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Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project

Pellinen, Jacob; Pardoe, Heath; Sillau, Stefan; Barnard, Sarah; French, Jacqueline; Knowlton, Robert; Lowenstein, Daniel; Cascino, Gregory D; Glynn, Simon; Jackson, Graeme; Szaflarski, Jerzy; Morrison, Chris; Meador, Kimford J; Kuzniecky, Ruben; ,
OBJECTIVE:Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. METHODS:Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12-60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1-weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. RESULTS:Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = -.007 to -.002, p = .0003). Each 10-year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = -.007 to -.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = -.014 to -.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. SIGNIFICANCE/CONCLUSIONS:This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.
PMID: 37517050
ISSN: 1528-1167
CID: 5618932

Empiric dosing strategies to predict lamotrigine concentrations during pregnancy

Barry, Jessica M; French, Jacqueline A; Pennell, Page B; Karanam, Ashwin; Harden, Cynthia L; Birnbaum, Angela K
INTRODUCTION:Maintaining seizure control with lamotrigine is complicated by altered pharmacokinetics and existence of subpopulations in whom clearance increases or remains constant during pregnancy. OBJECTIVE:Our objective was to characterize the potential for particular dosing scenarios to lead to increased seizure risk or toxicity. METHODS:Lamotrigine pharmacokinetic parameters obtained from our previous study were applied to a one-compartment model structure with subpopulations (75:25%) exhibiting different clearance changes. A single-patient simulation was conducted with typical pharmacokinetic parameter values from each subpopulation. Population-level simulations (N = 48,000) included six dosing scenarios and considered four preconception doses using the R package mrgsolve (Metrum Research Group). Thresholds for efficacy and toxicity were selected as drug concentration that are 65% lower than preconception concentrations and doubling of preconception concentrations, respectively. RESULTS:Individual simulation results demonstrated that without dose increases, concentrations fell below 0.65 at 6-8 weeks in the high clearance change (HC) subpopulation, depending on preconception clearance. While no simulated dosing regimen allowed all women in both subpopulations to maintain preconception concentrations, some regimens provided a more balanced risk profile than others. Predicted concentrations suggested potential increased seizure risk for 7%-100% of women in the HC group depending on preconception dose and subpopulation. Additionally, in 63% of dosing scenarios for women with low clearance change (LC), there was an increased risk of toxicity (34%-100% of women). SIGNIFICANCE:A substantial percentage of simulated individuals had concentrations low enough to potentially increase seizure risk or high enough to create toxicity. Early clearance changes indicate possible subpopulation categorization if therapeutic drug monitoring is conducted in the first trimester. An arbitrary "one-size-fits-all" philosophy may not work well for lamotrigine dosing adjustments during pregnancy and reinforces the need for therapeutic drug monitoring until a patient is determined to be in the LC or HC group.
PMID: 37475496
ISSN: 1875-9114
CID: 5618782

Impact of Seizures While Driving Prior to Diagnosis in People With Focal Epilepsy: Motor Vehicle Accidents and Time to Diagnosis

Bases, Benjamin; Barnard, Sarah; French, Jacqueline A; Pellinen, Jacob; ,
OBJECTIVES:To identify the type, frequency, and consequences of seizures while driving (SzWD) in people with epilepsy before diagnosis. METHODS:We performed a retrospective cohort study using the Human Epilepsy Project (HEP) to identify prediagnostic SzWD. Clinical descriptions from seizure diaries and medical records were used to classify seizure types and frequencies, time to diagnosis, and SzWD outcomes. Data were modeled using multiple logistic regression to assess for factors independently associated with SzWD. RESULTS:= 0.02). DISCUSSION:This study identifies the consequences of seizure-related MVAs and hospitalizations people experience before epilepsy diagnosis. This highlights the need for further research aimed at improving seizure awareness and improving time to diagnosis.
PMCID:10558166
PMID: 37286361
ISSN: 1526-632x
CID: 5631752

Time-to-event clinical trial designs: Existing evidence and remaining concerns

Kerr, Wesley T; Auvin, Stéphane; Van der Geyten, Serge; Kenney, Christopher; Novak, Gerald; Fountain, Nathan B; Grzeskowiak, Caitlin; French, Jacqueline A
Well-designed placebo-controlled clinical trials are critical to the development of novel treatments for epilepsy, but their design has not changed for decades. Patients, clinicians, regulators, and innovators all have concerns that recruiting for trials is challenging, in part, due to the static design of maintaining participants for long periods on add-on placebo when there are an increasing number of options for therapy. A traditional trial maintains participants on blinded treatment for a static period (e.g., 12 weeks of maintenance), during which participants on placebo have an elevated risk of sudden unexpected death in epilepsy compared to patients on an active treatment. Time-to-event trials observe participants on blinded treatment until a key event occurs (e.g., post-randomization seizure count matches pre-randomization monthly seizure count). In this article, we review the evidence for these designs based on re-analysis of prior trials, one published trial that used a time-to-second seizure design, and experience from an ongoing blinded trial. We also discuss remaining concerns regarding time-to-event trials. We conclude that, despite potential limitations, time-to-event trials are a potential promising mechanism to make trials more patient friendly and reduce placebo exposure, which are urgent needs to improve safety and increase recruitment to trials.
PMID: 37073881
ISSN: 1528-1167
CID: 5502842

Impact of genetic polymorphisms on the risk of epilepsy amongst patients with acute brain injury: A systematic review

Misra, Shubham; Quinn, Terence J; Falcone, Guido J; Sharma, Vijay K; de Havenon, Adam; Zhao, Yize; Eldem, Ece; French, Jacqueline A; Yasuda, Clarissa Lin; Dawson, Jesse; Liebeskind, David S; Kwan, Patrick; Mishra, Nishant K
BACKGROUND AND PURPOSE:The genetics of late seizure or epilepsy secondary to traumatic brain injury (TBI) or stroke are poorly understood. We undertook a systematic review to test the association of single-nucleotide polymorphisms (SNPs) with the risk of post-traumatic epilepsy (PTE) and post-stroke epilepsy (PSE). METHODS:We followed methods from our prespecified protocol on PROSPERO to identify indexed articles for this systematic review. We collated the association statistics from the included articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed study quality using the Q-Genie tool. We report odds ratios (OR) and hazard ratios with 95% confidence intervals (CIs). RESULTS:The literature search yielded 420 articles. We included 16 studies in our systematic review, of which seven were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Eleven SNPs were associated with a significantly increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, and CD40 -1C/T, were significantly associated with an increased risk of PSE, while two, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. The meta-analysis for the association of the APOE ɛ4 with PTE was nonsignificant (OR 1.8, CI 0.6-5.6). CONCLUSIONS:The current evidence on the association of genetic polymorphisms in epilepsy secondary to TBI or stroke is of low quality and lacks validation. A collaborative effort to pool genetic data linked to epileptogenesis in stroke and TBI patients is warranted.
PMID: 36912749
ISSN: 1468-1331
CID: 5542052

Mood and Anxiety Disorders and Suicidality in Patients With Newly Diagnosed Focal Epilepsy: An Analysis of a Complex Comorbidity

Kanner, Andres M; Saporta, Anita S; Kim, Dong H; Barry, John J; Altalib, Hamada; Omotola, Hope; Jette, Nathalie; O'Brien, Terence J; Nadkarni, Siddhartha; Winawer, Melodie R; Sperling, Michael; French, Jacqueline A; Abou-Khalil, Bassel; Alldredge, Brian; Bebin, Martina; Cascino, Gregory D; Cole, Andrew J; Cook, Mark J; Detyniecki, Kamil; Devinsky, Orrin; Dlugos, Dennis; Faught, Edward; Ficker, David; Fields, Madeline; Gidal, Barry; Gelfand, Michael; Glynn, Simon; Halford, Jonathan J; Haut, Sheryl; Hegde, Manu; Holmes, Manisha G; Kalviainen, Reetta; Kang, Joon; Klein, Pavel; Knowlton, Robert C; Krishnamurthy, Kaarkuzhali; Kuzniecky, Ruben; Kwan, Patrick; Lowenstein, Daniel H; Marcuse, Lara; Meador, Kimford J; Mintzer, Scott; Pardoe, Heath R; Park, Kristen; Penovich, Patricia; Singh, Rani K; Somerville, Ernest; Szabo, Charles A; Szaflarski, Jerzy P; Lin Thio, K Liu; Trinka, Eugen; Burneo, Jorge G
BACKGROUND AND OBJECTIVES/OBJECTIVE:Mood, anxiety disorders, and suicidality are more frequent in people with epilepsy than in the general population. Yet, their prevalence and the types of mood and anxiety disorders associated with suicidality at the time of the epilepsy diagnosis are not established. We sought to answer these questions in patients with newly diagnosed focal epilepsy and to assess their association with suicidal ideation and attempts. METHODS:statistics, and logistic regression analyses. RESULTS:A total of 151 (43.5%) patients had a psychiatric diagnosis; 134 (38.6%) met the criteria for a mood and/or anxiety disorder, and 75 (21.6%) reported suicidal ideation with or without attempts. Mood (23.6%) and anxiety (27.4%) disorders had comparable prevalence rates, whereas both disorders occurred together in 43 patients (12.4%). Major depressive disorders (MDDs) had a slightly higher prevalence than bipolar disorders (BPDs) (9.5% vs 6.9%, respectively). Explanatory variables of suicidality included MDD, BPD, panic disorders, and agoraphobia, with BPD and panic disorders being the strongest variables, particularly for active suicidal ideation and suicidal attempts. DISCUSSION/CONCLUSIONS:In patients with newly diagnosed focal epilepsy, the prevalence of mood, anxiety disorders, and suicidality is higher than in the general population and comparable to those of patients with established epilepsy. Their recognition at the time of the initial epilepsy evaluation is of the essence.
PMID: 36539302
ISSN: 1526-632x
CID: 5447782

A randomized Phase 2b efficacy study in patients with seizure episodes with a predictable pattern using Staccato® alprazolam for rapid seizure termination

French, Jacqueline; Biton, Victor; Dave, Hina; Detyniecki, Kamil; Gelfand, Michael A; Gong, Hui; Liow, Kore; O'Brien, Terence J; Sadek, Ahmed; DiVentura, Bree; Reich, Brittany; Isojarvi, Jouko
OBJECTIVE:Alprazolam administered via the Staccato® breath-actuated device is delivered into deep lung for rapid systemic exposure and is a potential therapy for rapid epileptic seizure termination (REST). We conducted an inpatient study (ENGAGE-E-001 [NCT03478982]) in patients with stereotypic seizure episodes with prolonged or repetitive seizures to determine whether Staccato® alprazolam rapidly terminates seizures in a small observed population after administration under direct supervision. METHODS:Adult patients with established diagnosis of focal and/or generalized epilepsy with a documented history of seizure episodes with a predictable pattern were enrolled. They were randomized 1:1:1 to double-blind treatment of a single seizure event with one dose of Staccato® alprazolam 1.0 mg or 2.0 mg, or Staccato® placebo in an inpatient unit. The primary endpoint of the study was the proportion of responders in each treatment group achieving seizure activity cessation within 2 mins after administration of study drug and no recurrence of seizure activity within 2 hours. RESULTS:A total of 273 patients were screened, and 116 randomized patients received treatment with study drug in the double-blind part. The proportion of treated patients who were responders was 65.8% for each of Staccato® alprazolam 1.0 mg (n=38; P=.0392) and 2.0 mg (n=38; P=.0392), compared with 42.5% for Staccato® placebo (n=40). Staccato® alprazolam was well tolerated when administered as a single dose of 1.0 or 2.0 mg: cough and somnolence were the most common adverse events (AEs) (both 14.5%), followed by dysgeusia (13.2%). AEs were mostly mild or moderate in intensity with no treatment-related serious AEs. SIGNIFICANCE/CONCLUSIONS:Both 1.0 mg and 2.0 mg doses of Staccato® alprazolam demonstrated efficacy in rapidly terminating seizures in an inpatient setting and were well tolerated. The next step is a Phase 3 confirmatory study to demonstrate efficacy and safety of Staccato® alprazolam for rapid cessation of seizures in an outpatient setting.
PMID: 36268811
ISSN: 1528-1167
CID: 5360582

Tackling the Unmet Therapeutic Needs in Nonsurgical Treatments for Epilepsy

Steriade, Claude; French, Jacqueline
PMID: 36066899
ISSN: 2168-6157
CID: 5332412

Protocol for the development of an international Core Outcome Set for treatment trials in adults with epilepsy: the EPilepsy outcome Set for Effectiveness Trials Project (EPSET)

Mitchell, James W; Noble, Adam; Baker, Gus; Batchelor, Rachel; Brigo, Francesco; Christensen, Jakob; French, Jacqueline; Gil-Nagel, Antonio; Guekht, Alla; Jette, Nathalie; Kälviäinen, Reetta; Leach, John Paul; Maguire, Melissa; O'Brien, Terence; Rosenow, Felix; Ryvlin, Philippe; Tittensor, Phil; Tripathi, Manjari; Trinka, Eugen; Wiebe, Samuel; Williamson, Paula R; Marson, Tony
BACKGROUND:A Core Outcome Set (COS) is a standardised list of outcomes that should be reported as a minimum in all clinical trials. In epilepsy, the choice of outcomes varies widely among existing studies, particularly in clinical trials. This diminishes opportunities for informed decision-making, contributes to research waste and is a barrier to integrating findings in systematic reviews and meta-analyses. Furthermore, the outcomes currently being measured may not reflect what is important to people with epilepsy. Therefore, we aim to develop a COS specific to clinical effectiveness research for adults with epilepsy using Delphi consensus methodology. METHODS:The EPSET Study will comprise of three phases and follow the core methodological principles as outlined by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. Phase 1 will include two focused literature reviews to identify candidate outcomes from the qualitative literature and current outcome measurement practice in phase III and phase IV clinical trials. Phase 2 aims to achieve international consensus to define which outcomes should be measured as a minimum in future trials, using a Delphi process including an online consensus meeting involving key stakeholders. Phase 3 will involve dissemination of the ratified COS to facilitate uptake in future trials and the planning of further research to identify the most appropriate measurement instruments to use to capture the COS in research practice. DISCUSSION/CONCLUSIONS:Harmonising outcome measurement across future clinical trials should ensure that the outcomes measured are relevant to patients and health services, and allow for more meaningful results to be obtained. CORE OUTCOME SET REGISTRATION/UNASSIGNED:COMET Initiative as study 118 .
PMCID:9670528
PMID: 36397081
ISSN: 1745-6215
CID: 5371692

Time to exceed pre-randomization monthly seizure count for perampanel in participants with primary generalized tonic-clonic seizures: A potential clinical end point

Kerr, Wesley T; Brandt, Christian; Ngo, Leock Y; Patten, Anna; Cheng, Jocelyn Y; Kramer, Lynn; French, Jacqueline A
OBJECTIVE:To evaluate the exploratory time to exceed pre-randomization seizure count (T-PSC) in the determination of efficacy of adjunctive perampanel in participants with primary generalized tonic-clonic (PGTC) seizures in generalized-onset epilepsy. METHODS:In this multicenter, double-blind study (ClinicalTrials.gov identifier: NCT01393743), participants ≥12 years of age with treatment-resistant idiopathic generalized epilepsy were randomized to receive placebo or adjunctive perampanel (≤8 mg/day) across a 17-week double-blind treatment phase (4-week titration; 13-week maintenance). We evaluated the pre-planned exploratory end point of the T-PSC using a Kaplan-Meier analysis. We also re-evaluated the correspondence of the primary end points of median percent seizure frequency change (MPC) and 50% responder rate (50RR) calculated at T-PSC and at the end of the trial. RESULTS:The exploratory end point of median T-PSC on placebo was 43 days and >120 days on perampanel (log-rank p < .001). The primary end points calculated at T-PSC did not differ significantly from the end points at the end of the trial (MPC -31% vs -42% at T-PSC; 50RR 32% vs 51% at T-PSC). After T-PSC was reached, participants had a median (interquartile range) of 5 (3-13) additional seizures on placebo and 5 (2-10) on perampanel. SIGNIFICANCE/CONCLUSIONS:The exploratory end point of T-PSC demonstrated the effectiveness of perampanel despite a shorter duration of monitoring. The seizures that occurred after T-PSC did not influence the conclusions of the trial; therefore, T-PSC may be a viable alternative to traditional trial end points that reduces the risk to participants.
PMID: 36106379
ISSN: 1528-1167
CID: 5351062