Potentially serious Lamotrigine-related skin rash
Mohammed M. Jan, MBChB, FRCP(C).
Lamotrigine (LTG) is a new antiepileptic drug
(AED), which has a broad spectrum of antiepileptic
properties.1 It works on voltage gated sodium channels,
To report our experience with lamotrigine
thereby stabilizing the neuronal membrane and
(LTG)-related skin rash in children with epilepsy.
inhibiting the release of excitatory neurotransmitters
We identified a series of consecutive children
such as glutamate and aspartate.2 Multiple randomized,
with epilepsy treated with LTG prospectively over a 5-
placebo-control ed and comparative studies demonstrated
year period ending 1st October 2005 at King Abdul-Aziz
LTG efficacy in partial and generalized pediatric
University Hospital and King Faisal Specialist Hospital
epilepsy.1,2 Open label trials also documented its
and Research Center, Jeddah, Kingdom of Saudi
efficacy against infantile spasms, absence and juvenile
myoclonic epilepsy.3 Co-administration of valproic acid
Of 207 children on LTG, 15 (7.2%) developed
(VPA) and LTG has a synergistic effect with enhanced
a skin rash with ages ranging between 3-12 years (mean
antiepileptic properties.4 We found this combination
7.5). We used LTG as monotherapy in 3/15 and as add
most effective in intractable epilepsy, such as that seen
on in 12/15, mostly (10/15) in addition to valproic acid
in Lennox-Gastaut syndrome.5 Children may not
(VPA). The rash was mild with complete recovery in 7
respond to VPA or LTG as monotherapy or with other
children (47%). The remaining 8 (3.9% of the total)
AED combinations, however, when used together they
had severe rash that necessitated admission to hospital.
can result in remarkable seizure control.4,5 Lamotrigine
Seven out of these 8 children were also receiving VPA.
One child had superimposed secondary bacterial
is wel tolerated and most side effects are related to
infection and admitted for intravenous antibiotics.
the CNS including headache, somnolence, nausea,
Two children recovered slowly with extensive post-
dizziness, diplopia, ataxia, and insomnia.6 The main
inflammatory hyperpigmentation. We diagnosed
serious adverse event associated with LTG treatment is a
Stevens-Johnson syndrome in 5 children (2.4% of the
hypersensitivity reaction primarily presenting as a rash,
total). One of these 5 children had progressive symptoms
which affects 8-20% of patients.7-10 The occurrence and
that evolved to toxic epidermal necrolysis. He required
severity of this idiosyncratic, immune-mediated rash
prolonged intensive care admission and developed
sepsis with disseminated intravascular coagulopathy.
are difficult to predict.7,11 If the drug is continued or
He deteriorated despite supportive therapy, and died 5
the dose escalated, the rash has a tendency to become
weeks after the initiation of LTG therapy.
worse.12 Close monitoring of these patients is needed
to detect features of Stevens-Johnson syndrome (SJS).13
Lamotrigine is a novel antiepileptic drug
Skin rash is observed in higher proportions of children
with a favorable therapeutic profile and good tolerability.
on VPA-LTG combination. The risk is higher if LTG
However, LTG-related skin rash is a potentially serious
was added to a patient already receiving VPA and not
adverse event that should be carefully monitored.
Although the risk is small, one should weigh this against
vice versa. Other risk factors include young age, previous
the potential benefits, particularly in children on VPA.
history of hypersensitivity, high LTG starting dose, and
rapid titration.10 Fol owing the increased recognition of
Neurosciences 2007; Vol. 12 (1): 17-20
serious skin rash, it was recommended that the starting
dose should be reduced with gradual dose escalation to
From the Department of Pediatrics (Neurology), King Abdul-Aziz
University Hospital, Jeddah, Kingdom of Saudi Arabia.
In this paper, we report the experience with LTG-
Received 12th April 2006. Accepted 15th June 2006.
related skin rash in children with epilepsy in view of
Address correspondence and reprint request to: Dr. Mohammed M. S. Jan,
the updated literature. We hypothesized that based
Associate Professor and Consultant of Pediatric Neurology, Department
of Pediatrics, King Abdul-Aziz University Hospital, PO Box 80215,
on the available pediatric literature, LTG-related skin
Jeddah 21589, Kingdom of Saudi Arabia. Tel. +996 (2) 6401000 Ext.
rash is potential y serious, particularly when used in
20208. Fax. +996 (2) 6403975. E-mail: firstname.lastname@example.org
Lamotrigine-related skin rash . Jan
We identified a series of consecutive Results.
During the study period, we gave 207
children with epilepsy treated with LTG prospectively children LTG for epilepsy. Most children had tried other
over a 5-year period ending the 1st of October, 2005. AEDs with no response. A total of 15 (7.2%) children
Patients were identified through referrals to the pediatric developed a skin rash (Table 1
). There were 7 males and
neurology services at King Abdul-Aziz University 8 females with ages ranging between 3-12 years (mean
Hospital (KAUH) and King Faisal Specialist Hospital 7.5). Four of these children had a previous history
and Research center (KFSH&RC), Jeddah, Saudi of hypersensitivity to other AEDs. We used LTG as
Arabia. Both are multispecialty adult and pediatric monotherapy in 3/15 and as add on in 12/15, mostly
hospitals providing tertiary medical care for most of the (10/15) in addition to VPA therapy. The initial LTG
regional population of western Saudi Arabia. Patients dose ranged between 5-25 mg/day (mean 9.5). The rash
received LTG as monotherapy or add on for treating developed in the 2nd-4th weak (mean 2.8) after the
children with epilepsy. The LTG initial dose was not initiation of LTG. Systemic symptoms were evident in
to exceed 25 mg/day or 1.5 mg/kg/day. The dose was 11 (73%) children in the form of malaise, anorexia, fever,
doubled every 2 weeks until the minimum effective dose and irritability. The rash was mild with complete recovery
was reached (achieving a seizure free outcome) or up to after LTG discontinuation in 7 children (47%). Two of
a maximum dose of 10 mg/kg/day (as monotherapy), 5 the 4 children with a previous history of hypersensitivity
mg/kg/day (with VPA), or 15 mg/kg/day (with enzyme to other AEDs recovered completely.
inducers).15 The risk of drug induced rash was explained
Also, 4 out of the 5 children not on concomitant
to al parents, who were instructed to stop and seek VPA therapy recovered wel when compared to only
medical advice at the first sign of such eruptions. They 3 of the 10 patients on VPA (Table 1
). We continued
were warned that the rash could become more severe if LTG in one case (patient 10) as the rash disappeared
they do not stop the drug immediately. Fol ow up by spontaneously after dose reduction. The remaining
one pediatric neurologist was performed to document 8 (3.9% of the total) had severe rash that necessitated
the occurrence of skin rash. The period of fol ow-up admission to hospital for symptomatic therapy. Seven
visits were standardized at 2, 4, and 6 weeks after LTG out of these 8 children were also receiving VPA. These
introduction. To be included, diffuse erythematous rash children had targetoid lesions with diffuse erythematous
should have been recognized 1-4 weeks fol owing LTG maculopapular eruptions. One child (patient 14) had
therapy and documented by the treating physician. superimposed secondary bacterial infection and we
Patient and disease related data were col ected at the time admitted him for intravenous antibiotic therapy. Two
of initial presentation with skin rash. Clinical course and other admitted children recovered slowly with extensive
outcome data were also col ected on fol ow-up visit or post-inflammatory cutaneous pigmentary change on
fol ow-up. This slowly recovered over a period of few
- Clinical details of 15 children with Lamotrigine-related skin rash.
PHB - Phenobarbitone, VPA - Valproic Acid, TPM - Topiramate, CBZ - Carbamazepine, SJS - Stevens-Johnson syndrome, TENS - toxic epidermal necrolysis
Lamotrigine-related skin rash . Jan
months. We diagnosed SJS in 5 (2.4% of the total) regimen, immediately before and during LTG therapy.
children with additional erosions of the conjunctiva, They did not start LTG within 2 weeks of a rash, viral
oral, and genital mucosa. One of these 5 children (patient il ness, or vaccination. They also asked their patients
4) had progressive symptoms that evolved to toxic to avoid new medications, new foods, detergents, and
epidermal necrolysis (TEN), confirmed by skin biopsy. fabric softeners in the first 3 months of treatment.
He required prolonged ICU admission and developed Fol owing these recommendations, skin rash occurred
sepsis with disseminated intravascular coagulopathy. He in 5% of their patients.9 Milder maculopapular skin
deteriorated despite supportive therapy and died 5 weeks rash beginning within 2 weeks of therapy may disappear
spontaneously in some patients, despite the continuation
of therapy.13 This is similar to one of our patients where
The patients described herein the rash disappeared spontaneously after dose reduction.
confirm that LTG-related skin rash is potential y The rash was mild with complete recovery after LTG
serious, as approximately 4% of the children required discontinuation in 7 of our 15 children. Recently, some
hospitalization, 2.4% had SJS, and one child died authors reported successful rechal enge with LTG after
with TEN. In general, children are at increased risk the initial drug-induced rash.7 It is possible that the rash
for developing LTG-related skin rash when compared in some of these children was not related to LTG, which
to adults.10 Increased liver cytochrome P450 catalyzed explains the successful rechal enge. Reintroducing LTG
metabolism could result in increased formation of the in children with history of rash that developed within
reactive metabolite and a higher incident of rash.10 In the first 4 weeks of therapy should be taken with extreme
addition, children frequently receive higher mg/kg doses caution. Such a child may be sensitized to LTG, which
resulting in increased LTG reactive metabolites. We had results in a stronger and severer reaction if LTG is
a lower overal incidence of skin rash (7.2%) as compared reintroduced. Of possible relevance is a rare LTG-related
to the rate in other studies (8-20%), most likely because lupus case diagnosed in an adult female patient.19 Her
of our dosing and slow increment. Other authors used symptoms and lupus serology gradual y normalized after
an even lower initial dose (5 mg/day) and much slower drug withdrawal.19
titration by 5 mg every 2 weeks.7,9 The incidence of
To conclude, LTG is a novel antiepileptic drug
LTG-related skin rash in these studies was 5-6%. Most of with a favorable therapeutic profile. The drug has good
our children with severe rash (8/15) were also receiving tolerability; however, skin rash is a potential y serious
VPA (7/8), which is similar to other literature reports.16 adverse event that the parents should careful y monitor
Valproic acid interferes with the metabolism of LTG by and promptly report to the treating physician. Although
inhibiting hepatic glucuronides, leading to increased the risk is smal , we should weigh this against the
LTG blood levels.12,16 Therefore, LTG dose should not potential benefits, particularly in children on VPA.
Steven and Johnson described SJS in 1922. The Acknowledgment. I grateful y acknowledge the Pediatric
syndrome includes systemic symptoms (fever) and a Consultants at King Abdul-Aziz University Hospital who participated
with their referred patients. I particularly would like to thank Prof. Ali
variety of skin and mucous membrane lesions including Shaabat for his support, advice, and guidance.
erythematous papules, targetoid lesions, bul ae, and
erosions.17 It is a hypersensitivity reaction to infections References
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after LTG therapy with a rapidly progressive rash. They 3. Choi H, Morrell MJ. Review of lamotrigine and its clinical
discontinued the LTG and he recovered after 26 days of
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