Necrotizing lymphadenitis associated with the phenytoin-induced hypersensitivity syndrome.

Abstract: A 32-year-old black female was started on phenytoin for seizure prophylaxis following the clipping of an aneurysm. This was stopped after 3 weeks when she developed a generalized skin rash. Over the next week she developed fever, sore throat, dysphagia, and headache. She had an erythematous throat with white exudates on the right tonsil and 1 to 3 cm firm, tender lymphadenopathy in multiple regions. Blood, throat swab and cerebrospinal fluid studies were negative for bacterial or viral infections, except for elevated liver enzymes. CT scan of chest, abdomen, and pelvis showed no lymphadenopathy. Lymph node biopsy suggested necrosis but no evidence of infection, granuloma, or lymphoma. Her lymphadenopathy resolved spontaneously and liver enzymes normalized in 3 weeks. Hypersensitivity syndrome due to antiepileptics manifests as fever, rash, generalized lymphadenopathy, and probably represents a T-cell mediated drug reaction. This reaction may persist despite cessation of the drug, and it may engender expensive evaluation. Careful observation up to 3 weeks after drug cessation may be the best management.

Key Words: phenytoin, hypersensitivity syndrome, necrotizing lymphadenitis

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Phenytoin, carbamazepine, and other aromatic anticonvulsants are commonly used in the treatment and prevention of seizures. Anti-epileptic hypersensitivity syndrome (AHS) is an idiosyncratic reaction to aromatic anticonvulsants. It has occasionally been reported in children, but is very rare in adults. It is characterized by a triad of fever, lymphadenopathy, and muco-cutaneous rash. Although generally self limiting, the syndrome may be life threatening, particularly among patients who develop severe cutaneous eruptions or hepatitis or who are undergoing subsequent radiotherapy (2) and in children. The differential diagnosis can be challenging particularly when histology is atypical or symptoms persist long after the drug is discontinued. We are presenting a case of phenytoin induced hypersensitivity syndrome in an adult female patient.

Case Report

Our patient is a 32-year-old black female who was transferred from a community hospital to our teaching hospital for evaluation of continuous headaches, difficulty in swallowing, sore throat, and elevated liver enzymes. She had a history of subarachnoid hemorrhage secondary to ruptured intracranial aneurysm, which was treated with surgical clipping 1 month before presentation. She received phenytoin for seizure prophylaxis after the surgery. This was discontinued 3 weeks later when she developed a generalized body rash. Over the next week she developed fever, sore throat, dysphagia, and continuous suboccipital headaches and was transferred to us for evaluation. On examination she had an erythematous throat with white exudates on the right tonsil and multiple firm, 1 to 3 cm, tender mobile lymphnodes in multiple regions. These included bilateral suboccipital, submandibular, supraclavicular, and inguinal areas, as well as submental and right axillary area. Patient's laboratory results were negative for atypical lymphocytosis, eosinophilia, pharyngeal streptococcal antigen, and gonococcal culture, blood culture and monospot test. The following serologic tests were also negative: Epstein-Barr viral capsid antigen IgM, Toxo IgG, Cytomegalovirus IgM, human immunodeficiency virus and hepatitis panel. WESR was 30 mm/h, aspartate aminotransferase 127 MU/mL, alanine aminotransferase 192 MU/mL, total bilirubin 0.8 mg/dL, alkaline phosphatase 93 U/L, albumin of 2.5 g/dL, prothrombin time 17.3 seconds and international normalized ratio of 2.3. Cerebrospinal fluid cultures were negative for bacteria and virus. Cerebrospinal fluid was negative for Epstein-Barr virus polymerase chain reaction, and herpes simplex virus polymerase chain reaction. CT scan of the neck showed multiple bilateral lymphadenopathies (Fig. 1) with some necrosis (Fig. 2). CT scan of the chest, abdomen and pelvis showed no significant lymphadenopathy. Lymph node biopsy from the neck suggested necrosis but no evidence of infection, granuloma or lymphoma (Fig. 3). Special stains for AFB were negative. She received only symptomatic treatment with analgesics and discharged to home. By 2 weeks after admission her lymphadenopathy resolved completely and spontaneously. Her liver function tests at three weeks were aspartate aminotransferase 15 U/L, alanine amino-transferase 15 U/L, alkaline phosphatase 50 U/L, total bilirubin 1.1 mg/dL, albumin of 3.7 g/dL, prothrombin time was 13.6 seconds and international normalized ratio of 1.4. Patient had completely normal liver enzymes 1 month before admission.

Discussion

Phenytoin hypersensitivity syndrome is a rare (1-4 in 10,000 patients) and important entity characterized by maculopapular rash, fever, lymphadenopathy, hypertransaminasemia, and peripheral eosinophilia. (2) It usually occurs 2 to 8 weeks after initiation of the therapy. (3) This rare syndrome seems to be related to the arene oxide metabolites of aromatic anticonvulsants (phenytoin, carbamazepine, and phenobarbital) with a frequent cross reactivity. (2) The newer nonaromatic anticonvulsant, lamotrigine, has also been associated with the hypersensitivity syndrome. (4) It has also been proposed that AHS is virally mediated in association with human herpes virus 6, and some in vitro and in vivo studies have shown that this mimics viral infection by activating CD4+ and CD8+ cells, with the concomitant production of interleukin 5. Diagnostic criteria for AHS includes fever in 90 to 100%, rash in 87 to 90%, lymphadenopathy in 70%, hepatitis in 50 to 60%, hematologic abnormalities in 25 to 50%, periorbital orofacial edema in 25%, myalgia, arthralgia in 20%, nephritis in 11%, and pharyngitis in 10% of cases. (5) Hematologic abnormalities include hemolytic anemia, thrombocytopenia, agranulocytosis, eosinophilia, leukoeytosis, leukopenia, and lymphocytosis.

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The pathology of the lymph node biopsy ranges between what was described as lymphoid hyperplasia, lymphoma, pseudo lymphoma syndrome (Fig. 4), and pseudo lymphoma. AHS can be fatal in children if not properly treated. (6) Clinical outcome does not depend on the type of anti-epileptic drug. However, outcome is worse with systemic involvement and can be fatal with liver involvement even though it is rare. (7) Literature supports the use of corticosteroids in extensive cases, or cases with involvement of internal organs although there are contrary data to suggest that only cutaneous manifestations are reversed.

Our patient received steroids for a short while before she was transferred to us and then received only symptomatic treatment. She had complete resolution of symptoms in 2 to 3 weeks. Because this reaction may persist despite cessation of the drug for weeks, it may mimic lymphoma or engender expensive, yet fruitless, evaluation. Careful observation for up to 3 weeks after drug cessation may be the best management.

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Conclusion

This report attempts to emphasize the importance of early diagnosis of this syndrome, the knowledge of the common cross reactivity among the major anticonvulsants and the need for an immediate discontinuation of the offending anti-epileptic as the most important step in improving outcome. Genetic factors are also thought to contribute, since siblings are said to have one in four risk of showing a similar reaction. First degree relatives should be counseled to avoid phenytoin and related anticonvulsant. (8)

References

1. Kruspe R, Broussard A, Santanilla J, et al. Journal of the Louisiana state medical society Lymphoma or pseudolymphoma? 2002;154:178-182.

2. Romero K, Maldonado N, Sendra Tello J, et al. Eur J Dermatology Anticonvulsant hypersensitivity syndrome with fatal outcome. 2002;12:503-505.

3. Kaur S, Sarkar R, Thami GP, et al. Pediatric Dermatology Anticonvulsant hypersensitivity syndrome. 2002;19:142-145.

4. Schaub KN, Bircher AJ. Severe hypersensitivity syndrome to lamotrigine confirmed by lymphocyte stimulation in vitro. Allergy 2000;55:191.

5. Kennebeck GA. Anticonvulsant hypersensitivity syndrome. J Am Board Fam Pract 2000;13:364-370.

6. Bessmertny O, Hatton RC, Gonzalez-Peralta RP. Antiepileptic hypersensitivity syndrome in children Ann Pharmacother 2001;35:533-53.

7. Vittorio CC, Muglia JJ., Anticonvulsant hypersensitivity syndrome. Arch Intern Med 1995;55:2285-2290.

8. Mahadeva M, Al-Mrayat Ksteer, Steer K, et al. Fatal phenytoin hypersensitivity syndrome. Postgrad Med J 1999;75:734-737.

Karthi Subbannan, MD and Jaspal S. Gujral, MBBS, FACP, MRCP 

From the Section of General Internal Medicine, Department of Medicine, Medical College of Georgia, Augusta, GA.

The authors acknowledge no financial support was received from any source toward the preparation of this case report.

The authors have no commercial or proprietary interest in any drug, device, or equipment mentioned in the above case report.

Reprint requests to Jaspal S. Gujral, Medical College of Georgia, 1120 15th Street, Suite HB-2010, Augusta, GA 30912-3104. Email: [e-mail]

Accepted April 21, 2005.

RELATED ARTICLE: Key Points

* Phenytoin and other anticonvulsants can cause generalized lymphadenopathy and necrotizing lymphadenitis as part of hypersensitivity syndrome.

* It is probably T-cell mediated reaction and extensive workup is not required.

* It is usually self-limiting when the offending drug is stopped but can be fatal with liver involvement. Genetic factors contribute and first-degree relatives should be counseled to avoid phenytoin and related anticonvulsants.