Case report Carbamazepine partial erytroderma 
Serious drug reactions to carbaT110zepine 
in oncologic patients 
after x-ray treatlllent. 
Repo rt oj four cases 
A. Kansky, A. Vodnik and L. Stanovnik 
SUMMARY 
Carbamazepine is a valuable and widely used drug tor treatment and prevention ot epileptitorm fits and 
turther neurological conditions. Milder general symptoms like dizziness ar drowsiness or cutaneous side 
effects like rashes, pruritus, urticaria, or multitorm erythema are not unusual. Sometimes serious cutane-
ous adverse reactions e.g., Stevens Johnson syndrome, generalized erythroderma or even toxic necrolysis 
may appear. 
We report on tour cases: in three temale patients, who have been operated tor malignant brain tumors 
and were given carbamazepine tor prevention ot seizures, partial erythroderma developed; the fourth 
died tram toxic epidermal necrolysis. AII were treated with x-rays, in the temale patients cutaneous 
manitestations disappeared atter systemic treatment with corticosteroids and replacement ot 
carbamazepine with other anticonvulsive drugs. 
Introduction 
Carbamazepine (CBZ) (Tegretol", Novartis), is avalu-
able and widely used anticonvulsant, but also anti-
neuralgic, antimanic and antidepressant drug. It is used 
for treatment of partial seizures, both simple and tonic-
clonic. It is preferred over phenobarbital for children 
because it has fewer adverse effects on behavior and 
alertness. The drug is also effective in treating pain of 
neurological origin (neuralgia), psychiatric disorders, 
including schizophrenia (1) manic depressive illness (2) 
and even aggression due to dementia. These numer-
ous indications explain the wide spread use of the drug. 
On the market it is available under a score of trade names 
e.g. CarbatroJI' (Shire Richwood), Epito]R (Tave) as well 
as others. 
A number of usually not dangerous side effects are 
known. General symptoms like dizziness, drowsiness, 
vomiting, diplopia, abnormal liver fuil.ction or bone-
marrow suppression may disappear after continued 
treatment at reduced dosage. Very rare side effects are 
aplastic anemia, agranulocytosis or thrombocythopenia. 
The frequency of cutaneous drug reactions due to 
carbamazepine (CBZ) is generally assessed at 3 to12 o/o 
Acta Dermatoven APA Vol 11, 2002, No 3 --- -----------------JOf 
Carbamazepine partial erytroderma 
(3,4). Cutaneous adverse effects like rashes, urticaria, 
pruritus, e1ythema, alteration of skin pigmentation, hir-
sutism or alopecia are not rare. More serious events like: 
syndrome Stevens Johnson, erythematous lupus , gen-
eralized erythroderma, purpura Henoch-Schonlein or 
even toxic necrolysis are also described. CBZ hyper-
sensitivity syndrome includes fever, lymphadenopathy 
ancl rash. Photosensitivity, pseudolymphoma are also 
mentioned. Cross sensitivity to oxacarbazepine, phe-
nytoine or barbital is possible. In his manual Litt men-
tionecl 326 references on cutaneous sicle-effects to CBZ 
(5). 
We report on severe drug reactions in four patients. 
Three females were opera teci because of malignant brain 
tumors ancl were given CBZ (TegretolR) for prevention 
of seizures. All three were after the brain operation 
treatecl with x-rays. A further patient was given carba-
mazepine because of brain metastases due to malig-
nant melanoma. 
Case reports 
Case 1. 
The 51-year-old female patient BB underwent a radi-
cal operation for a brain tumor locatecl in right parietal 
hemisphere on November 11, 2000. The cliagnosis was 
confirmecl by magnetic resonance imaging (MRI). Af-
ter the operation she received methylprednisolone 
(MeclrolR, Pharmacia & Upjohn) 32 mg daily. Due to 
symptomatic epileptic fits carbamazepine (TegretolR, 
Pliva), 200+200+400 mg was given. Xray treatment was 
also introcluced. 
About a week after the first X-ray dose a rash started 
to appear. Dermatologic examination revealed e1ythema 
a11d edema of the face as well as large areas of erythema-
tous skin on the chest, around the waist a11cl 011 the 
gluteal area. Similar lesio11s were on the extensor sites 
of arms, while on the clistal parts of the extremities a 
macular ancl papular rash was visible. Figures 1 a11cl 2. 
An increase of the methylpred11isolo11e close to 64 mg 
daily and the replacement of carhamazepine with 
valproic acicl (ApilepsinR, Krka & Sanofi) 450+300+450 
mg was suggested. At five weeks after the operation ali 
cutaneous symptoms were gone. 
Case 2. 
The 50-year olcl female patient M.Z. was operated 
011 November 8, 2000 because of a11 expancling brai11 
tumor of the left tempo ral lobe. The tumor was removed 
completely, histopathology showed a glioblastoma. The 
patient was given methylprednisolone (MedrolR) 32 mg 
and CBZ (Tegretol) 2 times 200 mg. Adclitionally she 
receivecl also X-ray treatment. 
About two weeks later a maculo-papular rash was 
obse1ved, which in a few days expanded into a pruritic 
erythema covering mainly the chest and extremities. 
Figure 3. The consulting dermatologist diagnosed a drug 
eruption, most probably due to CBZ. He suggestecl an 
increase of the methylprednisolone close to 64 mg and 
the replacement of CBZ. The neurologist proposed 4 
mg of diazepam (Apaurin'\ Krka) as replacement 
therapy. When the patient came for a reexamination 
four weeks after the operation, the rash has almost com-
pletely faded away. 
Case 3. 
The 31-year-old female patient G.K. suffered for 
about one year from seizures ancl spasms. Valproic acid 
relieved her of seizures, but spasms persisted. MRI dis-
closed an expanding brain tumor of the left fronta! lobe. 
October 14, 1999 the tumor was surgically removed and 
histopathology confirmed a malignant oligodendro-
glioma. The patient was additionally treated by x-rays. 
After the operation CBZ and later on also phenytoine 
(Difetoin'\ Pliva) were introduced. Shortly after the in-
troduction of the antiepileptics a pruritic rash with signs 
of a begi11ning erythroderma appeared. When CBZ was 
replaced with valproic acid 3 x 450 mg and primiclone 
(PrimidonR, Pliva) the cutaneous symptoms clisap-
pearecl. 
Case 4. 
This case is mentionecl only shortly as a11 extendecl 
publication is scheclulecl to be publishecl elsewhere. 
The 55-year old male patient was operated March 7, 
2000 for a Clark IV, Breslow V stage malignant mela-
noma on his back In Ja11uary 2001 computerized to-
mography disclosecl a melanoma metastasis in his brain. 
He was treated by x-rays , 011Ja11ua1y 7, CBZ 2 x 200 mg 
was given to prevent epileptic seizures. Four weeks la ter 
a macular rash started to appear on the lower half of his 
trunk, which continuously spread all over the body. 
Soon the whole skin of the face and chest became reci 
ancl large erosions started to appear. On February 15 
the diagnosis of toxic necrolysis w as made. Although 
he obtainecl all the 11ecessa1y care he died soon after-
wards. 
Discussion 
In three instances the developing erythroderma was 
recognized early enough, so that after a moderate dose 
of methylprednisolone claily and replacement of CBZ 
with valproic acid or other anticonvulsives, the patients 
recovered. The fourth patient with melanoma brain 
metastases, in whom toxic epidermal necrolysis clevel-
oped, has cliecl. It is interesting to note that the four 
patients unde1went an x-ray treatment far various ma-
Case report 
106 ----- - ---- ------------------------Acta Dermatoven APA Vol 11, 2002, No 3 
Case report 
Figure 1. Patient BB. Partial erythroderma due 
to carbamazepine (TegretolR). Large areas of 
erythematous skin appeared during 
Carbamazepine treatment, about one week 
after x-ray treatment tor cerebral tumor. 
lignant brain conditions, before or during the treatment 
with carbamazepine. 
CBZ is lipophilic and is distributed in CSF, brain, 
duodenal fluids , bile and saliva. The drug is 76% pro-
tein bound in adults. The plasma half-life is 25 to 65 
hours and falls to 12-17 hours after repeated dosing. 
Figure 3. Patient M.Z. Pruritic erythema 
covering mainly the chest and extremities, 
triggered by carbamazepine. The lesions 
appeared about 2 weeks after the x-ray 
treatment. 
Carbamazepine partial erytroderma 
Figure 2. Same patient 
CBZ is metabolized in the !iver by oxidation to an 
active metabolite, the carbamazepine 10,11-epoxide, 
which is subject to further hepatic metabolism. It is a 
potent enzyme inducer and can induce its own metabo-
lism, probablyvia CYP3A4 isoenzyme. Onset of enzyme 
induction is at about 3 days, with maximum effect at 
about 30 days. There is a high variability between indi-
viduals, concerning the extent to which induction oc-
curs. CBZ is excreted in the urine, 72% as unconjugated 
metabolites and only about 3% as unchanged drug, the 
rest is excreted in the feces (6,7). 
Unluckily, the diagnostic tests used for assessment 
of drug eruption like the blastic transformation of lym-
phocytes, macrophage inhibition and even determina-
tion of specific IgE are not reliable enough to confirm 
the diagnosis, and did not fulfill the expectations. There 
are some reports on positive patch tests to C BZ in pa-
tients suffering from eruptions due to this drug. It has 
been reported, however, that patch testing may rein-
troduce erythroderma (3,8). Mesec and cow. were able 
to prove contact hypersensitivity to. CBZ in a female 
patient with hypersensitivity syndrome (8). 
CBZ and its metabolite the 10,11-epoxide can be 
assayed in body fluids by immunbassay (9) and by high 
performance liquid chromatography (10), but these tests 
are not helpful for detecting allergy to CBZ. Thus the 
diagnosis of drug reaction to CBZ is stili based mainly 
on the patient's history, on the clinical experience of 
the physician, and on data from the literature. There is 
increasing evidence that T cells play a~ important role. 
The mechanisms of action of CBZ on the central 
nervous system are stili not completely understood. It 
blocks sodium channels by slowing their rate of recov-
ery from inactivation and thus inhibiting sustained re-
petitive firing. Like phenitoine CBZ reduces posttetanic 
Acta Dermatoven APA Vol 11, 2002, No 3 - ------------ - --- -107 
Carbamazepine partial erytroderma 
potentiation of synaptic transmission in the spina! cord. 
Pain relief is probably due to blockade of synaptic trans-
mission in the trigeminal nucleus. CBZ also shows anti-
cholinergic, antiarrhytmic, muscle relaxant, antidepres-
sant (possibly through blockade of nor adrenaline re-
lease), sedative and neuromuscular-blocking proper-
ties (6,7). 
Some authors believe that the CBZ acts on the cen-
tral nervous system similarly to lithium, which reduces 
the turnover of arachidonic acid. Lithium down-regu-
lates the gene expression and enzyme activity of cyto-
solic phospholipase A(2), an enzyme that selectively 
liberates arachidonic acid (11,12). 
Maculopapular eruptions are the most frequent hy-
persensitivity reactions to drugs (13). Erythroderma is 
a serious condition, especially when it has developed 
into a stable form, it is difficult to treat. Various drugs 
like pyrazolon derivatives, gold and lithium salts, cer-
tain anticonvulsants phenitoin, phenobarbital, CZB, 
primidon and clonazepam may cause erythroderma 
(14). Usually even the most severe drug reactions start 
as a macular or papular exanthema. Sigurdsson et al 
observed drug related erythroderma in 5 out of 102 
patients with erythroderma, CBZ was assumed to be 
the cause only in one case (15).Drugs are incriminated 
for triggering erythroderma in 5% (16) to 40% (17) of 
cases reported. 
Toxic epidermal necrolysis (TEN) is probably more 
often provoked by drugs. Blum et al reported that in 
one of theirlO TEN patients with toxic renal involve-
men t, the disorder was triggered by CBZ (18). 
Bahamdan mentioned a TEN patient, who developed 
also the toxic shock syndrome (19). Contrary to this , 
Lemitaphong et al did not incriminate CBZ in none of 
their 16 TEN cases, but considered CBZ responsible for 
four of their 44 cases with the Stevens Johnsone syn-
drome (20). 
The anticonvulsant hypersensitivity syndrome 
l ) f? ji' l{' l:) l/ t•T .r-;, R;' s . l . . ..t ... l.A . . l .J..',J ... " t. ... .l..".I'-....-
which is similar to toxic shock syndrome is character-
ized by high grade fever, ertythroderma, shock and in-
volvement of two or more organic systems: gastrointes-
tinal, renal, hepatic, musculoskeletal or central nervous 
system. The onset is usually between 4 weeks and 3 
months after starting the drug. CBZ was incriminated in 
a few instances (21,22). 
When an exanthema appears during the treatment 
with CBZ one bas to proceed very carefully: If the thera-
peutist decides not to withdraw CBZ, systemic corti-
costeroids should be introduced and the patient moni-
tored strictly. A better choice is to replace CBZ with 
another anticonvulsant, e.g.valproic acid, which seems 
to be safe. 
CBZ should be used with care in patients with atrio-
ventricular conduction abnormalities, or with a history 
ofblood disorders , cardiac, hepatic or renal disease and 
also in patienl~ with raised intraoccular pressure (4), as 
well as in patients simultaneously treated with x-rays. 
Conclusion 
CBZ is a widelyused and efficient drug, but one has 
to bear in mine! that serious complications like erythro-
derma, anticonvulsant hypersensitivity syndrome or 
TEN may develop. Eve1y rash appearing during CBZ 
treatment should be carefully monitored. If the thera-
peutist decides not to withdraw CBZ, we suggest that 
systemic corticosteroids should be introduced. A better 
choice is to replace CBZ with another anticonvulsant, 
e.g.valproic acid, which seems to be safer and to intro-
duce systemic corticosteroids. 
We firmly believe that due to the early recognition 
of the imminent erythroderma in the three female pa-
tients , the immediate replacement of CBZ with other 
anticonvulsants as well as the introduction of systemic 
corticosteroids prevented a more serious drug reaction. 
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disorder. Arch Gen Psychiatry 2002;59(7):592-6. 
3. Breathnach SM. Drug reactions. In: In RookA et al. Textbook ofDermatology, Champion RH et al eČ!s, 
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4. Martindale 30th ed. Reynolds JEF Editor. Antiepileptics/Carbamazepine 295-8. Pharmaceutical Press, 
London 1993. 
5. Litt JZ. Drug Eruption Reference Manual. Millennium ed. 2000 
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York 2002, 521-47 . 
Case report 
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Case report 
AUTHORS 1 
ADDRESSES 
Carbamazepine partial erytroderma 
8. Mesec A, Rot U. Perkovie T et al. Carbamazepine hypersensitivity syndrome presenting as vasculitis of 
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drugs on the IMMULITE 2000 automated analyzer. Am J Pathol 2002; 118: 124-31. 
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bipolar disorder? Arch Gen Psychiatry 2002; 59:592-6. 
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1973; 108: 788-97. 
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Dermatol 1996; 34: 1088-90 
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IntJDermatol 1995; 34: 661-4. 
20. Lemitaphong V, Sivayathorn A, Suthipinittharm et al. Stevens-Johnson syndrome and toxic epidermal 
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21. Handfield Jones SE, Jenkins RE, Wittaker SJ et al. The anticonvulsant hypersensitivity syndrome. Br J 
Dermatol 1993; 129: 175-7. 
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19(2): 142-5. 
Aleksej Kansky, MD, PhD, projessor oj dermatology, Dept. oj 
Dermatology, University Medical Centre, Ljubljana, Zaloška 2, SI-1525 
Ljubljana, Slovenia 
Alenka Vodnik, MD, oncologist, Institute oj Oncology, Zaloška 2, SI-1525 
Ljubljana, Slovenia 
Lovro Stanovnik, MD, PhD, projessor ojpharmacology, Institute oj 
Pharmacology, Medical Faculty, Iforytkova 7, 1000 Ljubljana, Slovenia 
Acta Dermatoven APA Vo l 11, 2002, No 3 ------------- ----- ~09