A better outcome for infantile spasms: What is the evidence?

Sri Lanka Journal of Child Health, 2015; 44(3): 129-

137

Professor C. C. de Silva Oration – 2014

A better outcome for infantile spasms: What is the evidence?

*Jithangi Wanigasinghe1

Sri Lanka Journal of Child Health, 2015; 44(3): 129-137

(Key words: Infantile spasms; outcome)

It is indeed a privilege to stand before you today and after one year is considered as “late onset epileptic
speak in honour of one of the great paediatricians spasms”, which rarely may occur even as late as four
produced by this country. Professor Cholomondley years of life. In our series of patients we had four rare
Chalmers de Silva, known to his friends as Chummy, cases of spasms that followed insults which occurred
became the first Professor of Paediatrics when he beyond 24 months of life2.
joined the then University of Ceylon in 1949. With this
he became a Visiting Paediatrician to the Lady The spasms are associated with a grossly abnormal
Ridgeway Hospital (LRH) as well. As an academic, electroencephalographic (EEG) pattern, known as
researcher and an administrator, he has rendered a hypsarrhythmia. This consists of multifocal epileptic
great service to this country. As an academic, he activity as high amplitude spikes occurring in a grossly
worked hard to improve the standard of paediatric altered background consisting of irregular slow waves
undergraduate and postgraduate education. of high amplitude, leading to a chaotic mixture of
Establishment of the Diploma in Child Health (DCH) arrhythmic and asynchronous brain activity. This
was one of his major accomplishments. He was one hypsarrhythmic EEG pattern is known to change with
of the best researchers in his era and made the time within the same patient, from its first appearance.
University Unit at LRH a centre for research. His main The typical hypsarrhythmia is seen during infancy,
interests included nutritional disorders, after which the discharges tend to become
haemoglobinopathies and infective diarrhoeas. He was synchronised.
instrumental in the establishment of the Convalescent
Home for nutritional rehabilitation of malnourished Developmental arrest or regression is the most
children at Thalagolla. As a member of the department devastating component of the triad of the West
which he headed, it is my greatest privilege to speak to Syndrome. Although considered to occur
you tonight on research which we have conducted in concomitantly, research has shown this regression to
the same unit he established many years ago. In precede the onset of spasms. Philippi et al in 2008
honour of this great paediatrician, I will now speak to demonstrated three distinct clinical stages
you about “A better outcome for infantile spasms: accompanied by three different evolving EEG
What is the evidence?” patterns3. Clinical stage one (few weeks to months),
known as the silent phase, presents with multifocal
Infantile spasms (IS) are a unique epilepsy syndrome epileptic discharges of over 50% in the non-rapid eye
that causes devastating effects on the developing movement (NREM) sleep record. Clinical stage 2,
brain. It is rare, affecting 3 to 5 per 10,000 live births. which may last for several weeks, shows the beginning
It was Dr. William James West who described this of the deterioration in development. The
condition for the first time in his own infant son in accompanying EEG shows increased bi-hemispheric
18411. Spasms are seizures manifesting as brief epileptic discharges occurring in more than 50% of the
contractions of any group of muscles, flexors, recording time within abnormal background activity.
extensors or a mix of the two. They occur in clusters Clinical stage 3 is associated with a definite
which are often associated with crying. Classically, deterioration of development manifesting as loss of
they occur during the first year of life, peaking gross motor abilities, loss of hand functions, auditory
between 4-6 months and hence the initial terminology agnosia and cortical blindness. The EEG in this stage
‘infantile spasms’. It is known to follow an insult is associated with classical hypsarrhythmia. All these
which precedes the onset by several months. Onset three clinical and EEG stages precede the occurrence
___________________________________________ of spasms.
1
Senior Lecturer and Honorary Paediatric
Neurologist, University of Colombo, Sri Lanka
*Correspondence: [email protected]

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Pathogenesis of spasm generation Vigabatrin

Although many different mechanisms are postulated Vigabatrin (VGB) which acts by inhibiting gamma
we have not yet clearly understood how the spasms are amino butyric acid (GABA) transaminase irreversibly
generated. This is in spite of major advances such as has been used for treatment of spasms since 1990. It
intracranial electroencephalography, functional neuro- remained the favoured therapy particularly in the
imaging, and even the development of an epileptic countries of the European Union (EU) till recent years.
spasm mouse model. There are many questions that In Europe, VGB was recommended as the drug of first
remain unanswered. In the absence of a clear choice for children with IS secondary to tuberous
understanding on the pathogenesis, treatment of this sclerosis (TSC) as well as other forms of symptomatic
condition has been largely empirical. The word and cryptogenic IS9. This preference for VGB was
empirical is defined as strategic but scientifically supported by the high response rate reported in a
unproven. One way to overcome this gap in cohort of children with TSC by Chiron et al10 and a
knowledge is rigorous analysis of the evidence for randomised placebo controlled trial by Appelton et
empirical standard treatments. Outcome of such al11. The main drawbacks related to VGB are the
rigorous analysis is hindered by several factors. There permanent peripheral visual field loss and the white
is a great paucity of prospective studies on treatment matter changes in subcortical regions4. It is also
of IS4,5. Well conducted randomised clinical trials are enormously costly, averaging 12,000 to 15,000 Sri
just a handful. Up to the 2013 Cochrane review, there Lankan rupees for a supply of medications for a
were only 18 clinical trials (16 small and 2 large)4. month. It is also not available or registered in many
Most treatment trials are under-powered due to small countries.
sample sizes. Another major limitation is that the
dosage regimens and treatment durations vary widely Prednisolone and other steroids
from study to study. Continental preferences are
another issue: Different regimes are promoted in Prednisolone and prednisone are other forms of
different continents and settings. What is promoted in hormonal therapy that have been used for IS for over
the European Union is different to that in the United 40 years. However, due to the absence of sufficient
States or the one in Japan6. Critical evaluation of the evidence, they have not been recognised as first-line
current literature reveals that the so called “empirical therapy for IS4,5,12. Case series, personal experience
evidence” is limited to “available evidence” and open label studies have been inadequate to
emanating from studies with small sample sizes, challenge the superior response rate established by
preferential doses of medications, and limited to trials such as that of Tali Baram’s group using high
studies from centres of favoured choices. dose of ACTH (150iu/square metre) against a low
dose of 2mg/kg/day of prednisone13. The best up to
Adrenocorticotropic hormone and steroids now has been equivalent responses shown for low
dose ACTH and 2mg/kg prednisone by Hrachovy and
Adrenocorticotropic hormone (ACTH) secreted from Lombroso et al in 198314. Similar outcome was shown
the pituitary gland has been used for treatment of IS in the United Kingdom Infantile Spams Study
since 19587. The long acting form, administered (UKISS) trial which compared the outcome of high-
intramuscularly is used for this treatment. Available dose oral prednisolone (40–60mg/day) with low dose
research on ACTH is less than 20 papers. This includes intramuscular ACTH, spasms responder rates at end of
randomized clinical trials, open label studies and even 14 days being 76% for synthetic ACTH and 70% for
retrospective case series. Different formulations of prednisolone15. Neither agent showed a significant
ACTH (natural versus synthetic) have been used in difference in the EEG response rate at 14 days
these studies. Dosages of ACTH were markedly (p=0.61). Similar findings of equal response rate were
variable from 0.2 IU/kg up to 150 IU/square metre. seen at 14 month follow up16. Unfortunately, due to
The duration of treatment as well as the reported inadequate power in the findings, this was insufficient
outcomes (42 to 87% response rate) vary widely4. The evidence to support prednisolone as being equal to
other important concern pertaining to ACTH treatment ACTH for treatment of IS. Prednisolone is a tablet,
is the enormous cost of therapy. In the United States easily dispensable from home and is very cheap. It
the cost of a vial exceeds 70,000 US dollars8. Recent costs less than 75 Sri Lankan rupees to complete 14
further increase in price has made this therapy not days of therapy and such low pricing is the same
affordable even across the Atlantic. In Sri Lanka, a vial worldwide.
of synthetic ACTH costs between 9,000 to 10,000
rupees.

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Research on IS in Sri Lanka therapy. Our multi-disciplinary team included me

(JW) as a paediatric neurologist and Principal
My personal interest in IS runs back to early 2003. Investigator, an epidemiologist, a clinical
Serial patients treated with intramuscular ACTH 40 IU pharmacologist cum paediatrician and a paediatrician
on a daily basis were followed up. There were 20 with special training in development assessment.
patients including 13 with IS. Others were classified Ethical clearance was obtained from the Ethical
as other syndromic epilepsies (myoclonic epilepsy, Review Committees of the Faculty of Medicine,
Lennox-Gastaut syndrome and Dravet syndrome). We Colombo (EC/010/081) and the Lady Ridgeway
documented 85% spasm freedom at 2 weeks and 15% Hospital, in October 2010. This trial was registered in
spasm freedom at 12 months. In the symptomatic the Sri Lanka Clinical Trials Registry
group, only one patient became seizure free with (SLCTR/2010/010).
ACTH17.
Method
Since the publication of UKISS trial, I was keen to
assess the response rate to this protocol in our patients. Selection of the sample
This was documented in a group of 30 infants treated Only newly diagnosed IS occurring in clusters were
using the UKISS protocol [oral prednisolone (40-60 eligible for inclusion in the study. The patients were
mg/day) or intramuscular ACTH (40-60 IU every directly admitted or referred by other paediatricians.
other day) for 14 days or Vigabatrin 100- The diagnosis of IS was confirmed based on spasms
150mg/kg/day for patients with tuberous sclerosis). directly observed by the Principal Investigator (JW) or
With this 66% were spasm free at 14 days and 93% in videos provided by parents. Of them, only those
showed improvement on the post treatment EEG18. who had hypsarrhythmia recorded on the EEG were
This spasm freedom was comparable to that described included. Age less than 2 months or more than 30
in the UKISS study. months or a diagnosis of tuberous sclerosis, previous
treatment for West Syndrome (WS), those with
It was also important to document the adverse events contraindications for using hormonal therapies and
profile of high dose hormonal therapies, particularly parents incapable of monitoring the response to
when used in the local setting with high turnover rates therapy were excluded.
and problems mostly related to infection. The adverse
event profile was documented in 35 children who were Prior to treatment allocation, detailed baseline
treated with the UKISS protocol. Contrary to developmental assessments were performed, using the
expectation, the detected rate of sepsis was minimal. Bayley III Infant and Toddler Developmental Scales
These findings confirmed the feasibility of using this by one of the investigators, who has had special
UKISS regime in settings like Sri Lanka19. training on using the Bayley developmental scales.

Next we followed up the same cohort to describe the Method of randomization

aetiologies, response to therapy, relapse rates and The minimum sample size required to achieve an
developmental outcomes. Follow up was at 3, 6, and expected effect size of 25% in the improvement of
12 months. Twenty eight had minimum of three electrical and clinical response in WS was 45 in each
months of follow up while 17 completed 12 months of treatment arm. Randomization was performed
follow up. Median time to relapse was 3 months (0.5- independently using computer-generated random
18 months). There were relapses in 48% and the numbers by one co-investigator who took no part in
frequency of spasms during relapse was lower (<50%) the recruitment or outcome assessment. Assignment to
than at the onset. Development showed improvement treatment arm was sequentially allocated and kept in
in all but two children20. sealed envelopes.

Since our personal experience documented 65-70% Allocation and monitoring of treatment
response rates with ACTH or oral prednisolone, the Treatment followed the guidelines of the UKISS
time was right to find the answer to the question “Can protocol15. Depot ACTH 40IU (0.5mg)
oral prednisolone also be considered a first line form intramuscularly every other day (EOD) for 14 days or
of therapy?” The answer to this could only be secured daily oral prednisolone 40 mg divided into 4 doses/day
with a proper clinical trial. A few colleagues from the for 14 days was allocated and patients were re-
Faculty of Medicine got together to develop the assessed on the 7th day of treatment. The same generic
background for a prospective, single blind, preparations were used throughout the clinical trial
randomized clinical trial on low dose intramuscular [Oral prednisolone (SPMC) and Acton Prolangatum
ACTH versus moderate to high dose oral prednisolone depot preparation of ACTH].

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Outcome assessment was 0, which was for a normal EEG. Same evaluation
There were two short term primary outcomes assessed. was performed in the post-treatment EEG. The
They were: improvement in the severity of improvement was assessed as a reduction in the
hypsarrhythmia (electrical response) and spasm hypsarrhythmia score, on this pre (D 0) and post (D14)
cessation (clinical response). The secondary outcome treatment EEG assessments. In order to assess the
was the development of adverse effects to treatment. intra-observer reliability of hypsarrhythmia scores,
The adverse effects were evaluated by one investigator randomly selected 40 EEGs (20 pre- and 20 post-
on day 14, using a comprehensive list of adverse treatment) were re-scored by the same investigator
effects reported for prednisolone (PNL) and ACTH. after two weeks. The level of agreement between the
Summary of all side effects experienced were scores and repeat-scores was assessed using
reviewed by the clinical pharmacologist. Spearman’s correlation co-efficient.

The electrical response was evaluated by assessing Spasm control was evaluated using parent reported
improvement of the severity of the hypsarrhythmia spasm diaries. Diary I was used to document spasm
after 14 days of treatment. This was quantified using a load from day 0-14. Diary II was used to document
hypsarrhythmia severity scale which had been spasm control from day 15-42. Following definitions
described by Kramer et al depicted in Table 121. were used to describe spasm control: Spasm cessation
was absence of any spasms (single or cluster) for more
Table 1: Hypsarrhythmia scoring system than 48 hours at review on day 14. Sustained spasm
Component Score control was defined by the West Delphi group as
A. Disorganization “cessation of spasms within the first 14 days of therapy
Good gradient & synchrony (normal for age 0 followed by sustained spasm control for the next 28
Partially formed gradient with some synchrony 1 consecutive days”. Spasm control on day 42 was
No gradient, some synchrony of background 2 absence of any spasm for 48 hours at the time of
Chaos, no synchrony, no gradient 3 review. Spasm control at 3, 6 and 12 months were
B. Diffuse delta activity absence of any spasm for at least one preceding week
<50% 0 at the time of these reviews.
≥50% but <75% 1
≥75% but <100% 2 Results
100% 3
C. Voltage There were 128 eligible infants with confirmed WS
<120 µV 0
120-200 µV 1
reviewed by us during the study period and 115 (90%)
200-500 µV 2 of them gave consent for participation. Only 110
>500 µV 3 underwent EEG evaluation and of them, 12 were
D. Spikes and sharp waves excluded due to absence of hypsarrhythmia and one
No spikes or sharp waves 0 due to spontaneous resolution of spasms, leaving 97
Spikes at a frequency of ≤1/5 sec 1 who were randomised to receive Prednisolone (PNL)
Spikes at a frequency of 1/5 sec-1/sec 2 [n=48] and Corticotrophin (ACTH) [n=49]. The
Spikes at a frequency of >1 per sec 3 majority (71%) had an identified cause (symptomatic)
E. Other items for WS, 18% had no cause found after detailed history
Electrodecremental discharges 1
and examination, imaging (CT or MRI brain) and
Burst suppression in sleep 1
Absence of normal sleep pattern 1
metabolic screening (cryptogenic) and 11% did not
Relative normalization in wakefulness 1 complete the investigations due to a plethora of
(Adapted from Kramer et al 199721) reasons. There was also no significant difference
between the two groups in demographic
A single relatively uniform 10-second segment that characteristics, baseline seizure duration and severity
contained the most representative and severe (p>0.05) as described in Table 2. No significant
hypsarrhythmic part of the tracing was chosen for differences were also noted in those who were lost for
scoring. The maximum total score was 16 for the most follow up and those who continued with the study
severe hypsarrhythmia and the minimum total score (p>0.05).

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Table 2: Baseline characteristics of the children treated with prednisolone and ACTH (n=97)
Baseline characteristic Prednisolone (n=48) ACTH (n=49) P value**
Age in months 8.55 (SD=6.20) 9.58 (SD=8.77) 0.53
Sex
Male 25 (52.1%) 31 (63.3) 0.26
Female 23 (47.9%) 18 (36.7)
Ethnicity
Sinhala 42 (87.5%) 42 (85.7%)
Tamil 01 (02.1%) 02 (04.1%) 0.85
Muslim 05 (12.8%) 05 (10.2%)
Gestation
Preterm 06 (10.4%) 05 (10.2%) 0.69
Term 41 (87.2%) 44 (89.8%)
Birth weight (Kg)
Mean 2.57 (SD= 0.53) 2.61 (SD= 0.53) 0.71
<2.5 Kg 17 (37.0%) 16 (33.3%)
2.5 Kg or > 29 (63.0%) 32 (66.7%) 0.71
Age of onset of spasms
<12 months 45 (95.7%) 43 (89.6%) 0.25
12 months or > 02 (04.3%) 05 (10.4%)
Preceding/ concurrent seizures
Present 16 (34.0%) 15 (30.6%) 0.72
Absent 31 (66.0%) 34 (69.4%)
Previous treatment with anti-epileptic drugs
Yes 11 (23.9%) 13 (27.1%) 0.72
No 35 (76.1%) 35 (72.9%)
**p values obtained for assessing significant differences between the two treatment arms in relation to baseline characteristics (chi-
square test used for categorical data; independent t test used for quantitative data)

Improvement in EEG treatment score of 10.45 (SD=2.65), improving with

Of the 97 randomized infants, post treatment treatment to an average post-treatment score of 3.45
evaluation was completed by 46 on prednisolone and (SD=2.67). The mean of (pre-post) treatment scores
47 on ACTH. Post-treatment EEGs on day 14 were was 7.0 (SD=2.84), which was statistically significant
performed by only 40 from each treatment arm. (paired t=21.72; df=77; p <0.01). All components of
Improvement in the severity of hypsarrhythmia of the the severity scale showed significant improvement22
entire sample treated with either form of hormonal (Table 3).
therapy was first considered. It showed an average pre-

Table 3: Improvement in the severity of hypsarrhythmia with hormonal therapies (N=80)

Components in the hypsarrhythmia Improvement in hypsarrhythmia scores* Level of significance**
assessment tool Mean (SD)
Background organization 1.74 (1.11) <0.001
Background slowing 1.50 (1.04) <0.001
Amplitude 1.12 (0.82) <0.001
Spike index 1.19 (0.98) <0.001
Burst suppression 0.42 (0.54) <0.001
Electro-decremental pattern 0.12 (0.49) 0.02
Normalization in wakefulness 0.43 (0.62) <0.001
Absence of sleep transients 0.43 (0.59) <0.001
Overall score 7.00 (2.84) <0.001
*Improvement in the severity of hypsarrhythmia was assessed by the mean (pre-post) treatment scores
**p values obtained for assessing the significance of the mean of (pre-post) treatment scores, using paired t test

When the mean (pre-post) treatment scores were treatment score of each individual component was
compared between the two groups, the PNL group assessed, all components improved better with PNL
showed a significantly greater improvement in than with ACTH but were significant only in the spike
severity than the ACTH group (7.95 ± 2.76 vs 6.00 ± index (Table 4).
2.61; p<0.01) (Table 4). When the mean (pre-post)

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Table 4: Comparison of the improvement of hypsarrhythmia severity between PNL group and ACTH group
Components in the Improvement in the hypsarrhythmia severity* Level of significance**
hypsarrhythmia scores PNL Group ACTH Group ‘p’ value
Mean (SD) Mean (SD)
Organization 1.90 (0.90) 1.57 (1.28) 0.2
Background slowing 1.57 (1.08) 1.42 (1.00) 0.51
Amplitude 1.30 (0.79) 0.94 (0.83) 0.05
Spike index 1.50 (0.90) 0.86 (0.96) 0.004
Burst suppression 0.52 (0.59) 0.31 (0.47) 0.09
Electro-decremental pattern 0.12 (2.76) 0.13 (0.57) 0.95
Normalization in wakefulness 0.48 (0.67) 0.38 (0.65) 0.48
Absence of sleep transients 0.50 (0.55) 0.36 (0.63) 0.33
Overall score 7.95 (2.76) 6.00 (2.61) 0.002
*Improvement in the hypsarrhythmia severity was assessed by the mean of (pre-post) treatment scores
**p values obtained for assessing the significant difference of the mean (pre-post) treatment scores between the two treatment
groups, using paired t test
Owing to multiple comparisons, the level of significance was adjusted to p <0.00625 by Bonferroni correction: αadjusted = α / c
(where α is the overall experiment wise alpha (0.05); c is the number of comparisons made (9)

Spasm control Secondary outcome - tolerability

Clinical response of spasm cessation at day 14 of Both forms of therapy were well tolerated. Weight
treatment was completed by 93 infants (46 PNL, 47 gain, increased appetite, frequent crying spells and
ACTH). Twenty eight (61%) were spasm free on day abdominal distension were experienced more
14 with PNL compared to 18 (38%) on ACTH frequently in those treated with PNL (Table 5).
(p=0.03). Average number of days for spasm cessation However, none were significant and did not result in
was 3.85 (SD 2.4) for PNL and 8.47 days (SD 3.83) any withdrawals. Withdrawal from the protocol was
for ACTH (p<0.01).When we looked at the percentage required only for one child in PNL group, due to
where no change occurred with the hormonal therapy, hypertension. This settled within 24 hours of
there were 4 infants (9.8%) on prednisolone compared observation in the ward with a single dose of
to 16 (39%) on ACTH without any clinical response sublingual nifedipine. During the trial period of five
(p=0.002). weeks which included the treatment regime and taper
off periods, no deaths were observed.

Table 5: Comparison of side effects experienced with prednisolone and ACTH (N=80)
Side effect Prednisolone ACTH Level of significance*
Number (%) Number (%) ‘p’ value
Increased appetite 25 (78.5) 15 (42.9) 0.006
Weight gain 17 (51.5) 10 (28.6) 0.05
Frequent crying spells 15 (45.5) 08 (22.9) 0.04
Drowsiness 03 (09.1) 06 (17.1) 0.32
Cushingoid features 08 (24.2) 05 (14.3) 0.29
Insomnolence 03 (09.1) 01 (02.9) 0.27
Lethargy 02 (06.1) 01 (02.9) 0.52
Reduction in social behaviour 02 (06.1) 01 (02.9) 0.52
Abdominal distension 07 (21.2) 00 (0.0) 0.004
Hypertension 01 (03.0) 01 (02.9) 0.99
Increased susceptibility to infection 00 (0.0) 01 (02.9) 0.32
Irritability 08 (24.2) 02 (05.7) 0.03
Nausea 01 (03.0) 00 (0.0) 0.29
Vomiting 01 (03.0) 00 (0.0) 0.29
Diarrhoea 02 (06.1) 01 (02.9) 0.52
Dyspepsia 01 (03.0) 01 (02.9) 0.96
Electrolyte imbalances 02 (06.1) 00 (0.0) 0.32
*Owing to multiple comparisons, the level of significance was adjusted to p <0.00294 by Bonferroni correction:
αadjusted = α / c (where α is the overall experiment wise alpha (0.05); c is the number of comparisons made (17).

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Ladies and Gentlemen, the findings in our trial with outcome was better if they were treated with hormonal
regard to immediate spasms control as well as therapies.
improvement of hypsarrhythmia were significantly
better with oral prednisolone. We are the first group to A highlight of our study is the detailed assessment of
document this therapeutic supremacy worldwide. the developmental outcomes. This was done using
Bayley III infant and toddler developmental scales,
Next we evaluated the effect on sustained spasm which is the gold standard for developmental
control. Out of the 93 evaluated on day 14, twenty nine assessment in research. The Bayley scales evaluate the
infants remained spasm free for more than 28 domains of cognition, language and motor
consecutive days. They included 19/46 treated with components. Raw scores were calculated and
prednisolone versus 10/47 given intramuscular converted to scaled and composite values. All
ACTH. This confirmed that oral prednisolone resulted assessments were performed by a single trained and
in better sustained spasms control (p=0.02). Sustained qualified researcher who remained blinded to
spasm control was considered a better indicator of treatment details. These developmental assessments
immediate spasm control by the West Delphi group23. were performed at diagnosis (baseline) and
subsequently at 1 year and 2 years post treatment.
Long term spasm control was assessed at two different Their developmental attainments at the baseline were
time points: a) short term follow up (6 weeks and 3 and analysed according to the age of presentation, the
6 months) and b) long term follow up (12 months). In duration of spasms prior to the presentation and the
the short term follow up, 40 of prednisolone and 37 of aetiology of spasms.
ACTH completed the 6 week evaluation. Spasm
cessation was seen in 32 (69%) given PNL against 17 Results
(36%) for ACTH at 6 weeks (p=0.002). At 3 months Baseline developmental assessments showed the
evaluation, 29 (63%) out of the 46 given PNL versus composite scores for cognitive 58.4 (+/- 8.046)
19 (40%) out of 47 given ACTH remained spasm free language 56.6 (+/- 12.752) and motor 50.74 (+/-
(p=0.003). This finding confirmed that during short 8.378) functions and all these mean scores were below
term follow up, spasm freedom was significantly average. The much anticipated finding would be the
higher if treated with prednisolone. developmental outcomes in the two groups of patients.
We have looked at the development at two years post
Likelihood of long term spasm freedom was evaluated treatment. Currently we have evaluated 47 at 1 year
at two further time points, 6 and 12 months. Six month and 29 at 2 years. In the 47 who completed one year
follow up was completed by 73 out of 90 by the time evaluations, all had a symptomatic aetiology. Mean
of submission of this manuscript for the oration. age of onset of spasms was 6.57 (SD=4.87) months.
Spasm control was seen in 77% treated with PNL as The mean age at presentation was 9.25 (SD=6.07)
against 53% being treated with ACTH (p=0.05). months. The mean gap between onset of spasms and
However, the 46 who completed 12 months review at the presentation was 71.15 days (SD=75.47). The
time of submission showed no significant difference mean duration of review from the commencement of
between the outcomes for the two treatment arms. treatment was 12.06 months (SD=3.51). All children
had mean Bayley scaled scores below average (less
During this follow up period of up to one year, 5 deaths than 4) at presentation and at one year. The mean
have occurred. None occurred during the treatment comparisons of the scaled scores showed a
phase or the taper-off period of three weeks. The deterioration of scores in all domains at one year.
causes of death are known in 4 and these were There was no significant relationship with any risk
aspiration pneumonia, hepatoblastoma, acute renal factors for adverse developmental outcome such as
failure due to sepsis and community acquired longer duration of spasms before treatment and poor
pneumonia. spasm control after initial 14 days of therapy.

Hormonal therapies and developmental outcome The Future

As outlined in several meta-analyses, although the We believe that we have achieved a milestone. We
short term control of spasms is better with hormonal have shown definitive evidence of efficacy and safety
therapies, we are still unable to show whether it results of prednisolone in the treatment of epileptic spasms.
in better developmental outcomes in the long term. This has been taken up by the world and is now in the
The assessment of the Vinyl Adoptive Behavioural world literature. This evidence, we deduce, will
Scores at 4 years post treatment via a telephone benefit children suffering from epileptic spasms and
interview in the UKISS study showed that in those their doctors, particularly in developing countries. The
with a cryptogenic aetiology, the developmental results have been welcomed even by those from the

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A better outcome for infantile spasms: What is the evidence? Sri Lanka Journal of Child Health, 2015; 44(3): 129-
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West. Do we stop here? I think NOT. How can we 4. Hancock EC, Osborne JP, Edwards SW.
target a better overall outcome? A better outcome Treatment of infantile spasms. The Cochrane
would be a possible prevention of development of Database of Systematic Reviews
spasms and reversal of EEG changes. This is the 2013;6:CD001770.
hypothesis of our next project titled “Interventional http://dx.doi.org/10.1002/14651858.cd00177
study on the role of prednisolone as a preventer of 0.pub3
development of West Syndrome”.

This new research hypothesis is based on evidence of 5. Go CY, Mackay MT, Weiss SK, Stephens D,
evolutionary stages of hypsarrhythmia prior to the Adams-Webber T, et al. Evidence-based
development of spasms (Pre-spasm stage)3,24,25. guideline update: medical treatment of
Utilising this EEG change as a biomarker of risk of infantile spasms. Report of the Guideline
spasm development, we hypothesise that treatment Development Subcommittee of the American
with oral prednisolone early would potentiate Academy of Neurology and the Practice
“prevention” of WS. This has never been tested Committee of the Child Neurology
anywhere prospectively. We are in the planning stage Society.Neurology 2012, 78:1974-80.
of this intervention in a cohort of infants with strong http://dx.doi.org/10.1212/WNL.0b013e3182
biomarkers for development of infantile spasms. This 59e2cf
I believe is indeed the future direction of research on PMid: 22689735 PMCid: PMC3369510
infantile spasms.
6. Watanabe K. Medical treatment of West
Acknowledgements syndrome in Japan. Journal of Child
Neurology 1995;10:143-7.
I wish to thank the Sri Lanka Medical Association for
http://dx.doi.org/10.1177/088307389501000
part funding this clinical trial, my coinvestigators and
217
the many collaborators who contributed to the success
PMid: 7782606
of this project, the staff of the University Paediatric
unit at the Lady Ridgeway Hospital for their support,
7. Sorel L, Dusaucy-Bauloye A: [Findings in 21
the patients and parents for their participation and to
cases of Gibbs' hypsarrhythmia; spectacular
Dr. B J C Perera for helping me in the preparation of
effectiveness of ACTH]. Acta Neurologica et
the manuscript.
Psychiatrica Belgica 1958; 58:130-41.
PMid: 13532578
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