Phenytoin-like hypersensitivity associated with lamotrigine

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function, whereas it has not in m a n y patients with decreased renal function, despite high iodine loads f r o m radiographic procedures. Allergic reactions to radiographic dyes are not u n c o m m o n , occurring in approximately 1% of patients.* However, these reactions are usually of the immediate hypersensitivity type (e.g., urticaria and flushing). In contrast, iod o d e r m a m a y be a delayed-type hypersensitivity reaction, although intradermal and patch testing and indirect immunofluorescence studies have been negative. In some studies, lymphocyte transformation tests with iodinated h u m a n serum albumin have been positive, suggesting that iodine acts as a hapten.10, 11 After recovery, patients should be instructed to avoid iodine in the diet, in medications, and in future radiographic studies. REFERENCES

1. Cleveland DEH. Iododerma from an asthma remedy. Can IVied Assoc J 1934;30:181-2. 2. Hollander L, Fetterman GH. Fatal iododerma: eleventh case reported in the literature. Arch Dermatol Syphilis 1936;34:228-41.

Journal of the American Academy of Dermatology June 1997

3. Welser FP. The mycotic type of bromoderma and iododerma: facial, pharyngeal and intraoral oedema, and swelling of salivary and thyroid glands in cases of idiosyncrasy towards iodides. Br J Dermatol 1923;35:169-80. 4. Boudoulas O, Siegle RJ, Grimwood RE. Iododerma occurring after orally administered iopanoic acid. Arch Dermatol 1987;123:387-8. 5. Heydenreich G, Olholm P. Iododerma after high dose urography in an oliguric patient. Br J Dermatol 1977;97: 567-9. 6. Janover ML, Hannan MA. Skin reactions with iocetamic acid. Radiology 1976; 118:301-2. 7. Kincaid MC, Green WR, Hoover RE, et al. Iododerma of the conjunctiva and skin. Am J Ophthalmo11981 ;88:121620. 8. Talner LB, Lang JH, Brasch RC, et al. Elevated salivary iodine and salivary gland enlargement due to iodinated contrast media. Am J Roentgenol 1971;112:380-1. 9. Talner LB, Coel MN, Lang JH. Salivary secretion of iodine after urography. Radiology 1973;106:263-4. 10. Rosenberg FR, Einbinder J, Walzer RA, et al. Vegetating iododerma: an immunologic mechanism. Arch Dermatol 1972;105:900-5. 11. Khan F, Einbinder JM, Seriff NS. Suppurative ulcerating iododerma: a rare manifestation of inorganic iodide hypersensitivity. N Engl J Med 1973;289:1018-20.

Phenytoin-like hypersensitivity associated with lamotrigine D e r e k Jones, M D , a Visoth Chhiap, M D , * Stanley Resor, M D , b Gerald Appel, M D , c and Marc E. Grossman, M D a New York, New York

Lamotrigine is an antiepileptic medication recently approved for use in the United States. Cutaneous side effects occurred in m o r e than 10% of patients during clinical studies) W e describe the first case o f phenytoin-like hypersensitivity syndrome f r o m lamotrigine in a 24-year-old man. From the Departxnentof Dermatology,a Department of Neurology,b and Depamnentof InternalMedicine,NephrologyDivision,c of ColumbiaUniversity,Collegeof Physiciansand Surgeons,New York. Reprint requests: Marc Grossman,MD, ColumbiaCollege of Physicians and Surgeons, Departmentof Dermatology, ! 61 Fort Washington Ave., AP 14, New York, NY 10032. *Dr. Chhiap is currentlyat Washington University,Division of Dermatology, St. Louis, Mo. J Am Acad Dermatol 1997;36:1016-8. Copyright © 1997 by the AmericanAcademyof Dermatology,Inc. 0190-9622/97/$5.00 + 0 16/54/80153

CASE REPORT

A 24-year-old white man with a chronic seizure disorder had been given a maintenance regimen of acetazolamide and intermittent nitrazepam. Because of poor control, nitrazepam was stopped, and oral lamotrigine, 200 mg twice daily, was begun. After 1 week, an eruption developed that progressively worsened during the next 2 weeks. After 3 weeks, fever developed, and lamotrigine was discontinued. The fever and eruption worsened during the next 5 days, requiring hospitalization. Examination revealed a fever to 39.56 ° C and a symmetric eruption consisting of erythematous and hemorrhagic papules with follicular accentuation and confluence into large plaques on the face, trunk, arms, and legs. The results of laboratory studies on admission included white blood cell count, 13,900/mm3; hematocrit, 46%; platelets, 153,000/mm3; erythrocyte sedimentation rate, 2

Journal of the American Academy of Dermatology Volume 36, Number 6, Part 1

mm/hr; potassium, 3.0 mmol/L; serum creatinine, 2.2 mg/dl; blood urea nitrogen, 28 mg/dl; phosphorus, 1.3 mg/dl; total bilirubin, 1.7 rag/N; direct bilirubin, 0.8 mg/ dl; alkaline phosphatase, 274 U/L; AST, 67 U/L; ALT, 130 U/L; and lactate dehydrogenase, 541 U/L. Urinalysis revealed trace albunfin, 1÷ ketones, 2÷ b'flimbin, and 2.0 urobilinogen. Urine microscopic examination revealed three to five white blood cells, no red blood ceils, and 1+ bacteria per high-power field. A hepatitis panel was negative. Blood cultures and a chest radiograph findings were negative. A biopsy specimen demonstrated epidermal spongiosis, extravasated erythrocytes extending into the epidermis, and a mononuclear cell dermal infiltrate. A few mononuclear cells were atypical in appearance. The features were thought to be consistent with a hemorrhagic drag eruption, although there were more atypical mononuclear cells than usually expected. Intravenous methylprednisolone, 60 mg every 8 hours, was started. Serum liver enzyme levels gradually increased during the next several days with lactate dehydrogenase peaking at 651 U/L, AST at 135 U/L, and ALT at 374 U/L. Blood urea nitrogen and serum creatinine became elevated to 44 mg/dl and 4.2 mg/dl, respectively, on hospital day 2 and returned to baseline by day 5. Urine electrolytes showed sodium, 33 mol/L; chloride, 41 retool/L; and potassium, 28 mol/L. These changes were considered to be consistent with acute interstitial nephritis. The patient's eruption resolved slowly, and intravenous methylprednisolone was changed to oral prednisone, 60 mg daily, on day 7. The patient's signs and symptoms gradually resolved, and he was discharged on day 8. DISCUSSION

The phenytoin hypersensitivity syndrome, first reported in 1950, is typically characterized by fever, an eruption, and hepatitis. 2 Other signs may include diffuse lymphadenopathy, leukocytosis with atypical lymphocytes, and nephritis. 3' 4 The reaction usually begins 2 to 3 weeks after initiation of therapy and may persist or worsen for days to weeks after the discontinuation of the drug. Fever is usually 38 ° to 39 ° C and may be spiking. Most eruptions are morbilliform, although follicular papules and pustules, erythroderma, and toxic epidermal necrolysis have been reported) Spongiotic dermatitis, unusual for most drug eruptions, is common. Hepatic injury is almost always present and may vary from a transient and mild elevation in serum transaminase levels to fulminant hepatitis. 5 Interstitial nephritis has been described in at least eight patients. 6-8 Systemic ste-

Brief communications 1017 roids usually hasten resolution, although the eventual outcome is variable. Some patients have a mild illness and recover without sequelae within 2 weeks, whereas others may have a chronic, relapsing course. In many, the syndrome may be fatal. One study documented a 38% mortality rate, with most deaths attributable to massive hepatic necrosis. 5 In a few patients, death was the result of renal failure or sepsis caused by toxic epidermal necrolysis. Lamotrigine is an antiepileptic medication that has recently been approved in the United States for use in adults. Most side effects are related to the central nervous system and include headache, nausea and vomiting, dizziness, diplopia, and ataxia. 9 Cutaneous reactions are the most common reason for drug discontinuation, with 2.3% of patients requiring drug withdrawal in clinical studies. However, lamotrigine-related eruptions are frequently transient even if the drug is continued. The eruption usually begins 2 to 3 weeks after initiation of therapy and is usually maculopapular. However, erythema multiforme, two cases of Stevens-Johnson syndrome, and one case of toxic epidermal necrolysis have been reported. 1 Concomitant use of valproic acid leads to decreased lamotrigine clearance and is associated with a higher incidence of cutaneous reactions. Hepatitis and interstitial nephritis have not yet been described. Fourteen deaths have been associated with lamolrigine therapy, but the drug did not appear causative. 1 Biopsy specimens of skin and enlarged lymph nodes in some patients with the phenytoin hypersensitivity syndrome may contain atypical or malignant-appearing lymphocytes. 1° In the pseudolymphoma syndrome associated with phenytoin, malignant changes are observed in lymph nodes without other clinical features of hypersensitivity. Similar to cases of phenytoin hypersensitivity syndrome, the skin biopsy specimen in our patient revealed a spongiotic dermatitis with atypical mononuclear cells in the dermis, although generalized lymphadenopathy was absent. REFERENCES

1. Gilman JT. Lamotrigine: an antiepileptic agent for the treatment of partial seizures. Ann Pharmacother 1995; 29:144-51. 2. Chaiken BH, Goldberg BI, Segal JP. Dilantin sensitivity: report of a case of hepatitis withjaundice, pyrexia, and exfofiative dermatitis. N Engl J Med 1950;242:897-8.

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Brief communications

3. TomsickRS.Thephenytoinsyndrome.Cutis 1983;32:53541. 4. Stanley J, Fallon-Pellicci V. Phenytoin hypersensitivity reaction. Arch Dermatol 1978;114:1350-3. 5. Parker WA, Shearer CA. Phenytoin hepatotoxicity: a case report and review. Neurology 1979;29:175-8. 6. McCarthy 1_2, Aguilar JC, Ransburg R. Fatal benign phenytoin lymphadenopathy. Arch Intem Med 1979; 139:367-8. 7. Hoffman EW. Phenytoin-induced interstitial nephritis. South Med J 1981;74:1160-1.

8. Josephs SH, Rothman SJ, Buckley RH. Phenytoin hypersensitivity. J Allergy (]fin Immunol 1980;66:166-72. 9. Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med 1996;334:1583-90. 10. Braddock SW, Harrington D, Vose J. Generalized nodular cutaneous pseudolymphoma associated with phenytoin therapy: use of T-cell receptor gene rearrangement in diagnosis and clinical review of cutaneous reactions to phenytoin. J Am mcad Dermatol 1992;27;337-40.

Hypersensitivity reaction to terbinafine Aditya K. Gupta, MD, FRCPC, a Jerome B. Kopstein, MD, FRCPC, c and Neil H. Shear, MD, F R C P C a'b Toronto, Ontario, Canada Terbinafme is a synthetic allylamine anlLftmgal agent that became available in the 1980s, initially in Europe and the United Kingdom. It was approved for use in Canada in M a y 1992. Approximately 4 million patients worldwide have been treated with this drug. Thus far, terbinafine has been generally well tolerated with adverse effects occurring in about 10% o f patients, usually transient in nature and o f mild to moderate severity. 1, 2 Cutaneous adverse effects have been reported in 3% o f patients3; there have been isolated reports o f more serious skin disorders such as toxic epidermal necrolysis and erythema multiforme. 4-8 A serum sickness-like reaction also m a y occur. 9 Significant hepatobiliary dysfunction has occurred in approximately 1:54,000 patients. 2 W e describe a patient in w h o m a hypersensitivity reaction to terbinafine developed with fever, rash, lymphadenopathy, and hepatitis. CASE REPORT A 35-year-old woman with pedal onychomycosis was treated with oral terbinafine, 250 mg/day. After 10 days,

From the Divisions of Dermatologya and Clinical Pharmacology,b Department of Medicine, Sunnybrook Health Science Centre, and the University of Toronto; Windsor Regional Hospital and Hotel Dieu Grace Hospital, Windsor. c Reprint are not available from the authors.

she noticed an erythematous, pruritic eruption with pustules on her chest. The patient felt ill and had a headache and diarrhea. During the next 2 days, the eruption became more erythematous and prudtic. It was now confluent and involved both the trunk and extremities. Pustules were present mainly on the arms. The mucous membranes were not affected. She was febrile at 38.9 ° C. Lymphadenopathy was present, but there was no hepatomegaly. The patient was treated with hydroxyzine, but it failed to relieve the pruritus. Terbinafme was discontinued. A tapering dose of prednisone, starting at 60 mg/day, was administered for 7 days, but it did not provide symptomatic relief. The patient was admitted to the hospital. She was febrile at 38.6 ° C. The blood count was hemoglobin, 136 (normal 120 to 160 g/L); leukocytes, 9 x 109/L (normal, 4 to 11 x 109]L); 94.3% neutrophils. The serum electrolytes, urea, and creafinine levels and liver function tests were within normal limits. Blood cultures were negative. The patient was treated with intravenous hydrocortisone (Solu-Cortet), 100 mg every 6 hours for 3 days, and then every 8 hours for 4 days. At day 3, the liver-function tests demonstrated an elevated ~/-glutamyl transferase of 95 (normal range, 0 to 55 U/L). The AST, alkaline phosphatase, and total b'llirubin remained within normal limits. The patient's condition improved and she was discharged on prednisone, starting at 40 mg/day and tapered to zero over a 2-week period. Two weeks later, there was resolution of the cutaneous eruption and normalization of the liver-ftmction tests. DISCUSSION

J Am Acad Dermatol 1997;36:1018-9. Copyright © 1997 by the American Academy of Dermatology, Inc. 0190-9622/97 $5.00 + 0 16/54/80151

A hypersensitivity syndrome has been described for several drugs including the anticonvulsants