Anticonvulsant hypersensitivity syndrome is an uncommon but potentially fatal condition that can occur in susceptible patients taking one of the aromatic anticonvulsants, such as phenytoin, carbamazepine, or phenobarbital. Signs and symptoms typically include high fever, rash, lymphadenopathy, and hematologic abnormalities. Elevated fever and skin rash that cannot be explained by other causes should alert the physician to the possibility of this syndrome in patients taking an anticonvulsant medication. Immediate discontinuation of the offending agent is necessary; early recognition can prevent permanent multiorgan damage.

Anticonvulsant hypersensitivity syndrome—also known as phenytoin pseudolymphoma syndrome—is a potentially fatal idiosyncratic drug reaction to certain anticonvulsant medications that break down into intermediate metabolites, specifically arene oxides. Responsible medications include phenytoin (Dilantin, Phenytek), carbamazepine (Carbatrol, Epitol, Tegretol), oxcarbazepine (Trileptal), and phenobarbital sodium (Table 1). The cross-reactivity of these drugs ranges from 50% to 80%.^1,2

Evidence suggests that other anticonvulsants—lamotrigine (Lamictal), primidone (Mysoline), and felbamate (Felbatol)—whose chemical structures and routes of metabolism are similar to that of carbamazepine, phenytoin, oxcarbazepine, and/or phenobarbital—may also cause the syndrome.¹ Some patients who are sensitive to phenytoin and carbamazepine may be able to tolerate phenobarbital, but once patients have had anticonvulsant hypersensitivity syndrome, they should no longer receive any anticonvulsant that can cause the syndrome.

Incidence
Anticonvulsant hypersensitivity syndrome affects between 1/1000 and 1/10,000 of patients.³ Some studies suggest that these ratios may be underestimates, because they are based on all users of antiepileptic medications over the entire duration of therapy. When the patient population is limited to new users and to reactions that occur within 60 days of the first or second prescription (ie, the time frame in which the syndrome typically occurs), the incidence is 2.3 to 4.5 per 10,000 among new phenytoin users and from 1.0 to 4.1 per 10,000 among new carbamazepine users.⁴ The actual incidence is unknown as a result of variable presentations, which often lead to diagnostic delays or to inaccurate testing. Among confirmed cases, and among patients with severe reactions, the incidence is reportedly highest in black men, particularly among the elderly.⁵

Pathophysiology
The mechanism of anticonvulsant hypersensitivity syndrome is unknown, but several theories have been proposed. What is known is that phenytoin, carbamazepine, and phenobarbital all have an aromatic benzene ring. When these medications are metabolized by the cytochrome (CY) P-450 enzyme system in the liver, they form arene oxide metabolites that, if not appropriately detoxified, may stimulate an immune reaction that can lead to cellular destruction.^6,7 Arene oxide metabolites can also establish covalent bonds with cells and neighboring macromolecules, thereby becoming directly cytotoxic to various tissues and organs (Figure).^6,7

Recent research suggests there may be a genetic component (possibly autosomal) that contributes to susceptibility, since siblings and other first-degree relatives of affected patients appear to be at increased risk.³ These individuals may have a genetic inability to detoxify the arene oxide, because of an absence, low concentration, or diminished activity of the enzyme epoxide hydrolase. This would allow the antiepileptic and its oxidized metabolites to accumulate, possibly activating cytokines and T cells through the major histocompatibility and other pathways.⁷ This T-cell–mediated chemotoxic reaction occurs in areas that contain cytochrome oxidase, such as the liver, lungs, skin, and mucosa, often affected organs that contain the CYP-450 enzyme and epoxide hydrolase.⁶ One study suggested an association between a cutaneous reaction to carbamazepine and the presence of the HLA-B*1502 gene in certain patients.⁸ Additional reports have shown a relationship between the hypersensitivity syndrome and reactivation of herpesvirus 6 and 7.^9,10 Other factors that may contribute to anticonvulsant hypersensitivity syndrome are allergic hypersensitivity and a form of graft-versus-host disease.

No connection to dosage or to drug serum levels has been found, but the syndrome is more severe in people who have had a reaction to anticonvulsant agents in the past and are thus sensitized.¹¹

In this population, signs and symptoms of the syndrome can develop within hours of reexposure. Such patients can also develop more severe and potentially fatal conditions, such as Stevens-Johnson syndrome or toxic epidermal necrolysis—a diffuse skin condition that resembles a second-degree burn and carries a mortality rate of 20% to 30%.¹²

Signs and Symptoms
Despite variability in the onset and severity of the clinical presentation, the overall constellation of signs and symptoms of fever, rash, lymphadenopathy, and hepatitis is the same with all the anticonvulsant medications that have been found to cause anticonvulsant hypersensitivity syndrome (Table 2). In addition, other multiorgan pathologies are seen in 60% of cases.^13,14 The most common feature of the syndrome is fever, which is seen in more than 90% of cases and is often high and spiking (between 38°C and 40°C).^15,16 Fever may occur before or simultaneously with skin rash, which occurs in an estimated 90% of cases.¹⁶ The rash typically begins as a patchy macular erythematous eruption on the face, arms, and torso. Although several types of drugs can cause a cutaneous eruption (Table 3), facial involvement is rare, except when the offending agent is an anticonvulsant, making this a potentially distinguishing feature of anticonvulsant hypersensitivity syndrome.¹⁷ The rash progresses to a pink-red, confluent, papular, and often pruritic condition that spreads to the legs. Eventually, blisters and erythroderma may form. In rare cases, the patient develops severe exfoliative dermatitis, Stevens-Johnson syndrome, or toxic epidermal necrolysis.

Lymphadenopathy is seen in 70% of cases.^15,16 Hepatomegaly and/or splenomegaly may occur, along with a coagulopathy.^16,18 About 50% of the patients have hematologic abnormalities (ie, leukocytosis or leukopenia, eosinophilia, anemia, agranulocytosis, and the appearance of atypical lymphocytes) and hepatitis.^15,16 The hepatitis is generally mild and anicteric; if severe, it can lead to liver failure—the most common cause of death in patients with this syndrome. The mortality rate in patients with anticonvulsant hypersensitivity syndrome and hepatitis ranges between 18% and 40%.¹⁶ Liver function test abnormalities are seen in 30% to 60% of patients.^11,14,15 Measurements of bilirubin level and prothrombin time may be higher than normal.

About 25% of patients have facial and periorbital edema.^15,16 Other features include thyroiditis, arthralgias, renal dysfunction, and pneumonitis.

Illustrative Case
A 30-year-old Asian woman was transferred to the hospital from the outpatient colorectal surgery clinic after physical examination revealed an anal fissure. She was admitted to the medical service and reported she had been having episodic seizures for 4 weeks. Her medications on transfer included carbamazepine, 200 mg/day; hydroxyzine HCl (Vistaril), 25 mg/day; methylprednisolone (Medrol); and cefadroxil (Duricef), 500 mg twice daily; these were all discontinued at admission.

During the previous week she developed cervical lymphadenopathy and a generalized pruritic rash, which spread to the face and rest of the body. She reported she had noted facial swelling, beginning 3 to 4 days before hospitalization, as well as having fevers and chills, headache, nausea, and vomiting for several days, along with abdominal tenderness and occult blood in the stool for the past 2 days.

Her temperature was 102.2°F. Physical examination confirmed the presence of a maculopapular rash over her face, trunk, arms, and legs, sparing the palmar and plantar surfaces, as well as cervical, inguinal, and submandibular adenopathy, along with facial edema.

An electroencephalogram demonstrated the occurrence of seizure activity. A thorough evaluation revealed that she was having complex partial seizures with automatisms, loss of consciousness, and postictal grogginess. The patient was subsequently restarted on carbamazepine, 200 mg/day. Magnetic resonance imaging (MRI) with gadolinium showed subependymal gray matter and heterotopia. Chest radiograph was suggestive of splenomegaly, but an abdominal ultrasound was normal.

Laboratory test results were normal, except for elevated markers of liver function: alkaline phosphatase, 450 U/L; aspartate aminotransferase (AST), 190 U/L; and alanine aminotransferase (ALT), 414 U/L. Both AST and ALT values increased during hospitalization to 288 U/L and 538 U/L, respectively. Other test results were negative.

Based on these findings and the recent drug history, sensitivity to carbamazepine was deemed the culprit, and the medication was promptly discontinued. It was replaced by systemic steroids, along with lorazepam (Ativan) and diazepam (Valium) on an as-needed basis for any seizure activity. The patient was administered diphenhydramine (eg, Banophen, Benadryl, Genahist), and hydroxyzine HCl for the allergic symptoms.

The symptoms gradually improved, no long-term liver damage was apparent, and no further workup was deemed necessary.

Diagnosis
Diagnosis of anticonvulsant hypersensitivity syndrome is based on a history of medication exposure and clinical signs and symptoms. A high index of suspicion is needed early in the diagnostic workup to recognize hypersensitivity reactions to anticonvulsants. Signs and symptoms usually occur within 3 months of initiating treatment with an anticonvulsant, most often within 2 to 6 weeks.⁷

Results of blood, throat, and urine cultures taken at the time of the patient’s initial presentation are negative, as was the case in our patient. Erythrocyte sedimentation rate and serum complement levels are also usually within normal limits. Liver function and hematologic abnormalities may be seen. Lymphocyte transformation and toxicity assays, as well as patch testing, may support the clinical diagnosis, but their use has not been standardized.¹⁹

Patch testing may be used to confirm that the reaction is related to a drug, if the diagnosis of anticonvulsant hypersensitivity syndrome is unclear and phenytoin anticonvulsant therapy is necessary.20 In vitro lymphocyte transformation is a very specialized test that can be used to confirm the diagnosis.⁶ But lymphocyte transformation and patch testing are considered reliable only after the acute phase of anticonvulsant hypersensitivity reaction has passed.

Histologic examination typically reveals a dense, superficial perivascular lymphocytic infiltrate.²¹ There may also be evidence of dermatitis (lichenoid or spongiotic) and edema.²¹

Imaging studies are not part of the standard workup for anticonvulsant hypersensitivity syndrome. (In our patient, the MRI was done to rule out the brain as the cause for the seizures.)

Symptoms of anticonvulsant hypersensitivity syndrome overlap with those of other conditions, including lymphoma, sepsis, and autoimmune processes. The differential diagnosis includes collagen vascular disease, viral diseases (such as hepatitis), influenza, cytomegalovirus, HIV infection, Epstein-Barr virus infection, Kawasaki syndrome, lymphoma, syphilis, porphyria, and hypereosinophilic syndrome.

Many drugs can cause reactions that may mimic some of the reactions seen with anticonvulsants (Tables 3, 4).¹⁶

Treatment
Once the diagnosis is suspected, the patient should immediately stop taking the anticonvulsant drug. Intermittent fever may continue for several weeks, and skin desquamation may occur while the syndrome is resolving.¹⁶ Liver function test abnormalities may take months or even a full year to resolve, along with the hepatitis. Other medications in the phenytoin family should not be used, because of a high rate of cross-reactivity.

A short-acting benzodiazepine may be substituted for the anticonvulsant. Valproic acid (Depakene), a nonaromatic anticonvulsant, may also be considered, but it should not be used during the acute or recovery phase because of its effects on the liver. Patients who have had a reaction to an antiepileptic agent may develop a rash when given valproic acid. Case reports suggest that gabapentin (Gabarone, Neurontin) may be effective in such situations.²²

The second-generation antiepileptics—tiagabine HCl (Gabitril Filmtabs), topiramate (Topamax), and levetiracetam (Keppra)—are associated with a low incidence of rash and fever and may be alternate choices as well, but they cannot be administered during the acute phase of the syndrome because they cannot be administered quickly and require delayed administration.

To avoid initiating or furthering liver damage, the new anticonvulsant should not be used until the acute phase of anticonvulsant hypersensitivity syndrome has subsided.

Be careful when abruptly discontinuing anticonvulsant medications. The obvious risk is the potential development of status epilepticus, in which case hospitalization must be considered. When stopping the causative antiepileptic agent, initiate an alternative antiepileptic and monitor the patient carefully.

Supportive therapy includes topical and systemic corticosteroids, antihistamines, and soaked tap-water wraps for the cutaneous manifestations. Further studies are needed to evaluate the efficacy of corticosteroids in this condition. Great care must be taken when weaning the steroids; anticonvulsant hypersensitivity syndrome can relapse if discontinuation occurs too rapidly. Fluid and electrolyte balance must be maintained, and thyroid function may need to be followed as well. N-acetylcysteine (Acetadote, Mucomyst) may be efficacious in situations where hepatitis has developed.²³

Because of the possible genetic component, first-degree relatives should be informed about the condition and cautioned to avoid aromatic anticonvulsants.

Genetic testing may one day be helpful in assessing a patient’s risk, but genetic susceptibility has not yet been determined.

Conclusion
Anticonvulsant hypersensitivity syndrome is a rare but potentially fatal condition, and early recognition is essential to avoid morbidity and possible mortality. Failure to recognize this condition and withdraw the causative medication may result in permanent multiorgan damage. The classic history and physical examination findings can yield a timely diagnosis. Recurrence can be prevented by continuity of care. Patients with the syndrome should wear a medical identification bracelet.

Self-assessment test
1. Which statement about anticonvulsant hypersensitivity syndrome is NOT true?
A. It is associated with aromatic anticonvulsants
B. Patients who have a hypersensitivity reaction to phenytoin will not be able to tolerate phenobarbital
C. Incidence is higher in elderly black men
D. Signs and symptoms usually occur within 2 to 6 weeks of starting therapy

2. All these are common features of anticonvulsant hypersensitivity syndrome, except:
A. Facial rash
B. Lymphadenopathy
C. Leg edema
D. Hematologic abnormalities

3. Which of the following factors has NOT been identified as a possible cause of anticonvulsant hypersensitivity syndrome?
A. Genetics
B. High drug dosages
C. Herpes virus 6
D. Allergy

4. Which drug is least likely to cause a reaction that mimics anticonvulsant hypersensitivity syndrome?
A. Metoclopramide
B. Captopril
C. Diltiazem
D. Isoniazid

5. Which of these strategies is NOT an appropriate treatment for anticonvulsant hypersensitivity syndrome?
A. Slowly taper the offending anticonvulsant
B. Wait until the acute phase has subsided before administering a new anticonvulsant agent
C. Substitute valproic acid for the offending agent during the recovery phase
D. Apply tap-water wraps to relieve cutaneous symptoms

(Answers at end of references list)

References
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2. Kaur S, Sarkar R, Thami GP, et al. Anticonvulsant hypersensitivity syndrome. Pediatr Dermatol. 2002;19: 142-145.

3. Gennis MA, Vemuri R, Burns EA, et al. Familial occurrence of hypersensitivity to phenytoin. Am J Med. 1991;91:631-634.

4. Tennis P, Stern RS. Risk of serious cutaneous disorders after initiation of use of phenytoin, carbamazepine, or sodium valproate: a record linkage study. Neurology. 1997;49:542-546.

5. Mendiratta V, Bhushan P. Phenytoin-induced DRESS with cross-reactivity to carbamazepine in a 10-year-old Indian child. Clin Exp Dermatol. 2006;31:720-721.

6. Shear NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk. J Clin Invest. 1988;82: 1826-1832.

7. Krauss G. Current understanding of delayed anticonvulsant hypersensitivity reactions. Epilepsy Curr. 2006;6:33-37.

8. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006;16:297-306.

9. Matsuda K, Ohnuma T, Fukuta M, et al. Case reports and literature review: the association between reactivation of human herpes virus-6 and peripheral white blood cell count in patients with carbamazepine-induced hypersensitivity syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:751-754.

10. Oskay T, Karademir A, Erturk OI. Association of anticonvulsant hypersensitivity syndrome with Herpesvirus 6, 7. Epilepsy Res. 2006; 70:27-40.

11. De Vriese AS, Philippe J, Van Renterghem DM, et al. Carbamazepine hypersensitivity syndrome: report of 4 cases and review of the literature. Medicine (Baltimore). 1995;74: 144-151.

12. Imahara SD, Holmes JH IV, Heimbach DM, et al. SCORTEN overestimates mortality in the setting of a standardized treatment protocol. J Burn Care Res. 2006;27:270-275.

13. Bertz RJ, Howrie DL. Diazepam by continuous intravenous infusion for status epilepticus in anticonvulsant hypersensitivity syndrome. Ann Pharmacother. 1993;27:298-301.

14. Braitberg G, Miller MB, Curry SC. Anticonvulsant hypersensitivity syndrome. Emerg Med (Australia). 1995;7:170-175.

15. Chang DK, Shear NH. Cutaneous reactions to anticonvulsants. Semin Neurol. 1992;12:329-337.

16. Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med. 1995;155:2285-2290.

17. Erwin MB, Barden A. Anticonvulsant hypersensitivity syndrome. J Crit Illn. 2001;16:71-76.

18. Handfield-Jones SE, Jenkins RE, Whittaker SJ, et al. The anticonvulsant hypersensitivity syndrome. Br J Dermatol. 1993;129:175-177.

19. Neuman MG, Malkiewicz IM, Shear NH. A novel lymphocyte toxicity assay to assess drug hypersensitivity syndromes. Clin Biochem. 2000;33:517-524.

20. Gaig P, Garcia-Ortega P, Baltasar M, et al. Drug neosensitization during anticonvulsant hypersensitivity syndrome. J Investig Allergol Clin Immunol. 2006;16:321-326.

21. Hashizume H, Takigawa M, Tokura Y. Characterization of drug-specific T cells in phenobarbital-induced eruption. J Immunol. 2002; 168:5359-5368.

22. Hamer HM, Morris HH. Successful treatment with gabapentin in the presence of hypersensitivity syndrome to phenytoin and carbamazepine: a report of three cases. Seizure. 1999;8:190-192.

23. Harrison PM, Wendon JA, Gimson AE, et al. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med. 1991;324:1852-1857.

Answers: 1. B; 2. C; 3. B; 4. A; 5. A.