Antiepileptic Drug Monitoring


Article Author:
Mohammad Selim
Arayamparambil Anilkumar


Article Editor:
Erica Cichowski


Editors In Chief:
Mohamed Hegazy
Najib Murr


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Kyle Blair
Trevor Nezwek
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
8/12/2019 5:19:34 PM

Introduction

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.

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].

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].

Issues of Concern

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.

Clinical Significance

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.

Other Issues

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]

Enhancing Healthcare Team Outcomes

Patients managed with antiepileptic drugs are frequently encountered by the nurse practitioner, internist, primary care provider, neurologist, and the 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 treatment plan based on a therapeutic clinician-patient relationship with the support of nurses and pharmacists is the key to success. 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. Only through such an interprofessional team approach can the morbidity of anti-convulsants be reduced and safe outcomes be achieved. [Level V]

Nursing Actions and 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 to be reasonable, the clinician should be contacted.

Nursing 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.


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Antiepileptic Drug Monitoring - Questions

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A 33-year-old female, diagnosed with grand mal epilepsy 2 years ago, was suffering from recurrent seizures until she was started on levetiracetam with dose titration to 1500 twice a day. She has been seizure-free for the last 6 months. Today, she is in the clinic for routine follow up, and labs show a sub-therapeutic levetiracetam drug level which is less than her levetiracetam drug level a year ago. What is the best next step?



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A 56-year-old male with cirrhosis secondary to hepatitis C and longstanding alcohol abuse has had multiple emergency department visits due to recurrent seizure activity. After evaluation with EEG and CT/MRI brain imaging, the decision was made to start the patient on phenytoin. He presents to his primary care provider in follow up and denies recent seizure activity. He is tolerating the phenytoin well and denies fever, rash, nausea, and vomiting. Which lab evaluations are indicated at this time?



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A 39-year-old female with obesity, major depression, and epilepsy sees her primary care physician to discuss weight loss. She has been seizure free for three years on a stable dose of levetiracetam 2000 mg per day. She feels her failure to lose weight with diet and exercise has triggered a relapse in her depression. Her primary care physician initiates orlistat therapy for weight loss. She presents to the emergency department weeks later with a seizure. What is the best next step?



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A 68-year-old male presents to the clinic for follow up. He has a history of epilepsy that was controlled for a long time on lamotrigine. He is brought in by her daughter, who lives 2 hours away but has been involved in her dad's clinical care slightly since his wife died 1 year ago. The daughter states that her dad had a seizure couple of weeks ago and she is concerned about her dad since nobody lives with him to take care of him and he has lost his interest in a lot of activities since her mom passed away. He reports adherence with the medication, and he takes his medication every day but at different times when he remembers. The patient lives 50 min away from the clinic. Which of the following is the most appropriate strategy to check on patient's adherence?



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A 3-year-old girl with refractory epilepsy currently on clobazam, carbamazepine, sodium valproate, and levetiracetam continues to have poor seizure control. Parents wanted her to be tried on cannabidiol as an add on anti-seizure medication. Which of the following drug levels will need to be checked and adjusted due to the propensity to increase therapeutic levels?



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Antiepileptic Drug Monitoring - References

References

Inappropriate requests for serum anti-epileptic drug levels in hospital practice., Walters RJ,Hutchings AD,Smith DF,Smith PE,, QJM : monthly journal of the Association of Physicians, 2004 Jun     [PubMed]
Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications., Krasowski MD,, Pharmaceuticals (Basel, Switzerland), 2010 Jun 11     [PubMed]
Therapeutic plasma levels of phenytoin, phenobarbital, and carbamazepine: individual variation in relation to seizure frequency and type., Schmidt D,Haenel F,, Neurology, 1984 Sep     [PubMed]
Improved control of epilepsy by monitoring plasma ethosuximide., Sherwin AL,Robb JP,Lechter M,, Archives of neurology, 1973 Mar     [PubMed]
Managing patient adherence and quality of life in epilepsy., Eatock J,Baker GA,, Neuropsychiatric disease and treatment, 2007 Feb     [PubMed]
Concordance, compliance, preference or adherence., Fraser S,, Patient preference and adherence, 2010     [PubMed]
Compliance, concordance, adherence., Aronson JK,, British journal of clinical pharmacology, 2007 Apr     [PubMed]
Monitoring antiepileptic drugs: a level-headed approach., St Louis EK,, Current neuropharmacology, 2009 Jun     [PubMed]
The benefits of antiepileptic drug (AED) blood level monitoring to complement clinical management of people with epilepsy., Stepanova D,Beran RG,, Epilepsy & behavior : E&B, 2015 Jan     [PubMed]
Potential problems and recommendations regarding substitution of generic antiepileptic drugs: a systematic review of literature., Atif M,Azeem M,Sarwar MR,, SpringerPlus, 2016     [PubMed]
A multicenter randomized controlled trial on the clinical impact of therapeutic drug monitoring in patients with newly diagnosed epilepsy. The Italian TDM Study Group in Epilepsy., Jannuzzi G,Cian P,Fattore C,Gatti G,Bartoli A,Monaco F,Perucca E,, Epilepsia, 2000 Feb     [PubMed]
Woo E,Chan YM,Yu YL,Chan YW,Huang CY, If a well-stabilized epileptic patient has a subtherapeutic antiepileptic drug level, should the dose be increased? A randomized prospective study. Epilepsia. 1988 Mar-Apr;     [PubMed]
Franco V,Perucca E, Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy. Drugs. 2019 Aug 1;     [PubMed]

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