Rethinking epilepsy care with therapeutic drug monitoring
A focused clinical approach to second-generation anti-seizure medications and laboratory diagnostics
8 Aug 2025
Dr. Rahiwa Gebre and Dr. Ken Tamama, University of Pittsburgh School of Medicine
With increasing demand for personalized epilepsy treatment, clinical laboratories play a pivotal role in the therapeutic drug monitoring (TDM) of second-generation anti-seizure medications (ASMs). This article explores current testing methodologies, including LC-MS/MS and immunoassays, and the strategies needed to implement TDM into routine practice that could help optimize long-term care for epilepsy patients.
Epilepsy affects roughly 50 million people worldwide, making it the fourth most common neurological condition across all age groups. Characterized by recurrent, unprovoked seizures, the disease is far from uniform in how it manifests. Seizures vary significantly in type, intensity, and cause, and effective treatment requires not only an accurate diagnosis but ongoing fine-tuning of therapeutic modalities.
ASMs, previously known as antiepileptic drugs (AEDs), remain the primary treatment strategy. While first-generation ASMs like valproic acid and phenytoin have long been in use, second-generation options such as lamotrigine and levetiracetam are now widely prescribed due to better safety profiles, fewer drug interactions, and more favorable outcomes, particularly for women of childbearing age. As the therapeutic landscape continues to shift, clinicians and laboratory professionals are paying closer attention to TDM as a strategy to optimize care.
A recent P.A.C.E.®- and ACCENT®-accredited webinar hosted by SelectScience®, with Siemens Healthineers: Therapeutic Drug Monitoring for Second-Generation Antiepileptic Drugs, brought together Dr. Rahiwa Gebre, neurologist and assistant professor of clinical neurology, and Dr. Ken Tamama, professor of pathology and medical director of clinical chemistry and toxicology at University of Pittsburgh School of Medicine, to discuss epilepsy management and laboratory-based ASM testing strategies. The event offered valuable clinical insights and laboratory-focused approaches for monitoring second-generation ASMs, particularly lamotrigine and levetiracetam.
Understanding epilepsy and why monitoring matters
Epilepsy is not a single disease but rather a group of disorders involving abnormal electrical activity in the brain. “It is defined as having at least two unprovoked seizures more than 24 hours apart,” says Dr. Gebre.
She explains that an accurate diagnosis is critical, as many patients experience events that may resemble seizures but have different underlying causes. “Sometimes epilepsy can mimic something else and people get misdiagnosed,” she adds. Conditions like cardiac syncope or psychogenic nonepileptic seizures can present with similar physical symptoms, which is why a thorough workup, including EEG and MRI, is often required.
Classification of seizure types follows criteria set by the International League Against Epilepsy (ILAE). “We divide seizures based on where they originate, focal or generalized, and then based on awareness and whether the seizure is motor or non-motor,” says Gebre. This helps guide not only the diagnosis, but also the choice of medication, since certain ASMs are more effective for specific types of seizures.
Once epilepsy is diagnosed, initiating the right ASM and adjusting dosage over time is crucial. Most patients respond to pharmacologic treatment, but the margin between efficacy and toxicity can be narrow. That’s where TDM becomes indispensable. Routine monitoring allows for confirmation of therapeutic adherence, identification of potential under- or over-dosing, and informs decisions about medication changes, especially if a patient’s clinical picture is complex or becomes more convoluted.
Second-generation ASMs
Treatment approaches have evolved significantly with the introduction of second-generation ASMs. “There are more than 25 anti-seizure medications right now,” says Dr. Gebre. She noted that newer agents like levetiracetam and lamotrigine are increasingly favored due to better adverse effect profiles and fewer risks in vulnerable populations.
“For women of childbearing age, we prefer not to use valproic acid unless we really have to,” she says. The risk of teratogenic effects and cognitive developmental issues in infants exposed to valproic acid in utero is well documented. In contrast, levetiracetam and lamotrigine are often considered safer alternatives, though they still require monitoring.
But even these second-generation drugs can have serious adverse effects if not dosed properly. Lamotrigine and levetiracetam are among the most widely used second-generation ASMs. Each comes with specific challenges and considerations that TDM can help manage. Lamotrigine, for instance, is metabolized by glucuronidation in the liver and can be affected by enzyme inducers or inhibitors. “Its metabolism changes significantly in pregnancy,” Dr. Gebre notes, pointing out that lamotrigine clearance can double or triple during gestation. Without proper monitoring, patients may be under-dosed, leading to breakthrough seizures that are particularly dangerous during pregnancy.
Levetiracetam, on the other hand, has a simpler pharmacokinetic profile. It is primarily excreted unchanged in the urine and is not metabolized by liver enzymes, making it more predictable in terms of interactions. However, TDM can still play a role, especially when patients are on polytherapy or present with unexpected adverse effects or poor seizure control.
How labs can approach TDM for second-generation ASMs
From the laboratory side, implementation of ASM testing must be both clinically useful and operationally feasible. Dr. Tamama discusses the current state of TDM in the clinical lab, highlighting how levetiracetam and lamotrigine are often measured using either chromatography-based methods (like LC-MS/MS) or immunoassays.
Chromatography however comes with higher costs, complex instrumentation, and longer turnaround times. For many hospitals and labs, especially those that need faster results to inform clinical decision-making, high-throughput immunoassay-based platforms offer a practical solution for monitoring levetiracetam and lamotrigine.
Still, immunoassays are not without challenges. Dr. Tamama notes one potential pitfall: cross-reactivity. “For levetiracetam, if the patient is also taking brivaracetam, the immunoassay will detect both,” he explains. Brivaracetam is structurally similar and shares a major metabolite with levetiracetam, making it hard to distinguish between the two in some assays. In those cases, LC-MS/MS may be needed for accurate measurement.
Dr. Tamama also shares data from his own lab showing correlation between immunoassay and LC-MS/MS methods. For levetiracetam, they found an acceptable agreement that supported immunoassay use for routine monitoring. The story was similar for lamotrigine, although variability increased slightly at higher concentrations. Despite these limitations, both assays met the needs of most routine epilepsy management situations.
Pregnancy and pediatric care require tighter monitoring
Pregnancy adds another layer of complexity to epilepsy management. Most women with epilepsy will require dose increases during pregnancy, especially those taking lamotrigine. Hormonal changes accelerate drug clearance, but the reverse happens postpartum, creating a risk of toxicity if the dose is not quickly reduced.
Dr. Gebre emphasizes the importance of proactive planning. “If we don’t adjust the dose during pregnancy, we see an increased risk of breakthrough seizures, which is dangerous for both the mother and the fetus,” she says. TDM allows for dynamic dose adjustments as pregnancy progresses, helping maintain seizure control without risking overmedication.
In pediatrics, the picture is similarly nuanced. Children's metabolic rates and body composition evolve rapidly, meaning their drug levels can fluctuate even with consistent dosing. For both pediatric and perinatal populations, standardized lab workflows with rapid result turnaround are critical.
Building lab capacity for future epilepsy care
The clinical need for TDM of second-generation ASMs is clear, but widespread implementation requires awareness, infrastructure, and collaboration. Labs need to work closely with neurologists and pharmacists to determine when TDM is warranted and how to interpret results effectively. This becomes especially important in cases of polypharmacy, renal or hepatic impairment, or fluctuating seizure control.
Dr. Gebre reinforces the importance of close monitoring, even if no symptoms are present, emphasizing that therapeutic levels do not always correlate with seizure presentation but can be predictive of stability or risk. TDM is not just about reacting to problems, it is a proactive tool that, when used correctly, can optimize long-term care for epilepsy patients.
As newer ASMs enter the market and guidelines continue to evolve, labs must adapt to provide fast, reliable, and cost-effective testing options. Whether through LC-MS/MS or immunoassays, incorporating TDM into standard epilepsy management workflows allows clinicians to personalize treatment, reduce adverse effects, and ultimately improve outcomes.
With epilepsy care advancing toward more tailored, precision-based approaches, laboratories have an increasingly central role. Investing in appropriate ASM testing capabilities now will help ensure patients receive the right dose, at the right time, for the best outcome.