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Indian Pediatr 2011;48: 55-58 |
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Add-on Lamotrigine in Pediatric Epilepsy in
India |
Rahul Jain, Devendra Mishra and Monica Juneja
From the Department of Pediatrics, Maulana Azad Medical
College (University of Delhi), Delhi 110002, India.
Correspondence to: Dr Devendra Mishra, Division of
Pediatric Neurology, Department of Pediatrics, Maulana Azad Medical
College, 2, Bahadur Shah Zafar Marg, Delhi 110002, India.
Email: [email protected]
Received: November 9, 2009;
Initial review: January 5, 2010;
Accepted: January 21, 2010.
Published online: 2010 March 15.
PII: S09747559090795-2
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Abstract
Lamotrigine is a newer antiepileptic drug useful as
oral adjunctive therapy in refractory epilepsy. Indian data on use of
lamotrigine is limited. This study was conducted to evaluate add-on
lamotrigine in Indian children with epilepsy. Twenty children (median
age 90 months) receiving lamotrigine as add-on therapy for mean 26.7
(19.1) months, were followed for a median period of 7.9 (6-10) months.
Follow-up was done every two weeks. The most common seizures types were
either generalized tonic-clonic (6, 30%) or myoclonic (8, 40%). The
average dose used was 3.86 mg/kg/day (with concomitant valproate). Good
response (>50% reduction) or complete seizure control was seen in 72%
patients. Side effects were seen in 27.5% patients and were ‘mild’ in
more than half of these. Lamotrigine was stopped in two patients due to
adverse reactions, which resolved on stopping the drug. Lamotrigine was
observed to be an effective, add-on, broad-spectrum antiepileptic with
‘mild’ side effects in Indian children.
Key words: Child, India, Intractable epilepsy, Lamotrigine,
Newer antiepileptics.
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L amotrigine,
a newer antiepileptic drug (AED), may be used add-on drug for both
generalized and partial seizures, and also as the first-line drug for
partial seizures [1,2]. The drug has shown to be effective for refractory
partial and generalized seizures in children, with a low incidence of
side-effects [3-5]. In India, the drug has been in clinical use since
2002, but scant data are available about the clinical use of lamotrigine
in Indian children [6]. We ascertained the effectiveness and safety of
lamotrigine as an add-on drug for epilepsy in Indian children.
Methods
The study was conducted from January to October 2009 at
the Pediatric Neurology Clinic of a tertiary-care hospital attached to a
medical college in North India. All children under 14 years (except one
patient of 16 years), attending the Clinic and already receiving
lamotrigine were retrospectively enrolled (n=14), after written
informed consent. Children started on lamotrigine therapy between January
to April 2009 were also enrolled prospectively (n=6). Decision
regarding starting lamotrigine in patients not responding to the
first-line AEDs was taken by a clinician not directly involved with the
study. All data were entered in a pre-tested structured proforma.
Neuroimaging (CT and/or MRI) and electroencephalography
were available for most children. All children at the clinic undergo a
comprehensive evaluation and management by a team consisting of
developmental pediatricians, speech therapist, occupational- and physiotherapists,
child psychologists and special educators. No additional investigations
were done as part of the study.
Seizure type and frequency during the study were
recorded using a seizure log filled by the parents or caretakers.
Information about previous seizures was obtained from records available
with the parents. The doses of antiepileptic used were (mg/kg/day):
carbamazepine, 10-30; clobazam, 0.1-2; clonazepam, 0.05-0.2;
phenobarbitone, 3-8; phenytoin, 5-8; and, valproate, 10-60. The
maintenance dose of lamotrigine used was between 1-6 mg/kg, once daily or
in 2 divided doses with valproate, and 5-15 mg/kg daily given in 2 divided
doses with enzyme-inducing AEDs (but not with valproate), with induction
and dose changes as per standard guidelines [1]. Patients were followed
prospectively for a period ranging from 6-10 months, on a two-weekly
basis. Occasionally the OPD visits were earlier than two weeks if seizure
control was inadequate, or child attended the casualty for breakthrough
seizures. A structured proforma was designed to include details pertaining
to diagnosis, age of onset of seizures, seizure type, frequency of
seizures, nature and dose of first line antiepileptics. On follow up,
details were obtained about change in seizure frequency, development of
side effects and any modification done in the dose of lamotrigine to
obtain seizure control or for addressing side-effects.
Therapeutic response was recorded as complete (100%
seizure control), good (>50% seizure reduction), or none. Enquiry was made
about the following side effects for all patients during the study period
and reviewed retrospectively from the case-records: skin rashes (including
severe skin reactions like Stevens-Johnson syndrome and toxic epidermal
necrolysis) with or without fever, malaise, flu-like symptoms, drowsiness,
lymphadenopathy and facial edema [1]. Others known adverse events like
angioedema and photosensitivity; diplopia, blurred vision, and
conjunctivitis; and dizziness, drowsiness, insomnia, headache, ataxia,
nystagmus, tremor, tiredness, nausea and vomiting, irritability and
aggression, hallucinations, agitation, and confusion, were also assessed
[1]. The side effects were categorized as ‘mild’ if they were not
spontaneously reported by the parent and were only elicited on enquiry.
Side effects were moderate, if parents spontaneously reported the
side effect, as a complaint developing after initiation of lamotrigine but
the symptom was not interfering with the child’s daily activity. Side
effects were severe if the parent spontaneously reported it and
asked for withdrawal of the drug as it was interfering with the child’s
daily activity [7]. All patients came regularly for follow-up during the
study period.
Results
Twenty patients received add-on lamotrigine during the
study period (17 males). Fourteen children were already on lamotrigine at
the time of starting the study and six were started during the study
period. The clinical profile is shown in Table I. Lennox
Gastaut syndrome and West syndrome were diagnosed in 1 case each.
Neurological co-morbidities were present in 14 cases. The deficits
included mental retardation in 12, cerebral palsy in four, autism in
three, and vision deficit in two children.
Table I
Clinical Profile of Study Children (N=20)
Characteristic |
No |
Age, median (range), mo |
90 (29-199) |
Duration of LTG therapy, mean (SD)*, mo |
26.7 (19.1) |
Median follow up (range), mo* |
7.9 (6-10) |
Predominant seizure type |
GTCS |
6 |
Atonic |
1 |
Myoclonic |
8 |
Absence |
1 |
Partial |
4 |
Etiologic diagnosis |
Idiopathic |
4 |
Remote symptomatic |
10 |
Cryptogenic |
6 |
AEDs used before LTG, median (range) |
3 (2-4) |
Concomitant AEDs used, median (range) |
2 (1-3) |
AED:
antiepileptic drug; LTG: lamotrigine; *n=18. |
The median age of onset of seizures was 10.5 months
(range, 1month-9yr 5 months). All the cases had previously been tried on
at least two appropriate AEDs and had seizure frequency of atleast one per
month at the time of starting lamotrigine. There were two types of
seizures in six children. All children were on sodium valproate and six
were additionally on clobazam at the time of starting lamotrigine. The
drugs previously tried in these patients included phenytoin, carbamazepine,
phenobarbitone, clonazepam and clobazam. The mean dose of lamotrigine used
in the cases was 3.86 mg/kg/day (excluding those in which the drug was
withdrawn due to adverse effects). Neuroimaging was available for 18
patients and showed some abnormality in 12 cases (sequelae of birth
asphyxia 5, sequelae of tubercular meningoencephalitis 2, diffuse cerebral
atrophy 2, cerebral malformation 2, and focal gliosis 1). Interictal-EEG
was available in only 16 cases and was abnormal in fourteen.
Efficacy: In two children, lamotrigine was
withdrawn due to adverse effects and these cases were excluded from
further analysis. Overall, 44.4% cases had good response with >50%
reduction in seizure frequency and 27.7 % becoming seizure free (Table
II). The response was good in all type of seizures except
myoclonic seizures. None of the patients with myoclonic seizures became
seizure free on lamotrigine. Lamotrigine was withdrawn in three patients
with myoclonic seizures, due to non response in two and due to adverse
effects in one.
TABLE II
Efficacy of Lamotrigine by Predominant Seizure Type (n=18)
Seizure type
|
Poor/no
response
No. (%) |
Good
response
No. (%) |
Seizure
No. (%) |
GTCS (n=5) |
1 (20) |
1 (20) |
3 (60) |
Atonic (n=1) |
– |
1 (100) |
– |
Myoclonic (n=7) |
4 (57.1) |
3 (42.8) |
– |
Absence (n=1) |
– |
– |
1(100) |
Partial (n=4) |
– |
3 (75) |
1 (25) |
Total |
5 (27.7) |
8 (44.4 ) |
5 (27.9) |
Poor/no response: <50% reduction; Good response: 50-99% reduction. |
Overall, lamotrigine was withdrawn in 6 patients during
the study period, 2 due to adverse effects and 4 due to non-response. In
patients with two types of seizures, > 50% reduction in other seizure
types was seen in four out of six cases. Worsening of seizures was not
observed in any child.
Adverse effects: Adverse effects were observed in
five children and all occurred within first three months of starting
lamotrigine. Drug was withdrawn in one child due to rash and in another
due to severe emotional lability and agitation. In both these cases,
symptoms subsided promptly on withdrawal of the drug. The side effects
noted in other three cases were anorexia in one, and drowsiness and
agitation in two. These were transient in nature.
Discussion
This observational follow-up study in Indian children
showed lamotrigine to be safe and efficacious second line anti-epileptic
drug for pediatric epilepsy resistant to first-line AEDs. Good response
was seen in generalized tonic-clonic, atonic, absence and partial seizure
types, whereas modest response was observed in myoclonic seizures. Serious
side effects were infrequent and responded promptly to drug withdrawal.
Studies from other countries have also shown
lamotrigine to be effective as add-on therapy in children with refractory
epilepsy [3,4,8-10]. In a multicentric study on 285 children with
treatment resistant epilepsy, one-third patient had 50% or more reduction
in seizure frequency on lamotrigine. Response was good in all seizure
types, particularly in absence and atonic seizures [8]. In another study
on 120 children with intractable epilepsy, 9.4% patients became seizure
free and 29% patients showed improvement after 3-month treatment with
lamotrigine [9]. Studies have also shown improvement in academic and
social functioning of the treated cases [10], which could be due to
improved seizure control. Others have also reported comparable responder
rates and side effect incidence with lamotrigine among Asian children with
intractable epilepsy [4,5].
The poorer response of myoclonic seizures to
lamotrigine has also been seen by others.
In various studies, only 0-30% patients with myoclonic seizures responded
to lamotrigine, although the number of cases with myoclonic seizures was
small in these studies [8,11,12]. Worsening of seizures with LTG has
previously been reported in patients with severe myoclonic epilepsy of
infancy [13].
The drugs commonly used at our clinic are the
first-line drugs (phenytoin, phenobarbitone, carba-mazepine, valproate and
clonazepam) because these are provided free-of-charge to the patients,
most of whom belong to lower or lower-middle classes. Thus, despite the
indications for newer AEDs in some patients, these can not be routinely
prescribed as the patients are unable to afford the same. Therefore, one
of the major limitations of this study was the small sample size. In
addition, there was no predetermined objective criterion for starting
lamotrigine, and it was based on the treating clinicians’ decision. The
strengths of the study were the long follow-up, complete data for all
patients, and frequent review of the patients for adverse effects and
efficacy.
To conclude, our study showed that lamotrigine has
infrequent side effects, and good efficacy as an add-on AED, with >50%
responder rate in all type of seizures, except myoclonic seizures. It is
indicated as adjunctive therapy for partial seizures, primary generalized
tonic-clonic seizures, and the generalized seizures of Lennox-Gastaut
syndrome in children ( ³2
years of age) with epilepsy in India, although it’s high cost will
preclude widespread use in low-resource settings.
Acknowledgments: Prof B Talukdar, Head, Department
of Pediatrics, Chacha Nehru Bal Chikitsalaya (MAM College), and Dr
Biswroop Chakrabarty, Child Neurology Division, Department of Pediatrics,
AIIMS, New Delhi for help in the conduct of the study.
Funding: None.
Competing interests: None stated.
What This Study Adds ?
• Lamotrigine is a
safe and efficacious add-on anti-epileptic in Indian children with
all forms of seizures, except myoclonic seizures.
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