General Hospital Psychiatry 36 (2014) 761.e9–761.

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General Hospital Psychiatry

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Case Report

Comorbidity of Stevens–Johnson syndrome and neutropenia associated

with lamotrigine: a case report
Norio Yasui-Furukori, M.D., Ph.D. ⁎, Kojiro Hashimoto, M.D., Koji Tsuruga, M.D., Kazuhiko Nakamura, M.D., Ph.D.
Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki 036–8562, Japan

a r t i c l e i n f o a b s t r a c t

Article history: A 19-year-old woman with a medical history of depressive mood arrived and was treated with lamotrigine at
Received 5 January 2014 25 mg/day. On day 10, a high fever of 39.3°C and a diffuse, erythematous, pruritic full-body rash involving the
Revised 21 July 2014 palms of her hands and the soles of her feet developed, and she was diagnosed with Stevens-Johnson
Accepted 22 July 2014
syndrome (SJS). On day 17, white blood cell count (WBC) result was 1,240/μl with 54.1% neutrophils (670/μl),
and the WBC decreased to 840/μl with 60.7% neutrophils (510/μl) on day 18. The trend toward improvement
Keywords:
Stevens–Johnson syndrome
included skin symptoms after steroid pulse therapy using 1000 mg/day. Based on the clinical course, we
Neutropenia concluded that the SJS and leukopenia and/or neutropenia are associated with lamotrigine. Monitoring of
Lamotrigine WBC should be kept in mind when administering lamotrigine.
Comorbidity © 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
Bipolar disorder (http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction
Lamotrigine is widely used in the treatment of epilepsy and bipolar
disorders. Although its precise mechanism of action remains
unknown, it is believed to act as an anticonvulsant via an effect on
sodium channels. In vitro pharmacological studies have suggested
that lamotrigine inhibits voltage-sensitive sodium channels, leading
to a stabilization of neuronal membranes and a consequent
modulation of the presynaptic transmitter release of excitatory
amino acids, such as glutamate and aspartate [1]. This pharmacolog-
ical profile may explain the therapeutic effects of this drug on bipolar
disorder [1]. A serious rash was defined as one that required a
hospitalization and included Stevens–Johnson syndrome (SJS) and
toxic epidermal necrolysis (TEN). SJS and TEN are severe, life-
threatening reactions that have been associated with over 100
medications [2,3]. These reactions are characterized by erythema
and tenderness of the skin and mucosa, fever, skin blistering or
crusting, ulceration of the mucous membranes, and subepidermal
separation. SJS is defined as epidermal detachment of less than 10%,
and TEN refers to epidermal detachment that exceeds 30%; transi-
tional SJS–TEN is defined as 10%–30% epidermal detachment.
Mortality rates for SJS and TEN are 5% or less and 25%–30%,
respectively [2,3]. The reported frequency of serious rash in adults
using lamotrigine for adjunct therapy in epilepsy is 0.3% [1]. In clinical
trials of lamotrigine for the treatment of bipolar and other mood
disorders, 0.08% of adults receiving lamotrigine as monotherapy
developed rashes [1]. Most cases occurred within 2 to 8 weeks of
⁎ Corresponding author. Tel.: +81 172 39 5066; fax: +81 172 39 5067.
E-mail address: yasufuru@cc.hirosaki-u.ac.jp (N. Yasui-Furukori).
treatment. Numerous case reports have described SJS and TEN in adult
patients receiving lamotrigine for antiepileptic indications [4];
however, reports of these dermatological reactions in patients
receiving lamotrigine for the treatment of bipolar disorder are limited
[5–8]. We encountered a case involving not only SJS but also
leukopenia and/or neutropenia during lamotrigine treatment.
2. Case
A 19-year-old woman with a medical history of atopic dermatitis
arrived at our hospital. She had suffered from a depressive mood for
3 months. Her diagnosis was bipolar disorder II due to her current major
depressive episode and a previous hypomanic episode. Lamotrigine at
25 mg/day was initiated and increased to 50 mg/day on day 10.
Although the mental status of the patient recovered immediately, a high
fever of 39.3°C and a diffuse, erythematous, pruritic full-body rash
involving the palms of her hands and the soles of her feet appeared on
day 13 (Fig. 1B and D). She went to a primary clinic, and the results of
laboratory tests were nearly normal with the exception of her white
blood cell (WBC) count, which was 2400/μl. She took 600 mg/day
ibuprofen and 120 mg/day fexofenadine for 3 days. In addition to rash,
slight bumps also appeared on her lips, spreading to her oral mucosa and
beginning to appear vesicular and crusty (Fig. 1C). However, conjunctiva
or genital mucosa was not involved. Lymphadenopathy, organomegaly,
and eosinophilia were not observed. We suspected a side effect
associated with lamotrigine and discontinued the medication on day
14. On Day 17, because of the SJS and WBC result of 1240/μl with
neutrophils 54.1% of 670/μl, we admitted her to the psychiatric ward
after consultation with dermatologists. Other laboratory tests, including
aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl

http://dx.doi.org/10.1016/j.genhosppsych.2014.07.010
0163-8343/© 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
761.e10 N. Yasui-Furukori et al. / General Hospital Psychiatry 36 (2014) 761.e9–761.e11
transferase, lactate dehydrogenase and C reactive protein, were normal.
Steroid pulse therapy using 1000-mg/day per drop infusion of
intravenous methylprednisolone injection was administered for
3 days on the same day. A pathological examination revealed that a
high level of apoptosis and a low level of lymphocyte permeation were
observed in the epidermis, with apoptosis and granulation tissue
formation at the dermis/epidermis basal layer (Fig. 2A and B). Her
symptoms and dermatological manifestations revealed a slight
improvement. However, the WBC decreased to 840/μl with neutrophils
60.7% 510/μl on day 18, but recovered to 3170/μl with neutrophils
72.9% 2310/μl on day 19 and increased to 6150/μl with neutrophils 55.5%
3410/μl and 4440/μl with neutrophils 72.4% 3210/μl on day 20 and day
24, respectively. Because the trend toward improvement included
skin symptoms, the steroid dose was gradually decreased from 60 to
30 mg/day on day 27, and she was discharged. Her mental status
remained stable.
3. Discussion
The present case demonstrated that SJS and leukopenia and/or
neutropenia developed after lamotrigine administration and recovered
after the discontinuation of lamotrigine. Based on the clinical course, we
concluded that the SJS and leukopenia and/or neutropenia are associated
with lamotrigine, and this is the first report to make this assertion.
Though one case series study suggested that comorbidity between SJS
and leukopenia and/or neutropenia is common (56%) [9], another such
study demonstrated that leukopenia was not commonly observed with
SJS, appearing in 2 of 29 cases (6.9%) [10]. Neither of these cases was
associated with lamotrigine. The time course for starting the reaction
and prodromal symptoms, such as fever, in this case was typical.
A)
C)
Fig. 1. This clinical photograph shows skin eruptions, erythematous papules and superficial erosions in addition to atypical target lesions, which are primarily located on the face
(A), hands (B) and arm (C) of the patient. Mucosal involvement with mild oral labial ulceration and superficial keratoconjunctivitis (D).
An antiepileptic drug hypersensitivity syndrome (AHS) is
characterized by fever, internal organ involvement and rash.
Mucous membrane involvement is neither as prominent nor as
severe as in SJS and TEN. Fever and systemic syndrome typically
precede or are coincident with cutaneous eruption. Occasionally,
patients develop a rash first and then rapidly develop fever with
other systemic symptoms. Rash usually begins with patchy
macular erythema that may become pruritic and papular, which
was not observed in this case. A review revealed 18 cases before
2004. Among these cases, fever and rash were noted in 100% of
patients. Specifically, maculopapular rashes were observed, with
elevated transaminase levels and eosinophilia being the next
most common findings. Neutropenia was observed in only 4
(22%) of the 18 patients suffering from AHS [11]. In addition, no
abnormality was observed in our case with respect to liver
function tests, peripheral lymphadenopathy, eosinophilia or
increased C reactive protein, which represent the constellation
of clinical and laboratory features of AHS [12]. We therefore
concluded that the present case does not follow the typical
symptoms and clinical features of AHS.
The cross-sensitivity rates of skin rash between certain antiepi-
leptic drugs are high, particularly when involving carbamazepine,
phenytoin and lamotrigine [13]. The cross-sensitivity rates from
lamotrigine to carbamazepine are 26.3%, those from lamotrigine to
phenytoin are 38.9%, and those from lamotrigine to oxcarbamazepine
are 20.0%. Therefore, other antiepileptic agents should be avoided in
the case of potential cross-sensitivity reactions.
In conclusion, we encountered a case of comorbidity between
SJS and leukopenia and/or neutropenia during lamotrigine treat-
ment. Monitoring of WBC should be kept in mind when adminis-
tering lamotrigine.
B)
D)
 N. Yasui-Furukori et al. / General Hospital Psychiatry 36 (2014) 761.e9–761.e11
A)
Fig. 2. The photomicrograph shows the vacuolar change in the basal layer of epidermis, with early separation of the basal layer from the papillary dermis (A). Apoptosis of individual
keratinocytes and granulation under dermis and apoptosis and lymphocytic infiltrate in the epidermis are noted (B) (hematoxylin and eosin, ×100).
Declaration of interests
Norio Yasui-Furukori has received grant/research support or
honoraria from, and been a speaker for, Astra, Dainippon, Eli
Lilly, GSK, Janssen-Pharma, Meiji. Mochida, MSD, Otsuka, Pfizer,
Takada and Yoshitomi. The remaining authors declare that they
have no competing interests. The funders had no role in study
design, data collection and analysis, decision to publish or pre-
paration of the manuscript.
Acknowledgments
The authors would like to thank all of their coworkers and
dermatologists and hematologists of Hirosaki University Hospital on
this case for their skillful contributions.
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