the risks and benefits of vigabatrin in that individual
child should be re-evaluated.
Visual field testing should be carried out whenever possible for
school-age children with vigabatrin exposure in infancy, as even
subjectively asymptomatic pVFD may impair demanding behav-
ioral tasks such as driving [58] . The results should be reported
as there are very few data on the risk of pVFD after vigabatrin
exposure in infancy. It is important to appreciate, however, that
the results may be falsely abnormal in young children, as the test
requires good attention and cooperation. All abnormal findings
should be confirmed by repeated testing until conclusive results
are obtained.
Despite the high prevalence of the hyperintense MRI abnormal­
ities, routine MRI follow-up of asymptomatic infants during
vigabatrin treatment is probably not justified, as the structural
changes seem to be transient and not associated with any perma-
nent morbidity. Infants who display new neurological abnormal­ity
such as dystonic movements during vigabatrin therapy should
have a diagnostic MRI, bearing in mind that hypersignal in
the basal ganglia may also rarely be associated with metabolic
diseases, such as mitochondrial disorders [59] .
Five-year view
Improving cognitive and seizure outcome in IS remains a demand-
ing task. Vigabatrin will probably retain its position as a valu-
able treatment choice for infants who have a contra­indication for
ACTH/hormonal therapy, such as immuno­deficiency or chronic
283
 Drug Profile Gaily

infections, or who have been resistant to ACTH/hormonal
therapy.
At present, vigabatrin is the treatment of choice for IS associ-
ated with tuberous sclerosis, attributed to mutations in the TSC1
and TSC2 genes. The mutations cause loss of inhibitory control
of the mTOR pathway, leading to excessive cell proliferation and
cortical dysplasia. mTOR-inhibiting drugs, such as rapamycin and
everolimus, are already in clinical use in the treatment of giant-cell
astrocytomas in patients with tuberous sclerosis [60] . Recent studies
have shown that rapamycin, an inhibitor of the mTOR complex 1, is
efficacious against IS in an experimental rat model of IS [61] . In the
future, mTOR inhibitors may challenge the role of vigabatrin as the
preferred drug for IS caused by tuberous sclerosis. mTOR inhibitors
may also prove useful for spasms caused by other etiologies.
Future investigations, such as the ongoing registry study [39] ,
will hopefully clarify the magnitude of the risk of pVFD caused
by vigabatrin exposure in infancy. Improved understanding of
retinal pathophysiology of vigabatrin-attributed visual defects
will perhaps allow prediction and prevention of those defects
in patients who benefit from long-term vigabatrin treatment.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.

Key issues
• Vigabatrin is the first-choice treatment for infantile spasms caused by tuberous sclerosis.
• For other etiologies, adrenocorticotropic hormone (ACTH)/hormonal therapy seems to be more efficacious than vigabatrin in stopping
spasms within 2 weeks.
• In infantile spasms of cryptogenic etiology, ACTH/hormonal treatment may be associated with better developmental outcome than
vigabatrin.
• For symptomatic etiology other than tuberous sclerosis, long-term seizure prognosis and cognitive outcome seem to be similar
regardless of whether treatment was started with vigabatrin or ACTH/hormonal therapy.
• All patients receiving vigabatrin should have regular visual field examinations every 3 months, as vigabatrin may cause permanent
peripheral visual field constriction.
• Infants on vigabatrin may demonstrate transient hyperintensive MRI abnormalities in the central parts of the brain. Routine MRI
follow-up of asymptomatic infants is not necessary.

References
Papers of special note have been highlighted as:
• of interest
•• of considerable interest
1 Lux AL, Osborne JP. A proposal for case
definitions and outcome measures in studies
of infantile spasms and West syndrome:
consensus statement of the West Delphi
group. Epilepsia 45(11), 1416–1428 (2004).
2 Pellock JM, Hrachovy R, Shinnar S et al.
Infantile spasms: a U.S. consensus report.
Epilepsia 51(10), 2175–2179 (2010).
3 Cowan LD, Hudson LS. The epidemiology
and natural history of infantile spasms.
J. Child Neurol. 6(4), 355–364 (1991).
4 Granström ML, Gaily E, Liukkonen E.
Treatment of infantile spasms: results of a
population-based study with vigabatrin as
the first drug for spasms. Epilepsia 40(7),
950–957 (1999).
5 Cohen-Sadan S, Kramer U, Ben-Zeev B
et al. Multicenter long-term follow-up of
children with idiopathic West syndrome:
ACTH versus vigabatrin. Eur. J. Neurol.
16(4), 482–487 (2009).
6 Osborne JP, Lux AL, Edwards SW et al.
The underlying etiology of infantile spasms
(West syndrome): information from the
United Kingdom infantile spasms study
(UKISS) on contemporary causes and their
classification. Epilepsia 51(10), 2168–2174
(2010).
7 Dulac O, Plouin P, Jambaque I. Predicting
favorable outcome in idiopathic West
syndrome. Epilepsia 34(4), 747–756 (1993).
8 Lagae L, Verhelst H, Ceulemans B et al.
Treatment and long term outcome in West
syndrome: the clinical reality. A
multicentre follow up study. Seizure 19(3),
159–164 (2010).
9 Kivity S, Lerman P, Ariel R, Danziger Y,
Mimouni M, Shinnar S. Long-term
cognitive outcomes of a cohort of children
with cryptogenic infantile spasms treated
with high-dose adrenocorticotropic
hormone. Epilepsia 45(3), 255–262
(2004).
• Emphasizes the importance of early
treatment for cognitive outcome.
10 Chiron C, Dumas C, Jambaqué I,
Mumford J, Dulac O. Randomized trial
comparing vigabatrin and hydrocortisone
in infantile spasms due to tuberous
sclerosis. Epilepsy Res. 26, 389–395 (1997).
•• Shows the efficacy of vigabatrin in
infantile spasms due to tuberous sclerosis
in a randomized controlled setting.
11 Chiron C, Dulac O, Luna L et al.
Vigabatrin in infantile spasms. Lancet 335,
363–364 (1990).
12 Pesaturo KA, Spooner LM, Belliveau P.
Vigabatrin for infantile spasms.
Pharmacotherapy 31(3), 298–311 (2011).
•• Extensive review on the chemistry,
pharmacodynamics, pharmacokinetics
and metabolism of vigabatrin.
13 Lerner JT, Salamon N, Sankar R. Clinical
profile of vigabatrin as monotherapy for
treatment of infantile spasms.
Neuropsychiatr. Dis. Treat. 6, 731–740
(2010).
14 Vigevano F, Cilio MR. Vigabatrin versus
ACTH as first-line treatment for infantile
spasms: a randomized, prospective study.
Epilepsia 38(12), 1270–1274 (1997).
15 Appleton RE, Peters ACB, Mumford JP,
Shaw DE. Randomised, placebo-controlled
study of vigabatrin as first-line treatment of
infantile spasms. Epilepsia 40(11),
1627–1633 (1999).
•• Only study comparing vigabatrin with
placebo in infantile spasms.
16 Elterman RD, Shields WD, Mansfield KA,
Nagakawa J; the US Infantile Spasms
Vigabatrin Study Group. Randomized trial

284 Expert Rev. Neurother. 12(3), (2012)


of vigabatrin in patients with infantile
spasms. Neurology 57(8), 1416–1421
(2001).
17 Elterman RD, Shields WD, Bittman RM,
Torri SA, Sagar SM, Collins SD.
Vigabatrin for the treatment of infantile
spasms: final report of a randomized trial.
J. Child Neurol. 25(11), 1340–1347
(2010).
18 Lux AL, Edwards SW, Hancock E et al.
The United Kingdom infantile spasms
study comparing vigabatrin with
prednisolone or tetracosactide at 14 days: a
multicentre, randomised controlled trial.
Lancet 364, 1773–1778 (2004).
•• Largest randomized study comparing
vigabatrin with adrenocorticotropic
hormone (ACTH)/hormonal treatment
in infantile spasms.
19 Lux AL, Edwards SW, Hancock E et al.
The United Kingdom infantile spasms
study (UKISS) comparing hormone
treatment with vigabatrin on
developmental and epilepsy outcomes to
age 14 months: a multicentre randomised
trial. Lancet Neurol. 4(11), 712–717
(2005).
• Randomized study showing that ACTH
may be associated with better cognitive
outcome in cryptogenic infantile spasms
than vigabatrin at 14 months.
20 Darke K, Edwards SW, Hancock E et al.
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. Arch. Dis. Child. 95(5), 382–386
(2010).
•• Randomized study showing that ACTH
may be associated with better cognitive
outcome in cryptogenic infantile spasms
than vigabatrin at 4 years of age.
21 Camposano SE, Major P, Halpern E,
Thiele EA. Vigabatrin in the treatment of
childhood epilepsy: a retrospective chart
review of efficacy and safety profile.
Epilepsia 49(7), 1186–1191 (2008).
22 Karvelas G, Lortie A, Scantlebury MH,
Duy PT, Cossette P, Carmant L. A
retrospective study on aetiology based
outcome of infantile spasms. Seizure 18(3),
197–201 (2009).
23 Ibrahim S, Gulab S, Ishaque S, Saleem T.
Clinical profile and treatment of infantile
spasms using vigabatrin and ACTH – a
developing country perspective. BMC
Pediatr. 10(1), 1 (2010).
24 Mohamed BP, Scott RC, Desai N, Gutta P,
Patil S. Seizure outcome in infantile spasms
www.expert-reviews.com
Vigabatrin monotherapy for infantile spasms
– a retrospective study. Epilepsia 52(4),
746–752 (2011).
25 Eke T, Talbot JF, Lawden MC.
Severe persistent visual field constriction
associated with vigabatrin. BMJ 314,
180–181 (1997).
26 Kälviäinen R, Nousiainen I, Mäntyjarvi M
et al. Vigabatrin, a gabaergic antiepileptic
drug, causes concentric visual field defects.
Neurology 53(5), 922–926 (1999).
27 Maguire MJ, Hemming K, Wild JM,
Hutton JL, Marson AG. Prevalence of
visual field loss following exposure to
vigabatrin therapy: a systematic review.
Epilepsia 51(12), 2423–2431 (2010).
28 Gaily E, Jonsson H, Lappi M. Visual fields
at school-age in children treated with
vigabatrin in infancy. Epilepsia 50(2),
206–216 (2009).
•• First study reporting visual fields after
exposure to vigabatrin in infancy.
29 Wohlrab G, Leiba H, Kastle R et al.
Vigabatrin therapy in infantile spasms:
solving one problem and inducing
another? Epilepsia 50(8), 2006–2008
(2009).
30 Westall CA, Logan WJ, Smith K, Buncic
JR, Panton CM, Abdolell M. The Hospital
for Sick Children, Toronto, longitudinal
ERG study of children on vigabatrin. Doc.
Ophthalmol. 104, 133–149 (2002).
31 Willmore LJ, Abelson MB, Ben-Menachem
E, Pellock JM, Shields WD. Vigabatrin:
2008 update. Epilepsia 50(2), 163–173
(2009).
32 Durbin S, Mirabella G, Buncic JR,
Westall CA. Reduced grating acuity
associated with retinal toxicity in children
with infantile spasms on vigabatrin therapy.
Invest. Ophthalmol. Vis. Sci. 50(8),
4011–4016 (2009).
33 Lawthom C, Smith PE, Wild JM. In utero
exposure to vigabatrin: no indication of
visual field loss. Epilepsia 50(2), 318–321
(2009).
34 Sorri I, Herrgard E, Viinikainen K,
Paakkonen A, Heinonen S, Kalviainen R.
Ophthalmologic and neurologic findings in
two children exposed to vigabatrin in utero.
Epilepsy Res. 65(1–2), 117–120 (2005).
35 Best JL, Acheson JF. The natural history of
vigabatrin associated visual field defects
in patients electing to continue their
medication. Eye 19(1), 41–44 (2005).
36 Kinirons P, Cavalleri GL, O’Rourke D
et al. Vigabatrin retinopathy in an Irish
cohort: lack of correlation with dose.
Epilepsia 47(2), 311–317 (2006).
Drug Profile
37 Jammoul F, Wang Q, Nabbout R. Taurine
deficiency is a cause of vigabatrin-induced
retinal phototoxicity. Ann. Neurol. 65(1),
98–107 (2009).
38 Sorri I, Brigell MG, Malyusz M,
Mahlamaki E, de Meynard C,
Kalviainen R. Is reduced ornithine-
aminotransferase activity the cause of
vigabatrin-associated visual field defects?
Epilepsy Res. 92(1), 48–53 (2010).
39 Pellock JM, Faught R, Sergott RC et al.
Registry initiated to characterize vision
loss associated with vigabatrin therapy.
Epilepsy Behav. 22(4), 710–717 (2011).
40 Cohen JA, Fisher RS, Brigell MG,
Peyster RG, Sze G. The potential for
vigabatrin-induced intramyelinic edema in
humans. Epilepsia 41(2), 148–157 (2000).
41 Pearl PL, Vezina LG, Saneto RP et al.
Cerebral MRI abnormalities associated
with vigabatrin therapy. Epilepsia 50(2),
184–194 (2009).
•• First study demonstrating new structural
brain abnormalities on MRI after
vigabatrin exposure in infancy.
42 Wheless JW, Carmant L, Bebin M et al.
Magnetic resonance imaging
abnormalities associated with vigabatrin in
patients with epilepsy. Epilepsia 50(2),
195–205 (2009).
43 Dracopoulos A, Widjaja E, Raybaud C,
Westall CA, Snead OC 3rd. Vigabatrin-
associated reversible MRI signal changes in
patients with infantile spasms. Epilepsia
51(7), 1297–1304 (2010).
44 Horton M, Rafay M, Del Bigio MR.
Pathological evidence of vacuolar
myelinopathy in a child following
vigabatrin administration. J. Child Neurol.
24(12), 1543–1546 (2009).
45 Perheentupa J, Riikonen R, Dunkel L,
Simell O. Adrenocortical hyporesponsiveness
after treatment with ACTH of infantile
spasms. Arch. Dis. Child. 61(8), 750–753
(1986).
46 Riikonen R, Donner M. ACTH therapy in
infantile spasms: side effects. Arch. Dis.
Child. 55(9), 664–672 (1980).
47 Hrachovy RA, Frost JD, Glaze DG.
High-dose, long-duration versus low-dose,
short-duration corticotropin therapy for
infantile spasms. J. Pediatr. 124(5),
803–806 (1994).
48 Heiskala H, Riikonen R, Santavuori P et al.
West syndrome: individualized ACTH
therapy. Brain Dev. 18, 456–460 (1996).
49 Sergott RC, Wheless JW, Smith MC et al.
Evidence-based review of recommendations
for visual function testing in patients
285
 Drug Profile Gaily
treated with vigabatrin. Neuro-
Ophthalmology 34(1), 20–35 (2010).
50 Capovilla G, Beccaria F, Montagnini A
et al. Short-term nonhormonal and
nonsteroid treatment in West syndrome.
Epilepsia 44(8), 1085–1088 (2003).
51 Nabbout R, Melki I, Gerbaka B, Dulac O,
Akatcherian C. Infantile spasms in Down
syndrome: good response to a short course
of vigabatrin. Epilepsia 42(12), 1580–1583
(2001).
52 Jambaqué I, Chiron C, Dumas C,
Mumford J, Dulac O. Mental and
behavioral outcome of infantile epilepsy
treated by vigabatrin in tuberous sclerosis
patients. Epilepsy Res. 38(2–3), 151–160
(2000).
53 Kröll-Seger J, Kaminska A, Moutard ML,
Guët A, Dulac O, Chiron C. Severe relapse
of infantile spasms after vigabatrin
withdrawal: for how long should we treat
286
symptomatic infantile spasms? Epilepsia
48(3), 612–613 (2007).
54 Humphrey A, Neville BG, Clarke A,
Bolton PF. Autistic regression associated
with seizure onset in an infant with
tuberous sclerosis. Dev. Med. Child Neurol.
48(7), 609–611 (2006).
55 Jambaqué I, Chiron C, Dulac O, Raynaud
C, Syrota P. Visual inattention in West
syndrome: a neuropsychological and
neurofunctional imaging study. Epilepsia
34(4), 692–700 (1993).
56 Mirabella G, Morong S, Buncic JR et al.
Contrast sensitivity is reduced in children
with infantile spasms. Invest. Ophthalmol.
Vis. Sci. 48(8), 3610–3615 (2007).
57 Wild JM, Robson CR, Jones AL,
Cunliffe IA, Smith PE, Philip EM.
Detecting vigabatrin toxicity by imaging of
the retinal nerve fiber layer. Invest.
Ophthalmol. Vis. Sci. 47(3), 917–924 (2006).
58 Naili F, Boucart M, Derambure P,
Arndt C. Visual impairment at large
eccentricity in participants treated by
vigabatrin: visual, attentional or
recognition deficit? Epilepsy Res. 87(2–3),
213–222 (2009).
59 Desguerre I, Pinton F, Nabbout R et al.
Infantile spasms with basal ganglia MRI
hypersignal may reveal mitochondrial
disorder due to T8993G MT DNA
mutation. Neuropediatrics 34(5), 265–269
(2003).
60 Campen CJ, Porter BE. Subependymal
giant cell astrocytoma (SEGA) treatment
update. Curr. Treat. Options Neurol. 13,
380–385 (2011).
61 Raffo E, Coppola A, Ono T, Briggs SW,
Galanopoulou AS. A pulse rapamycin
therapy for infantile spasms and associated
cognitive decline. Neurobiol. Dis. 43,
322–329 (2011).
Expert Rev. Neurother. 12(3), (2012)