Anticonvulsant Hypersensitivity Syndrome With Marked Eosinophilia in Treatment of Diabetic Neuropathy

A 50-year-old man with type 2 diabetes was prescribed carbamazepine for painful diabetic neuropathy. At 5 weeks after exposure, he suffered from malaise, appetite loss, rash, and intermittent fever. Carbamazepine was immediately stopped and he was admitted. He appeared drowsy and had intermittent fever (temperatures to 39.0°C), lymphadenopathy at the left axillary without tenderness, and purpuric skin rash on his face, trunk, and extremities. Laboratory studies revealed an alanine aminotransferase level of 754 IU/l, aspartate aminotransferase of 359 IU/l, alkaline phosphatase of 1,685 IU/l, γ-glutamyl transpeptidase of 1,483 IU/l, total bilirubin of 0.6 mg/dl, and peripheral white blood cell (WBC) count of 9,200/mm³ with eosinophilia (23.1%, 2,125/mm³).

Although liver dysfunction had improved immediately after cessation of the drug, his lymphoadenopathy had worsened, and his body temperature fluctuated between 37.5 and 39.0°C for another 2 weeks. The counts of both WBC and eosinophils increased considerably, reaching peaks of 23,100/mm³ and 8,400/mm³, respectively. He developed bilateral pleural effusion without any sign of congestion, although his cardiac function, including echocardiography, and renal function were normal. He also had marked hyponatremia of 124 mEq/l, with a urinary sodium level of 60 mEq/l, an arginine vasopressin of 1.2 pg/ml, and plasma osmolality of 268 mOsm/l. SIADH was diagnosed due to the absence of other diseases known to cause hyponatremia.

His eosinophilia and fever gradually improved, with the disappearance of pleural effusion 2 weeks after the cessation of carbamazepine. Concomitantly, his hyponatremia became normalized, with marked diuresis.

The diagnostic criteria for AHS are the triad of fever, rash, and internal organ involvement (1). The onset usually occurs 1–8 weeks after exposure (1). The fever may persist for several weeks, even after cessation of the drug (2). In AHS, hepatitis is the most common cause of death (2). Liver dysfunction may be worsened even after the discontinuation of the drug.

Hematological abnormalities such as leukocytosis with atypical lymphocytes, eosinophilia, or leukopenia are frequently observed (2). An absolute eosinophil count of >1,500/mm³ can lead to multiple organ failure (4). In our case, the appearance of pleural effusion was notable, and its clinical course suggested that eosinophilia was involved in its pathogenesis, probably by causing pleuritis. Hyponatremia due to SIADH was also observed in our case, and carbamazepine has been reported as a cause (5,6). SIADH caused by carbamazepine is generally normalized by its discontinuation in a short period (6). But hyponatremia worsened even after cessation of the drug in our case. It was likely that AHS with eosinophilia and/or its organ involvement, such as pleural lesion, was involved in SIADH.

Phenytoin, carbamazepine, and phenobarbital are metabolized to hydroxylated aromatic compounds, and the insufficient detoxification of these metabolites by epoxide hydrolase might be involved in the development of AHS (7). This might be one of the reasons for the potential cross-reactivity with other aromatic anticonvulsants in AHS. The rechallenge was reported to induce the immediate toxic reaction, which might be fatal in some cases (2).

In vitro testing using lymphocyte toxicity assay has shown a familial occurrence of AHS, with an autosomal pattern of inheritance (7). This suggests the risk of patients’ siblings’ for a reaction to aromatic anticonvulsants. Because it is common that patients have a strong familial predilection for type 2 diabetes, the accurate diagnosis of AHS will also be important for siblings, especially in families with a strong history of diabetes.

The timely recognition of AHS and discontinuation of the drug are critical for avoiding fatal multiple organ failure. Attention must also be paid to the cross-reactivity of other aromatic anticonvulsants for the treatment of diabetic neuropathy in patients with AHS as well as the risk to siblings of patients.