Carbamazepine (Carbatrol, Epitol, Tegretol) is a known cause of DRESS (drug rash with eosinophilia and systemic symptoms) syndrome—a multisystem disorder resulting from a reaction to certain drugs and manifested as a rash with eosinophilia and systemic symptoms. We discuss a recent case of DRESS syndrome caused by carbamazepine in the context of the published literature pertaining to this condition.

Case Presentation
A 34-year-old woman was admitted to our hospital with a 3-week history of facial swelling, dysphagia, a pruritic rash, fever, generalized abdominal pain, and diarrhea. Her symptoms started 1 week after taking carbamazepine for postherpetic neuralgia. She had been seen at another hospital, where she was treated with oral steroids and diphenhydramine. She came to our hospital complaining that her symptoms did not improve.

Her medical history included well-controlled bronchial asthma, herpes infection, and a cesarean section. In addition to carbamazepine, she was also taking ibuprofen and inhaled albuterol (Proventil, AccuNeb). She reported she had a history of allergy to phenobarbital sodium.

Physical examination showed an obese, ill-appearing woman. A diffuse, erythematic, and fine vesicular rash involved the entire body (Figure 1). Nikolsky’s sign, defined as dislodgment of the epidermis with the appearance of a moist, glistening defect after pushing or rubbing the skin, was negative in this patient. Marked swelling of the face and eyelids was also seen, as well as tender posterior cervical and maxillary lymph nodes. In the mouth, crusting of the lips and erosions on the hard palate were evident.

Abdominal examination revealed suprapubic and right lower-quadrant tenderness. Initial laboratory data were significant for leukocytosis, 23.7 x 10⁹/L, with 10% eosinophils, among other results (Table 1).

A computed tomography scan of the abdomen without contrast revealed mesenteric lymph nodes, the largest measuring 14 x 11.5 mm.

On hospital day 3, a presumptive diagnosis of DRESS syndrome was made after a dermatology consult. A skin biopsy from the left arm revealed deep lymphocytic perivasculitis and interface vacuolar dermatitis, consistent with drug eruption.

Colonoscopy done the following day revealed edema with loss of vascularity in the rectosigmoid area, with patchy erythematous areas in the ascending and transverse colon (Figure 2). Biopsies revealed acute colitis and many eosinophils, consistent with eosinophilic colitis.

The patient became febrile and her liver enzymes deteriorated. No evidence of encephalopathy was found. She was switched to intravenous (IV) dexamethasone on hospital day 5. The fever persisted. On hospital day 7, she was transferred to a liver transplant center, where her liver enzymes improved, and she was discharged.

Discussion
A systemic allergic reaction to anticonvulsant therapy was first described in 1950 and was named anticonvulsant hypersensitivity syndrome when associated with phenytoin (Dilantin, Phenytek) therapy.¹ It has since been known as drug hypersensitivity syndrome, and is now more often referred to as DRESS syndrome, when it involves a case of “drug rash with eosinophilia and systemic symptoms.”² 

DRESS syndrome is a specific, severe, idiosyncratic drug reaction characterized by a skin rash with fever, facial edema, lymphadenopathy, and visceral involvement (hepatitis, pneumonitis, myocarditis, nephritis, and colitis). The diagnosis can be difficult, because many of the clinical features can be nonspecific, and the syndrome often mimics infectious, neoplastic, or rheumatologic conditions.

The diagnosis of DRESS syndrome involves 3 criteria²:

1. Drug-induced skin eruption

2. Eosinophilia ≥1.5 x 10⁹/L, or atypical lymphocytes

3. At least 1 of the following systemic abnormalities: enlarged lymph nodes at least 2 cm in diameter, hepatitis, interstitial nephropathy, interstitial lung disease, or myocardial involvement.

Anticonvulsants, such as phenytoin, phenobarbital sodium, or carbamazepine, are the most common causes of DRESS syndrome. Other drugs, including other antiepileptics (eg, lamotrigine [Lamictal]), valproic acid (Depakene),³ allopurinol (Zyloprim),⁴ sulfasalazine (Azulfidine),⁵ nonsteroidal antiinflammatory drugs, nevirapine (Viramune),⁶ and vancomycin (Vancocin, Vancoled),⁷ have also been associated with this syndrome (Table 2).

An association between human herpesvirus 6 infection and the development of DRESS syndrome has been suggested in susceptible patients.⁸ 

Life-threatening multiorgan failure has been documented in DRESS syndrome; it carries a mortality rate of about 10%,⁹ especially in patients who have liver involvement.

The pathogenesis is believed to be a drug-induced hypersensitivity caused by abnormalities in the production and detoxification of its active metabolites. The condition is more common in slow acetylators.¹⁰ A genetic predisposition may also exist, as evidenced by an increased risk in patients with a family history of DRESS syndrome. The syndrome may be related to epoxide hydrolase deficiency, which leads to accumulation of toxic metabolites, known as arene oxides, that may trigger an immunologic response.

Our patient was exposed to carbamazepine. Carbamazepine-induced fulminant hepatic failure in the setting of DRESS syndrome has been described.¹¹ Cases of DRESS syndrome associated with colitis have also been described.¹² To our knowledge, this is the first report of concomitant subfulminant hepatitis and colitis in the same patient.

Early withdrawal of the offending medication is needed once the diagnosis is established. The recovery from this condition has been reported to be slow, lasting several weeks to months; recurrences have also been reported.¹³ 

Glucocorticoids remain the most widely used agents for treatment of DRESS syndrome and can result in clinical improvement, although well-controlled clinical trials are lacking. Relapse can occur during the tapering of glucocorticoids.¹⁴ Successful use of IV immune globulin in nevirapine-induced DRESS syndrome has been reported,¹⁵ as well as N-acetylcysteine (Acetadote, Mucomyst) in a patient with sulfasalazine-induced DRESS syndrome.¹⁶

Avoiding reexposure of aromatic anticonvulsants is recommended, because the incidence of cross-reactivity among the aromatic anticonvulsants is more than 75%.¹⁷ This may have been the case in our patient, based on her history of allergy to phenobarbital. First-degree relatives of an afflicted individual have a 4-fold increased risk of drug sensitivity⁴; therefore, family counseling is recommended.

Conclusion
DRESS syndrome is a multisystem, potentially life-threatening condition associated with certain drugs and infectious agents in predisposed individuals. It is imperative to discontinue the causative medication and avoid reexposure. If an anticonvulsant is the etiology, it is important to avoid exposure to other aromatic anticonvulsants.  

References
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