Antiepileptic drug-level monitoring has been a common clinical practice since the advent of antiepileptic drugs (AEDs). The practice of maintaining AEDs within laboratory defined therapeutic ranges is a myth, with professionals overestimating values in most of the clinical settings. In this review, this article will explore the efficacy, variability, and utility of monitoring anti-epileptic drugs levels in various settings. Epilepsy, in general, is a clinical diagnosis, with diagnostic modalities such as EEG and MRI considered to be complementary investigations. The assessment of AED efficacy should also be clinical and the AED level utilized as a complementary tool in selected situations.

Patient-Specific AED Levels

It is reasonable to check a single AED level while the patient is seizure free to serve as a “benchmark” for future reference if seizure control deteriorates or symptoms suggestive of toxicity develop [1].

Status Epilepticus

The goal of management in status epilepticus is aborting the attack using a benzodiazepine followed by an AED load, often with phenytoin.  Monitoring AED levels in this setting could guide further loading if clinically indicated [2].

Drug Substitution

Variation exists between different generic and brand name AEDs. Thus, guidelines recommend against switching between different generics and brands. However, when substitution is necessary, monitoring AED levels can guide dose adjustments [3].

Pharmacokinetics

AED efficacy can be impacted by pregnancy, liver and renal disease, polypharmacy and aging. Therefore, drug levels can be helpful in adjusting the dose to achieve seizure free quality of life [1].

Variability in AED Levels

Multiple clinical studies had been conducted to test the efficacy of monitoring AEDs levels in various clinical settings. One study involved 114 inpatients in the UK. The medications studied included phenytoin, valproate, carbamazepine, lamotrigine, and phenobarbitone. To a lesser extent, other levels had been ordered such as benzodiazepines, topiramate, gabapentin and vigabatrin. The study concluded that AED levels were most helpful and useful with phenytoin, carbamazepine, and phenobarbitone. Lamotrigine has different ranges which made interpretation of the levels unhelpful and led to inappropriate dosage changes [4]. Valproate has a short half-life which makes its measurement low-yield and primarily reflective of short-term compliance. Conversely, Phenytoin has a long half-life, and hence, AED level is more reflective of long-term usage. The newer AEDs have wider indications and tend to be safer than the older ones. Also, there are no generalizable reference ranges for some of them. For these reasons, level monitoring with newer agents is not useful [5]. Furthermore, variability in AED levels exists within patient populations and between clinical settings and often based on the type and severity of the seizure [6]. One study demonstrated that AED levels vary considerably between patients treated for idiopathic generalized tonic-clonic seizures with phenytoin. The variety of an AED level may provide some patients seizure free quality of life and yet correlate with symptoms of toxicity in other patients. Thus, it is impractical to generalize the efficacy of AED level monitoring [7].

Clinical monitoring versus Drug-Level Monitoring

Multiple studies concluded that clinical monitoring optimally achieves achievement of seizure control. One investigation studied patients taking phenytoin and compared medication adjustment based on clinical grounds in one arm and adjustment based on drug level in the other. They found that the majority of cases could successfully be managed clinically and only a small number of patients benefited from drug level monitoring [8]. This study was conducted using an old AED with a long half-life, so AED level more closely correlated with medication compliance. Trying to achieve a therapeutic level in seizure-free patients with subtherapeutic level has not shown any difference in seizure control and was associated with more neurotoxicity [7].

AED Compliance

Compliance with epilepsy treatment plans is challenging due to the chronicity of the disease often requiring long-term pharmacologic therapy. There are different types of noncompliance. Erratic noncompliance is the most common and manifests as inconsistent dosing. This results in unreliable therapeutic AED levels and variability in seizure control [9].  Some patients tend towards “white coat adherence,” taking their medications one or more days before their office visit which often results in AED levels within the normal ranges. In general, compliance studies are limited by their short-term nature and are difficult to correlate with actual behavior which is known to vary over long periods of time in chronic conditions such as epilepsy [10]. Compliance and adherence had been used interchangeably to describe the status of not taking the medication or following the treatment plan [11]. Compliance implies a paternalistic approach and fails to consider the patient perspective. Adherence reflects the patient role and perspective in the treatment plan. Compliance/adherence to a treatment plan is a complex process stemming from the strength of the relationships between the physician, the patient, and the healthcare system. Compliance is paternalistic, passive and episodic. However, adherence is collaborative, active, and continuous. Therefore, many clinicians prefer to use the term adherence as opposed to compliance to position the patient at the center of their treatment plan and emphasize a holistic approach to achieving positive long-term outcomes in the treatment of complex chronic conditions such as epilepsy [12].

Other Ways to Promote AED-Level Monitoring

While the clinicians are responsible for directing the patients about their medications, explore the reasons for non-adherence and try to help the patients to overcome them. However, it depends on the patient eventually to adhere to their medications. Many methods help to measure compliance such as:

1. Patient reporting, which depends on the patient recalling, whether the reliable patient historian and the pattern of compliance with other medications
2. Drug level which has been used as the only reliable way to monitor adherence by most of the clinicians
3. Diaries
4. Direct observation of drug taking
5. Pill counts

Many effective ways help patients to be adherent to their medication other than monitoring drug level. The dilemma with monitoring the drug level that it is costly, non-reliable, and in some instances would lead to unnecessary dosage changes which could increase the risk of side effects.

Achieving optimal outcomes in the treatment of epilepsy rarely requires monitoring of AED levels. While this has been a common clinical practice for years, newer AEDs and more recent evidence suggest the value of AED level monitoring is low except for the few scenarios mentioned above. Clinical monitoring within the context of a supportive, patient-centered treatment plan based on a therapeutic physician-patient relationship is the key to success.

In the current environment of patients seeking health foods, herbal and non-proprietory medications, therapeutic drug monitoring can pose challenges. Thorough knowledge of the patient's medication list is important to consider potential drug-drug interactions and to minimize undesired changes in the antiepileptic drug levels. The recent increase in the use of cannabidiol as an antiepileptic drug has increased the need for frequent monitoring of certain medications like clobazam during concomitant therapy.[13]