Continuing Education Activity

Antiepileptic drug-level monitoring has been a common clinical practice since the advent of antiepileptic drugs (AEDs). Maintaining AEDs within laboratory-defined therapeutic ranges is a myth, with professionals overestimating values in most clinical settings. Epilepsy, in general, is a clinical diagnosis, with diagnostic modalities such as EEG and MRI considered complementary investigations. The assessment of AED efficacy should also be clinical, and the AED level should be utilized as a complementary tool in selected situations. This activity reviews antiepileptic drug monitoring and the role of the interprofessional team in monitoring patients taking antiepileptic drugs.

Objectives:

• Explain why the practice of maintaining AEDs within laboratory-defined therapeutic ranges is a myth.
• Describe the efficacy, variability, and utility of monitoring anti-epileptic drug levels in various settings.
• Review the clinical assessment of AED efficacy.
• Outline antiepileptic drug monitoring and the role of the interprofessional team in monitoring patients taking antiepileptic drugs.

Introduction

Antiepileptic drug-level monitoring has been a common clinical practice since the advent of antiepileptic drugs (AEDs). Maintaining AEDs within laboratory-defined therapeutic ranges is a myth, with professionals overestimating values in most clinical settings. This review will explore the efficacy, variability, and utility of monitoring antiepileptic drug levels in various settings.

Epilepsy, in general, is a clinical diagnosis, with diagnostic modalities such as EEG and MRI considered complementary investigations. The assessment of AED efficacy should also be clinical, and the AED level should be utilized as a complementary tool in selected situations.

Function

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]

Breakthrough Seizures

In an epilepsy patient who has been stable over a period presenting with unprovoked breakthrough seizures, it may be worthwhile checking drug levels to guide management.[2]

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, monitoring AED levels can guide dose adjustments when substitution is necessary.[3]

Pharmacokinetics

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

Issues of Concern

Variability in Anti-Seizure Medication Levels

Multiple clinical studies have 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, making interpretation of the levels unhelpful and leading to inappropriate dosage changes.[4] Valproate has a short half-life, making its measurement low-yield and primarily reflective of short-term compliance.

Conversely, phenytoin has a long half-life, and hence, the AED level is more reflective of long-term usage. The newer AEDs have broader 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 is 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 AED levels 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]

Drug-Drug interactions affecting Anti Seizure medications

Clinicians should be aware of the pharmacokinetics of medications because of polypharmacy. Drugs utilizing metabolic pathways through the liver are often affected by interactions. These are commonly seen in medications like valproic acid and carbamazepine, to cite two examples. Non-seizure medications are also an important consideration, especially in the hospital setting. Carbapenem, an antibiotic, can reduce valproic acid levels significantly and cause breakthrough seizures.[8] In that scenario, it is important to monitor levels to guide therapy. Enzyme-inhibiting medications like valproic acid can affect the metabolism of lamotrigine, increasing the level and increasing its half-life, versus medications like estrogen-containing oral contraceptives reduce lamotrigine levels by increased glucuronidation.[9][10][11]

Clinical Monitoring versus Drug-Level Monitoring

Multiple studies concluded that clinical monitoring could optimally achieve 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 most cases could successfully be managed clinically, and only a small number of patients benefited from drug-level monitoring.[12] This study was conducted using an old AED with a long half-life, so the AED levels are more closely correlated with medication compliance. Trying to achieve a therapeutic level in seizure-free patients with subtherapeutic levels has not shown any difference in seizure control and was associated with more neurotoxicity.[7]

Anti-Seizure Medication 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 non-compliance. Erratic non-compliance is the most common and manifests as inconsistent dosing. This results in unreliable therapeutic AED levels and variability in seizure control.[13] Some patients tend towards “white coat adherence,” taking their medications one or more days before their office visit, often resulting 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.[14] 

Compliance and adherence had been used interchangeably to describe the status of not taking the medication or following the treatment plan.[15] 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 versus compliance to position the patient at the center of their treatment plan and emphasize a holistic approach to achieving positive long-term outcomes when treating complex chronic conditions such as epilepsy.[16]

Other Ways to Promote AED-Level Monitoring

To assume responsibility for directing the patients about their medications, clinicians must explore the reasons for non-adherence and try to help the patients 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 traditionally been used as the only reliable way to monitor adherence by most the clinicians
3. Diaries
4. Direct observation of drug taking
5. Pill counts

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

Clinical Significance

[17]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 bigger picture of a supportive, patient-centered treatment plan based on a therapeutic physician-patient relationship is the key to success.

Other Issues

In the current environment of patients seeking healthy foods, and herbal and non-proprietary medications, therapeutic drug monitoring can pose challenges. Thorough knowledge of the patient's medication list is essential to consider potential drug-drug interactions and minimize undesired changes in the antiepileptic drug levels. The recent increase in the use of cannabidiol (CBD) as an antiepileptic drug has increased the need for frequent monitoring of certain medications, like clobazam, during concomitant therapy. CBD, in combination with valproate or clobazam, can result in increased liver enzymes, notably ALT and AST., so patients receiving this combination may benefit from additional liver enzyme monitoring. Animal studies have shown CBD to increase clobazam anticonvulsant activity via CYP3A4 activity, but only when an anticonvulsant dose of CBD was used; sub-anti-convulsant CBD dosing did not promote increased anticonvulsant effects despite increased serum clobazam concentrations.[17][18][19]

Enhancing Healthcare Team Outcomes

Patients managed with antiepileptic drugs are frequently encountered by the nurse practitioner, internist, primary care provider, neurologist, and emergency department physician. In the past, it was widely believed that routine drug monitoring of antiepileptics was beneficial, but except for a few cases, this is no longer recommended. Instead, clinical monitoring within the context of a supportive, patient-centered, interprofessional team treatment plan based on a therapeutic clinician-patient relationship with the support of nurses and pharmacists is the key to success.

This interprofessional team will include physicians (MDs and DOs), specialists, mid-level practitioners (NPs and PAs), nurses, and pharmacists. In addition to checking for appropriate dosing and performing medication reconciliation, the pharmacist should emphasize the importance of medication compliance to the patient and the need for close follow-up. If there is evidence of non-compliance, the pharmacist should discuss the situation with the clinician managing the case. Pharmacists and nurses should assist in educating patients about the adverse effects of the drugs so that they know when to report back to the clinician; they must also be alert to signs of therapeutic failure, which must be documented and reported to other team members as necessary so regimen modification can be implemented if necessary. Only through such an interprofessional team approach with open communication channels between all team members can the morbidity of anti-convulsants be reduced and safe outcomes be achieved. [Level 5]

Nursing, Allied Health, and Interprofessional Team Interventions

Nurses who dispense antiepileptic drugs should always check the dose and the route of administration independently. In addition, nurses should read about the potential side effects of the drugs and educate the patient. This ensures extra safety for patients. If a dose does not appear reasonable, the nurse should contact the prescribing clinician immediately.

Nursing, Allied Health, and Interprofessional Team Monitoring

Several anticonvulsants have the potential to cause adverse cardiac effects when administered intravenously. Thus patients should be placed on a cardiac monitor, and their vital signs should be measured frequently. Any untoward effects should be immediately reported to the prescriber.