What is the best treatment for a patient with Lennox-Gastaut syndrome on valproic acid (Valproate) and lamotrigine (Lamictal) who develops thrombocytopenia?

From the Guidelines

For a patient with Lennox-Gastaut syndrome on valproic acid and lamotrigine who develops thrombocytopenia, the best treatment approach is to reduce or discontinue valproic acid, as it is the more likely cause of thrombocytopenia, and consider replacing it with an alternative antiepileptic medication while maintaining lamotrigine therapy. This recommendation is based on the potential complications associated with valproic acid, including thrombocytopenia and hepatotoxicity, as noted in a recent study 1. The patient should undergo immediate laboratory monitoring with a complete blood count to determine the severity of thrombocytopenia.

• If platelet counts are severely low (below 50,000/μL), valproic acid should be discontinued completely and replaced with an alternative antiepileptic medication such as rufinamide, clobazam, or topiramate, while lamotrigine therapy is maintained.
• If thrombocytopenia is mild to moderate, a gradual dose reduction of valproic acid may be attempted while monitoring platelet counts weekly.
• Consultation with hematology is warranted if thrombocytopenia is severe or does not improve within 2-4 weeks after medication adjustment. Valproic acid is known to cause dose-dependent thrombocytopenia through direct bone marrow suppression and increased peripheral platelet destruction, whereas lamotrigine rarely causes this side effect 1. When changing antiepileptic medications in Lennox-Gastaut syndrome, it's crucial to overlap therapies gradually to prevent seizure exacerbation, as abrupt discontinuation can trigger status epilepticus in this fragile population.

From the FDA Drug Label

In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 10^9/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy The probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≤ 110 µg/mL (females) or ≥ 135 µg/mL (males)

The best treatment for a patient with Lennox-Gastaut syndrome on valproic acid and lamotrigine who develops thrombocytopenia is to reduce the dosage or withdraw valproic acid therapy 2.

• Monitor platelet counts and adjust treatment as needed to prevent further complications.
• Consider alternative treatments for Lennox-Gastaut syndrome that do not increase the risk of thrombocytopenia.
• Weigh the benefits and risks of continued valproic acid treatment against the risk of thrombocytopenia and other potential adverse effects.

From the Research

Treatment Options for Lennox-Gastaut Syndrome

The treatment of Lennox-Gastaut syndrome (LGS) typically involves a combination of pharmacological and non-pharmacological therapies. For a patient with LGS on valproic acid and lamotrigine who develops thrombocytopenia, the following options can be considered:

• Valproic acid is generally considered the first-line treatment for LGS, and lamotrigine is often used as an adjunctive therapy 3, 4.
• If thrombocytopenia develops, the patient's treatment regimen may need to be adjusted to minimize the risk of bleeding complications.
• Alternative treatment options for LGS include rufinamide, cannabidiol, clobazam, felbamate, fenfluramine, and topiramate, although the evidence for these treatments is more limited 3.
• Non-pharmacological therapies, such as the ketogenic diet, vagus nerve stimulation, and corpus callosotomy, may also be considered as adjunctive treatments 3, 4.

Management of Thrombocytopenia

Thrombocytopenia is a potential side effect of valproic acid, and its development may require adjustments to the patient's treatment regimen. The following considerations can be taken into account:

• The patient's valproic acid dose may need to be reduced or discontinued to minimize the risk of bleeding complications.
• Alternative antiepileptic drugs with a lower risk of thrombocytopenia may be considered, such as lamotrigine or levetiracetam.
• The patient's platelet count should be closely monitored, and adjustments to the treatment regimen should be made as needed to minimize the risk of bleeding complications.

Clinical Evidence

Several studies have investigated the treatment of LGS, including the use of valproic acid and lamotrigine. For example:

• A prospective follow-up study found that a combination of valproic acid, clobazam, and levetiracetam was effective in reducing seizure frequency in patients with LGS 5.
• A case report described the successful use of valproic acid in a patient with LGS who had undergone a liver transplant, highlighting the potential for valproic acid to be used safely in patients with a history of liver disease 6.
• A study of lamotrigine as an add-on therapy in patients with LGS found that it was effective in reducing seizure frequency and was well-tolerated 7.