Characteristics and Neural Correlates of Emotional Behavior during Prefrontal Seizures.

OBJECTIVE: This study was undertaken to characterize clinical expression and intracerebral electroencephalographic (EEG) correlates of emotional expression during prefrontal epileptic seizures. METHODS: We performed a descriptive analysis of seizure semiology in patients explored with stereo-EEG (SEEG) for pharmacoresistant prefrontal epilepsy, using a semiquantitative score for seizure-related emotional behavior. Two independent observers scored occurrence and intensity of objective emotional features (face/body movements/vocalization/overall appearance), testing interobserver reliability. Intracerebral electrophysiological changes were documented. Cluster analysis and principal component analysis (PCA) compared behavioral signs with neural SEEG correlates. For each patient, the clinical and anatomoelectrophysiological scores were established, based on a prototypical emotional seizure. RESULTS: Forty-two patients (469 seizures) were included. Interobserver correlation for emotional signs was satisfactory (kappa = 0.6-0.8). Prevalence of any subjective and/or objective ictal emotional phenomena was 79% (33/42); objective emotional signs occurred in 27 of 42 subjects (64%). Negatively valenced emotional semiology (ictal feeling of fear, defensive and/or aggressive behaviors) was much more prevalent than positively valenced, prosocial behaviors. Cluster analysis and PCA identified 4 groups with different occurrence of emotional signs and cerebral correlates. Two main clusters of negatively valenced behavior were identified: "active threat response," associated with seizure organizations involving posterior orbitofrontal cortex, anterior cingulate, and dorsolateral and/or ventrolateral prefrontal cortex; and "passive fear," associated with amygdala, other mesial temporal structures, and posterior orbitofrontal cortex. INTERPRETATION: Emotional behaviors, especially fear/threat response, are common in prefrontal seizures, reflecting the role of the prefrontal cortex in emotional control. Different cortical seizure localizations were associated with "passive fear" and "active threat response" seizure behaviors at the group level. ANN NEUROL 2022;92:1052-1065.

How May a Brief Seizure Lead to Prolonged Epileptic Amnesia?

Pure amnestic seizures are defined as self-limited episodes with isolated, anterograde memory loss and have been attributed to bilateral dysfunction of mesial temporal structures. This type of seizure can occur in patients with different forms of temporal lobe epilepsy and has been more recently associated with a late-onset epileptic syndrome, called transient epileptic amnesia (TEA). The mechanisms of such prolonged manifestations are not well known and notably its ictal or post-ictal origin remains poorly understood. We report a case of prolonged anterograde amnesia (lasting several hours) following a brief seizure induced by stimulation of the left entorhinal cortex, recorded during stereo-EEG (SEEG). This episode was associated with prolonged changes in the intracerebral EEG signal complexity (entropy) within bilateral mesial temporal structures, particularly the entorhinal cortices, with a progressive normalization paralleling the clinical recovery. Our case shows that long-lasting (hours) memory impairment may follow brief seizure that led to prolonged electrophysiological signals alterations in bilateral mesial temporal structures.

Mapping the Insula with Stereo-Electroencephalography: The Emergence of Semiology in Insula Lobe Seizures.

OBJECTIVE: Insula epilepsy is rare and can be evaluated effectively by Stereotactic intracerebral EEG (SEEG). Many previous studies of insulo-opercular seizures have been unable to separate insular and opercular onset. With adequate sampling of the insula, this study shows this is possible. METHODS: We analyzed intrainsular dynamics and extrainsular propagation in 12 patients with "pure" insula epilepsy (n = 9) or insular and only deepest opercular involvement (n = 3) at seizure onset. Review of semiology defined clinical groups, agglomerative cluster, and principal component analysis of semiological features were performed. Quantitative epileptogenicity, and intrainsular and extrainsular propagation were computed via time frequency analysis and epileptogenicity mapping. RESULTS: Seizure onset patterns were heterogeneous; the seizure onset zone was focal. Seizure onset and first ictal change within insula functional subdivision correlated with aura and reflex component. No paninsular spread occurred; contralateral insular spread was very early. While the discharge was intrainsular, clinical signs related to aura or vegetative signs. Extrainsular propagation was early and related to the emergence of the majority of clinical signs. Cluster analysis found an anterior, intermediate, and posterior insula seizure onset group. The largest principal component separated anterior insula manifestations, including early hypermotor signs, early recovery, and no aura from posterior insula features of early dystonia, early tonic motor features, and sensorimotor aura. INTERPRETATION: Aura is vital to identifying seizure onset and relates to insula functional subdivision. Seizures are heterogenous; extrainsular propagation occurs early, accounting for most of the semiology. With adequate sampling, "pure" insula epilepsy can be identified and focal curative resection is possible. ANN NEUROL 2020;88:477-488.

Insular interictal positron emission tomography hypometabolism in patients with ictal asystole.

We aimed to explore brain area(s) involved in the generation of ictal asystole (IA) by analyzing the interictal positron emission tomography (PET) metabolism of patients with IA recorded by video-electroencephalography or video-stereo-electroencephalography. We identified in our cohort of focal epilepsy patients who had undergone presurgical evaluation those who had a recorded period of IA of more than 3 s. We investigated the anatomometabolic changes (interictal 18 F-fluorodeoxyglucose PET) of these patients in comparison with (1) healthy subjects with similar age and sex distribution (n = 19) using whole-brain voxel-based analysis (p-voxel < .001, p-cluster < .05, uncorrected) and (2) patients without IA with similar age and seizure onset zone (n = 55). We found 12 patients with IA. Epilepsy was mainly temporal (four right temporal mesial, four bitemporal, two left temporal lateral, one right temporal lateral, and one right temporal "plus"). Seven patients had negative magnetic resonance imaging. Whole-brain statistical analysis of PET imaging was performed at the voxel level, showing that in comparison to healthy subjects and to epileptic patients without IA, a hypometabolism in the right posterior insula characterized epileptic patients with IA. Our study suggests involvement of the right posterior insula-a part of the central autonomic network-in the pathophysiological mechanism of IA.

Prefrontal seizure classification based on stereo-EEG quantification and automatic clustering.

PURPOSE: Frontal seizures are organized according to anatomo-functional subdivisions of the frontal lobe. Prefrontal seizures have been the subject of few detailed studies to date. The objective of this study was to identify subcategories of prefrontal seizures based on seizure onset quantification and to look for semiological differences. METHODS: Consecutive patients who underwent stereoelectroencephalography (SEEG) for drug-resistant prefrontal epilepsy between 2000 and 2018 were included. The different prefrontal regions investigated in our patients were dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), dorsomedial prefrontal cortex (DMPFC), ventromedial prefrontal cortex (VMPFC), and orbitofrontal cortex (OFC). The seizure onset zone (SOZ) was determined from one or two seizures in each patient, using the epileptogenicity index (EI) method. The presence or absence of 16 clinical ictal manifestations was analyzed. Classification of prefrontal networks was performed using the k-means automatic classification method. RESULTS: A total of 51 seizures from 31 patients were analyzed. The optimal clustering was 4 subgroups of prefrontal seizures: a "pure DLPF" group, a "pure VMPF" group, a "pure OFC" group, and a "global prefrontal" group. The first 3 groups showed a mean EI considered epileptogenic (>0.4) only in one predominant structure, while the fourth group showed a high mean EI in almost all prefrontal structures. The median number of epileptogenic structures per seizure (prefrontal or extrafrontal) was 5 for the "global prefrontal" group and 2 for the other groups. We found that the most common signs were altered consciousness, automatisms/stereotypies, integrated gestural motor behavior, and hyperkinetic motor behavior. We found no significant difference in the distribution of ictal signs between the different groups. CONCLUSION: Our study showed that although most prefrontal seizures manifest as a network of several anatomically distinct structures, we were able to determine a sublobar organization of prefrontal seizure onset with four groups.

Investigating adults with early-onset epilepsy and intellectual or physical disability.

This article focuses on investigating adults with early-onset epilepsy and intellectual or physical disability within adult neurology services. We aim to guide general neurologists in the diagnostic reassessment of people with epilepsy and complex neurological problems of unknown cause. Following an overview, we address imaging, electroencephalography, genetic studies and metabolic testing, and give examples where diagnosis directly influences treatment. Aetiological diagnosis serves to inform prognosis, guide treatment and provide a framework for genetic counselling.

Ammonium release in synthetic and human urine by a urease immobilized nanoconstruct.

In this work, we have studied the ability of urease immobilized on glutaraldehyde crosslinked chitosan coated magnetic iron oxide nanoparticles (Urease/GA/CS/MIONPs), for the hitherto unreported comparative hydrolysis of urea in synthetic (SUr) and real human urine (HUr). The prepared Urease/GA/CS/MIONPs were characterized by a combination of Fourier transform infrared spectroscopy (FTIR), field emission-scanning-electron-microscopy (FESEM), energy dispersive X-ray spectroscopy (EDX) and dynamic light scattering (DLS). The nanoconstructs display the highest ammonium ion liberation post-urea hydrolysis in 1/20 or 1/24-fold dilutions of SUr and HUr, respectively. The optimum activity of immobilized urease is observed at pH 7, and the nanoconstructs facilitate efficient urea-hydrolysis till at least 45 °C. Kinetic analysis of the immobilized urease shows km and vmax of 14.81 mM, 12.36 mM, and 18.55 µM min-1 and 10.10 µM min-1, towards SUr and HUr, respectively. The magnetization of the immobilized urease is suitable for reuse across multiple cycles of urea hydrolysis in SUr and HUr. The robust performance of Urease/GA/CS/MIONPs in SUr and HUr is promising for generating ammonium as a useable source of nitrogen from human urine, and underscores the suitability of SUr as a urine mimic for such interventions.

Blockchain-enabled access control to prevent cyber attacks in IoT: Systematic literature review.

Internet of Things (IoT) enables communication among objects to collect information and make decisions to improve the quality of life. There are several unresolved security and privacy concerns in IoT due to multiple resource constrained devices, which lead to various cyber attacks. The conventional access control techniques depend on a central authority that further poses privacy and scalability issues in IoT. Various problems with access control in IoT can be resolved to prevent various cyber attacks using the decentralization and immutability properties of the blockchain. This study explored the current research trends in blockchain-enabled secure access control mechanisms and also identifies their applicability in creating reliable access control solutions for IoT. The basic properties of blockchain, such as decentralization, auditability, transparency, and immutability, act as the propulsion that provides integrity and security, disregarding the participation of an external entity. Initially, the application of blockchain was created only for cryptocurrencies but with the introduction of Ethereum, which allows the writiting and execution of smart contracts, applications other than cryptocurrencies are also being created. As various research articles have been written on the usage of different types of blockchains for creating secure access control solutions for IoT, this study intends to find and examine such primary researches as well as come up with a systematic review of various findings. This study perceives the most frequently utilized blockchain for creating blockchain-based access control solutions to prevent various cyber attacks and also discusses the improvement in access control mechanisms using blockchain along with smart contracts in IoT. The present study also discusses the obstacles in building decentralized access control solutions for IoT systems as well as future research areas. For new researchers, this article is a nice place to start and a strong reference point.

Consensus features of CP-MLR and GA in modeling HIV-1 RT inhibitory activity of 4-benzyl/benzoylpyridin-2-one analogues.

The HIV-1 reverse transcriptase (RT) inhibitory activity of benzyl/benzoylpyridinones is modeled with molecular features identified in combinatorial protocol in multiple linear regression (CP-MLR) and genetic algorithm (GA). Among the features, nDB and LogP are found to be the most influential descriptors to modulate the activity. Although the coefficient of nDB suggested in favor of benzylpyridinones skeleton, the coefficient of LogP suggested the favorability of hydrophilic nature in compounds for better activity. The partial least squares analysis of the descriptors common to CP-MLR and GA has displayed their predictivity over the total descriptors identified in both the approaches. The back-propagation artificial neural networks model from the five most significant common descriptors (nDB, T(O..O), MATS8e, LogP, and BELp4) has explained 93.2% variance in the HIV-1 RT activity of the training set compounds and showed a test set r(2) of 0.89. The results suggest that the descriptors have the ability to identify the patterns in the compounds to predict potential analogues.

Common miRNAs, candidate genes and their interaction network across four subtypes of epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is categorized into four major histological subtypes such as clear cell carcinoma (CCC), endometrioid carcinoma (EC), mucinous carcinoma (MC), and serous carcinoma (SC). Heterogeneity of the EOC leads to different clinical outcomes of the disease, although all the subtypes are originated from the same layer of tissue. Therefore, it is of interest to identify the common candidate genes, miRNA and their interaction network in four the subtypes of EOC. A comparative gene expression analysis identified 248 common differentially expressed genes (DEGs) in the four subtypes of EOC. Identified common DEGs were found to be enriched in cancer specific pathways. A protein-protein interaction (PPI) network of the common DEGs were constructed, and subsequent module and survival analyses identified seven key candidate genes (CCNB1, CENPM, CEP55, RACGAP1, TPX2, UBE2C, and ZWINT). We also documented 10 key candidate miRNAs (hsa-mir-16-5p, hsa-mir-23b-3p, hsa-mir-34a-5p, hsa-mir-103a-3p, hsa-mir-107, hsa-mir-124-3p, hsa-mir-129-2-3p, hsa-mir-147a, hsa-mir-205-5p, and hsa-mir-195-5p) linked to the candidate genes. These derived data find application in the understanding of EOC.

A Biocompatible, pH-Sensitive, and Magnetically Separable Superparamagnetic Hydrogel Nanocomposite as an Efficient Platform for the Removal of Cationic Dyes in Wastewater Treatment.

A series of environment-friendly cationic dye adsorbents, namely, pH-sensitive superparamagnetic hydrogel nanocomposite AA-VSA-P/SPIONs systems with different concentrations of superparamagnetic iron oxide nanoparticles (SPIONs; 1.2, 3.2, and 5.2 wt %), was synthesized by free-radical polymerization reaction using two pH-sensitive monomers, acrylic acid (AA) and vinylsulfonic acid (VSA), in an optimum ratio, in the presence of presynthesized SPIONs. The structural properties, thermal stability, and chemical configuration of AA-VSA-P/SPIONs systems with different weight percentages of SPIONs were characterized by XRD, TGA, Raman spectroscopy, and FTIR spectroscopy. The systems show substantial efficiency as dye adsorbents for removing cationic dyes (MB dye) from aqueous solution in neutral to alkaline medium. Further, these systems exhibit easy magnetic separation capabilities from aqueous solutions after dye adsorption, even for a very low weight percentage of SPIONs. The adsorption kinetics, mechanism, and isotherms of these systems were evaluated. The study suggests consistency with the pseudo-second-order kinetic model, following an intraparticle diffusion mechanism, where the heterogeneous surface of the system having different activation energies for adsorption plays the crucial role in dye adsorption via chemisorption for higher pH medium, which was further substantiated by excellent data fit with the Freundlich isotherm model. Biocompatibility and regeneration-ability studies establish the environment-friendliness and cost effectivity of the system.

Target-Specific Superparamagnetic Hydrogel with Excellent pH Sensitivity and Reversibility: A Promising Platform for Biomedical Applications.

Superparamagnetism has been widely used for many biomedical applications, such as early detection of inflammatory cancer and diabetes, magnetic resonance imaging (MRI), hyperthermia, etc., whereas incorporation of superparamagnetism in stimulus-responsive hydrogels has now gained substantial interest and attention for application in these fields. Recently, pH-responsive superparamagnetic hydrogels showing the potential use in disease diagnosis, biosensors, polymeric drug carriers, and implantable devices, have been developed based on the fact that pH is an important environmental factor in the body and some disease states manifest themselves by a change in the pH value. However, improvement in pH sensitivity of magnetic hydrogels is a dire need for their practical applications. In this study, we report the distinctly high pH sensitivity of new synthesized dual-responsive magnetic hydrogel nanocomposites, which was accomplished by copolymerization (free-radical polymerization) of two pH-sensitive monomers, acrylic acid (AA) and vinylsulfonic acid (VSA) with an optimum ratio, in the presence of presynthesized superparamagnetic iron oxide nanoparticles (Fe3O4(OH) x ). The monomers contain pH-sensitive functional groups (COO- and SO3 - for AA and VSA, respectively), and they have also been widely used as biomaterials because of the good biocompatibility. The pH sensitivity of the superparamagnetic hydrogel, poly(acrylic acid-co-vinylsulfonic acid), PAAVSA/Fe3O4, was investigated by swelling studies at different pH values from pH 7 to 1.4. Distinct pH reversibility of the system was also demonstrated through swelling/deswelling analysis. Thermal stability, chemical configuration, magnetic response, and structural properties of the system have been explored by suitable characterization techniques. Furthermore, the study reveals a pH-responsive significant change in the overall morphology and packing fraction of iron oxide nanoparticles in PAAVSA/Fe3O4 via energy-dispersive X-ray (EDX) elemental mapping with the field emission scanning electron microscopy (FESEM) study (for freeze-dried PAAVSA/Fe3O4, swelled at different pH values), implying a drastic change in susceptibility and induced saturation magnetization of the system. These important features could be easily utilized for the purpose of diagnosis using magnetic probe and/or impedance analysis techniques.

Centromedian thalamic nuclei deep brain stimulation and Anakinra treatment for FIRES - Two different outcomes.

Febrile infection-related epilepsy syndrome (FIRES) is a severe epilepsy disorder that affects previously healthy children. It carries high likelihood of unfavourable outcome and putative aetiology relates to an auto-inflammatory process. Standard antiepileptic drug therapies including intravenous anaesthetic agents are largely ineffective in controlling status epilepticus in FIRES. Deep brain stimulation of the centromedian thalamic nuclei (CMN-DBS) has been previously used in refractory status epilepticus in only a few cases. The use of Anakinra (a recombinant version of the human interleukin-1 receptor antagonist) has been reported in one case with FIRES with good outcome. Here we describe two male paediatric patients with FIRES unresponsive to multiple anti-epileptic drugs, first-line immune modulation, ketogenic diet and cannabidiol. They both received Anakinra and underwent CMN-DBS. The primary aim for CMN-DBS therapy was to reduce generalized seizures. CMN-DBS abolished generalized seizures in both cases and Anakinra had a positive effect in one. This patient had a favourable outcome whereas the other did not. These are the first reported cases of FIRES where CMN-DBS has been used.

Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study.

BACKGROUND: The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. METHODS: We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. FINDINGS: We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. INTERPRETATION: The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

A common polymorphism in the SCN1A gene associates with phenytoin serum levels at maintenance dose.

OBJECTIVES: A broad range of phenytoin doses is used in clinical practice, with the final 'maintenance' dose normally determined by trial and error. A common functional polymorphism in the SCN1A gene (one of the genes encoding the drug target) has been previously associated with maximum dose of phenytoin used clinically, and also maximum dose of carbamazepine, another antiepileptic drug with the same drug target. METHODS: We have related variation at the SCN1A IVS5-91 G>A polymorphism to maximum dose and to maintenance dose of phenytoin in 168 patients with epilepsy treated with phenytoin. We also related genotype to phenytoin serum levels at maximum dose and at maintenance dose of phenytoin. We genotyped the polymorphism using an Applied Biosystems Taqman assay. RESULTS: The polymorphism is associated with phenytoin serum concentration at maintenance dose (P=0.03). In a reduced cohort of 71 patients receiving phenytoin monotherapy this association is also significant (P=0.03). Neither association remains significant after Bonferroni correction for multiple testing. CONCLUSIONS: These results are not a replication of the original study. They do, however, support the hypothesis that this polymorphism influences the clinical use of phenytoin. They also demonstrate the utility of using multiple phenotypes in pharmacogenetics studies, particularly when attempting to separate pharmacokinetic and pharmacodynamic effects. As the SCN1A polymorphism affects phenytoin pharmacodynamics, it is particularly useful to obtain data on serum levels in addition to dose because association of a pharmacodynamic variant may be stronger with serum levels than dose as the serum level may eliminate or reduce pharmacokinetic variability.

Rapid and sensitive real-time polymerase chain reaction method for detection and quantification of 3243A>G mitochondrial point mutation.

Maternally inherited diabetes and deafness and mitochondrial encephalomyopathy, lactic acidosis with stroke-like episodes result from the 3243A>G mitochondrial point mutation. Current methods to detect the presence of the mutation have limited sensitivity and may lead to potential misclassification of patients with low levels of heteroplasmy. Here, we describe development and validation of a rapid real-time polymerase chain reaction (PCR) method for detection and quantification of levels of heteroplasmy in a single assay. Standard curve analysis indicated that the sensitivity of detection was less than 0.1%. Time from sample loading to data analysis was 110 minutes. We tested 293 samples including 23 known positives, 40 known negatives, and 230 samples from patients clinically classified as having type 2 diabetes. All positive samples were correctly detected, and of those samples previously quantified, heteroplasmy levels determined using the real-time assay correlated well (r(2) = 0.88 and 0.93) with results from fluorescently labeled PCR-restriction fragment length polymorphism and pyrosequencing methods. Screening of 230 patients classified as having type 2 diabetes revealed one patient with 0.6% heteroplasmy who had previously tested negative by PCR-restriction fragment length polymorphism. Real-time PCR provides rapid simultaneous detection and quantification of the 3243A>G mutation to a detection limit of less than 0.1%, without post-PCR manipulation.

A pharmacogenetic exploration of vigabatrin-induced visual field constriction.

INTRODUCTION: Use of the antiepileptic drug (AED) vigabatrin is severely limited by irreversible visual field constriction, an adverse reaction to the drug reported in approximately 40% of patients. Given the evidence suggesting an idiosyncratic drug response, we set out to detect genetic variation of strong, clinically relevant effect that might guide clinicians in the safe, controlled prescribing of this otherwise usefuldrug. METHODS: Patients with a history of at least 1-year exposure to vigabatrin were enrolled at two independent referral centers. Using Goldmann perimetry, visual fields and the extent of constriction were calculated for each patient. We examined the correlation between the extent of vigabatrin induced visual field constriction and genetic variation across six candidate genes (SLC6A1, SLC6A13, SCL6A11, ABAT, GABRR1 and GABRR2). We availed of HapMap data and used a tagging SNP technique in an effort to efficiently capture all common variation within these genes. We attempted to replicate any positive associations before drawing conclusions from our results. RESULTS: The degree of visual field constriction correlated with three SNPs and one haplotype in a cohort of 73 patients. However we were unable to replicate these findings in a second independent cohort consisting of 58 patients, suggesting the initial results were possibly false positives, or variants of weak effect. CONCLUSION: Common variants of strong, clinically relevant effect do not appear to reside in the candidate genes studied here. This does not rule out the presence of genetic variants of weak effect in these genes, nor of variants of strong effect in other genes.

The long-term retention of pregabalin in a large cohort of patients with epilepsy at a tertiary referral centre.

Pregabalin (PGB) is a new antiepileptic drug (AED) which is a structural, non-functional analogue of gamma-aminobutyric acid. It acts at presynaptic calcium channels to modulate neurotransmitter release in the CNS. While the efficacy and tolerability of PGB have been demonstrated in several randomised controlled trials, few studies have addressed long-term outcome in large groups of patients. A cohort of patients attending a tertiary referral centre for epilepsy was identified as having started taking PGB. Patients' data were obtained through medical records. Of 402 patients included, 42% of patients were still taking PGB at last follow-up. The estimated 2.5-year retention rate was 32%. Males appeared more likely to continue on PGB therapy than females. The common adverse experiences (AEs) leading to withdrawal were CNS-related, psychiatric AEs and weight gain. Published retention rates for levetiracetam appear to be higher, and those for gabapentin lower, than the rates estimated for PGB.

Potential genetic causes of heterogeneity of treatment effects.

Nongenetic biologic and lifestyle-related factors, including age, sex, hepatic/renal function, diet/exercise practices, illness severity, smoking, and alcohol consumption habits can account for the heterogeneity of treatment effects (HTE). However, even when these factors are taken into account, considerable variation remains unexplained and could potentially be attributable to genetic differences between patients. Drug response may be dictated by variation in genes involved in both pharmacokinetic (PK) (absorption, distribution, metabolism, excretion [ADME]) and pharmacodynamic (PD) (receptors, ion channels, enzymes, immune system) pathways. Functional variants of the ADME genes can result in patients being poor, intermediate, efficient, or ultrarapid metabolizers of specific agents, thereby affecting efficacy and/or susceptibility to adverse drug reaction and necessitating individualized dosing. A well-documented example of ADME gene variation is the debrisoquine polymorphism, which is characterized by markedly different metabolism of numerous commonly prescribed drugs based on variants of the cytochrome P450 2D6 gene. Variants of genes regulating PD pathways cause altering of drug target pathways, which may affect efficacy in a more pronounced manner. Examples of gene variants affecting PD pathways include those coding for dopamine metabolism, synthesis, and transport. These gene variants may act independently, in combination with each other, and/or in combination with PK genes to affect drug response, for example to antipsychotic medications. Increased understanding of a patient's genotype and its corresponding effect on drug response would be useful to the practicing clinician in choosing an effective drug and in optimizing the dose in a timely manner.