Anticonvulsant hypersensitivity syndrome: treatment with corticosteroids and intravenous immunoglobulin.

Abstract: We describe the case of a patient in whom anticonvulsant hypersensitivity syndrome developed during treatment with phenytoin and progressed when therapy was changed to phenobarbital. Although therapeutic options remain controversial, corticosteroids and IV immunoglobulin were used in our patient. The patient had a complete recovery, suggesting the potential benefit of corticosteroids and IV immunoglobulin for anticonvulsant hypersensitivity syndrome.

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Anticonvulsant hypersensitivity syndrome (AHS) is a rare but potentially life-threatening adverse drug reaction associated with the aromatic anticonvulsant drugs phenytoin, phenobarbital, primidone, and carbamazapine. (1-5) This serious reaction is characterized by a triad of fever, skin eruption, and internal organ involvement (ie, hepatitis, nephritis, lymphadenopathy). The rash or skin eruption can range from a mild exanthematous eruption to the more serious Stevens-Johnson syndrome and is present in approximately 90% of patients with this syndrome. (3,5) Most cases occur 1 to 8 weeks after exposure to the drug and are manifested by fever and malaise accompanied by pharyngitis and cervical lymphadenopathy. (3) Early discontinuance of the offending agent is essential to avoid syndrome progression. In addition, future avoidance of all aromatic anticonvulsants should be considered because cross-reactivity may be as high as 75%. Although medical care is mostly supportive, other treatment modalities include the controversial use of glucocorticoids and anecdotal reports of plasmapheresis, cyclophosphamide, cyclosporine, and IV immunoglobulin. (1,3) We report the case of a patient who had AHS as a result of a cross-sensitivity reaction to phenytoin and phenobarbital. The clinical manifestations improved during steroid and immunoglobulin therapy and then recurred after withdrawal of glucocorticoids. After the reinstitution of glucocorticoids with a prolonged taper, signs and symptoms resolved completely.

Case Report

A 43-year-old black woman with a medical history of mental retardation due to static encephalopathy was admitted because of fever, cough, facial and lower extremity swelling for approximately 1 week, and a rash for approximately 4 weeks. Two months earlier, a possible seizure disorder had been diagnosed, and the patient had been treated with phenytoin 300 mg/d. After 1 month of phenytoin therapy, the patient had a diffuse rash over most of her body. Two weeks later, facial and lower extremity swelling developed accompanied by fever and cough. Four days before this admission, she presented to the emergency room with similar complaints. Findings on physical examination included temperature of 39[degrees]C (102.2[degrees]F); erythematous tonsils; anterior bilateral cervical lymphadenopathy; and an erythematous maculopapular rash noted on the face, neck, trunk, arms, and legs. Pharyngitis and a possible drug-induced skin eruption were diagnosed, and the patient received ceftriaxone (1 g), diphenhydramine (25 mg every 6 hours as needed for itching), acetaminophen (1,000 mg), and amoxicillin (500 mg three times per day), and was encouraged to follow up with her primary care physician. Two days later, her primary care physician discontinued the phenytoin, and phenobarbital therapy (60 mg/d) was initiated. Other prescribed medications included famotidine (20 mg twice daily), diphenhydramine (50 mg every 4 hours as needed), and a methylprednisolone dose pack. Within 2 days, she returned to the emergency room, where she was admitted and AHS was diagnosed.

Vital signs at admission were blood pressure 120/54 mm Hg, pulse rate 108 beats/min, respiratory rate 24 breaths/min, and temperature 39.8[degrees]C (103.7[degrees]F). Physical examination showed a clear oropharynx without mucous membrane involvement. The diffuse macular rash over the face, trunk, and extremities was morbilliform in distribution and was exfoliative on the face and neck. There was also pretibial and periorbital edema. Initial laboratory values included direct bilirubin 2.15 mg/dl (normal, 0.0-0.2 mg/dl), alkaline phosphatase (ALP) 258 U/L (normal, 32-92 U/L), aspartate aminotransferase (AST) 520 IU/L (normal, 10-42 IU/L), alanine aminotransferase (ALT) 303 IU/L (normal, 10-40 IU/L), albumin 2.3 g/dl (normal, 3.5-5.0 g/dl), and total protein 4.7 g/dl. Basic metabolic values were within normal limits except for serum creatinine of 1.2 mg/dl (normal, 0.6-1.3 mg/dl) and glucose of 118 mg/dl (normal, 65-110 mg/dl). The white blood cell count was 11,500/[mm.sup.3], the hemoglobin value was 11.6 g/dl, the hematocrit was 34.9%, and the platelet count was 285,000/[mm.sup.3]. The differential count showed 79% polymorphonuclear cells (31% mature forms, 17% band forms, and 31% eosinophils), 14% lymphocytes, 7% monocytes, and rare basophils. Microscopic examination of a urine specimen showed pyuria (20-30 white blood cells per high-powered field), two to five red blood cells, frequent squamous cells, and moderate bacteria. The urine was also positive for Trichomonas. A diagnosis of acute AHS was made, along with concurrent urinary tract infection and vaginal trichomoniasis.

On the first hospital day, phenobarbital therapy was discontinued, IV fluid was administered, hydroxyzine (25-50 mg) was administered for pruritus, and acetaminophen (650 mg every 4 hours) was administered for fever. Over the ensuing 3 days, the dermatitis and peripheral edema worsened, mucosal lesions developed, and a right cervical lymph node became enlarged. By Day 6, significant laboratory values included ALP 183 U/L, AST 1,162 IU/L, ALT 676 IU/L, total bilirubin 10.2 mg/dl (normal, 0.2-1.0 mg/dl), serum creatinine 3.6 mg/dl, potassium 6.8 mmol/L (normal, 3.6-5.0 mmol/L), and ammonia 93 [micro]mol/L (normal, 11-35 [micro]mol/L). The patient had shortness of breath, and a chest radiograph revealed left basilar subsegmental atelectasis and large right basilar opacity. Pneumonia could not be excluded. She was transferred to the intensive care unit. Acetaminophen therapy was discontinued because of elevated liver transaminase values. IV methylprednisolone (125 mg) was administered every 6 hours. A nephrology consultant initiated therapy for hyperkalemia. On Day 7, she received 30 g (0.41 g/kg) of IV immunoglobulin, and her clinical status improved rapidly. Mucosal membrane involvement decreased, allowing her to restart an oral diet. Oxygen saturations remained high on room air, and transaminase levels began to normalize. She was transferred from the intensive care unit to a regular room. By Day 11, a steroid-tapering regimen had begun. On Day 14, oral prednisone therapy at 15 mg/d was started. On Day 16, laboratory values were serum creatinine 0.8 mg/dl, potassium 3.8 mmol/L, total bilirubin 3.8 mg/dl, direct bilirubin 1.95 mg/dl, ALP 284 U/L, AST 96 IU/L, ALT 257 IU/L, and eosinophils 3.0%. She was discharged with a 2-day prednisone taper, levofloxacin (500 mg daily for 9 days), oral nystatin suspension, famotidine (20 mg twice daily), cetirizine (10 mg/d), and Eucerin cream (sodium lactate, urea, and glycerin).

Three days after discharge and 1 day after stopping the prednisone, the patient was readmitted with increased facial and lower extremity swelling, erythema, and fever. She was administered prednisone (40 mg/d). After 9 days of treatment, the fever resolved and she showed overall clinical improvement. She was discharged on a very gradual steroid taper. After hospitalization, severe exfoliation occurred, especially of the hands and soles. After 4 months, the patient had no evidence of rash, mucosal involvement, edema, eosinophilia, or atypical lymphocytes. Renal and hepatic function remained normal (Figs. 1 and 2).

Discussion

Because phenytoin and phenobarbital are both aromatic anticonvulsants, AHS induced by one of these agents precludes the safe use of the other because of a high rate of immunologic cross-reactivity. In the patient described, the skin eruption worsened when treatment was switched from phenytoin to phenobarbital. Therefore, avoidance of all aromatic anticonvulsants in patients with AHS is essential. Alternatives for seizure control include benzodiazepines, valproic acid (not in the acute phase because of the risk of hepatitis), or newer anticonvulsants (gabapentin, topiramate, vigabatrin). (3,4)

The role of immunosuppression is controversial in the management of AHS. (1,3,5) Because of the severity of multiple organ dysfunction in this patient, however, a trial of immunosuppression was deemed warranted. Her excellent clinical response, during steroid and IV immunoglobulin therapy, and then recurrence of signs and symptoms with initial taper of glucocorticoids suggests the potential value of a gradual steroid taper with possible addition of IV immunoglobulin. However, her improvement cannot be attributed solely to immunoglobulin, because she received only one dose and its role is not validated. We believe this is the fourth reported case of an adult to receive IV immunoglobulin for AHS/Stevens-Johnson syndrome.

[FIGURE 1 OMITTED]

Conclusion

Although information is limited and controversial regarding the use of steroids and IV immunoglobulin in the treatment of AHS, pending controlled studies of these two regimens, careful consideration should be given to these options when supportive care has been exhausted.

[FIGURE 2 OMITTED]

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Accepted April 24, 2002.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9703-0319

References

1. Scheuerman O, Nofech-Moses Y, Rachmel A, et al. Successful treatment of antiepileptic drug hypersensitivity syndrome with intravenous immune globulin. Pediatrics 2001;107:E14.

2. Vittorio C, Muglia J. Anticonvulsant hypersensitivity syndrome. Arch Intern Med 1995;155:2285-2290.

3. Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome. Drug Safety 1999;21:489-501.

4. Griebel ML. Acute management of hypersensitivity reactions and seizures. Epilepsia 1998;39(Suppl):S17-S21.

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

RELATED ATRICLE: Key Points

* Anticonvulsant hypersensitivity syndrome is a rare but potentially life-threatening adverse drug reaction.

* Avoidance of all aromatic anticonvulsants should be considered because cross-reactivity may be as high as 75%.

* The role of immunosuppression is controversial in the management of anticonvulsant hypersensitivity syndrome.

* The combination of IV immunoglobulin and steroids may be a viable treatment option.

Jenester Mostella, PHARMD, Robert Pieroni, MD, Richard Jones, MD, and Christopher K. Finch, PHARMD

From the Department of Clinical Pharmacy, Druid City Hospital, and the Department of Internal Medicine and Family Medicine, University of Alabama School of Medicine, Tuscaloosa, AL.

Reprint requests to Christopher K. Finch, PharmD, Critical Care Specialist, Department of Pharmacy, Methodist University Hospital, 1265 Union Avenue, Memphis, TN 38104. Email: [e-mail]