Report on Infantile spasm

View With Charts And Images 

Introduction

Infantile spasm, also known as West’s
Syndrome or salaam spasm were first described by Dr. West in a letter he wrote
to the Lancet in 1841. ¹

Infantile Spasm, which is one of the
most recognized but peculiar types of epileptic encephalo-pathies  recognized  as catastrophic
epileptic syndromes having a special type of seizure
characterized by clusters of brief muscle contractions² followed by a more sustained
tonic phase which remains distinct from myoclonic and tonic seizures. Seizures in infantile spasm is
typically divided into 3 types: flexor, extensor and mixed spasms; but can also
be asymmetric³ and
involves brief contractions of neck, trunk and extremities lasting upto few
seconds and frequently in clusters ⁴
as electroencephalography (EEG) demonstrates it distinctly typical pattern
called hypsarrhythmia. (Report on Infantile spasm)

They often occur in clusters and as many as 100 spasms occurring in a
single cluster, each individual spasm lasting few seconds only. These clusters
frequently occur as the infant is awaking from sleep and are commonly
associated with a cry.¹

Hypsarrhythmia is used to describe an
EEG pattern that is characterized by random, high voltage and slow waves. The
most striking features of hypsarrhythmia are high –voltage slow waves from many
foci, and varying with time and a lack of synchrony, with a generally “chaotic”
appearance. The typical appearance is more likely to be found in earlier stage
of infantile spasm and when onset occurs at a younger age. The hypsarrhythmic
pattern may disappear during rapid-eye-movement (REM) sleep, but it may be
found with greater sensitivity in some other stages of sleep⁵.

Infantile Spasm occurs mostly between
3-7 months and 90% occurs in 1^st year of life⁶ though it reportedly occurs
within 4 years of age. In most cases they resolve by the age of three, though
rarely can persist up to 10-15 years of age ¹

The incidence of infantile spasm
ranges between 2-3.5/10,000 live births.⁴ From
China reported an incidence rate of infantile spasm have been reported to
range  between  1 in every 2,000- 4,000 infants constituting
2 – 3% of childhood epileptic syndrome^{2  .}Another study
shows the incidence of infantile spasm ranges from 0.25-0.6 per 1000 live birth⁷

Despite huge advances in medicine infantile
spasm still remains a poorly understood entity, although with newer imaging
techniques it is possible to elicit underlying causes of these spasms, still their
patho-physiological basis and treatment remains problematic.¹  Infantile
spasm occurs in children from all ethnic groups and boys are affected with infantile
spasm slightly more often than girls (ratio 60:40)

Of several predisposing factors of
infantile spasm (genetic, perinatal and postnatal etiologies) ⁶ >50%
have underlying neurologic disorders often leading to physical and mental
handicaps.⁵  

^{Etiological classifications of
infantile spasm include:}

(i)
(have clearly defined underlying
cause and /or significant developmental delay prior to spasm onset and

(ii)
 Cryptogenic (no underlying cause and had normal development prior
to onset of spasms).

(iii)

Causes of infantile spasm may be
prenatal, perinatal and postnatal.
The percentage of symptomatic infantile spasm has increased due to
improved diagnostic techniques such as metabolic and genetic testing and
neuroemaging.⁴

There is an association with a number
of disorders –some of which are known at disease on set (e.g. cerebral palsy,
Down’s syndrome etc.), whilst other are discovered on investigation after the
onset of spasm (e.g. tuberous sclerosis, neuronal migration disorder etc).
However, in a significant minority of cases the etiologies remain unknown. ¹

Outcome of infantile spasm dependent
on etiology and may be more favourable in cryptogenic infantile spasm. Delay in
diagnosis is common and negatively influenced final seizure outcome.⁸ Outcome assesses by cessation
of spasms, quantitative reduction of spasms, and resolution of EEG abnormality.

Among the many pharmacological agents
tried for management of infantile spasm, ACTH,
oral corticosteroids and vigabatrin have yielded the most significantly
favorable results.⁹

Second-line drugs include B6, nitrazepam, valporic acid, leviteracetam, zonisamide, and
topiramate. (Where ACTH or Vigabatrin has failed) ¹⁰

Common side
effect of ACTH and prednisolone:
Irritability, acne, weight gain, increased appetite, “moon face”,
hypertension, hyperglycemia, gastrointestinal bleeding. ACTH may often cause anaphylaxis,
hypertension, and growth retardation. Vigabatrin causes irreversible peripheral
severe visual handicaps.⁵ it
is generally accepted that the adverse effect of ACTH are primarily dose
dependent.¹¹

ACTH act directly inhibiting corticotrophin releasing hormone (CRH)
secretion and it also has negative feedback effect on CRH secretion by
increasing blood steroid level.²

In the United States, many physicians
perceive ACTH as first-line therapy, as this was the only treatment in the 2004
American Academy of Neurology practice parameter classified as “probably”
effective.¹²_­­
Efficacy of ACTH for resolution of clinical spasms has varied from as low as
33% to as high as 100%, with relapse rates of 8-50%. Resolution of
hypsarrhythmia on with ACTH also varied with rates as low as 21% and as high as
100%.

On reviewing some randomized
controlled trials (RCT) and crossover studies, to evaluate the efficacy and safety
of high-dose and low-dose ACTH evidencing a trend towards more
complete cessation of spasm in low-dose ACTH group and no difference in
disappearance of hypsarrhythmia between high and low-dose ACTH but high-dose ACTH produced more adverse
effects then lower concluding
that low-dose ACTH might be preferable for its comparative efficacy and lower
risk of adverse effects.²

Two large surveys were performed
independently by United States Consensous and Japan to determine the drug of
choice for infantile spasm treatment. ACTH, as initial therapy is used in~88% patients in USA
most frequently at a dose of 40IU/day for 1-2months, irrespective to etiology.³

United states consensus reported that
in a study patients were given 10mg prednisolone 4 times/day for 2wks or, 20mg
prednisolone 3 times/day after 1 wk
if spasm continued. Thus 70% (21/300) patients with prednisolone had a good
clinical response .⁴ Since Sept 2007, they
replaced ACTH with high -dose oral prednisolone (40-60mg/day) according to 2004
United Kingdom infantile spasms study (UKISS). They now routinely recommend
oral prednisolone to all families of children with infantile spasms.

Recently, high-dose prednisolone
treatment produced high clinical efficacy for infantile spasm cessation using 40mg oral
prednisolone/day for 2 weeks.⁵

From 1958-2002, 24 studies of case
reports were examined where they observed that ATCH & prednisolone was the
most common agent used.⁴

In Pakistan experienced the efficacy
of ACTH was marginally better than prednisolone 33% in ACTH and 24% in prednisolone group of infantile
spasm children remained spasm free.  ACTH
and prednisone both are used, when response being defined as either complete
cessation or >=50% reduction in the spasm frequency as judged by the parents⁶

Though ACTH is used more selectively
in Europe in comparison to prednisolone whereas ~88% of pediatric neurologists
in United States use ACTH as the first choice.⁶ initially, it was thought that prednisolone was as
effective as ACTH. More
recently, it has been shown that ACTH is superior to 2 mg/kg/day prednisone and
high dose is no better than low-dose ACTH. ⁶ The 2 mg/kg/day
dose of prednisone has been suggested to be too low in the Cochrane review. ¹

Infantile spasm clinical trial treatment
protocol

Ref. No.

References

N

Agent

Dose

Duration of full dose
(Weeks)

% Patients spasms stopped

% Patients resolution
hypsarrhythmia

5

Barm et al. (1996)

15

ACTH

150 IU/m²/day

divided b.i.d.

2

93

87

10

Hrachovy et al. (1994b)

24

26

ACTH

ACTH

20-30 IU/day or

150 IU/m²/day

2-6

3

58

50

58

50

3

Lux et al. (2001)

25

ACTH

40-60 IU (0.5-0.75mg)

alternate days

2

76

89

2

Hrachovy et al. (1983)

12

Predsolone

2 mg/kg/day

2-6

33

33

3

Lux et al. (2004)

30

Predsolone

40-60 mg/day

2

70

71

RATIONALE

And ideal treatment of infantile spasm
still remains unclear, but many study advocate hormonal treatment. In some
studies ACTH was superior to prednisolone, ¹³ and in others prednisolone was as effective as ACTH.¹⁴   Most of the studies have been retrospective
and have not been well controlled.¹⁵
Though ACTH and prednisolone are the most effective available
agents in controlling  infantile spasm
but there is no universal standard exists for treating infantile spasm.  So
adequately designed further studies are required to perform to determine the
most effective therapies for optimal treatment of children with infantile
spasm.

RESEARCH QUESTION: 

Is injectable ACTH more effective than
oral Prednisolone in clinical management of infantile spasm?

HYPOTHESIS:

Injectable ACTH is more effective than
oral Prednisolone in clinical management of infantile spasm.

OBJECTIVES:

General Objective:

To find out comparative efficacy of
injectable ACTH and oral prednisolone in clinical management of infantile spasm.

Specific objectives:

To determine
the clinical response of ACTH.

2. To determine the clinical response of prednisolone.

3. To compare the clinical outcome of injectable ACTH versus oral
Prednisolone.

METHODOLOGY

Type
of study Study
Period   December 2011 to November 2012

Place of
study :  Study
will be conducted in pediatric neurology unit of Dhaka Medical Colleges
Hospital (DMCH) and Centre for Neurodevelopment and Autism in children, Bangabandhu
Sheikh Mujib Medical University (BSMMU) in Dhaka.

Reference
population: All the infantile spasm patients seeking
treatment at the above mentioned hospitals in all the working days will be the
reference population.

Consecutive case will be enrolled in
the study who met the inclusion criteria and exclusion criteria and their
willingness to participate in this study.

: 60 children

Sample size estimation:

epi¹⁷

http://www.brixtonhealth.com/pepi4windows.html)

We
select Situation 1 where the software allows to us to compare proportions.

Assuming
95% confidence level (= 5% significance level) and 80% power also,

Proportion in B = Outcome in study group – Proportion of patients who
will be convulsion free after receiving ACTH = p₂ = 0.95

The required sample size is calculated by WinPepi = 54.
Considering 10%

refusal/attrition the study will require a total of 54×0.1+54
= 59.4 .To take equal numbers the study will consider this as 60 meaning each
group will need 30.

(B)Using Formula:

•
Outcome
in control group – Proportion of patients who will be convulsion free after

Receiving Prednisolone =
p₁

•
•
?_{= critical value for confidence level
(1.96 for 95% confidence level)}

•
?= area under the curve corresponding
to power of the study to detect the true alternative hypothesis (0.84 for 80%
power)

•
Assuming
95% confident level and 80% power we know that,

•
 =
(Reference: Jennifer L. et al. (1997) Methods in Observational
Epidemiology, pp. 333) 

•
The
formula for required sample size ‘n’ in each group to test if such an effect
exist is

Assuming
p1 = 0.65 and p2 = 0.95 we get,

Considering 10%
refusal/attrition the study will require a total of (25×2)x0.1+50 = 55 To take
equal numbers the study will consider this as 56 meaning each group will need
28.

Inclusion criteria:

1. Clinical
   symtomatology of infantile spasm as elicited by through physical
   examination and detailed history.
2. Accompanying
   EEG findings at initial EEG.
3. Child’s
   guardian/attendant who would agree (in written) that their children may
   take part in the study 

Exclusion
criteria:

1. All children who were diagnosed
   to have tuberous sclerosis.
2. Children who had already
   received any of the investigational drugs prior to their first encounter
   were also excluded.
3. Child’s guardian/attendant who
   would not agree to consent on their children may take part in the study
4. The child who would present any other serious illness or
   co-morbidities

Methods: All
the infantile spasm patients seeking treatment in department of pediatrics,
Dhaka medical college hospital and BSMMU will be the reference population. Detailed
history and clinical examination of all infantile spasm patients will be done.
From reference population patients fulfilling the selection criteria will be
enrolled consecutively as study population. Necessary exclusion will be done.
After taking written informed consent and randomization, drugs will be given
according to dose schedule. During the continuation of drugs patients will be
followed up by principal investigator and will be recorded in follow up sheet.

Randomization: Randomization
will be done by lottery method, i.e. the mother/father/caregiver will be given
a chance to pick up a brown coloured  envelop,
containing the name of drug  from a group
of 8 envelop, 4 containing the name of ACTH and the other 4 containing the name
of prednisolone.

Drug administration: After group allocation, drug
will be given according to following dose schedule.

13

Dose: A. Two weeks treatment
schedule:

150IU/m2/day two divided doses for 2
weeks.

B. Tapering schedule:

30IU/m2/day every morning for 3 days

15IU/m2/day
every morning for 3 days

10IU/m2/day
every morning for 3 days

10IU/m2/day
every alternate morning for 3 days

 Prednisolone:  ⁵

Route: Oral as liquid suspension (5mg/5ml)

Dose: 40-60mg/day three divided doses for 2 weeks.

20mg/day two divided doses for 1 week

10mg/day once daily for 1 week

Data collection and analysis: Data will be collected by a preformed questionnaire. Data
analysis will be done using computer software SPSS (Win version 17).Mean,
median, standard deviation will be determined. For comparing the descriptive
value Z-test will be used. For comparing the continuous variables chi-square
test will be used. A p-value of <0.05(at95% CI) will be considered
significant.

Flow Chart:
Work Organization:

Ethical Considerations:

All proper steps to fulfill the
ethical considerations will be sought from Research review committee,
department of pediatrics and Ethical review committee of Dhaka Medical College
time based on the following ethical grounds:

Informed written consent from the
parents/attendant will be taken prior to include the child in the study after
detailing the aims & objectives of the study and its implication on the child
and overall in pediatric science in Bangladesh and in the world.

The parents will be informed on the
anonymity of the study child and to ensure the parents of not publishing the
data or any report of the child anywhere except for scientific presentations or
publications (with anonymity).

BIBLIOGRAPHY

1. Hancock
E, Osborne J. Treatment of infantile spasms (Rev)…This version first published
online: 22 April 2002 in Issue 2, 2002

2.   Linan
Zeng, Rong Luo & Lingli Zhang. Efficacy of high-dose ACTH vs. low- dose
ACTH in infantile spasm: A Meta -analysis with direct & indirect comparison
of randomized trials. J pediatr Neurol
2011; 9: 141-49 [pharmacy Dept, West China Second Univ Hosp, Sichuan,
China.]

3.   Mackay
MT, Weiss SK, Adams-Webber T, Ashwal , Stephens D, Ballaban-Gill K, Baram TZ,
Duchowny M, Hirtz D, Pellock JM, Shields WD, Shinnar S, Wyllie E and Snead OC. Neurol 2004; 62:1668-1681. Rep Am
Acad Neurol & Child Neurology Society

4.    Pellock JM, Harachovy R, Shinnar S, Baram TZ,
Bettis D, Dlugos DJ, Gaillard WD, Gibson PA, Holmes GL, Nordli DR, Christine
O’Dell, Shields WD, Trevathan E and Wheless JW. Infantile spasms: A US
Consensus Report. Epilepsia, 2010; 51(10): 2175-2189.

6.  7.   Shahnaz
Ibrahim, Shamshad Gulab, Sidra Ishaque & Taimur Salem. Clinical profile
& treatment of infantile spasms using vigabatrin and ACTH-a developing
country perspective……Published: 15 Jan. 2010

8.   Veena Kalra, Sheffali
Gulati, RAvindra Mohan Pandey, Shaji Menon. West syndrome and other infantile epileptic
encephalopathies-Indian hospital experience.

9.    Harinder Jaseja. A plausible explanation for
superiority of adreno-cortico-trophic hormone (ACTH) over oral corticosteroids
in management of infantile spasms (West syndrome). 24 April 2006.

10. Bradley
Peltzer, BM, William D. Alonso, BS, and Brenda E. Proter, MD, PhD. Topiramate
& Adrenocorticotropic Hormone(ACTH) as Initial Treatment for Infantile
Spasms. J Child Neurol 2009; 24(4):400-05

12. Eric
H. Kossoff, Adam L. Hartman James E. Rubenstein, Eileen P.G. Vining. High-dose
oral prednisolone for infantile spasms; an effective and less expensive
alternative to ACTH. Epilepsy & Behavior 2009; 14: 674-76.

13. Tallie Z. Baram , Wendy G. Mitchell, Anne
Tournay, BSc, , O. Cartr Snead, III,  Rebecca A, Hanson, and E.J. Horton,. High-dose
Corticotropin (ACTH) versus prednisone for Infantile Spasms: A prospective,
Randomized, Blinded Study. Pediatrics 1996 March; 97(3): 375-379.

14. Richard
A. Hrachovy, James D. Frost, Jr., Peter Kellaway, and Thomas E. Zion.
Double-blind study of ACTH vs. prednisone therapy in infantile spasms J
Pediatr 103:641, 1983. Houston, Texas 1996 March; 97(3): 375-379.

15. Daniel
G, Glaze, Richard A, Hrachovy, James D. Frost, Jr., Peter Kellaway & Thomas
E. Zion, Prospective Study of outcome of infants with infantile spasms treated
during controlled studies of ACTH and prednisone. J Pediatr 1988; 112:389-96.

16. Tallie
Z. Baram. What are the reasons for the strikingly different approaches to the
use of ACTH in infants with wast syndrome. Brain & Development 23
(2001) 647-648.

17. Joseph
H Abramson.  WINPEPI (PEPI-for-Window):
computer program for epidemiologists. Epidemilogist Pespectives and Innovations
2004, 1:6 17 December 2004.

18. Richard
A, Hrachovy, MD, James D. Frost, Jr., MD, and Daniel G. Glaze, MD. High-dose,
long-duration versus low-dose, short-duration corticotrophin therapy for
infantile spasms. Pediatric Pharmacology And Therapeutics. 1993.

19. Shin-Ichiro Hamano, Shintaro Yamashita, Manabu Tanaka, Satoshi
Yoshinari, Motoyuki Minamitani, And Yoshikatsu Eto, Therapeutic
efficacy and adverse effects of adrenocorticotropic hormone therapy in west
syndrome: differences in dosage of adrenocorticotropic hormone, onset of age,
& cause. …Nov 30, 2005…… No 3, 2005.

20. Cesare
T. Lombroso. A prospective study of Infantile Spasms: Clinical and Therapeutic
Correlations. Epilepsia, 24:135-158,
1983.

21.  Yong
Seung Hwang, the Korean Child Neurology Society. National

Survey on West Syndrome in Korea. Brain
& Development 2001; 23: 565-569.

22.   Eric
H. Kossoff, Erika F. Hedderick, Zahava Turner, and John M. Freeman. A
case-control evaluation of the ketogenic diet versus ACTH for new-onset infantile
spasms. ………. March 4, 2008.

23.
Federico
Vigevano and Maria Roberta Cilio. Vigabatrin vs. ACTH as First-Line
Treatment for Infantile Spasms: A Randomized, Prospective Study. Epilepsia 1997,
38 (12): 1270-1274

Time Schedule

December, 2011 – November, 2012

Budget

2. Drugs 1,
00,000/-

4. Investigation 50,000/-

6. Auxiliary stuff 10,000/-

Total 1,
90,000/-