european journal of paediatric neurology 14 (2010) 13–18

Official Journal of the European Paediatric Neurology Society

Review article

Favourable prognostic factors with infantile spasms

Raili S. Riikonen*
Kuopio University Hospital, Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland

article info abstract

Article history: The following aspects are reviewed: Does the aetiology influence the outcome of infantile
Received 14 August 2008 spasms? Does the treatment influence the outcome? Can the outcome be predicted? Can
Received in revised form we improve the prognosis?
28 March 2009 Favourable factors are the following: cryptogenic aetiology, age at onset 4 months,
Accepted 29 March 2009 absence of atypical spasms and partial seizures, and absence of asymmetrical EEG
abnormalities, short treatment lag, and an early and sustained response to treatment.
Keywords: Not only patients with a cryptogenic aetiology have a favourable outcome. We can already
Infantile spasms at the first clinical evaluation tell the parents if the prognosis looks favourable.
Favourable factors The final goal of the treatment is improved mental outcome. Steroids and vigabatrin are
Prognosis the first-line drugs for infantile spasms in Europe. In a prospective study from the United
Kingdom short-term outcome was better with hormonal than with vigabatrin therapy
(tuberous sclerosis excluded). However, the numbers of patients who were seizure-free at
3–4 months in different studies have been very similar. Moreover, an early response to
treatment seems to be of predictive value for the cognitive outcome in children with
cryptogenic spasms. The long-term outcome is known only after hormonal therapy. The
side effects of steroids are usually treatable and reversible. In Finland ACTH therapy is
given at the minimum effective dose and for the minimum effective time with minimal
side effects. The risks of VGB are irreversible visual field defects. As of yet there is no
method to examine the visual fields in patients with infantile spasms. Early treatment of
infantile spasms seems to be important. Prevention of infantile spasms with some aetio-
logical groups might be possible.
ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.

Contents

1. Does the aetiology influence the outcome? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

2. Does the treatment influence the outcome? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.1. What is the most effective treatment? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.2. Hormonal treatment or VGB? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.3. Side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.4. Long-term outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3. Can the outcome be predicted? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

* Tel./fax: þ358 19 668418.

E-mail address: raili.riikonen@kuh.fi
1090-3798/$ – see front matter ª 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ejpn.2009.03.004
14 european journal of paediatric neurology 14 (2010) 13–18

3.1. Treatment lag? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

3.2. Is initial response important? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4. What interventions might prevent infantile spasms or further improve neurodevelopmental outcomes? . . . . . . . . . . . . 16
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
6. Future . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
7. Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
8. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

West syndrome is an epileptic syndrome consisting of clinical mutation genes, ARX and CDKL5, have been found responsible
spasms, usually in clusters, with hypsarrhythmia or ‘‘modi- for cryptogenic spasms.5
fied’’ hypsarrhythmia on interictal EEG, with onset usually Cryptogenic spasms have an onset between 4 and 9
under two years of age.1 months. Spasms are symmetric.
Outcome measures of infantile spasms in reported studies In the EEG of cryptogenic cases there is mainly symmetric
should include the presence or absence of infantile spasms, hypsarrhythmia, or multifocal epileptiform discharges that
hypsarrhythmia, epilepsy or epileptiform EEG, relapse rate, are seen with similar frequency in left and right hemi-
and cognitive and behavioural outcome, death and adverse spheres.6 Hypsarrhythmia reappears between spasms of
events.2 The primary goals of the therapy are cessation of the a cluster. Focal interictal abnormalities will disappear after
spasms and the improvement of mental developmental intravenous diazepam.7
outcome. Long-term outcome has been evaluated in a few Symptomatic spasms are often atypical, and may be
studies. asymmetric, asynchronous, focal, subtle, or combined with
Infantile spasms are divided into three groups1,2: partial seizures.6 EEG often shows asymmetric hypsar-
1) symptomatic spasms, in which there is a history of pre-, rhythmia and asymmetric multifocality.
peri-, or postnatal damage or disease and the predisposing Biochemically the cryptogenic and symptomatic groups
aetiology can be identified. 2) Cryptogenic spasms there is no can be distinguished. Compared with symptomatic patients,
known cause or the underlying cause remains hidden, and the patients with cryptogenic spasms have high inhibitory factors
nuclear magnetic resonance imaging (MRI) is normal. 3) Idio- such as beta nerve growth factor (NGF),8 GABA9 and ACTH10
pathic spasms (approximately 5%) in which there is a pure and low excitatory factors such as nitrite metabolites.11
functional cerebral dysfunction. Genetic factors play an When there is persistence of multifocal spikes or hypsar-
important role. This definition will be replaced over time by rhythmia over weeks there are always spasms on video-EEG.
identification of monogenic or polygenic causes of risk factors. They are often subtle.6
Idiopathic cases recover completely with no residual Treatment may make the spasms milder. However, the
dysfunction. This definition is based on the later outcome, and prognosis is still poor.12
cannot be confirmed with certainty based on the history and Serial video-EEG recordings show that during vigabatrin
presenting symptoms. The terms idiopathic and cryptogenic (VGB) treatment there has been transition of motor spasms to
have been used as synonyms of each other in some studies. subtle spasms.6 It seems that ‘‘little seizures may have big
The key questions being addressed in this review are the consequences’’.13
following: What are the factors associated with favourable We can already at the first clinical evaluation tell the
outcome? Does the aetiology influence the outcome? Does the parents if the prognosis looks favourable. If the aetiology
treatment influence the outcome? Can the outcome be pre- seems to be cryptogenic the spasms will cease and the
dicted? Can we make the prognosis better? What are the goals development will be normal or almost normal in about 80%.
of future research? However, some symptomatic spasms may also have
a favourable prognosis; the spasms will cease in 50% and the
development will be roughly normal in 20%.14 Down’s
syndrome,15–17 neurofibromatosis-1,15 in premature infants
1. Does the aetiology influence the outcome? with periventricular leucomalacia,18 and in infants with
neonatal hypoglycaemia19 may be associated with a relatively
There are at least 200 aetiologies associated with infantile benign course.
spasms. Careful etiological investigations must be made in
every case. Studies including symptomatic and idiopathic or
cryptogenic infantile spasms have always reported better
outcomes, in the latter groups. However, not all cryptogenic 2. Does the treatment influence the
spasms have a good outcome. outcome?
Aetiological categories of infantile spasms in Finland were
studied during two fifteen-year periods. Here idiopathic and 2.1. What is the most effective treatment?
cryptogenic cases are here grouped together.3,4 They con-
sisted 20% of all cases. The proportion of cryptogenic spasms More than 50 trials have been carried out in the treatment of
will decrease as diagnostic methods become more refined. infantile spasms. Recently, in a large data-based critical
Increased numbers of malformations were seen during the review by American Academy of Neurology (AAN) and Child
latter period of the Finnish study, which is probably due to Neurology Society (CNS)20 nine prospective studies were
improved neuroradiological techniques. Recently two novel analyzed. It was concluded that there are insufficient data to
 european journal of paediatric neurology 14 (2010) 13–18 15

recommend any optimal treatment for infantile spasms; Infections should be prevented, or when arising treated
ACTH being probably effective, and VGB being possibly promptly. For infants with a history of frequent respiratory
effective. The AAN and CNS review does not, however, include infections prophylactic trimetoprim–sulfamethaxazole
some important studies. therapy is recommended (based on personal experience).
Steroids and VGB are the first-line drugs for infantile Hypertension should be monitored and treated. In hyper-
spasms in Europe. In this review only the three prospective tensive patients the heart should be studied by ultrasound to
studies that compared ACTH and VGB are presented. rule out hypertrophic cardiomyopathy.
Hydrocortisone substitution should be given after ACTH
therapy and continued until the adrenal axis has normalized
2.2. Hormonal treatment or VGB?
(basal serum cortisol 150–200 nmol/l). Appropriate cortisol
substitution is necessary during periods of stress.
1. In a new prospective randomized study from the United
In Finland we give the therapy at minimal effective dose
Kingdom (UK) 107 patients were included.21 Tuberous
(0.03–0.06 mg/kg/2nd day) and for the minimal effective time
sclerosis (TS) was excluded ‘‘since evidence suggests that
(2–6 weeks). With such treatment, no serious side effects were
VGB is the best choice in treatment of these patients’’.22 The
found.35
cessation of the spasms was more likely with hormonal
The side effects of steroid treatment will not to lead to
treatment. VGB was effective in 54% and hormonal treat-
permanent harm, if there is suitable vigilance. Side effects of
ment 70% on day 14 ( p ¼ 0.043). Hypsarrhythmia resolved
VGB are irreversible. The use of VGB has been restricted by
more often with hormonal treatment ( p ¼ 0.009).
evidence showing that it causes permanent visual field defects
2. An open, randomized prospective study with 42 children
(VFDs). They occur in about 33% in older children.36–41 It is not
from Italy23 showed that 74% of the patients responded to
known how often they occur in children treated in the first year
ACTH and 48% to VGB. However, the difference in favour of
of life for infantile spasms. Wild et al. (2007)42 showed that
ACTH did not reach statistical significance. Relapse rate
VFDs are not age-dependent including children aged 8–12
was similar.
years in the study. VGB accumulates at high concentrations in
3. In a Finnish prospective study14 VGB was given as the first-
retina43 and the damage may arise from elevated GABA levels
line drug to all patients. Twenty-six per cent of the patients
in the retina. Decreased visual acuity and contrast sensitivity
responded to VGB. ACTH was then offered in combination
were seen in children with infantile spasms on VGB therapy.44
with VGB. The total response rate was 60% corresponding
Nousiainen et al. (2000)45 demonstrated a correlation between
with the general response rates of ACTH. The response rate
a contrast sensitivity and the extent of visual field constriction
was here defined as a total cessation of the spasms,
in patients taking VGB. The prevalence of VGB-induced retinal
absence of hypsarrhythmia and/or multifocal spikes in
defects in infants ranged from 15 to 31%.46 The earliest sus-
video-EEG while awakening, awake and sleeping. Some
tained retinal defect in infants was 3 months.47
studies have suggested that the response with VGB will
Recent knowledge from animals has shown that drugs
come later than with ACTH. In the recent study by Elterman
which increase brain concentrations of GABA like VGB can
et al. (2004)24 the response rates with VGB were very similar
cause apoptotic degeneration in the developing brain.48 ACTH
with the Finnish study 23% at day 14 but later in 65% (at 3
has not shown to have this effect. Reversible basal ganglia,
months).
thalamic, brainstem, or dentate nucleus abnormalities in 32%
infants are a newly described side effect of VGB.49
Comparing the two drugs, when data of 7 separate trials
(prospective or retrospective) were pooled VGB was effective
2.4. Long-term outcome
in 47% of 468 patients.14,21,23–27
When data of 7 separate studies (prospective and retro-
The primary goals of the treatment of infantile spasms are
spective) were pooled, ACTH was effective in 58% of 462
cessation of the spasms and improvement of the mental
patients.14,21,23,28–31
developmental outcome. We know the long-term outcome
Both drugs are effective. In the short-term, hormonal
after ACTH therapy but not after VGB therapy.
treatment seems to be more effective than VGB. Relapse rates
In Finland 214 children were followed up for 20–35 years or
are frequent with both treatments. They are frequent in TS.32
until death.19,50 This study assessed the death rate, autopsy
However, the numbers of patients who are seizure-free at 3–4
findings, intellectual outcome using standardized psycho-
months after treatment are very similar (42–44%). In the UK
metric tests, education, occupations, psychiatric disorders
study the numbers of patients who were spasm-free at 14
and occurrence of epilepsy and follow-up EEG. The patients
months were also very similar.33
had been participants in a prospective study conducted in
1960s, and follow-up was obtained in 100% of the cases. The
2.3. Side effects patients had been on the following treatments: large doses
of ACTH (120 IU ¼ 0.12 mg/d) (N ¼ 54) or lower doses
The risks of therapy should be avoided to achieve a good (20–40 IU ¼ 0.02–0.04 mg) (N ¼ 97). Large doses given for
prognosis. Both drugs have side effects. The common side a relatively short period of six weeks were not more effective
effects of both drugs are irritability, sleep disturbances, and than the smaller doses. The long-term intellectual outcome
drowsiness. The specific side effects of ACTH are infections, was better treated with lower doses than with larger doses.
arterial hypertension and adrenal hypofunction after The two groups were very homogenous concerning the
therapy.30,34,35 number of drop-outs, definition of response (‘‘all-or-nothing’’),
16 european journal of paediatric neurology 14 (2010) 13–18

proportion of cryptogenic and symptomatic groups, treatment 14 months,33 in cryptogenic cases. It seems highly likely that
lag and duration of treatment.31 hypsarrhythmia is responsible, at least in part, for the cognitive
One third died, of which a third died before the age of 3 decline, irrespective of other seizure types. The spasm cessation
years. Normal or mildly abnormal intelligence was present in is much improved for children who respond to treatment.
a quarter. Our study was consistent with later study of Gaily et Hormone treatments could therefore be a better first treatment
al. (1999)51 in which some patients (40%) with normal intelli- for children with no identified underlying aetiology. ACTH
gence had some specific learning deficits. Psychiatric disor- treatment may offer a better prognosis.
ders, hyperkinetic behaviour and infantile autism were seen
in a quarter. Temporal abnormalities were found in 70% of the
4. What interventions might prevent
patients with autism.52 This corresponds with the PET studies
infantile spasms or further improve
of Chugani et al.53 and of De Long and Heinz54 where 70% of
neurodevelopmental outcomes?
the patients with infantile spasms and autism had bitemporal
hypometabolism. Location of tubers in the temporal lobes,
Can we prevent infantile spasms? In general, little can be done
however, does not seem not be a sufficient risk factor for
to prevent infantile spasms because the spasms often are of
development of autism.55
prenatal origin.
A third of the Finnish cohort was seizure-free, a fifth had
daily seizures and the rest had less frequent seizures.19 EEG
1. Some small etiological groups might be prevented.
was normal in 60% in patients with favourable outcome but
a) The number of children whose spasms were associated
only in 13% in another group. Focal abnormalities were seen in
with neonatal hypoglycaemia decreased significantly
37 and 36%, respectively. Focal abnormalities in EEG do not
during two fifteen-year periods. Also the number of small-
seem to necessarily be associated with poor outcome. In
for-gestational (SGA) children with neonatal hypo-
several studies investigators have failed to find any correlation
glycaemia decreased significantly.3 Every effort should be
between various EEG features and long-term outcome.31,37,38
made to reduce the number of SGA children and to treat
Patients with a favourable outcome had a cryptogenic
neonatal hypoglycaemia optimally.
aetiology in 9/25 (36%), normal development before the onset
b) Herpes encephalitis should be treated early.56
of the spasms 21/25 (84%), short treatment lag (0–29 days) 22/
c) It has been suggested that early treatment of pre-hypsar-
22 (100%), good response to therapy 22/22 (100%), few relapses
rhythmic states may prevent infantile spasms, e.g. in
3/22 (13%), and were free of seizures at follow-up 22/25 (88%).19
preterm infants with periventricular leucomalacia and
epileptic discharges before three months of corrected
age.62,63 Early treatment of neonatal TS and epileptic
3. Can the outcome be predicted?
discharges, may also prevent infantile spasms.64 However, it
is still controversial whether we should treat pre-hypsar-
Structural abnormalities strongly influence the prognosis. In
rhythmic EEG but also whether to treat hypsarrhythmic EEG
cryptogenic cases normal development was seen in 70%. The
in the absence of clinical spasms. Closer video-EEG moni-
outcome was worst in children with severe brain malforma-
toring would be likely to identify some form of clinical ictus.
tions (lethal in 15 cases),50 post-infectious aetiology (mental
2. Treat infantile spasms early.
retardation in 90% of 29 patients),56 and with tuberous scle-
3. Use ACTH in cryptogenic patients as the first choice treat-
rosis (in all 24 patients).57
ment because it might improve the neurodevelopmental
outcome. ACTH might be also the first choice of treatment for
3.1. Treatment lag?
symptomatic spasms because more cases will response and
response will be faster than with VGB (Personal opinion).
In one study it was stated that the outcome was not influ-
4. Use small doses of ACTH (generally less than 0.06 mg/kg/
enced by the duration of treatment lag or response to therapy.
every 2nd day, approximately 0.5 mg/every 2nd day) for 2–6
However, in several other studies short treatment lag corre-
weeks.
lated with more favourable cognitive outcomes in both the
patients with symptomatic and the cryptogenic
spasms.17,19,29,58–61 Furthermore, Kivity et al. (2004)61 showed 5. Conclusions
that all (100%) of the cryptogenic patients had a normal IQ if
the delay was less than 4 weeks whereas in others where Factors associated with a favourable outcome include:
a favourable outcome was seen in 40%. It seems to be
important to treat without delay! 1. No other seizures before onset of infantile spasms.
2. Absence of atypical spasms, partial seizures and asym-
3.2. Is initial response important? metric EEG abnormalities.
3. Age of onset after the age of 4 months.58
In our large cohort of 214 children patients who had responded
to ACTH had a better cognitive outcome than the other groups.50 These above-mentioned factors are also associated with
This held true both for those with a cryptogenic aetiology 14/20 cryptogenic/idiopathic aetiology.
(70%) and for those with a symptomatic aetiology (18/78 23%).
Also in the UK study the response rate (spasm cessation) 4. Early and sustained response to treatment.
correlated favourably with the cognitive outcome at the age of 5. Short duration of hypsarrhythmia.
 european journal of paediatric neurology 14 (2010) 13–18
6. Future
We should know
1) How long to treat the infants? Can the relapses be avoided
with prolonged steroid or VGB treatment, or in contrast,
will we induce glucocorticoid-induced dementia,65–67 or
VGB-induced VFDs and apoptosis in the brain.48 It is known
that glucocorticoid stimulation induced by mild stress has
positive effects on hippocampus, but severe stress induces
apoptosis which would favour use of small doses of steroids
2) What is the long-term outcome of children after VGB
therapy (relapse rate, cognition, behaviour)? How does it
compare with steroid treatment?
3) Do the children with infantile spasms have VFDs? Can we
predict who will have VFDs? What is the pharmacogenetic
basis of VGB-induced VFD?68
Understanding of brain maturation, aetiologies, mechanisms
and genetics underlying infantile spasms is the main focus of
studies to facilitate more effective pharmacologic therapies.
Acknowledgements
This study was financially supported by the University
Hospital of Kuopio, Finland.
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