It is clear from both clinical observations of women, and research in laboratory animals, that gonadal hormones exert a profound influence on neuronal excitability, seizures, and epilepsy. These studies have led to a focus on two of the primary ovarian steroid hormones, estrogen and progesterone, to clarify how gonadal hormones influence seizures in women with epilepsy. The prevailing view is that estrogen is proconvulsant, whereas progesterone is anticonvulsant. However, estrogen and progesterone may not be the only reproductive hormones to consider in evaluating excitability, seizures, or epilepsy in the female. It seems unlikely that estrogen and progesterone would exert single, uniform actions given our current understanding of their complex pharmacological and physiological relationships. Their modulatory effects are likely to depend on endocrine state, relative concentration, metabolism, and many other factors. Despite the challenges these issues raise to future research, some recent advances have helped clarify past confusion in the literature. In addition, testable hypotheses have developed for complex clinical problems such as "catamenial epilepsy." Clinical and animal research, designed with the relevant endocrinological and neurobiological issues in mind, will help advance this field in the future.

/pdf/the-influence-of-gonadal-hormones-on-neuronal-excitability-52tc0q8fem.pdf

The Influence of Gonadal Hormones on Neuronal Excitability, Seizures, and Epilepsy in the Female

Summary: Development of tolerance (ie, the reduction in response to a drug after repeated administration) is an adaptive response of the body to prolonged exposure to the drug, and tolerance to antiepileptic drugs (AEDs) is no exception Tolerance develops to some drug effects much more rapidly than to others The extent of tolerance depends on the drug and individual (genetic?) factors Tolerance may lead to attenuation of side effects but also to loss of efficacy of AEDs and is reversible after discontinuation of drug treatment Different experimental approaches are used to study tolerance in laboratory animals Development of tolerance depends on the experimental model, drug, drug dosage, and duration of treatment, so that a battery of experimental protocols is needed to evaluate fully whether tolerance to effect occurs Two major types of tolerance are known Pharmacokinetic (metabolic) tolerance, due to induction of AED-metabolizing enzymes has been shown for most first-generation AEDs, and is easy to overcome by increasing dosage Pharmacodynamic (functional) tolerance is due to “adaptation” of AED targets (eg, by loss of receptor sensitivity) and has been shown experimentally for all AEDs that lose activity during prolonged treatment Functional tolerance may lead to complete loss of AED activity and cross-tolerance to other AEDs Convincing experimental evidence indicates that almost all first-, second-, and third-generation AEDs lose their antiepileptic activity during prolonged treatment, although to a different extent Because of diverse confounding factors, detecting tolerance in patients with epilepsy is more difficult but can be done with careful assessment of decline during long-term individual patient response After excluding confounding factors, tolerance to antiepileptic effect for most modern and old AEDs can be shown in small subgroups of responders by assessing individual or group response Development of tolerance to the antiepileptic activity of an AED may be an important reason for failure of drug treatment Knowledge of tolerance to AED effects as a mechanism of drug resistance in previous responders is important for patients, physicians, and scientists

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1528-1167.2006.00607.x

Experimental and Clinical Evidence for Loss of Effect (Tolerance) during Prolonged Treatment with Antiepileptic Drugs

Epilepsy and sleep disturbance.

Introduction: An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. The International League Against Epilepsy classifies seizures in two broad categories: partial (localized to one cerebral hemisphere) and generalized (localized to both cerebral hemispheres). One indirect pathway for the treatment of epilepsy includes the inhibition of carbonic anhydrase (CA), thereby increasing CO2 levels in the brain. Areas covered: Carbonic anhydrases (EC 4.2.1.1) are ubiquitous metalloenzymes that catalyze the reversible hydration/dehydration of CO2/HCO3 -, respectively. CA inhibitors (CAIs) such as acetazolamide, methazolamide, topiramate, zonisamide, and sulthiame can reduce seizures through perturbation of the CO2 equilibrium and/or the inhibition of ion channels. This review focuses on the mechanism of epilepsy, CA catalysis, and recent developments in the treatment of epilepsy using CAIs. Expert opinion: Based on the observ...

Anticonvulsant/antiepileptic carbonic anhydrase inhibitors: a patent review.

SummaryObjective
Sleep is considered restorative, and good quantity and quality sleep is required for memory consolidation and synaptic plasticity. Sleep disorders are common in patients with epilepsy. Poor sleep quality or quantity may worsen seizure control. On the other end, seizures and epilepsy may worsen the sleep quality and set a vicious cycle. In addition, antiepileptic drugs have an effect on sleep architecture. We performed a systemic literature review with a goal to evaluate the effect of antiepileptic drugs and nondrug treatments for epilepsy on sleep architecture to help better understand treatment effects, especially in patients with epilepsy and sleep problems.

Methods
We searched PubMed and identified studies that evaluated objective sleep outcomes for an antiepileptic drug. We also searched for studies with objective sleep outcomes that evaluated other epilepsy treatments such as epilepsy surgery, vagus nerve stimulation, and ketogenic diet.

Results
The studies were categorized based on evidence class and study population for an individual antiepileptic drug or treatment. We identified that most antiepileptic drugs and nondrug treatments for epilepsy affect sleep architecture.

Significance
We identified that gabapentin, tiagabine, pregabalin, clobazam, and carbamazepine reduce sleep latency and/or improve sleep efficiency. Phenobarbital, valproic acid, and higher-dose levetiracetam aggravate daytime sleepiness, whereas topiramate and zonisamide do not. Vagus nerve stimulation reduces daytime sleepiness, and ketogenic diet improves slow-wave sleep. Epilepsy surgery may improve nocturnal sleep only in a subgroup of patients with improved seizure frequency. Further studies are needed to evaluate the dose-dependent sleep effects of antiepileptic drugs and nondrug treatments independent of the improvement of epilepsy, and to identify if these changes are clinically significant.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/epi.12478

Effects of epilepsy treatments on sleep architecture and daytime sleepiness: An evidence‐based review of objective sleep metrics

Summary:  Purpose: The older antiepileptic drugs (AEDs) have a variety of effects on sleep, including marked reduction in REM, slow-wave sleep (SWS) and sleep latency, and increased percentage of light sleep. The effects of the newer AEDs on sleep are unknown. Our purpose was to study the effect of lamotrigine (LTG) on sleep.



Methods: Ten adults with focal epilepsy, in whom the decision was made to add LTG to either phenytoin (PHT) or carbamazepine (CBZ) for control of seizures, were the subjects of this study. Patients underwent pre- and posttreatment polysomnography (PSG) and completed sleep questionnaires. Polygraphic variables and Epworth Sleepiness Scale (ESS) scores, a subjective measure of sleep propensity, were compared by using the Wilcoxon sign rank test.



Results: Seven patients were taking CBZ, and three were treated with PHT. All subjects were titrated to an LTG dose of 400 mg/day. Treatment with LTG produced a significant decrease in SWS and an increase in stage 2 sleep percentage. No significant difference in ESS or any of the other polygraphic variables was observed. However, LTG treatment was associated with a reduction in arousals and stage shifts and an increase in REM periods. No subjects reported insomnia with treatment.



Conclusions: LTG appears to be less disruptive to sleep than some of the older AEDs.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1528-1157.2001.46100.x

The Effects of Lamotrigine on Sleep in Patients with Epilepsy

Summary: Purpose: Catamenial epilepsy is a condition characterized by an increase in seizures during particular phases of the menstrual cycle. The incidence of catamenial epilepsy varies widely, partly because of a lack of a universally adopted definition. Specific treatment options for these patients are limited. The use of acetazolamide (AZ) has been based largely on anecdotal reports demonstrating efficacy in small or poorly characterized populations. The purpose of this study was to analyze retrospectively the efficacy, safety profile, and tolerability of AZ in women with catamenial epilepsy. Methods: Women with catamenial epilepsy identified from 1990 through 1999 were invited to participate in a retrospective telephone questionnaire addressing the relationship of seizures and the menstrual cycle and the use, efficacy, and adverse effects of AZ. Seizure outcome was classified as: seizure free (SF), significantly improved (SI), or not significantly improved (NSI). Responses to AZ were compared in women with different types of epilepsy and comparing continuous versus intermittent dosing using Fisher’s exact tests. Results: Twenty women were identified who had received or were currently taking AZ. The drug was given continuously in 55% and intermittently in 45% of patients. A $50% decrease in the seizure frequency was reported by 40% of subjects. Response rates were similar in generalized and focal epilepsy and in temporal and extratemporal epilepsy. There was no significant difference in effectiveness comparing continuous with intermittent dosing. A loss of efficacy over 6‐24 months was reported by 15% of women. Conclusions: Despite our small sample and retrospective design, AZ appears to demonstrate efficacy for catamenial epilepsy. Key Words: Catamenial epilepsy—Acetazolamide— Diamox—Focal epilepsy.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1528-1157.2001.33600.x

Julia Lee

Papers

The Effects of Lamotrigine on Sleep in Patients with Epilepsy

Acetazolamide in women with catamenial epilepsy.