How does Lamotrigine (Lamictal) cause Hemophagocytic Lymphohistiocytosis (HLH)?

From the Guidelines

Lamotrigine can cause Hemophagocytic Lymphohistiocytosis (HLH) through immune system dysregulation, though this is a rare adverse effect. The mechanism involves lamotrigine triggering an excessive immune response in genetically susceptible individuals, leading to hyperactivation of T lymphocytes and macrophages. This immune hyperactivation results in uncontrolled cytokine production (cytokine storm) with elevated levels of inflammatory markers like ferritin, triglycerides, and cytokines such as IL-6, TNF-alpha, and IFN-gamma 1. The drug likely acts as an antigenic trigger that initiates this abnormal immune cascade in predisposed patients.

Key Points to Consider

• HLH is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells 1
• Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders 1
• The treatment protocols HLH-94 and HLH-2004 have been established as scientific cornerstones for diagnosis, classification, and treatment of HLH in patients younger than 18 years, but may not be directly applicable to adults 1
• Patients taking lamotrigine who develop persistent fever, unexplained cytopenias, liver dysfunction, or neurological symptoms should be promptly evaluated for HLH, as early recognition and discontinuation of the medication are crucial for management

Management of HLH

• Decision to start HLH-directed treatment depends on clinical judgment and assessment of organ function 1
• Pulsed corticosteroids and elements of HLH-94 (dexamethasone 10 mg/m2 with/without a modified dose of etoposide) may be used 1
• Addition of IV immunoglobulin (IVIG) may be considered, but its use has been questioned in adult-onset Still’s disease 1
• Anakinra may reduce mortality in sepsis patients with MAS features 1

Important Considerations

• Early recognition and discontinuation of lamotrigine are crucial for management of HLH
• Patients with HLH often suffer from recurrent fever, cytopenia, liver dysfunction, and a sepsis-like syndrome that may rapidly progress to terminal multiple organ failure 1
• Subspecialists in various fields should be aware of HLH, as it can present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome 1

From the Research

Clinical Characteristics of Lamotrigine-Induced HLH

• The clinical characteristics of lamotrigine-induced HLH include fever, cytopenia, rash, and hyperferritinaemia, with bone marrow showing haemophagocytosis 2.
• Symptoms of lamotrigine-induced HLH typically occur within 6-24 days after treatment initiation, with doses ranging from 25 mg every other day to 800 mg once daily 2, 3.
• The majority of patients improve with drug discontinuation, but some cases can be fatal if left untreated 2, 3.

Association between Lamotrigine and HLH

• Lamotrigine is associated with immune-related adverse reactions, including HLH, which can be a potentially fatal event 3.
• The temporal relationship between lamotrigine initiation and HLH onset is typically within a 24-day interval 3.
• HLH is a rare but potentially serious adverse reaction to lamotrigine, and patients should be informed to seek medical attention immediately if they experience any symptoms of HLH while taking the medication 2.

Case Reports and Treatment

• There have been several case reports of lamotrigine-associated HLH in adult patients, with only a few cases reported in the literature 4, 5.
• Treatment typically involves discontinuing lamotrigine and using steroid hormones, such as dexamethasone, to control the condition 4.
• Prompt diagnosis and initiation of immunosuppressive, immunomodulatory, and cytostatic medications are critical to improve survival in affected patients 5.