Generalized pustulosis and severe tubulointerstitial nephrophaty as manifestations of carbamazepine hypersensitivity syndrome

374 Letters to the Editor growth factor and its receptor mRNA in angiosarcoma. No statistical diVerences were found in serum VEGF Lab Invest 1995; 73: 859–863. levels between the other angiosarcoma patients (cases 2. Masood R, Cai J, Zheng T, Smith L, Naidu Y, Gill PS. 3–11) in whom the p53 gene point mutation was not Vascular endothelial growth factor/vascular permeability detected; these patients include those without metastasis factor is an autocrine growth factor for AIDS-associated (153 ±70 pg ml Õ1, range 65–223, n=4), those with Kaposi’s sarcoma. Proc Natl Acad Sci USA 1997; 94: metastasis to parotid lymph nodes (166 ±70 pg ml Õ1,979–984. 3. Naka N, Tomita Y, Nakanishi H, Araki N, Hongyo T, range 62–244, n=6), and those with remote metastasis Ochi T, et al. Mutation of p53 tumor-suppressor gene in (119 ±101 pg ml Õ1, range 7–269, n=7) (Fig. 1). angiosarcoma. Int J Cancer 1997; 71: 952–955. Because of serious heart failure, the patient who had 4. Masuzawa M, Fujimura T, Hamada Y, Fujita Y, Hara H, detectable p53 gene point mutation (case 1) was treated Nishiyama S, et al. Establishment of a human hemangiosarwith local radiation therapy alone. The other patients coma cell line (ISO-HAS). Int J Cancer 1999; 81: 305–308. were treated with surgery, radiation therapy, local or 5. Amo Y, Masuzawa M, Hamada Y, Takasu H, Fujimura T, Katsuoka K, et al. Serum levels of vascular endothelial systemic administration of recombinant interleukin-2 growth factor in a hemangiosarcoma patient with a new- (IL-2), and immunotherapy using IL-2 and IL-2typed p53 gene point mutation. Br J Dermatol 2000; 143: activated lymphocytes. The eVect of these treatments 1118–1119. may have contributed to the serum VEGF levels. 6. Amo Y, Masuzawa M, Hamada Y, Katsuoka K. Expression Therefore, serum VEGF levels may not be correlated of vascular endothelial growth factor in a human hemanwith clinical course in most cases of angiosarcomas giosarcoma cell line (ISO-HAS ). Arch Dermatol Res 2001; without p53 gene mutation. 293: 296–301. 7. Hollstein M, Sidransky D, Vogelstein B, Harris SR. p53 mutations in human cancers. Science 1991; 253: 49–53. REFERENCES 1. Hashimoto M, Ohsawa M, Ohnishi A, Naka N, Hirota S, Kitamura Y, et al. Expression of vascular endothelial Generalized Pustulosis and Severe Tubulointerstitial Nephropathy as Manifestations of Carbamazepine Hypersensitivity Syndrome David Moreno-Ramõ´rez1, Begona Garcõ´a-Bravo1, Antonio Rodrõ´guez-Pichardo1, Clotilde Rõ´os Camacho2and Francisco Camacho Martõ´nez1 Departments of 1Dermatology and 2Nephrology, University Hospital ‘‘Virgen Macarena’’, Seville, Spain. E-mail: [email protected] Accepted 3 June, 2002. Sir, severely aVected, accompanied by mild oedema. A large number of pinhead-sized pustules were observed on herAnticonvulsant hypersensitivity syndrome (AHS) is a multisystemic disorder with cutaneous changes and typface and upper back with an intensely erythematous skin (Fig. 1). A biopsy taken from these pustular lesionsical blood abnormalities that may be triggered by any of the aromatic antiepileptic drugs (1, 2). We present revealed follicular and non-follicular intraepidermic spongiform pustules, with a perivascular in ltration ofthe case of a patient who, following carbamazepine treatment, developed AHS with major cutaneous and lymph cells and eosinophils in the upper dermis. Vasculitis was absent. These histological changes weresystemic manifestations that are not common in the consistent with an acute generalized exanthematouscontext of this syndrome. pustulosis. Systemic examination revealed a deteriorated overall CASE REPORT condition of the patient, fever, hepatomegaly and swolA 26-year-old woman was referred to our department len bilateral inguinal lymph nodes. The  rst laboratory for evaluation of a 10-day history of malaise, fever of tests disclosed eosinophilia (13.5%) and elevated up to 40°C and a generalized exanthem. The patient liver function tests: aspartate aminotransferase 63 U/l had been on carbamazepine therapy (400 mg daily) for (0–37 U/l ), alanine aminotransferase 262 U/l (0– 1 month because of temporal epileptic seizures. She 40 U/l ) and gamma glutamyltranspeptidas e 335 U/l reported no previous history of drug allergies. (11–49 U/l ). Examination revealed a red-violet exanthem involving In view of the clinical and histological changes, we considered the case to be related to carbamazepine, sothe trunk, extremities, palms and soles; the face was Acta Derm Venereol 82 Letters to the Editor 375 patient was  nally discharged from hospital 30 days after admission. Once completely recovered, the patient was patchtested with carbamazepine 0.1%, 1%and 10%in petrolatum, showing positive results. Seven months later, she developed a morbiliform exanthem after 4 weeks of treatment with phenytoin, but on this occasion the eruption disappeared with no systemic involvement after withdrawal of the drug. DISCUSSION DiVerential diagnosis of generalized pustular eruptions in adults includes subcorneal pustular dermatosis, eosinophilic pustular folliculitis, pustular psoriasis and acute generalized exanthematous pustulosis, among others. AHS is one of the adverse eVects of aromatic antiepileptic drugs such as phenytoin, carbamazepine, phenobarbital and primidone. Most cases have been related to phenytoin and carbamazepine because they are more widely used (1, 2). The true incidence of this syndrome is not well established because of the lack of reliable diagnostic criteria. Nevertheless, among patients on carbamazepine treatment the incidence may range from 1:1000 to 1:10 000. Although the pathogenesis is not well understood, the most accepted hypotheses suggest the inability of these patients to detoxify certain oxides, which are formed Fig. 1. Mild facial oedema with pustules, erythema and desquamation. from the metabolism of anticonvulsants. Constitutional factors, HHV-6 infection and a speci c T-cell response, are also being discussed as possible pathogenic mechan-the treatment was discontinued and the patient was admitted for observation. The disease did not evolve isms (3). AHS clinical manifestations usually start 2 to 8 weeksfavourably, renal impairment developing into severe renal failure within a few days: creatinine 12.1 mg/dl after the initiation of anticonvulsant therapy and consist of fever, skin rash, lymphadenopathy, hepatopathy and(0.7–1.4 mg/dl ) and urea 121 mg/dl (18–38 mg/dl ). Urinalysis showed proteinuria (100 mg/dl ), leucocyturia eosinophilia (4, 5). Cutaneous changes are present in up to 87%of the patients with AHS, and usually consistand microhematuria. Serologic tests for ANA, antiDNA and ANCA antibodies were all negative. A renal biopsy of a morbiliform exanthem, although some cases of exanthematous pustulosis have been reported (1, 4).disclosed an acute tubulointerstitial nephritis with no involvement of glomeruli or vascular structures, and Fever is the most common systemic complaint and the liver is the internal organ most frequently aVected inwith no immune deposits on direct immuno- uorescence. Therapy with oral prednisone followed by this syndrome, with an incidence of 100%and 51%, respectively. Hepatic changes range from transitory highintravenous methylprednisolone was administered, but oliguric renal failure was severe enough to require transaminase levels to fulminant hepatic failure. This patient showed the mildest form of liver impairment.hemodialysis. Renal function gradually improved, allowing discontinuation of dialysis treatment. Her Renal involvement is not common, but when it is present a prerenal failure secondary to hypovolaemia is the mostrecovery was complete 4 weeks later. The liver and cutaneous symptoms resolved more frequent clinical feature. Our patient developed severe parenchymatous renal failure which, although notsatisfactorily, with complete remission 10 days after admission. Nevertheless, the patient developed a widecommon, has been described in isolated cases of AHS (1, 2, 6).spread exfoliation in the  nal stage of the cutaneous disease, and numerous micropurpuric lesions on her Treatment consists of discontinuing the suspected drug, regulation of nutritional and  uid imbalance and ngertips. A biopsy specimen taken from these micropurpuric lesions revealed non-speci c perivascular dermathe management of possible complications, which in this patient even required haemodialysis. Unlike ourtitis with no deposits on direct immuno- uorescence. These non-speci c lesions spontaneously faded and the case, the prognosis is good for most patients, with Acta Derm Venereol 82 376 Letters to the Editor spontaneous healing a few weeks after withdrawal of REFERENCES the drug (1, 2). 1. Schlienger RG, Shear NH. Antiepileptic drug hyperAn essential issue to take into account in these patients œsensitivity syndrome. Epilepsia 2000; 39: S3–7. is the high prevalence of cross-reactivity between the 2. Knowles SR, Shapiro LE, Shear NH. Anticonvulsant diVerent aromatic anticonvulsants, which in some hypersensitivity syndrome: incidence, prevention and reports is up to 80%and makes the choice of an management. Drug Saf 1999; 21: 489–501. alternative drug for these patients diYcult. Although 3. Sullivan JR, Sheal NH. The drug hypersensitivity syndrome. Arch Dermatol 2001; 137: 357–364. valproic acid, lamotrigine and vigabatrine are considered 4. Kleier RS, Breneman DL, Boiko S. Generalized pustulation the safest antiepileptic drugs for these patients, some as a manifestation of the anticonvulsant hypersensitivity cases of hypersensitivity anticonvulsant syndrome have syndrome. Arch Dermatol 1991; 127: 1361–1364. been reported to be triggered by them (1, 2). 5. Hand el-Jones SE, Jenkins RE, Whittaker SJ. The antiIn conclusion, we present an extremely unusual case convulsant hypersensitivity syndrome. Br J Dermatol 1993; of AHS, since both pustular exanthem and severe tubu129: 175–177. lointerstitial nephropathy are exceptional in the context 6. Lambert M, Fournier A. InsuYsance renale aigue compliquof this syndrome, especially if we consider their comant une hypersensibilite a `la carbamazepine. Rev Neurol (Paris) 1992; 148: 574–576.bined appearance. A Four-Year History of Pruriginous Erythroderma Leading to the Diagnosis of Idiopathic Hypereosinophilic Syndrome David Launay1, Benoõˆt Catteau1, Ariane Dubost-Brama1, Monique Capron2, Fre´de´ric Piette1and Emmanuel Delaporte1* 1Department of Dermatology, Claude-Huriez Hospital, 1, Place de Verdun, 59037 Lille, France, and 2INSERM 545, Institut Pasteur de Lille, Lille, France. *E-mail: [email protected] Accepted April 22, 2002. Sir, Idiopathic hypereosinophilic syndrome (IHS) is characterized by persistent eosinophilia (above 1.5 ´109/l for more than 6 months) of unknown origin in association with dysfunction of one or more organs due to tissue in ltration by eosinophils (1). Cutaneous, cardiac, neurologic and/or pulmonary manifestations are often observed. Among the skin lesions, erythroderma is a rare complication of IHS and has only been reported in a few cases (2–6). CASE REPORT In December 1994, a 67-year-old man with no history of atopy or current medication was referred due to severely itching erythroderma of a few weeks’ duration (Fig. 1), small bullae on the upper limbs (Fig. 2), a palmo-plantar keratoderma and slight edema of the skin. White cell count was 12.2 ´109/l with 9%eosinophils (1.1 ´109/l, normal range 0–0.5). A skin biopsy showed non-speci c, mild vasculitis with eosinophils Topical treatment was not suYciently eVective but prednisone (1 mg/kg daily) relieved the skin lesions and pruritus, with normalization of blood eosinophilia. Between April 1996 and March 1997 the patient’s symptoms relapsed, with blood eosinophilia ranging between 1.5 ´109/l and 4.0 ´109/l. Short courses of prednisone Fig. 1. Erythroderma with papulous and eczematous lesions. In 1942 temporarily improved the skin lesions. the patient had a plate in his right femur following a fracture. Removal of the plate did not improve his skin condition.In June 1997 the patient was admitted to our Acta Derm Venereol 82