Predictors of Seizure Recurrence in Women With Idiopathic Generalized Epilepsy Who Switch From Valproate to Another Medication.

BACKGROUND AND OBJECTIVES: To investigate the predictors of seizure recurrence in women of childbearing age with idiopathic generalized epilepsy (IGE) who switched from valproate (VPA) to alternative antiseizure medications (ASMs) and compare the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) as VPA alternatives after switch. METHODS: This multicenter retrospective study included women of childbearing age diagnosed with IGE from 16 epilepsy centers. Study outcomes included worsening or recurrence of generalized tonic-clonic seizure (GTCS) at 12 months and 24 months after the switch from VPA to an alternative ASM. The comparative effectiveness of LEV and LTG as alternative ASM following VPA discontinuation was assessed through inverse probability treatment-weighted (IPTW) Cox regression analysis. RESULTS: We included 426 women with IGE, with a median (interquartile range) age at VPA switch of 24 (19-30) years and a median VPA dosage of 750 (500-1,000) mg/d. The most common reason for VPA switch was teratogenicity concern in 249 women (58.6%), and the most common ASM used in place of VPA was LEV in 197 (46.2%) cases, followed by LTG in 140 (32.9%). GTCS worsening/recurrence occurred in 105 (24.6%) and 139 (32.6%) women at 12 and 24 months, respectively. Catamenial worsening of seizures, higher VPA dosage during switch, multiple seizure types, and shorter duration of GTCS freedom before switch were independent predictors of GTCS recurrence or worsening at 12 months according to mixed multivariable logistic regression analysis. After internal-external validation through 16 independent cohorts, the model showed an area under the curve of 0.71 (95% CI 0.64-0.77). In the subgroup of 337 women who switched to LEV or LTG, IPTW Cox regression analysis showed that LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG (adjusted hazard ratio 0.59, 95% CI 0.40-0.87, p = 0.008) during the 24-month follow-up. DISCUSSION: Our findings can have practical implications for optimizing counselling and treatment choices in women of childbearing age with IGE and may help clinicians in making informed treatment decisions in this special population of patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with IGE switching from VPA, LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG.

Structural basis for antiepileptic drugs and botulinum neurotoxin recognition of SV2A.

More than one percent of people have epilepsy worldwide. Levetiracetam (LEV) is a successful new-generation antiepileptic drug (AED), and its derivative, brivaracetam (BRV), shows improved efficacy. Synaptic vesicle glycoprotein 2a (SV2A), a putative membrane transporter in the synaptic vesicles (SVs), has been identified as a target of LEV and BRV. SV2A also serves as a receptor for botulinum neurotoxin (BoNT), which is the most toxic protein and has paradoxically emerged as a potent reagent for therapeutic and cosmetic applications. Nevertheless, no structural analysis on AEDs and BoNT recognition by full-length SV2A has been available. Here we describe the cryo-electron microscopy structures of the full-length SV2A in complex with the BoNT receptor-binding domain, BoNT/A2 HC, and either LEV or BRV. The large fourth luminal domain of SV2A binds to BoNT/A2 HC through protein-protein and protein-glycan interactions. LEV and BRV occupy the putative substrate-binding site in an outward-open conformation. A propyl group in BRV creates additional contacts with SV2A, explaining its higher binding affinity than that of LEV, which was further supported by label-free spectral shift assay. Numerous LEV derivatives have been developed as AEDs and positron emission tomography (PET) tracers for neuroimaging. Our work provides a structural framework for AEDs and BoNT recognition of SV2A and a blueprint for the rational design of additional AEDs and PET tracers.

Sudden Cardiac Death or Ventricular Arrythmia in Patients Taking Levetiracetam or Oxcarbazepine.

BACKGROUND AND OBJECTIVES: Levetiracetam is a widely used antiseizure medication. Recent concerns have been raised regarding the potential prolongation of the QT interval by levetiracetam and increased risk of sudden cardiac death. This could have profound implications for patient safety and for prescribing practice. This study assessed the potential association of levetiracetam with cardiac outcomes related to QT interval prolongation. We compared outcomes of patients taking levetiracetam with those taking oxcarbazepine as a comparator medication that has not been associated with prolongation of the QT interval. METHODS: The sample included patients who were newly prescribed levetiracetam or oxcarbazepine from January 31, 2010, to December 31, 2019, using administrative claims data from the OptumLabs Data Warehouse (OLDW). The analysis focused on a combined endpoint of sudden cardiac death or ventricular arrythmia, which are both linked to QT interval prolongation. We used a new user design and selected oxcarbazepine as an active comparator with levetiracetam to minimize bias. We used propensity score weighting to balance the levetiracetam and oxcarbazepine cohorts and then performed weighted Cox regressions to evaluate the association of levetiracetam with the combined endpoint. RESULTS: We identified 104,655 enrollees taking levetiracetam and 39,596 enrollees taking oxcarbazepine. At baseline, enrollees taking levetiracetam were older, more likely to have diagnosed epilepsy, and more likely to have diagnosed comorbidities including hypertension, cerebrovascular disease, and coronary artery disease. In the main analysis, we found no significant difference between levetiracetam and oxcarbazepine in the rate of the combined endpoint for the Cox proportional hazards model (hazard ratio [HR] 0.79, 95% CI 0.42-1.47) or Cox regression with time-varying characteristics (HR 0.78, 95% CI 0.41-1.50). DISCUSSION: When compared with oxcarbazepine, levetiracetam does not correlate with increased risk of ventricular arrythmia and sudden cardiac death. Our finding does not support the concern for cardiac risk to indicate restriction of levetiracetam use nor the requirement of cardiac monitoring when using it. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that sudden cardiac death and ventricular arrythmia are not more frequent in patients older than 17 years newly prescribed levetiracetam, compared with those prescribed oxcarbazepine.

Comparison of the effect of phenobarbital & levetiracetam in the treatment of neonatal abstinence syndrome (NAS) as adjuvant treatment in neonates admitted to the neonatal intensive care unit: a randomized clinical trial.

BACKGROUND: Infants who are born from mothers with substance use disorder might suffer from neonatal abstinence syndrome (NAS) and need treatment with medicines. One of these medicines is phenobarbital, which may cause side effects in long-term consumption. Alternative drugs can be used to reduce these side effects. This study seeks the comparison of the effects of phenobarbital & levetiracetam as adjuvant therapy in neonatal abstinence syndrome. METHODS: This randomized clinical trial was performed in one year from May 2021 until May 2022. The neonates who were born from mothers with substance use disorder and had neonatal abstinence syndrome in Afzalipoor Hospital of Kerman were studied. The treatment started with morphine initially and every four hours the infants were checked. The infants who were diagnosed with uncontrolled symptoms After obtaining informed consent from the parents were randomly divided into two groups and treated with secondary drugs, either phenobarbital or levetiracetam. RESULTS: Based on the obtained results, it was clear that there was no significant difference between the hospitalization time of the two infant groups under therapy (phenobarbital: 18.59 days versus Levetiracetam 18.24 days) (P-value = 0.512). Also, there was no significant difference between both groups in terms of the frequency of re-hospitalization during the first week after discharge, the occurrence of complications, and third treatment line prescription (P-value = 0.644). CONCLUSIONS: Based on the obtained results, like hospitalization duration time (P-value = 0.512) it seems that levetiracetam can be used to substitute phenobarbital in treating neonatal abstinence syndrome. TRIAL REGISTRATION: The current study has been registered in the Iran registry of clinical trials website (fa.irct.ir) on the date 25/2/2022 with registration no. IRCT20211218053444N2.

Effect of levetiracetam on DNA oxidation and glutathione content in a temporal lobe epilepsy model.

Levetiracetam (LEV) is a drug commonly used as an anticonvulsant. However, recent evidence points to a possible role as an antioxidant. We previously demonstrated the antioxidant properties of LEV by significantly increasing catalase and superoxide dismutase activities and decreasing the hydrogen peroxide (H2O2) levels in the hippocampus of rats with temporal lobe epilepsy (TLE) showing scavenging properties against the hydroxyl radical. The aim of the present work was to evaluate, the effect of LEV on DNA oxidation, by determining 8­hydroxy­2­deoxyguanosine (8­OHdG) levels, and glutathione content, through reduced (GSH) and oxidized (GSSG) glutathione levels, in the hippocampus of rats with TLE. Male Wistar rats were assigned to the control (CTRL), CTRL+LEV, epileptic (EPI) and EPI+LEV groups. TLE was induced using the lithium­pilocarpine model. Thirteen weeks after TLE induction, LEV was administered for one week through osmotic pumps implanted subcutaneously. The determination of 8­OHdG, GSH and GSSG levels were measured using spectrophotometric methods. We showed that LEV alone significantly increased 8­OHdG and GSSG levels in the hippocampus of control rats compared to those in epileptic condition. No significant differences in GSH levels were observed. LEV could induce changes in the hippocampus increasing DNA oxidation and GSSG levels under nonepileptic condition but not protecting against the mitochondrial dysfunction observed in TLE probably by mechanisms related to changes in chromatin structure, neuroinflammation and alterations in redox components.

Efficacy and Safety of Levetiracetam for Childhood Epilepsies.

Background: Levetiracetam (LEV) is a broad spectrum second-generation antiepileptic drug (AED). Objective: The objective of the study was to investigate the efficacy and safety of levetiracetam for childhood epilepsies. Methods: This is single, tertiary centre observational, prospective study, that included paediatric patients who were treated with levetiracetam at Paediatric hospital University Clinical Centre Sarajevo, during the period of 15 years (2008-2022). Inclusion criteria were: paediatric patients age > 1 month, diagnosed with epilepsy according to International League Against Epilepsy. After the introduction of levetiracetam, each patient has been followed up at least 12 months. According to the outcome the patients were divided into 5 groups: seizure reduction >50%, seizure reduction <50%, complete seizure freedom, the same number of seizures and increased number of seizures. From these groups two intergroups have been formed: responders (seizure reduction >50% and complete seizure freedom) and non-responders (seizure reduction <50%, the same number of seizures and increased number of seizures). Results: The study enrolled 259 patients (141 female and 118 male), with mean age 7 years (3,0-12.0). Comorbidities were present at 129/259 (49.8%) patients. After 12 months of treatment, 25/259 (9.7%) patients had seizure reduction >50%, 30/259 (11.6%) patients had seizure reduction <50%, 154/259 (56.5%) patients had achieved seizure freedom, 31/259 (12%) patients had same number of seizures, while 19/259 (7.3%) patients had increased number of seizures. Seizure frequency between responders and non-responders, before treatment and after 12 months of treatment was statistically significant (p<0.001). Discussion: Non responders had the best outcome with ditherapy (30/79; 38%), while responders had the best outcome with monotherapy (161/180;89.4%). Conclusion: Levetiracetam is efficient antiepileptic drug for different types of epilepsies in childhood, used as mono, di or polytherapy.

Diagnosing epileptic seizures in patients with Alzheimer's disease and deciding on the appropriate treatment plan.

INTRODUCTION: Alzheimer's disease (AD) is the predominant cause of dementia and a significant contributor to morbidity among the elderly. Patients diagnosed with AD face an increased risk of epileptic seizures. AREAS COVERED: Herein, the authors review the challenges in the diagnosis of seizures in patients with AD, the risks of seizures related to medications used in AD and the pharmacological treatment of seizures in AD. The authors also provide the reader with their expert opinion on the subject matter and future perspectives. EXPERT OPINION: Healthcare professionals should maintain a vigilant approach to suspecting seizures in AD patients. Acute symptomatic seizures triggered by metabolic disturbances, infections, toxins, or drug-related factors often have a low risk of recurrence. In such cases, addressing the underlying cause may suffice without initiating antiseizure medications (ASMs). However, unprovoked seizures in certain AD patients carry a higher risk of recurrence over time, warranting the use of ASMs. Although data is limited, both lamotrigine and levetiracetam appear to be reasonable choices for controlling seizures in elderly AD patients. Decisions should be informed by the best available evidence, the treating physician's clinical experience, and the patient's preferences.

Status epilepticus: what's new for the intensivist.

PURPOSE OF REVIEW: Status epilepticus (SE) is a common neurologic emergency affecting about 36.1/100 000 person-years that frequently requires intensive care unit (ICU) admission. There have been advances in our understanding of epidemiology, pathophysiology, and EEG monitoring of SE, and there have been large-scale treatment trials, discussed in this review. RECENT FINDINGS: Recent changes in the definitions of SE have helped guide management protocols and we have much better predictors of outcome. Observational studies have confirmed the efficacy of benzodiazepines and large treatment trials indicate that all routinely used second line treatments (i.e., levetiracetam, valproate and fosphenytoin) are equally effective. Better understanding of the pathophysiology has indicated that nonanti-seizure medications aimed at underlying pathological processes should perhaps be considered in the treatment of SE; already immunosuppressant treatments are being more widely used in particular for new onset refractory status epilepticus (NORSE) and Febrile infection-related epilepsy syndrome (FIRES) that sometimes revealed autoimmune or paraneoplastic encephalitis. Growing evidence for ICU EEG monitoring and major advances in automated analysis of the EEG could help intensivist to assess the control of electrographic seizures. SUMMARY: Research into the morbi-mortality of SE has highlighted the potential devastating effects of this condition, emphasizing the need for rapid and aggressive treatment, with particular attention to cardiorespiratory and neurological complications. Although we now have a good evidence-base for the initial status epilepticus management, the best treatments for the later stages are still unclear and clinical trials of potentially disease-modifying therapies are long overdue.

The Effect of Levetiracetam Compared with Enzyme-Inducing Antiseizure Medications on Apixaban and Rivaroxaban Peak Plasma Concentrations.

BACKGROUND AND OBJECTIVE: Post-stroke epilepsy represents an important clinical challenge as it often requires both treatment with direct oral anticoagulants (DOACs) and antiseizure medications (ASMs). Levetiracetam (LEV), an ASM not known to induce metabolizing enzymes, has been suggested as a safer alternative to enzyme-inducing (EI)-ASMs in patients treated with DOACs; however, current clinical guidelines suggest caution when LEV is used with DOACs because of possible P-glycoprotein induction and competition (based on preclinical studies). We investigated whether LEV affects apixaban and rivaroxaban concentrations compared with two control groups: (a) patients treated with EI-ASMs and (b) patients not treated with any ASM. METHODS: In this retrospective observational study, we monitored apixaban and rivaroxaban peak plasma concentrations (Cmax) in 203 patients treated with LEV (n = 28) and with EI-ASM (n = 33), and in patients not treated with any ASM (n = 142). Enzyme-inducing ASMs included carbamazepine, phenytoin, phenobarbital, primidone, and oxcarbazepine. We collected clinical and laboratory data for analysis, and DOAC Cmax of patients taking LEV were compared with the other two groups. RESULTS: In 203 patients, 55% were female and the mean age was 78 ± 0.8 years. One hundred and eighty-six patients received apixaban and 17 patients received rivaroxaban. The proportion of patients with DOAC Cmax below their therapeutic range was 7.1% in the LEV group, 10.6% in the non-ASM group, and 36.4% in the EI-ASM group (p < 0.001). The odds of having DOAC Cmax below the therapeutic range (compared with control groups) was not significantly different in patients taking LEV (adjusted odds ratio 0.70, 95% confidence interval 0.19-2.67, p = 0.61), but it was 12.7-fold higher in patients taking EI-ASM (p < 0.001). In an analysis in patients treated with apixaban, there was no difference in apixaban Cmax between patients treated with LEV and non-ASM controls, and LEV clinical use was not associated with variability in apixaban Cmax in a multivariate linear regression. CONCLUSIONS: In this study, we show that unlike EI-ASMs, LEV clinical use was not significantly associated with lower apixaban Cmax and was similar to that in patients not treated with any ASM. Our findings suggest that the combination of LEV with apixaban and rivaroxaban may not be associated with decreased apixaban and rivaroxaban Cmax. Therefore, prospective controlled studies are required to examine the possible non-pharmacokinetic mechanism of the effect of the LEV-apixaban or LEV-rivaroxaban combination on patients' outcomes.

Anti-seizure medication-induced developmental cell death in neonatal rats is unaltered by history of hypoxia.

BACKGROUND: Many anti-seizure medications (ASMs) trigger neuronal cell death when administered during a confined period of early life in rodents. Prototypical ASMs used to treat early-life seizures such as phenobarbital induce this effect, whereas levetiracetam does not. However, most prior studies have examined the effect of ASMs in naïve animals, and the degree to which underlying brain injury interacts with these drugs to modify cell death is poorly studied. Moreover, the degree to which drug-induced neuronal cell death differs as a function of sex is unknown. METHODS: We treated postnatal day 7 Sprague Dawley rat pups with vehicle, phenobarbital (75 mg/kg) or levetiracetam (200 mg/kg). Separate groups of pups were pre-exposed to either normoxia or graded global hypoxia. Separate groups of males and females were used. Twenty-four hours after drug treatment, brains were collected and processed for markers of cell death. RESULTS: Consistent with prior studies, phenobarbital, but not levetiracetam, increased cell death in cortical regions, basal ganglia, hippocampus, septum, and lateral thalamus. Hypoxia did not modify basal levels of cell death. Females - collapsed across treatment and hypoxia status, displayed a small but significant increase in cell death as compared to males in the cingulate cortex, somatosensory cortex, and the CA1 and CA3 hippocampus; these effects were not modulated by hypoxia or drug treatment. CONCLUSION: We found that a history of graded global hypoxia does not alter the neurotoxic profile of phenobarbital. Levetiracetam, which does not induce cell death in normal developing animals, maintained a benign profile on the background of neonatal hypoxia. We found a sex-based difference, as female animals showed elevated levels of cell death across all treatment conditions. Together, these data address several long-standing gaps in our understanding of the neurotoxic profile of antiseizure medications during early postnatal development.

Toxic optic neuropathy associated with lamotrigine and levetiracetam dual therapy.

We report the case of an early adolescent male on lamotrigine and levetiracetam therapy with a 1-month history of progressive, bilateral, painless visual loss which resolved on cessation of lamotrigine. To our knowledge, we present the first case of lamotrigine and levetiracetam dual therapy associated with toxic optic neuropathy, supported by electrophysiology and optical coherence tomography (OCT) changes. Electrophysiology findings were consistent with retinal ganglion cell dysfunction, with bilateral optic nerve involvement. Macula OCT showed mild retinal ganglion cell loss in all inner quadrants bilaterally. This case highlights the importance of asking patients with epilepsy treated with lamotrigine and levetiracetam about visual problems and considering early dose reduction or cessation of treatment.

Titania-based fabric phase sorptive extraction approach for the determination of antiepileptic drugs, levetiracetam and lamotrigine in urine samples using high-performance liquid chromatography-photo diode array detection.

A new fabric phase sorptive extraction (FPSE) based separation and enrichment method was developed for sensitive determination of two antiepileptic drug molecules, Levetiracetam (LEV) and Lamotrigine (LTG). The analysis of these drug molecules was performed with high-performance liquid chromatography equipped with photodiode array detector (HPLC-PDA) after FPSE. HPLC analysis was carried out by using phenyl hexyl column, under isocratic conditions with the mobile phase composed of pH 3.0 buffer-acetonitrile (77:23 v: v). All parameters affecting the separation and enrichment process were studied and optimized step by step. The linear working range of the developed method was calculated in the range of 10.0-1000.0 ng mL-1 for both the drug molecules (LEV and LTG). The limits of detection of the method (LODs) were calculated as 2.72 and 3.64 ng mL-1, respectively. The relative standard deviation (%RSD) values of the developed method as an indicator of precision were varied between 4.0 and 7.3. The accuracy of the optimized FPSE method was determined by the recovery tests utilizing spiked samples and results were assessed in the range from 94.6 to 106.3%. This is the first application of sol-gel Titania polycaprolactone-polydimethylsiloxane-polycaprolactone (Ti-PCAP-PDMS-PCAP) based FPSE membrane in the determination of antiepileptic drug molecules.

Behavioral and neurotransmitter changes on antiepileptic drugs treatment in the zebrafish pentylenetetrazol-induced seizure model.

Epilepsy, a recurrent neurological disorder involving abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic seizures is thought to involve a relative imbalance between excitatory and inhibitory neurotransmitters. Despite the recent advances in clinical and basic research on the pathogenesis of epilepsy, the complex relationship between the neurotransmitter changes and behavior with and without antiepileptic drugs (AEDs) during seizures remains unclear. To investigate the effects of AEDs such as levetiracetam (LEV), carbamazepine (CBZ), and fenfluramine (FFR) on key neurotransmitters in the pentylenetetrazol (PTZ)-induced seizures in adult zebrafish, we examined the changes in glutamic acid, gamma-aminobutyric acid (GABA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), choline, acetylcholine, norepinephrine, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and adenosine. In this study, we observed that 5-HT and DA levels in the brain increased immediately after PTZ-induced seizures. Behavioral tests clearly showed that all of these AEDs suppressed the PTZ-induced seizures. Upon treatment of PTZ-induced seizures with these AEDs, CBZ decreased the glutamic acid and FFR increased the GABA levels; however, no neurotransmitter changes were observed in the brain after LEV administration. Thus, we demonstrated a series of neurotransmitter changes linked to behavioral changes during PTZ-induced epileptic seizures when LEV, CBZ, or FFR were administered. These findings will lead to a more detailed understanding of the pathogenesis of epilepsy associated with behavioral and neurotransmitter changes under AED treatment.

Development of a physiologically based pharmacokinetic model for levetiracetam in patients with renal impairment to guide dose adjustment based on steady-state peak/trough concentrations.

Levetiracetam may cause acute renal failure and myoclonic encephalopathy at high plasma levels, particularly in patients with renal impairment. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict levetiracetam pharmacokinetics in Chinese adults with epilepsy and renal impairment and define appropriate levetiracetam dosing regimen.PBPK models for healthy subjects and epilepsy patients with renal impairment were developed, validated, and adapted. Furthermore, we predicted the steady-state trough and peak concentrations of levetiracetam in patients with renal impairment using the final PBPK model, thereby recommending appropriate levetiracetam dosing regimens for different renal function stages. The predicted maximum plasma concentration (Cmax), time to maximum concentration (Tmax), area under the plasma concentration-time curve (AUC) were in agreement (0.8 ≤ fold error ≤ 1.2) with the observed, and the fold error of the trough concentrations in end-stage renal disease (ESRD) was 0.77 - 1.22. The prediction simulations indicated that the recommended doses of 1000, 750, 500, and 500 mg twice daily for epilepsy patients with mild, moderate, severe renal impairment, and ESRD, respectively, were sufficient to achieve the target plasma concentration of levetiracetam.

Hepatotoxicity of newer antiseizure medications in children: an overview and disproportionality analysis of VigiBase.

BACKGROUND: We aimed to characterize newer antiseizure medications (ASMs)-induced hepatotoxicity in children and identify signals of disproportionate reporting of hepatotoxicity-related adverse drug events (ADEs). RESEARCH DESIGN AND METHODS: Case reports reported to VigiBase were accessed using Empirica™ Signal software. To summarize characteristics of the retrieved cases, descriptive statistics were used. A disproportionality analysis was conducted using the Multi-item Gamma Poisson Shrinker algorithm, which calculates Empirical Bayesian Geometric Mean value and its lower and upper 95% confidence limits (EB05 and EB95, respectively). EB05 > 2, N > 0 was considered a signal. RESULTS: Based on 870 analyzed cases, a higher proportion of cases was reported in girls than in boys and in patients aged 2-11 years than in other age groups. Most cases were serious. In 25 cases, hepatotoxicity resulted in death. A high proportion of patients (n = 275, 31.61%) experienced hypersensitivity reactions, mostly due to lamotrigine. The disproportionality analysis yielded 17 signals concerning felbamate, lamotrigine, levetiracetam, oxcarbazepine, stiripentol, and topiramate. Four signals were for severe liver injury and concerned felbamate, lamotrigine, levetiracetam, and topiramate. Gender-biased reporting frequency was detected for four ASM-ADE combinations. CONCLUSION: Our results should serve to raise clinicians' awareness about the potential association between several newer ASMs and drug-induced liver injury in children.

Effects of sodium valproate and levetiracetam on posterior segment parameters in children with epilepsy.

PURPOSE: To evaluate changes in posterior segment parameters in pediatric patients with epilepsy using sodium valproate or levetiracetam monotherapy for at least 12 months. METHODS: This study included 45 children with generalized epilepsy aged 6-17 years and 32 age- and gender-matched healthy subjects. The patients were assigned to three groups: Group 1 included patients using valproate monotherapy at a dose of 20-40 mg/kg/day, group 2 included patients using levetiracetam monotherapy at a dose of 20-40 mg/kg/day, and group 3 consisted of healthy controls. Peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer-inner plexiform layer (mGCIPL) thicknesses were measured using spectral-domain optical coherence tomography (OCT). RESULTS: No significant differences were noted between the groups regarding age, gender distribution, visual acuity, spherical equivalent, and intraocular pressure (p > 0.05). The average and temporal, nasal, and superior quadrants RNFL values were significantly thinner in group 1 than in group 2 (p = 0.001, p = 0.023, p = 0.011, and p = 0.001, respectively) and group 3 (p < 0.001, p = 0.032, p < 0.001, and p = 0.001, respectively). The OCT parameters were similar in groups 2 and 3 (p > 0.05). A negative correlation was observed in group 1 between only the average mGCIPL and the treatment dose (r = - 0.501). In group 2, no significant correlation was found between OCT parameters and the duration of epilepsy treatment, dose of treatment, and age at treatment onset values (p > 0.05). CONCLUSION: These findings support that there is an association between sodium valproate treatment and the reduction of RNFL thickness in epilepsy. Levetiracetam treatment appears to be a safe option, but care should be taken regarding ocular side effects that may occur with long-term and high-dose use of sodium valproate.

Benzodiazepines for pediatric epilepsies and their risks in a cohort within the French health care data.

OBJECTIVE: The management of antiseizure treatment in patients with epilepsy relies on the benefit-risk ratio. Data on antiseizure medication (ASM) use in children are limited. We described antiseizure medication use in children with epilepsy (CwE) in France, with a focus on the chronic use of benzodiazepines and related implications. METHODS: We conducted a 5-year cohort study from January 2012, using data from the French national health care data system (Système National des Données de Santé). We included CwE identified through International Classification of Diseases, 10th Revision codes and medications from January 2012 to December 2015 and followed them until December 2016. We described ASMs and assessed whether the risk of initiating a polytherapy after a bitherapy depends on whether benzodiazepine was included in the bitherapy. RESULTS: We identified 62 885 CwE. Valproate was the most reimbursed ASM (40%), followed by lamotrigine (17.6%), levetiracetam (9.3%), clobazam (6.1%), and carbamazepine (5.8%). Prescriptions were initiated at the hospital in 74.5% of CwE. We observed a decrease in the number of CwE with at least one benzodiazepine reimbursement from 15.3% in 2013 to 10.1% in 2016 (p < .0001). The prevalence of CwE with levetiracetam reimbursements increased, whereas that of CwE with valproate decreased. A switch from a bitherapy to a polytherapy was more likely when the bitherapy included a benzodiazepine (subdistribution hazard ratio [sHR] = 1.20 [1.03-1.39]). SIGNIFICANCE: The prevalence of CwE with at least one benzodiazepine reimbursement decreased during the study period. Benzodiazepines were associated with an increased use of subsequent ASM polytherapy.

Comparing the efficacy of anti-seizure medications using matched cohorts on a large insurance claims database.

Epilepsy is a severe chronic neurological disease affecting 60 million people worldwide. Primary treatment is with anti-seizure medicines (ASMs), but many patients continue to experience seizures. We used retrospective insurance claims data on 280,587 patients with uncontrolled epilepsy (UE), defined as status epilepticus, need for a rescue medicine, or admission or emergency visit for an epilepsy code. We conducted a computational risk ratio analysis between pairs of ASMs using a causal inference method, in order to match 1034 clinical factors and simulate randomization. Data was extracted from the MarketScan insurance claims Research Database records from 2011 to 2015. The cohort consisted of individuals over 18 years old with a diagnosis of epilepsy who took one of eight ASMs and had more than a year of history prior to the filling of the drug prescription. Seven ASM exposures were analyzed: topiramate, phenytoin, levetiracetam, gabapentin, lamotrigine, valproate, and carbamazepine or oxcarbazepine (treated as the same exposure). We calculated the risk ratio of UE between pairs of ASM after controlling for bias with inverse propensity weighting applied to 1034 factors, such as demographics, confounding illnesses, non-epileptic conditions treated by ASMs, etc. All ASMs exhibited a significant reduction in the prevalence of UE, but three drugs showed pair-wise differences compared to other ASMs. Topiramate consistently was associated with a lower risk of UE, with a mean risk ratio range of 0.68-0.93 (average 0.82, CI: 0.56-1.08). Phenytoin and levetiracetam were consistently associated with a higher risk of UE with mean risk ratio ranges of 1.11 to 1.47 (average 1.13, CI 0.98-1.65) and 1.15 to 1.43 (average 1.2, CI 0.72-1.69), respectively. Large-scale retrospective insurance claims data - combined with causal inference analysis - provides an opportunity to compare the effect of treatments in real-world data in populations 1,000-fold larger than those in typical randomized trials. Our causal analysis identified the clinically unexpected finding of topiramate as being associated with a lower risk of UE; and phenytoin and levetiracetam as associated with a higher risk of UE (compared to other studied drugs, not to baseline). However, we note that our data set for this study only used insurance claims events, which does not comprise actual seizure frequencies, nor a clear picture of side effects. Our results do not advocate for any change in practice but demonstrate that conclusions from large databases may differ from and supplement those of randomized trials and clinical practice and therefore may guide further investigation.