Anticonvulsant hypersensitivity syndrome

Overview

Anticonvulsant Hypersensitivity Syndrome (AHS), also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) when severe, is a potentially life-threatening adverse reaction to certain anticonvulsant (antiepileptic) medications. It typically develops within 2 to 8 weeks of starting the drug and involves a combination of fever, skin rash, eosinophilia, and internal organ involvement, particularly the liver.

AHS is a form of delayed hypersensitivity reaction that may require urgent medical attention and long-term monitoring. Early recognition and drug withdrawal are critical to prevent serious complications.

Causes

AHS is most commonly triggered by aromatic anticonvulsant drugs, including:

• Phenytoin

• Carbamazepine

• Phenobarbital

Less frequently, it may occur with other medications such as lamotrigine, oxcarbazepine, or even non-anticonvulsant drugs. Key contributing factors include:

• Genetic predisposition: HLA alleles such as HLA-B*1502 (especially in Asian populations) increase risk

• Slow drug metabolism: Leading to accumulation of toxic drug metabolites

• Viral reactivation: Particularly human herpesvirus 6 (HHV-6), which may amplify immune response

Symptoms

Symptoms of AHS typically develop within 2–6 weeks after initiating the offending drug and may continue to worsen even after the drug is stopped. Common features include:

Systemic and Constitutional:

• High fever (>38.5°C)

• Malaise and fatigue

Dermatologic:

• Widespread maculopapular rash (may become exfoliative or progress to Stevens–Johnson syndrome)

• Facial edema

Hematologic:

• Eosinophilia

• Atypical lymphocytosis

Organ Involvement:

• Liver: Hepatitis, elevated liver enzymes, potential liver failure

• Kidneys: Nephritis

• Lungs: Pneumonitis

• Heart: Myocarditis (rare but fatal if untreated)

Diagnosis

Diagnosis is clinical and based on the presence of typical features in the setting of recent anticonvulsant use. Diagnostic criteria often used include those from the RegiSCAR group. Key steps include:

• History: Exposure to anticonvulsants within the past 2–8 weeks

• Physical examination: Rash, facial swelling, lymphadenopathy

• Blood tests: Eosinophilia, leukocytosis, elevated liver function tests, atypical lymphocytes

• Serology/PCR: Testing for HHV-6 or other viral reactivation if suspected

• Skin biopsy: May support diagnosis if rash is unclear

Treatment

Immediate withdrawal of the offending drug is the most critical step in management. Treatment may include:

Supportive and Symptomatic Care:

• Hospitalization: For moderate to severe cases

• Antipyretics and fluid support

Medications:

• Systemic corticosteroids: Prednisone or equivalent is commonly used to reduce inflammation

• Topical corticosteroids and antihistamines: For skin symptom relief

• Immunosuppressants (rare): Used in steroid-refractory cases (e.g., cyclosporine)

Monitoring:

• Liver and kidney function tests

• Long-term follow-up due to risk of relapse or autoimmune complications

Prognosis

The prognosis of AHS depends on the severity and timeliness of treatment. Early recognition and immediate drug cessation lead to favorable outcomes in most cases. However, delayed diagnosis can result in serious complications, including:

• Hepatic failure

• Renal impairment

• Respiratory or cardiac involvement

Mortality is estimated at 10% in severe cases, especially with multiorgan failure. Long-term sequelae such as autoimmune thyroiditis or diabetes have been reported in some patients. Patients should avoid re-exposure to the offending drug and structurally similar medications.