ARTICLE
Auteur(s) : Mi-Sun Yum, Tae-Sung Ko
Department of Pediatrics, Asan Medical Center, University
of Ulsan College of Medicine, Seoul, Korea
Article reçu le 3 Avril 2009, accepté le 18 Novembre
2009-11-19
West syndrome is an age-related epilepsy syndrome occurring in
infancy that is characterized by infantile spasms, hypsarrhythmia
and developmental regression (West, 1841; Lux and Osborne, 2004).
In view of the presence of profound neurodevelopmental sequelae,
treatment of infantile spasms is usually initiated quickly and
aggressively after diagnosis, with the aim of changing the natural
history of the disease. Due to the vague underlying
pathophysiology, treatment of infantile spasms has remained
empirical, and the mechanisms of action of drugs used to treat this
disorder are not fully understood. Because infantile spasms in many
patients are resistant to conventional antiepileptic drugs, the
treatments of choice have included adrenocorticotropic hormones and
steroids, but these agents have been associated with severe adverse
effects (Dulac and Tuxhorn, 2005).
Zonisamide (3-sulfamoylmethyl-1,2-benzisoxazole; ZNS) is a new
antiepileptic drug with an efficacy profile similar to those of
phenytoin and carbamazepine (Peters and Sorkin, 1993). Although the
exact mechanism of action of ZNS is not known, the drug most likely
acts by blocking T-type calcium channels (Suzuki et al.,
1992), inhibiting slow sodium channels (Schauf, 1987) and/or
inhibiting glutamate release (Okada et al., 1998). In
addition, ZNS may block the propagation of seizure discharge and
suppress the epileptogenic focus (Takano et al., 1995).
Although several recent reports have described the efficacy of
ZNS in infantile spasms, these reports were restricted mainly to
Japanese populations (Suzuki, 2001; Yanagaki et al., 2005;
Yanai et al., 1999). We have assessed the efficacy, safety,
and tolerability of high-dose ZNS in the treatment of infantile
spasms in patients eligible for treatment within two months of
diagnosis.
Materials and methods
From October 2005 to November 2007, patients with infantile
spasms beginning at ≤ 12 months of age and hypsarrhythmia
identified by electroencephalogram (EEG) analysis at the Pediatric
Neurology department at the Asan Medical Center were eligible for
this study. Prior to study entry, we obtained Ethical Committee and
Institutional Review Board approval, and the risks and benefits of
ZNS and alternative treatment regimens were discussed with each
patient’s caregivers.
Patients were treated with ZNS within two months of diagnosis as
initial monotherapy or as add-on therapy. Patients older than
12 months at diagnosis were excluded, as were patients in whom
spasms were successfully treated with other drugs before the
introduction of ZNS.
The initial daily dose of ZNS was 2-8 mg/kg body weight,
administered orally in one or two doses. Daily dosage was increased
by 2-5 mg/kg every three to four days until the spasms
disappeared or to a maximum daily dosage of 30 mg/kg. Routine
EEGs were repeated at the time caregivers reported clinical spasm
cessation. Outcome measurements included clinical response, EEG
evaluation, dosing parameters and tolerability. Complete response
was defined as clinical cessation of infantile spasms reported by
their caregivers for ≥ 28 consecutive days from the time of
the last witnessed spasm, according to the West Delphi consensus
(Lux and Osborne, 2004), and disappearance of hypsarrhythmia on EEG
between study days 14 and 28 (figure 1). The exit
criteria were defined as no cessation of spasms and extant
hypsarrhythmia of EEG 21 days from start of ZNS therapy. For
those who met the exit criteria, therapy was started without any
delay.
Results
During the inclusion period, 17 patients newly diagnosed with
infantile spasms were admitted to our hospital and treated with
ZNS. The group comprised 13 males and four females, and in all
but one patient, developmental milestones at the time of diagnosis
were markedly inferior to age-matched normal profiles. The maximum
daily ZNS dosage was 9.9-27.8 mg/kg.
Of these 17 patients, seven (41.2%) showed complete
resolution of spasms and disappearance of spasms (figures 1, 2), including
five of 12 (42.0%) cryptogenic patients and two of five
(40.0%) symptomatic patients.
The effective daily dose ranged from 10-22.5 mg/kg and the
mean time interval before spasm disappearance was eight days. Spasm
recurrence within six months was observed in three of the seven
patients (table 1).
ZNS treatment was not effective in 10 patients; these
10 patients received a maximum daily dose of
9.9-27.8 mg/kg (mean 19.8 mg/kg). There was no
significant difference in age at clinical spasm onset, lead time
from onset of spasms or dose of ZNS between responders and
non-responders. Adverse effects included irritability in four
patients (patient 5, 13, 14, and 15) and poor oral intake in two
(patient 5 and 14).
Table 1 Summary of the patient characteristics (n =
17).
|
Patient number/sex
|
Onset age (mo.)
|
Etiology
|
Concomitant drug
|
Max. ZNS dose (mg/kg)
|
At spasm control
|
Spasm recurrence (day)
|
Add-on therapy after ZNS*
|
|
Time (day)
|
EEG
|
|
1/M
|
7
|
Crypto.
|
VPA
|
17.9
|
20
|
Normal
|
48**
|
CLB
|
|
2/M
|
8
|
Crypto.
|
VPA
|
22.2
|
15
|
Normal
|
-
|
-
|
|
3/M
|
6
|
Crypto.
|
-
|
22.5
|
5
|
Normal
|
36**
|
VGB†
|
|
4/F
|
5
|
Crypto.
|
-
|
10.0
|
8
|
Both P-O spikes
|
115§
|
VGB
|
|
5/M
|
8
|
Crypto.
|
VPA, VGB
|
11.0
|
3
|
Normal
|
-
|
-
|
|
6/M
|
11
|
PVL
|
-
|
12.4
|
6
|
Normal
|
-
|
-
|
|
7/M
|
7
|
Infarct
|
CBZ, CLB, VGB
|
16.5
|
4
|
Normal
|
-
|
-
|
|
8/M
|
4
|
Crypto.
|
VGB, TPM
|
9.9
|
-
|
-
|
-
|
KD
|
|
9/F
|
12
|
Crypto.
|
-
|
14.3
|
-
|
-
|
-
|
VGB
|
|
10/M
|
12
|
Crypto.
|
-
|
20.4
|
-
|
-
|
-
|
VGB†
|
|
11/F
|
6
|
Crypto.
|
-
|
24.1
|
-
|
-
|
-
|
VGB†
|
|
12/M
|
2
|
Crypto.
|
-
|
27.3
|
-
|
-
|
-
|
VGB†
|
|
13/F
|
8
|
Crypto.
|
-
|
19.6
|
-
|
-
|
-
|
VGB
|
|
14/M
|
6
|
Crypto.
|
-
|
22.2
|
-
|
-
|
-
|
VGB†
|
|
15/M
|
12
|
TS
|
VGB
|
17.4
|
-
|
-
|
-
|
TPM, KD†
|
|
16/M
|
2
|
TS
|
PHB
|
15.3
|
-
|
-
|
-
|
VGB†
|
|
17/M
|
12
|
Ventriculomegaly
|
VPA
|
27.8
|
-
|
-
|
-
|
F/U loss
|
Discussion
A review of the current treatment for West syndrome in Japan (Tsuji
et al., 2007) noted that ZNS use has significantly increased
in recent years and that ZNS is now the second or third choice
among the non-hormonal, antiepileptic drugs for treating West
syndrome in Japan. Here, we report a relatively high response rate,
with complete clinical efficacy in 41.2% of patients with newly
diagnosed infantile spasms. We administered ZNS as monotherapy in
nine patients and as add-on therapy in eight patients. Three of the
nine patients (33.3%) who received ZNS monotherapy and four of the
eight patients (50%) who received ZNS add-on therapy achieved a
seizure-free outcome. In the natural course of infantile spasms,
though, there is a known spontaneous remission rate of
approximately 20% during the first year of diagnosis (Hrachovy and
Frost, 2003). Considering some of our patients relapsed, the
response rate was 2/12 (16.7%) for cryptogenic cases and
4/17 (23.5%) for all patients, which does not seem too
different from the potential spontaneous remission rate.
A review of the literature revealed six reports of the clinical
response of ZNS in West syndrome (table
2). In summary, for patients with infantile spasms,
3.3-35 mg/kg of ZNS was associated with an overall clinical
response rate of 0-33.3%. Including our cases, 40 patients of
a total of 163 (24.5%) responded completely to ZNS. When
administered as initial monotherapy, 21 of 89 patients
(23.6%) completely responded. Except for one study in the United
States (Lotze and Wilfong, 2004), all previous studies reported
lower response rates to the present study; however, these previous
studies used a lower dose, suggesting that the better outcome
reported in our study may be due to the higher dose of ZNS
(Yanagaki et al., 2005; Yanai et al., 1999; Suzuki
et al., 1997). Analysis of response rates in these previous
studies according to etiology indicated that the patients with
cryptogenic etiology (8/19, 42.1%) showed better responses than
those with symptomatic etiology (26/113, 23.0%).
In contrast, our study showed similar outcomes in both groups,
suggesting the need for additional, larger studies.
The present observation that there were no serious side effects
associated with high dose and rapid titration of ZNS in infants is
in agreement with previous reports (Yanagaki et al., 2005;
Mandelbaum et al., 2005). Despite the limitations of our
study, including the open-label design and the lack of a control
group, our results provide evidence that ZNS may be effective and
safe in patients newly diagnosed with infantile spasms.
Table 2 Summary of studies examining zonisamide
efficacy in patients with infantile spasms.
|
References
|
N
|
Response rate* (%) (responder/total numbers of
patients)
|
Dosage (mean), mg/kg/day
|
S/E
|
|
Overall
|
Initial monotherapy**
|
Cryptogenic
|
Symptomatic
|
|
Yanagihara et al., 1995
|
9
|
33.3
|
-
|
0
|
33.3 (3/9)
|
-
|
None
|
|
Yanai et al., 1999
|
27
|
33.3
|
0
|
100 (2/2)
|
28.0 (7/25)
|
5-12.5 (7.8)
|
None
|
|
Kawawaki et al., 1999
|
16
|
25.0
|
25.0 (4/16)
|
66.7 (2/3)
|
15.4 (2/13)
|
4-8 (5.8)
|
1/16
|
|
Suzuki, 2001; Suzuki et al., 1997
|
54
|
20.4
|
20.4† (11/54).
|
28.6 (4/14)
|
17.5 (7/40)
|
10-13 (-)
|
None
|
|
Lotze and Wilfong, 2004
|
23
|
26.1
|
30.0 (3/10)
|
0
|
26.1 (6/26)
|
8-32 (18)
|
5/23
|
|
Santos and Brotherton, 2005
|
7
|
0
|
0
|
-
|
-
|
3.3-35 (15.9)
|
-
|
|
Lee et al., 2009
|
26
|
0
|
0
|
-
|
-
|
7.2-14 (8.5)
|
-
|
|
Our study
|
17
|
41.2
|
33.3 (3/9)
|
42.0 (5/12)
|
40 (2/5)
|
9.9-27.8 (18.3)
|
4/17
|
Disclosure
None of the authors has any conflict of interest to disclose.
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