The benefits of mass spectrometry for epilepsy: The case for 24/7 therapeutic drug monitoring

• Treatment with antiseizure medications (ASMs) is highly individualized, supported by therapeutic drug monitoring (TDM) to optimize patient safety and treatment efficacy
• Mass spectrometry is the preferred lab method for measuring ASMs, due to its unmatched analytical specificity, which is crucial for selectively and accurately detecting the target molecule
• Timely lab results are required for urgent clinical decision-making in emergency situations such as status epilepticus

Epilepsy poses a major global public health challenge, affecting more than 50 million individuals worldwide. As one of the most common neurological diseases, it impacts people of all ages, with a high incidence in infants, children, and the elderly.^1,2 Moreover, the stakes are high: Seizure-related injuries can occur in up to 40% of patients, with a mortality rate up to three-fold higher than the general population.^1,3 Comorbidities, such as depression and autism spectrum disorders, increase polypharmacy, raising the risk for adverse effects and drug-drug interactions (DDIs).^4,5 Yet, the World Health Organization estimates that up to 70% of people living with epilepsy could become seizure-free if appropriately diagnosed and treated.¹

As the cornerstone of treating patients with epilepsy, antiseizure medications (ASMs) are among the most common classes of medications for which therapeutic drug monitoring (TDM) is performed.⁶ The preferred method for the TDM of ASMs is liquid chromatography-tandem mass spectrometry (LC-MS/MS). Compared to alternative techniques, LC-MS/MS offers superior sensitivity and specificity, and allows for the selective quantification of parent drugs and their clinically relevant metabolites, even in patients on polytherapy.^6,7

ASM treatment is highly individualized, reflecting the complex and diverse pathophysiological causes of seizures. In addition to the narrow therapeutic ranges of some ASMs, several patient-specific factors must be considered, including age, co-medications, physiological states such as pregnancy or childbearing potential, and the presence of comorbidities.^7,8

Initiating ASM treatment typically requires slow up-titration. Gradually increasing the dose helps improve drug tolerance, minimizing the risk of adverse effects and toxicity.⁹ Titration schedules vary between ASMs and are influenced by multiple factors, such as whether the ASM is used as a monotherapy or an adjunctive therapy, its pharmacokinetic profile, and the patient’s individual response to treatment. Up-titration is typically stopped once the patient becomes seizure-free, indicating the individual target dose has been reached, which may be lower for one patient and higher for another, depending on their unique pharmacodynamic response despite carrying the same diagnosis.⁹ Monitoring plasma drug concentrations supports this delicate process, helping to prevent toxicity while establishing a patient's individual therapeutic target concentration.⁶

Numerous patient demographics and clinical indications warrant closer monitoring of therapeutic drug levels:^6,10

• Children: Rapid development makes dose requirements less predictable. Children may need a higher ASM dose (per kg body weight) than adults to achieve the same plasma concentration.
• Elderly: Polytherapy is common, resulting in a higher risk of DDIs. Variable adherence is a contributing factor to variability. Clearance can be lower due to decreased renal or liver function. They are more sensitive to adverse effects because of pharmacodynamic changes. Thus, they would often need lower doses of ASMs.
• Pregnancy: Expectant mothers might warrant changes in their pharmacotherapy. Rapid physiological changes result in altered pharmacokinetics requiring dose adaptations. Often a dosage increase is needed due to increased clearance of the most commonly used ASMs in women, and the variability is unpredictable (e.g., lamotrigine, levetiracetam).
• Patients with comorbidities: Comorbidities can impact pharmacokinetics, such as absorption, distribution, elimination (poor organ function), and protein binding of ASMs as well as other comedications. The risk of DDIs increases with the number of concomitant medications, further contributing to changes in pharmacokinetics that require monitoring.
• Vulnerable groups: TDM can help HCPs to treat patients who have difficulty communicating adverse events, such as young children or those with intellectual disabilities.

In emergency situations, such as breakthrough seizures, status epilepticus, overdose, or acute neurological events (e.g., stroke or trauma), the rapid availability of ASM levels is essential for guiding immediate and appropriate clinical interventions.^6,11

The clinical presentation alone is often inconclusive, as symptoms of toxicity may mimic seizure activity, particularly in cases of overdose.¹¹ This highlights the need for prompt and reliable TDM to support diagnostic clarity and treatment decisions.

Certain ASMs, such as carbamazepine, introduce additional complexity because measuring the parent compound alone might be insufficient. Its pharmacologically active metabolite, carbamazepine-10,11-epoxide (CBZE), plays a role in both therapeutic efficacy and toxicity, and can reach high concentrations even when parent drug levels appear to be within the reference range. In the worst cases, such intoxications can be fatal.¹²

Especially in cases of overdose or altered metabolism, or when DDIs are present, CBZE can rise quickly, while falling carbamazepine levels can be falsely reassuring.^12,13 A complete picture of the bioactive drug load is more accurate by quantifying both the parent drug and its metabolites, requiring testing with chromatographic methods such as LC-MS/MS.^12,13   

Another clinical scenario where urgent laboratory results are needed is status epilepticus (SE). SE is widely regarded as the most common serious neurological emergency worldwide, and long-term mortality has been reported as high as 22% in children and 57% in adults.¹⁴ SE is generally defined as a single seizure lasting more than five minutes or recurrent seizures without return to baseline.¹⁵ In the presentation of SE, intravenous administration of levetiracetam, valproic acid, phenytoin, and other ASMs is used to decrease ongoing epileptic activity.^7,11

Because acute illness and emergency treatment alter albumin levels and shifts protein binding, the unbound fraction of highly bound drugs like phenytoin and valproate unpredictably exceed the typical 10% ratio.^7,11 Phenytoin is further complicated by a transition from first-order to zero-order saturable kinetics at high exposures, making binding equilibrium and elimination unpredictable.^7,11 Consequently, high-dose IV administration during SE requires rapid and close monitoring of both total and unbound concentrations to guide safe, individualized therapy.^6,11,16-18

Despite its high analytical performance, LC-MS/MS has traditionally been limited by batch-based testing and lower throughput, affecting turnaround times in urgent care settings.¹⁹ However, advances in LC-MS/MS technology and workflows are overcoming these limitations, enabling faster, more flexible, and even 24/7 implementation in central laboratories.^20-23

Integrating LC-MS/MS into a laboratory’s 24/7 service offering presents a powerful opportunity to transform emergency care. Making LC-MS/MS-based TDM available around the clock could significantly enhance the clinical management of epilepsy and other neurological emergencies. In this context, the benefits of mass spectrometry include reinforcing the central laboratory’s role in critical care decision-making while contributing to more cost-effective healthcare delivery.^21-23

With aging populations, increasing polypharmacy, and broader access to new therapies, the range of molecular structures found in patient specimens continues to grow. This expanding complexity underscores the need for greater analytical specificity.

Long considered the gold standard for small-molecule analysis, LC-MS/MS was traditionally limited to research settings. It is now commonly used in clinical practice, enabling the delivery of highly specific, state-of-the-art results. These insights serve as a reliable foundation for clinical decision-making, elevate the quality of patient care, and foster interprofessional collaboration as part of treatment evaluations. Providing 24/7 LC-MS/MS-based TDM results will only further optimize the management of neurological emergencies, enabling faster clinical decisions and maximizing healthcare resources. As medicine realizes its potential to implement highly-tailored approaches to patient care, unlocking the continuous availability of mass spectrometry is increasingly essential.