Levetiracetam in Newly Diagnosed Glioma, Epilepsy

Abstract & Commentary

By Padmaja Kandula, MD, Assistant Professor of Neurology and Neuroscience, Comprehensive Epilepsy Center, Weill Medical College of Cornell University. Dr. Kandula reports no financial interest in this field of study

Synopsis: This prospective case series reports on the efficacy and safety of levetiracetam in central nervous system gliomas.

Sources: Rosati A, et al. Efficacy and safety oflevetiracetam in patients with glioma: A clinical prospective study. Arch Neurol 2010;67: 343-346.

Seizures may occur as the initial presentation or later in the medical course of a primary brain tumor. The treatment of central nervous system glioma patients is multimodal, requiring the use of anti-epileptic agents, systemic steroids, and chemotherapeutics. Thus, anti-seizure medications such as levetiracetam with no clinically relevant drug interactions and lack of hepatic P-450 induction or inhibitory effects is very desirable. Although levetiracetam has been used extensively in both the United States and Europe in glioma patients, few long-term studies assessing the efficacy of the medication are available. The authors of this study present the clinical treatment response of newly diagnosed glioma patients with epilepsy.

Only newly diagnosed glioma and epilepsy patients were included in this clinical prospective trial. Patients previously on anti-epileptic agents or prior diagnosis of glioma were excluded. Epilepsy was defined as either recurrent clinical seizures with or without interictal epileptiform abnormalities (IEAs) on electroencephalogram recording, single focal or convulsive seizure with associated IEAs, single convulsion and history of prior episodes suggestive of focal seizures with or without IEAs, or seizures occurring de novo during medical follow up with or without IEAs. Patients were then treated with initial dosages of either 500 mg bid (< 70 years of age) or 250 mg bid (>70 years of age) of levetiracetam.

At subsequent follow up visits (every 1-3 months), seizure recurrence and causative factors were assessed. Seizure recurrence was categorized as either daily, weekly, monthly, rare (< 1 seizure per month), or no seizures. Cause of seizure recurrence was categorized as follows:

1. radiographic tumor recurrence after prior radiographic response;

2. malignant (radiographic or pathologic) tumor progression;

3. subtherapeutic anticonvulsant levels in the absence of clear tumor progression and cessation of seizures with dose increase;

4. refractory seizures that occurred despite optimal therapeutic anticonvulsant levels and absence of tumor recurrence; or

5. radiotherapy induced seizures. Seizures secondary to causes 1-3 were treated with levetiracetam dose increase.

Condition 4, refractory seizures, was treated with add on treatment with either oxcarbazepine, topiramate, or valproic acid. Radiotherapy induced seizures were treated only with corticosteroids. All patients were categorized based on the extent of neurosurgical resection (neurosurgeon report and post contract CT scan) as partial (< 50%), subtotal (50%–80%) or total tumor removal.

Out of the 176 consecutive newly diagnosed glioma patients in the nearly three-year study, 82 patients had epilepsy and met study criteria. In 75 of 82 patients (91%), epilepsy was the presenting symptom and nearly two thirds of enrolled patients had grade IV glioma; 75 of 82 patients were seizure-free at the last evaluation either with monotherapy with levetiracetam (73 patients), topiramate (1 patient), or valproic acid (1 patient). The mean follow-up time was 13.1 months. Levetiracetam was stopped in the above two patients receiving topiramate and valproic acid monotherapy due to intolerable side effects. In the 7 of 82 drug-resistant patients, all patients were either grade III or IV.

Commentary

The results of this study suggest that levetiracetam is safe and effective for primary brain tumors with epilepsy. The authors found no definite laboratory abnormalities associated with concomitant use of levetiracetam and chemotherapeutic agents (temozolomide and fotemustine). Nearly 90% of patients achieved seizure control with levetiracetam monotherapy . Nearly two-thirds of these patients achieved control with levetiracetam doses of 1500-3000 mg per day, suggesting that moderate dosing of this agent may be efficacious.

Despite widespread use of levetiracetam, the exact mechanism of action is still not clear. The most recent evidence points to SV2A (synaptic vesicle protein) as the brain-binding site for levetiracetam. This glycoprotein has been suggested as a modulator of vesicular fusion and synaptic vesicular release (prevention of exocytosis of excitatory glutamate). Furthermore, whether levetiracetam has any inherent mechanistic properties that are useful in brain tumor patients also needs elucidation. An article by Haghikia et al suggests, in animal models, that levetiracetam has the ability to prevent astroglial dysregulation under inflammatory conditions as might be seen in recurrent seizures.1

Although levetiracetam is currently not FDA-approved in the United States as monotherapy, its lack of drug interactions, efficacy, and safety profile suggest that the medication be considered in glioma patients, particularly in patients who demonstrate side effects from other FDA approved monotherapy anticonvulsants. In the interim, slowly accumulating evidence suggests the safety of levetiracetam, but head-to-head efficacy comparisons with other anticonvulsants, particularly other second-generation anticonvulsants are still needed.

Reference

1. Haghikia A, et al. Implications of anti-inflammatory properties of the anticonvulsant drug levetiracetam in astrocytes. J Neurosci Res 2008;86:1781-1788.