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Case presentation
Overlap Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: a case report
Overlap Stevens-Johnson Syndrome/Toxic
Epidermal Necrolysis: a case report
Overlap Sindrom Stevens Johnson/Necroliza
epidermică toxică: prezentare de caz
Dr. Radu-Nicolae Grigore(1), A/Prof. Carmen Maria Sălăvăstru(1,2), Prof. Dr. George Sorin Țiplică(1,2)
(1)
- 2nd Clinic of Dermatology, Colentina Clinical Hospital
(2)
- University of Medicine and Pharmacy “Carol Davila”, Bucharest, Romania
Corresponding author:
A/Prof. Carmen Maria Sălăvăstru, 2nd Clinic of Dermatology, Colentina Clinical Hospital,
Șoseaua Ștefan cel Mare Nr. 19-21, Bucharest, Romania
Email: [email protected]
Open Access Article
Abstract
Keywords:
Stevens Johnson
Syndrome, Toxic
Epidermal Necrolysis,
Lamotrigine,
Overlap SJS / TEN
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are
rare but potentially lethal acute dermatologic condition. SJS and TEN can
be induced by drugs. We present the case of a 30 year-old woman who
was admitted for generalized skin eruption consisting of erythematous,
dusky-red macules which evolved to flaccid blisters, painful mucous
erosions, conjunctivitis, malaise, fever and chills. Three weeks before
admission she started taking Lamotrigine for bilateral temporal arachnoid
cysts. Based on the affected body surface area (> 10%, but <30%) the
diagnosis was: Overlap SJS/TEN induced by Lamotrigine. The patient was
successfully treated with corticosteroids and supportive measures and was
discharged after 26 days in good health. The chronic complications that
occurred, involved the eyes (entropion, trichiasis) and nails (onychomadesis
and nail plate detachment).
Rezumat
Cuvinte-cheie:
Received:
August 2014
Accepted:
September 2014
Cite this article:
Dr. Radu-Nicolae
Grigore, A/Prof. Carmen
Maria Sălăvăstru, Prof.
Dr. George Sorin Țiplică,
Overlap Stevens-Johnson
Syndrome/Toxic Epidermal
Necrolysis: a case report.
RoJCED 2014; 1(1):28-31.
28
Sindrom Stevens
Johnson, necroliză
epidermică toxică,
lamotrigină,
overlap SJS / TEN
Sindromul Stevens-Johnson (SJS) şi necroliza epidermică toxică (TEN) sunt
afecţiuni dermatologice rare, acute şi cu potenţial letal. SJS şi TEN pot fi
induse de medicamente. Prezentăm cazul unei femei în vârstă de 30 de ani
care a fost internată pentru o erupție cutanată generalizată constituită din
macule roșii-violacee pe care s-au dezvoltat bule flasce, eroziuni mucoase
dureroase, conjunctivită, stare generală alterată, febră și frisoane. Cu 3
săptămâni înaintea internării pacienta a început tratament cu Lamotrigină
pentru chisturi arahnoidiene temporale bilaterale. A fost stabilit
diagnosticul Overlap SJS/TEN indus de Lamotrigină datorită suprafeței
corporale afectate mai mare de 10%, dar mai mică de 30%. Pacienta a
fost tratată cu succes folosind terapia cu corticosteroizi și măsuri suportive
și a fost externată după 26 de zile cu stare generală bună. Singurele
complicații cronice au fost afectarea oculară (entropion și trichiazis) și
unghială (onicomadeză).
R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY
Radu-Nicolae Grigore, Carmen Maria Sălăvăstru, George Sorin Țiplică
Introduction
Stevens-Johnson syndrome (SJS) and toxic
epidermal necrolysis (TEN) are rare but potentially
lethal acute adverse drug reactions, characterized
by erythema and epidermal detachment of the skin
and mucous membranes. They are estimated to
occur in 1–3people/million/year in Europe and the
USA(1, 2). They are characterized by a low incidence
but high mortality, and drugs are most commonly
implicated in 80% of cases(3, 4).
The most common triggers are antibiotics,
nonsteroidal anti-inflammatory drugs and
anticonvulsants. Symptoms usually occur
within 1–3 weeks after the first drug intake.
Pathophysiology of the disease is characterized
by cytotoxic T-lymphocytes and other cytokine
pathways which cause keratinocyte apoptosis(5).
It presents clinically with cutaneous purpuric
macules disseminated over the trunk and limbs and
characteristic periorificial purpuric macular lesions
covered by hematic crusts. Oral mucosa is affected
(painful erosions covered by membranes) and
also conjunctivitis can be present. The skin lesions
progress to superficial (epidermal) necrosis. A
positive Nikolsky sign can be elicited, and the skin
resembles wet cigarette paper when detached(6).
The SJS and TEN are considered the same
disease process; the distinction is made based
on body surface area involvement. The SJS is
characterized by <10% of the body surface area
of epidermal detachment, SJS/TEN overlap by
10–30%, and TEN by >30%(7).
The SCORTEN level(7) is used to predict disease
severity and mortality, and is calculated within
24 hours of admission and on day 3. The score is
the sum of 7 variables, each contributing 1 point,
including the following: (1) Age > 40 years; (2)
Heart rate > 120 beats per minute; (3) Positive
cancer history; (4) Epidermal detachment > 10%
body area; (5) Blood urea nitrogen > 28 mg/dL;
(6) Glucose > 252 mg/dL; (7) Bicarbonate < 20
mEq/L. A score of 2 or less is associated with a
maximum of 12% mortality; a score of 4 predicts
58% mortality, and a score of 5 or more is predictor
for a 90% death rate(8).
SJS/TEN positive diagnosis relies on clinical
symptoms and on histological features: full
thickness epidermal necrolysis due to extensive
keratinocyte apoptosis(9).
Differential diagnosis includes Erithema
multiforme major, Acute generalized exanthematous pustulosis, Generalized bullous fixed
drug eruption, Thermal burns, Chemical burns,
Phototoxic reactions, Paraneoplastic pemphigus
and Staphylococcal scalded skin syndrome.
Several therapies have been proposed, with
contradictory results. Currently, intravenous
immunoglobulins (IVIG) and plasmapheresis are
considered most effective(10, 11). Corticosteroids are
Figure 1. The skin lesions at admission to hospital: 9% of body
surface area was involved. Note the “atypical target”
aspect that the lesions presented
effective if administered within 72 h from the onset
of first symptoms(12). The use of Cyclosporine A was
associated with lower levels of hepatic, renal and
cardiac injury and lower mortality(13).
Despite the increased knowledge regarding the
immunological aspects, only prompt withdrawal of
suspect medication and general management of
the patient as a burn patient are the only evidencebased therapies(14,15).
Case report
A 30 year old non-smoker female patient
presented with generalized skin eruption
consisting of erythematous, dusky-red macules
which evolved to flaccid blisters, painful mucous
erosions, conjunctivitis affecting both eyes,
malaise, fever and chills. The patient had no history
of allergies and was diagnosed 6 months before
admission with bilateral temporal arachnoid cysts
(right one 15/19/10 mm, left one 32/31/23 mm).
The patient was on Valproic acid 1000 mg/
day for the past 6 months (for chronic headache
induced by the arachnoid cysts). Three weeks
before admission her neurologist decided to
replace Valproic acid with Lamotrigine 25 mg/day
with progressive increase of dosage, because the
patient was willing to obtain a pregnancy. One
week before symptoms began, the patient was on a
50 mg of Lamotrigine/day dose. Symptomatology
began 2 days before admission and she was
treated as outpatient with antihistaminics and
intravenous Hydrocortisone hemisuccinate.
The clinical examination revealed fever (39.1oC)
and slight tachycardia (100 beats/minute).
Examination of the skin and mucous membranes
revealed generalized skin eruption consisting
of erythematous, dusky-red, irregularly shaped
macules, with symmetrical distribution, atypical
target lesions with dark center, which evolve to
flaccid blisters (with 9% of BSA that presented a
October 2014
29
Case presentation
Overlap Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: a case report
Figure 2. Patient in the 10th day of admission:
27% of body surface area was involved
positive Nikolsky sign at admission (Figure 1). On
face, neck, palms and soles the lesions tended to
coalesce. The patient had erosions, grayish-white
pseudomembranes on the surface of the lips,
oral cavity and tongue erosions. Both eyes were
affected by conjunctival hyperemia, grey-yellow
adherent pseudomembranes. Genital erosions
were also present. All the skin and mucous lesions
were extremely painful.
Lab tests at admission showed hiperglycaemia –
152 mg/dl, slightly elevated liver enzymes, slight
lymphopenia and thrombocytopenia.
The patient was treated with corticosteroids in
high doses for the first three days (1 g/day), then
the dosage was tapered. Antipyretics, antibiotics,
anticoagulants, fluid replacement solutions,
diuretics and vitamins were also used. The patient
was fed with standardized solutions with high
calories count (1 mL = 1 kcal). Lamotrigine was
excluded from the patient’s treatment scheme and
Acetaminophen was used instead for the patient’s
headaches.
Topical treatment with antiseptics, colloidal
silver cream, corticosteroids and biomembrane
dressings were used for the skin lesions. Mucous
lesions were treated with antibiotics and
corticosteroids.
Blood pressure, pulse, body temperature and
renal function were closely monitored and the
patient was seen by an Ophthalmologist every day.
New lesions continued to appear during the first
10 days of admission. Older lesions followed their
course leaving massive areas of skin denudated.
30
By day ten 27% of BSA was affected (Figure 2).
Mucous membranes became more and more
affected, causing difficulty to eat and breath. The
patient was able to open the eyes with great effort.
Fever ceased after the 5th day of admission.
The laboratory tests showed: leucopenia,
neutropenia and thrombocytopenia, elevated
liver enzymes (4x normal values), anemia (HGB –
9.52g/dL), hyperglycemia (maximum value 195
mg/dL), hypoalbuminemia (lowest value 2.52 g/
dL), hypoproteinemia (lowest value 4.28 g/dL)
and hypokalemia (lowest value 3.01 mmol/L).
Treatment was supplemented with human albumin
and potassium. Urea and creatinine had normal
values during the hospitalization.
SCORTEN in the 3rd day after admission was 1
(BSA=11%) and stayed the same during admission
period. Predicted mortality based on SCORTEN
was 3.2%.
No new lesions occurred after the 10th day,
the areas of skin which were denudated began
to heal (Figure 3), the mucous membrane lesions
healed at a lower pace than the skin lesions and
the lab test results slowly returned to normal
values. Her headaches were easily controlled with
acetaminophen during hospitalization.
Discussions
Anti-epileptic drugs can be associated
with a wide spectrum of cutaneous adverse
reactions. These rashes are well documented
with older antiepileptic drugs like phenytoin,
phenobarbital and carbamazapine. Lamotrigine
is a newer antiepileptic drug used in the
treatment of partial and generalized seizures
and as maintenance treatment of bipolar I
disorder(16, 17). It is known to cause skin rashes in
3-10% of new users(18). Several factors are likely to
increase the development of serious rashes. Coadministration of valproic acid with lamotrigine
significantly increases the risk for development
of serious adverse cutaneous reactions(19).
It has been hypothesized that valproic acid
interacts with lamotrigine by inhibiting its
hepatic inactivation. The elimination half life of
lamotrigine when used as monotherapy is 25-30
hours and it is more than doubled to 60 hours
when combined with valproic acid(20,21). It has
also been suggested that a high starting dose
and a rapid dose escalation may increase the
occurrence of skin rashes with lamotrigine(19,21).
Severe cutaneous reactions to antiepileptic
drugs are more frequently associated with
female sex, probably due to hormonal factors(22).
The skin lesions in SJS/TEN are similar to seconddegree burns(3) and lead to extreme pain, massive
loss of fluid and protein, bleeding, evaporative
heat loss with subsequent hypothermia, and
infection. Our patient didn’t suffer an infection
of the cutaneous lesions, thus the prognosis
R O M A N I A N J O U R N A L o f C L I N I CA L a n d E X P E R I M E N TA L D E R M ATO LO GY
Radu-Nicolae Grigore, Carmen Maria Sălăvăstru, George Sorin Țiplică
remained favorable. She did suffer tough a
massive loss of fluid and proteins that required
prompt intervention. She received important
quantities of replenishment fluids, electrolytes
and human albumin. A patient with TEN is suffering
from “acute skin failure” and the condition can be
complicated by major metabolic abnormalities,
sepsis, multi-organ failure, pulmonary embolism
and gastrointestinal hemorrhage(23). Our patient
did not suffer any of those complications. Apart
of the acute complications, SJS/TEN patients
can develop long term complications: late
ophthalmic complications (synblepharon, corneal
ulcerations, ectropion, entropion, trichiasis,
dryness of the eye), postinflamatory skin hypo/
hyperpigmentation, nail plate abnormalities,
genital complications (dyspareunia, dryness,
pain, bleeding, adhesions), post traumatic stress
disorder. At a follow-up visit one month after checkup the patient had disseminated hyperpigmented
macular lesions, onychomadesis, entropion,
trichiasis and dry eyes. At the two months followup visit the main complaints of the patient were
eye dryness, entropion and trichiasis. New nail
plates were growing normally on all fingers. The
patient had no episode of headache that couldn’t
be controlled by using acetaminophen during
those two months after discharge.
Conclusions
Skin failure can be induced by antiepileptic
drugs. Lamotrigine or lamotrigine potentiated
by previous chronic intake of valproic acid
Figure 3. Patient in the 15th day of admission (left image)
versus the 26th day of admission (right image)
was the inducer of the SJS/TEN overlap in our
patient. The avoidance of skin supra-infection
and the iv support (albumin, potassium) were
essential in the recovery of the patient.
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