Antiepileptic Drug Blood Research Articles

Salivary Biomarkers of Anti-Epileptic Drugs: A Narrative Review.

Saliva is a biofluid that reflects general health and that can be collected in order to evaluate and determine various pathologies and treatments. Biomarker analysis through saliva sampling is an emerging method of accurately screening and diagnosing diseases. Anti-epileptic drugs (AEDs) are prescribed generally in seizure treatment. The dose-response relationship of AEDs is influenced by numerous factors and varies from patient to patient, hence the need for the careful supervision of drug intake. The therapeutic drug monitoring (TDM) of AEDs was traditionally performed through repeated blood withdrawals. Saliva sampling in order to determine and monitor AEDs is a novel, fast, low-cost and non-invasive approach. This narrative review focuses on the characteristics of various AEDs and the possibility of determining active plasma concentrations from saliva samples. Additionally, this study aims to highlight the significant correlations between AED blood, urine and oral fluid levels and the applicability of saliva TDM for AEDs. The study also focuses on emphasizing the applicability of saliva sampling for epileptic patients.

Pharmacokinetic changes for newer antiepileptic drugs and seizure control during pregnancy.

ObjectiveTo investigate pharmacokinetic changes in newer antiepileptic drugs (AEDs) and assess seizure frequencies and risk factors of increased seizures during pregnancy in women with epilepsy (WWE).MethodsA total of 56 pregnancies in 53 WWE who received newer antiepileptic drugs (AEDs) were enrolled. Data on seizure activity and types, daily dose, and AEDs blood levels were derived from routine clinical follow‐up. Changes in AEDs clearance were compared between each trimester and nonpregnant baseline. The ratio of AED levels of each trimester to their targets (nonpregnant baseline) concentrations (RTC) was compared between patients with and without an increased seizure. A binary logistic regression was used to investigate the risk factors contributing to seizure worsening during pregnancy.ResultsIncreased clearances of LTG, LEV, and OXC were observed in all trimesters versus nonpregnant baseline. The peak changes in the clearance of LTG (3.42‐fold baseline clearance) (p < 0.001) and LEV (2.78‐fold) (p < 0.001) occurred in the second trimester during pregnancy, followed by oxcarbazepine (2.11‐fold) in the third trimester (p < 0.03). Plasma concentrations of LTG and LEV during pregnancy were significantly decreased compared to baseline levels, except for OXC. However, no significant differences in RTC values were observed between patients with and without seizure worsening. Some risk factors as seizures for the prior nine months could significantly affect seizure frequency during pregnancy.ConclusionWe found substantial changes in the pharmacokinetics of multiple newer AEDs in WWE, reinforcing the need for therapeutic drug monitoring (TDM) during pregnancy. We would encourage at least one monitoring every trimester and probably more frequently for women with poorly seizure control before pregnancy, and AEDs dose adjustment should keep up with clearance changes. In addition, a well‐controlled seizure nine months before pregnancy could lower the risks of seizure during pregnancy, highlighting the importance of pre‐pregnancy counseling and seizure management before pregnancy.

Prognostic tests and antiepileptic drug withdrawal after epilepsy surgery.

Approximately one in three patients with a successful epilepsy surgery will have seizure recurrence following antiepileptic drugs (AED) withdrawal. The value of postoperative testing for predicting seizure relapse after AED tapering is not clear. The purpose of this study was to review the literature for evidence on the use of postoperative investigations before AED discontinuation after successful epilepsy surgery. We were unable to identify studies on the prognostic value of postoperative magnetic resonance imaging and AED blood levels. The literature review yielded seven studies on the predictive value of electroencephalography. Four studies found no association between interictal discharges (IED) and seizure relapse. These studies suffered from various limitations due to their retrospective design and generally small cohorts. Two of the three studies reporting a positive association were prospective and provided strong evidence of an increased risk of seizure recurrence with presence of postoperative IED in successfully operated patients undergoing AED withdrawal.

Anti-epileptic drugs: a guide for the non-neurologist

Epilepsy is the most common serious chronic neurological disorder affecting between 0.5% and 1% of Western populations. Most patients take anti-epileptic drugs (AEDs) for years if not decades, and are commonly admitted to hospital with seizures. Many have symptomatic epilepsy, arising as a consequence of another disorder, for example a brain tumour. General practitioners, emergency physicians and most hospital teams (especially general medicine) commonly encounter difficulties surrounding AEDs yet often require assistance from neurology services. This can be difficult when neurology services are not on-site or easily available. This article gives a practical overview of difficulties relating to AEDs and their management, with the focus on problems commonly encountered by non-neurologists. These include the patient who is acutely unwell, pregnant or elderly; AED side effects and drug interactions; status epilepticus and AED blood levels.

Monitoring Antiepileptic Drugs: A Level-Headed Approach

Despite advances in epilepsy therapeutics, some physicians feel uncomfortable with newer antiepileptic drugs (AEDs) due to difficulty in promptly obtaining blood levels to guide medication adjustment, and even when levels for newer AEDs are obtained, many practitioners feel they are not very useful. Lacking confidence in AEDs whose levels that cannot readily or expeditiously be measured, many clinicians share uncertainty about proper use of the newer AEDs and monitoring AED administration. Similarly, some epilepsy patients inflate the importance of AED blood level monitoring, feeling that blood levels falling within traditionally therapeutic ranges are a fail-safe for seizure control, regardless of their compliance or personal behavior aggravating seizure burden, such as poor sleep or use of illicit substances. This review examines the elusive concept of therapeutic AED blood levels and potential uses and abuses of blood level monitoring, reinforcing appropriate uses for blood levels to ensure compliance and adjust for altered AED pharmacokinetics in the context of aging and disease states, pregnancy, or drug interactions.

Laboratory controls and therapeutic antiepileptic drug monitoring during the treatment of children with epilepsy – sense or nonsense – Contra

A singular laboratory control of blood parameters (i.e. red and white count, chemistry and coagulation) is necessary to perform at the beginning of antiepileptic treatment as a screening of body functions and basal determination before possible complications later on. Regular controls lack evidence based studies and are a waste of ressources in many cases. Instead genuine medical attitude should focus on well being and symptoms of the patient with epilepsy. In the guidelines for therapeutic monitoring of antiepileptic drugs (TMA) of the International League Against Epilepsy (ILAE) it is stated, that regular TMA is redundant in such cases, if the patient is free of seizures and/or no side effects can be detected. Accordingly, it is even dangerous to change antiepileptic drug (AED) dosages because the AED blood level is not in the "therapeutic range". Two categories of clinical situations are cited in which TMA might be considered: 1. Regular TMA due to theoretical considerations (after begin of AED treatment, once or twice annually for surveillance of compliance, after every change of AED or concomittant medication) and 2. tailored TMA (in cases of side effects, in situations lacking therapeutic success despite adequate medication, in cases with metabolic, hepatic and renal diseases, during pregnancies, during polytherapy). There should always be a good clinical reason for venipuncture and laboratory expense, that means the gain of knowledge of such a blood value should be of therapeutic relevance otherwise not achievable. In a recently published randomised, controlled multicenter study (2000) on the clinical importance of TMA it was shown, that the vast majority of patients with epilepsy can be treated successfully without TMA. The experience with the application of some AED without common TMA (e.g. benzodiazepines, topiramate, felbamatem acetacolamide) teaches that good AED tretament is possible without TMA. The patient with epilepsy, not the epilepsy and at least the blood values should be treated.

Cognitive and Behavioral Effects of Epilepsy Treatment

Summary:Behavior and cognition in patients with epilepsy may be affected by multiple factors including seizure etiology, type, frequency, duration, and severity; cerebral lesions acquired before seizure onset; age at seizure onset; intraictal and interictal physiological dysfunction due to the seizures; structural cerebral damage due to repetitive or prolonged seizures; hereditary factors; psychosocial factors; sequelae of epilepsy surgery; and untoward effects of antiepileptic drugs (AEDs). Although the behavioral and cognitive effects of AEDs are less than the total of other factors in epilepsy, AEDs are of special concern because they are the major therapeutic modality for seizures. The risk of AED cognitive side effects is increased with polypharmacy and at higher dosages and higher AED blood levels. In general, the cognitive effects of AEDs are modest when used in monotherapy with AED blood levels within the standard therapeutic ranges. Further, the cognitive effects of AEDs are offset in part by reduced seizures. However, the cognitive effects of AEDs may be clinically significant. The most common AED cognitive effects include psychomotor slowing, reduced vigilance, and impairments in memory. Phenobarbital (PB) and benzodiazepines (BZDs) possess the most marked adverse cognitive effects. Regarding the other major older AEDs, carbamazepine (CBZ), phenytoin (PHT), and valproate (VPA) have cognitive effects that are similar to each other. In contrast, some of the newer AEDs appear to produce fewer adverse cognitive effects. Gabapentin (GBP) and lamotrigine (LTG) have demonstrated fewer cognitive effects than CBZ and minimal effects compared with placebo. Tiagabine (TGB) and vigabatrin (VGB) also have shown few cognitive effects compared with placebo. Of the new AEDs, topiramate (TPM) appears to have the greatest cognitive side effects, but slow titration during drug initiation reduces these effects. Additional studies are needed to delineate fully the relative effects of all the new AEDs to each other and to the older AEDs. The elderly have increased susceptibility to the cognitive effects of AEDs for both pharmacodynamic and pharmacokinetic reasons. However, only a few studies have examined the cognitive effects of AEDs in the elderly. Although incomplete, the available data reflect a pattern of relative effects similar to those seen in younger adults. Children also may have increased susceptibility because the relatively modest effects of AEDs could be additive over the course of neurodevelopment. Again in children, the cognitive effects of CBZ, PHT, and VPA are comparable, whereas the effects of PB are worse. Unfortunately, there are no studies on the cognitive effects of the new AEDs in children. The effects of AEDs on cognition may have even greater consequences for the children of mothers with epilepsy, who are exposed to AEDs in utero. Animal studies have demonstrated that in utero AED exposure can impair behavioral neurodevelopment at dosages below those required to produce somatic malformations and at clinically relevant blood levels. However, the magnitude and differential effects of in utero AED exposure on neurodevelopment in humans remain uncertain. AEDs may produce positive or negative behavioral alterations (e.g., mood stabilization, irritability/agitation, depression, psychosis). CBZ, GBP, LTG, and VPA have demonstrated positive psychotropic effects. Patients with epilepsy are at increased risk for behavioral disorders, and these AEDs may be particularly useful in such patients. The most severe negative behavioral effects of AEDs occur in a small percentage of patients. However, more subtle adverse behavioral effects are much more common. A patient's perception of his or her quality of life is correlated more with neurotoxicity symptoms and mood than with seizure frequency in the absence of seizure freedom. Even subtle behavioral effects can reduce the patient's quality of life. Thus, the behavioral effects of AEDs should be considered in the choice of AED along with other side effects and efficacy for seizure control.

Management of antiepileptic drugs following epilepsy surgery: a review.

The favourable impact of surgery for intractable epilepsy on seizures is well documented. However, few studies have determined what changes in antiepileptic drug (AED) therapy occur following surgery. Alterations in AED blood levels in the immediate postoperative period can result in breakthrough seizures. In long term follow-up, one-third to one-half of seizure-free patients after temporal lobectomy, the most common type of epilepsy surgery, still require AED treatment which usually has been reduced from polytherapy to monotherapy. In our study of 93 patients followed two years after temporal lobectomy, polytherapy decreased from 78% before surgery to 14% postoperatively, while medication was discontinued in 44%. Early reduction from polytherapy to monotherapy can often be carried out in the immediate postoperative period but the most appropriate timing of cessation of AED treatment has yet to be determined. Patients undergoing extratemporal resections and other forms of epilepsy surgery associated with less favourable postoperative seizure control may achieve comparatively less reduction in antiepileptic medication. We generally do not recommend stopping AEDs prior to one year after surgery.

Management of Acute Seizure Episodes

Summary: Acute seizures may represent the initial manifestation of epilepsy or isolated events. Urgent treatment of these episodes is indicated to reduce the risk for permanent neurologic damage. Status epilepticus (SE), one form of acute seizure, has an estimated annual incidence of 100,000–150,000 cases per year in the United States. Management of SE focuses on terminating clinical and electrical seizure activity while providing supportive care and identifying the precipitating factors. Physician preference and patient‐related factors may dictate the choice of pharmacologic treatment of SE. However, benzodiazepines, which enter the brain rapidly and offer the opportunity for most rapid seizure cessation, are the foundation for SE management. At our institution, first‐line treatment consists of i.v. lorazepam followed by a long‐acting antiepileptic drug (AED). When i.v. access cannot be attained, high AED blood levels can be rapidly achieved with rectally administered diazepam (DZP). For management of acute repetitive seizures, it is desirable to have an effective drug that can be safely administered by caregivers outside of the hospital setting. Clinical trial data indicate that rectal administration of a prepackaged viscous DZP solution fulfills these criteria. In these studies, rectal DZP gel reduced seizure frequency and recurrence compared to seizure control, improved patient and family quality of life, and was cost‐effective because it reduced the need for emergency and inpatient treatment.

Review

Epilepsy has widespread direct and indirect effects on the patient's quality of life. These patients generally have neuropsychological impairments that lower their educational and occupational levels of achievement, and many have additional emotional and/or behavioral disorders. Multiple factors underlie the cognitive changes associated with epilepsy, including the effect of antiepileptic drug (AED) therapy itself. Although it is recognized that the beneficial results of reduced seizure frequency may compensate at least in part for detrimental cognitive AED side effects, polypharmacy and higher AED blood levels can shift this balance. Further, there is much debate concerning the existence and clinical importance of differential AED cognitive side effects. While all the major AEDs can produce cognitive side effects, more recent research indicates that the magnitude of these effects may not be clinically significant with monotherapy within standard therapeutic range. The impact of AED differential cognitive side effects on the patient's quality of life is only beginning to be appreciated as research focuses on this important aspect of patient management. The information gained from such investigations will influence not only current therapeutic decisions, but also the development of future anticonvulsants.