Current Neuropharmacology - Volume 7, Issue 2, 2009

The process of conversion between AED monotherapies is frequently necessary in epilepsy care, yet little practical guidance is available to practitioners. This article introduces an issue of Current Neuropharmacology devoted to the theme of AED conversions and related issues. In this series of articles, we reviewed the role of AED monotherapy in newly diagnosed epilepsy, the practice of transitional polytherapy during AED monotherapy conversions in patients experiencing breakthrough seizures or adverse effects, chronic maintenance polytherapy for refractory epilepsy, and the related topics of strategies for minimizing adverse effects, appropriate blood level monitoring, and patient-related factors in AED conversions. Successful conversion between AED monotherapies and polytherapy drug sequencing requires that practitioners possess and apply a thorough knowledge of epilepsy, AED pharmacology, and clinical reasoning, while being sensitive and reactive to patient reported adverse effects of treatment.

Antiepileptic drug (AED) monotherapy is the preferred initial management approach in epilepsy care, since most patients may be successfully managed with the first or second monotherapy utilized. This article reviews the rationale and evidence supporting preferential use of monotherapy when possible and guidelines for initiating and successfully employing AED monotherapy. Suggested approaches to consider when patients fail monotherapy include substituting a new AED monotherapy, initiating chronic maintenance AED polytherapy, or pursuit of non-pharmacologic treatments such as epilepsy surgery or vagus nerve stimulation. Reducing AED polytherapy to monotherapy frequently reduces the burden of adverse effects and may also improve seizure control. AED monotherapy remains the optimal approach for managing most patients with epilepsy.

The goal of epilepsy therapy is to help patients achieve seizure freedom without adverse effects. While monotherapy is preferable in epilepsy treatment, many patients fail a first drug due to lack of efficacy or failure to tolerate an initial medication, necessitating an alteration in therapy. Sudden changes between monotherapies are rarely feasible and sometimes deleterious given potential hazards of acute seizure exacerbation or intolerable adverse effects. The preferred method for converting between monotherapies is transitional polytherapy, a process involving initiation of a new antiepileptic drug (AED) and adjusting it toward a target dose while maintaining or reducing the dose of the baseline medication. A fixed-dose titration strategy of maintaining the baseline drug dose while titrating the new medication is preferable when breakthrough seizures are occurring and no adverse effects are present. However, a flexible titration strategy involving reduction of the baseline drug dose to ensure adequate tolerability of the new adjunctive medication is preferred when patients are already experiencing adverse effects. This article reviews pharmacokinetic considerations pertinent for ensuring successful transitional polytherapy with the standard and newer antiepileptic drugs. Practical consensus recommendations “from an expect panel (SPECTRA, Study by a Panel of Experts Considerations for Therapy Replacement and Antiepileptics) for a successful monotherapy” AED conversions are then summarized. Transitional polytherapy is most successful when clinicians appropriately manage the titration strategy and consider pharmacokinetic factors germane to the baseline and new adjunctive medication.

While several newer AEDs have study data that support monotherapy usage, most possess FDA indications for adjunctive treatment of partial onset seizures, leading to their initial (and often persistent) clinical use as adjunctive polytherapy for patients with refractory epilepsy. This review considers a practical approach to the appropriate role for polytherapy in epilepsy, presents the evidence for AED polytherapy, reviews the mythic but practically reasonable concept of “rational polytherapy,” and concludes with practical strategies for avoiding and employing polytherapy in clinical practice. The appropriate indications for AED polytherapy include transitional polytherapy during titration of a new adjunctive AED toward monotherapy or long-term maintenance AED polytherapy in medically refractory epilepsy.

The goals of epilepsy therapy are to achieve seizure freedom while minimizing adverse effects of treatment. However, producing seizure-freedom is often overemphasized, at the expense of inducing adverse effects of treatment. All antiepileptic drugs (AEDs) have the potential to cause dose-related, “neurotoxic” adverse effects (i.e., drowsiness, fatigue, dizziness, blurry vision, and incoordination). Such adverse effects are common, especially when initiating AED therapy and with polytherapy. Dose-related adverse effects may be obviated in most patients by dose reduction of monotherapy, reduction or elimination of polytherapy, or substituting for a better tolerated AED. Additionally, all older and several newer AEDs have idiosyncratic adverse effects which usually require withdrawal in an affected patient, including serious rash (i.e., Stevens-Johnson Syndrome, toxic epidermal necrolysis), hematologic dyscrasias, hepatotoxicity, teratogenesis in women of child bearing potential, bone density loss, neuropathy, and severe gingival hyperplasia. Unfortunately, occurrence of idiosyncratic AED adverse effects cannot be predicted or, in most cases, prevented in susceptible patients. This article reviews a practical approach for the definition and identification of adverse effects of epilepsy therapies, and reviews the literature demonstrating that adverse effects result in detrimental quality of life in epilepsy patients. Strategies for minimizing AED adverse effects by reduction or elimination of AED polytherapy, appropriately employing drugsparing therapies, and optimally administering AEDs are outlined, including tenets of AED selection, titration, therapeutic AED laboratory monitoring, and avoidance of chronic idiosyncratic adverse effects.

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.

When discussing AED conversion in the clinic, both the patient and physician perspectives on the goals and risks of this change are important to consider. To identify patient-reported and clinician-perceived concerns, a panel of epilepsy specialists was questioned about the topics discussed with patients and the clinician's perspective of patient concerns. Findings of a literature review of articles that report patient-expressed concerns regarding their epilepsy and treatment were also reviewed. Results showed that the specialist panel appropriately identified patient-reported concerns of driving ability, medication cost, seizure control, and medication side effects. Additionally, patient-reported concerns of independence, employment issues, social stigma, medication dependence, and undesirable cognitive effects are important to address when considering and initiating AED conversion.

Several lines of evidence suggest that the modulation of presynaptic GABA release is mediated by a variety of receptors including; presynaptic AMPA, cannabinoid, GABAB, kainate, metabotropic glutamate, NMDA, and opioid receptors. The evidence supporting presynaptic modulation of inhibition is predominantly obtained from studying stimulus elicited, spontaneous or miniature synaptic events, where the information regarding the identity of the presynaptic cell is lost. This article summarises these findings then focuses on another approach to study the presynaptic modulation of GABA release by comparing the modulation of GABA release at unitary synapses identified morphologically, immunocytochemically and electrophysiologically. To date, evidence for cell-type specific regulation of presynaptic inhibition at identified synapses involving most of the above presynaptic receptors does not exist. Therefore, the key presynaptic modulators that will be focused on here are kainate and cannabinoid receptors and their intracellular signalling cascades that orchestrate GABA release. There will be some discussion on presynaptic modulation via opioid receptors at identified synapses. This review provides evidence to suggest a cell-type specific modulation of presynaptic inhibition in cortical regions.

According to the current model of the basal ganglia organization, simultaneous activation of the striato-nigral direct pathway by glutamatergic and dopaminergic neurotransmission should lead to a synergistic facilitatory action on locomotor activity, while in contrast activation of the indirect pathway by these two neurotransmittions should lead to antagonistic effects on locomotor activity. Based on published data, as a break with the current thinking, we propose a reconceptualization of functional interactions between dopaminergic and glutamatergic neurotransmission. In this model, dopaminergic neurotransmission is seen as a motor pacemaker responsible for the basal and primary activation of striatal output neurons and glutamate as a driver providing a multiple combination of tonic, phasic, facilitatory and inhibitory influxes resulting from the processing of environmental, emotional and mnesic stimuli. Thus, in the model, glutamate-coded inputs would allow tuning the intrinsic motor-activating properties of dopamine to adjust the production of locomotor activity into goal-oriented movements.

The blood-brain barrier (BBB) impedes the influx of intravascular compounds from the blood to the brain. Few blood-borne macromolecules are transferred into the brain because vesicular transcytosis in the endothelial cells is considerably limited and the tight junction is located between the endothelial cells. At the first line of the BBB, the endothelial glycocalyx which is a negatively charged, surface coat of proteoglycans, and adsorbed plasma proteins, contributes to the vasculoprotective effects of the vessels wall and are involved in maintaining vascular permeability. In the endothelial cytoplasm of cerebral capillaries, there is an asymmetrical array of metabolic enzymes such as alkaline phosphatase, acid phosphatase, 5'-nucleotidase, adenosine triphosphatase, and nucleoside diphosphatase and these enzymes contribute to inactivation of substrates. In addition, there are several types of influx or efflux transporters at the BBB, such as Pglycoprotein (P-gp), multidrug resistance associated protein, breast cancer resistance protein, organic anion transporters, organic cation transporters, organic cation transporter novel type transporters, and monocarboxylic acid transporters. P-gp, energy-dependent efflux transporter protein, is instrumental to the barrier function. Several findings recently reported indicate that endothelial P-gp contributes to efflux of undesirable substances such as β-amyloid protein from the brain or periarterial interstitial fluid, while P-gp likely plays a crucial role in the genesis of multiple vascular abnormalities that accompany hypertension. In this review, influx and efflux mechanisms of drugs at the BBB are also reviewed and how medicines pass the BBB to reach the brain parenchyma is discussed.

Autism is a severe childhood disorder already presenting in the first 3 years of life and, therefore, strongly correlated with neurodevelopmental alterations in prenatal, as well as postnatal period. Neurotransmitters hold a pivotal role in development by providing the stimulation needed for synapses and neuronal networks to be formed during the critical period of neuroplasticity. Aberrations of the serotonergic system modify key processes in the developing brain and are strongly implicated in the pathophysiology of developmental disorders. Evidence for the role of serotonin in autism emerges from neuropathological, imaging and genetic studies. Due to its developmental arrest, autism requires early intervention that would, among others, target the disrupted serotonergic system and utilize brain plasticity to elicit clinically important brain changes in children.