Medicine (RMH) - Research Publications

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Predictive models for starting antiseizure medication withdrawal following epilepsy surgery in adults

Ferreira-Atuesta, C ; de Tisi, J ; McEvoy, AW ; Miserocchi, A ; Khoury, J ; Yardi, R ; Vegh, DT ; Butler, J ; Lee, HJ ; Deli-Peri, V ; Yao, Y ; Wang, F-P ; Zhang, X-B ; Shakhatreh, L ; Siriratnam, P ; Neal, A ; Sen, A ; Tristram, M ; Varghese, E ; Biney, W ; Gray, WP ; Peralta, AR ; Rainha-Campos, A ; Goncalves-Ferreira, AJC ; Pimentel, J ; Arias, JF ; Terman, S ; Terziev, R ; Lamberink, HJ ; Braun, KPJ ; Otte, WM ; Rugg-Gunn, FJ ; Gonzalez, W ; Bentes, C ; Hamandi, K ; O'Brien, TJ ; Perucca, P ; Yao, C ; Burman, RJ ; Jehi, L ; Duncan, JS ; Sander, JW ; Koepp, M ; Galovic, M (OXFORD UNIV PRESS, 2023-06-01)

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7-11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8-0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.
Applications for Deep Learning in Epilepsy Genetic Research

Zeibich, R ; Kwan, P ; O'Brien, TJ ; Perucca, P ; Ge, Z ; Anderson, A (MDPI AG, 2023-10)

Epilepsy is a group of brain disorders characterised by an enduring predisposition to generate unprovoked seizures. Fuelled by advances in sequencing technologies and computational approaches, more than 900 genes have now been implicated in epilepsy. The development and optimisation of tools and methods for analysing the vast quantity of genomic data is a rapidly evolving area of research. Deep learning (DL) is a subset of machine learning (ML) that brings opportunity for novel investigative strategies that can be harnessed to gain new insights into the genomic risk of people with epilepsy. DL is being harnessed to address limitations in accuracy of long-read sequencing technologies, which improve on short-read methods. Tools that predict the functional consequence of genetic variation can represent breaking ground in addressing critical knowledge gaps, while methods that integrate independent but complimentary data enhance the predictive power of genetic data. We provide an overview of these DL tools and discuss how they may be applied to the analysis of genetic data for epilepsy research.
Levetiracetam Pharmacokinetics and Brain Uptake in a Lateral Fluid Percussion Injury Rat ModelS

Coles, LD ; Saletti, PG ; Lisgaras, CP ; Casillas-Espinosa, PM ; Liu, W ; Li, Q ; Jones, NC ; Shultz, S ; Ali, I ; Brady, R ; Yamakawa, G ; Hudson, M ; Silva, J ; Braine, E ; Mishra, U ; Cloyd, JC ; O'Brien, TJ ; Moshe, SL ; Galanopoulou, AS (AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS, 2023-08-01)

Post-traumatic epilepsy (PTE) occurs in some patients after moderate/severe traumatic brain injury (TBI). Although there are no approved therapies to prevent epileptogenesis, levetiracetam (LEV) is commonly given for seizure prophylaxis due to its good safety profile. This led us to study LEV as part of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Project. The objective of this work is to characterize the pharmacokinetics (PK) and brain uptake of LEV in naïve control rats and in the lateral fluid percussion injury (LFPI) rat model of TBI after either single intraperitoneal doses or a loading dose followed by a 7-day subcutaneous infusion. Sprague-Dawley rats were used as controls and for the LFPI model induced at the left parietal region using injury parameters optimized for moderate/severe TBI. Naïve and LFPI rats received either a bolus injection (intraperitoneal) or a bolus injection followed by subcutaneous infusion over 7 days. Blood and parietal cortical samples were collected at specified time points throughout the study. LEV concentrations in plasma and brain were measured using validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods. Noncompartmental analysis and a naive-pooled compartmental PK modeling approach were used. Brain-to-plasma ratios ranged from 0.54 to 1.4 to 1. LEV concentrations were well fit by one-compartment, first-order absorption PK models with a clearance of 112 ml/h per kg and volume of distribution of 293 ml/kg. The single-dose pharmacokinetic data were used to guide dose selection for the longer-term studies, and target drug exposures were confirmed. Obtaining LEV PK information early in the screening phase allowed us to guide optimal treatment protocols in EpiBioS4Rx. SIGNIFICANCE STATEMENT: The characterization of levetiracetam pharmacokinetics and brain uptake in an animal model of post-traumatic epilepsy is essential to identify target concentrations and guide optimal treatment for future studies.
Impact of epilepsy surgery on quality of life: Systematic review and meta-analysis

Shakhatreh, L ; Foster, E ; Siriratnam, P ; Neal, A ; Carney, PW ; Jackson, GD ; O'Brien, TJ ; Kwan, P ; Chen, Z ; Ademi, Z (WILEY, 2023-07)

Improved quality of life (QoL) is an important outcome goal following epilepsy surgery. This study aims to quantify change in QoL for adults with drug-resistant epilepsy (DRE) who undergo epilepsy surgery, and to explore clinicodemographic factors associated with these changes. We conducted a systematic review and meta-analysis using Medline, Embase, and Cochrane Central Register of Controlled Trials. All studies reporting pre- and post-epilepsy surgery QoL scores in adults with DRE via validated instruments were included. Meta-analysis assessed the postsurgery change in QoL. Meta-regression assessed the effect of postoperative seizure outcomes on postoperative QoL as well as change in pre- and postoperative QoL scores. A total of 3774 titles and abstracts were reviewed, and ultimately 16 studies, comprising 1182 unique patients, were included. Quality of Life in Epilepsy Inventory-31 item (QOLIE-31) meta-analysis included six studies, and QOLIE-89 meta-analysis included four studies. Postoperative change in raw score was 20.5 for QOLIE-31 (95% confidence interval [CI] = 10.9-30.1, I2 = 95.5) and 12.1 for QOLIE-89 (95% CI = 8.0-16.1, I2 = 55.0%). This corresponds to clinically meaningful QOL improvements. Meta-regression demonstrated a higher postoperative QOLIE-31 score as well as change in pre- and postoperative QOLIE-31 score among studies of cohorts with higher proportions of patients with favorable seizure outcomes. At an individual study level, preoperative absence of mood disorders, better preoperative cognition, fewer trials of antiseizure medications before surgery, high levels of conscientiousness and openness to experience at the baseline, engagement in paid employment before and after surgery, and not being on antidepressants following surgery were associated with improved postoperative QoL. This study demonstrates the potential for epilepsy surgery to provide clinically meaningful improvements in QoL, as well as identifies clinicodemographic factors associated with this outcome. Limitations include substantial heterogeneity between individual studies and high risk of bias.
Inherent Susceptibility to Acquired Epilepsy in Selectively Bred Rats Influences the Acute Response to Traumatic Brain Injury

Leung, WL ; Dill, LK ; Perucca, P ; O'Brien, TJ ; Casillas-Espinosa, PM ; Semple, BD (MARY ANN LIEBERT, INC, 2023-10-01)

Traumatic brain injury (TBI) often causes seizures associated with a neuroinflammatory response and neurodegeneration. TBI responses may be influenced by differences between individuals at a genetic level, yet this concept remains understudied. Here, we asked whether inherent differences in one's vulnerability to acquired epilepsy would determine acute physiological and neuroinflammatory responses acutely after experimental TBI, by comparing selectively bred "seizure-prone" (FAST) rats with "seizure-resistant" (SLOW) rats, as well as control parental strains (Long Evans and Wistar rats). Eleven-week-old male rats received a moderate-to-severe lateral fluid percussion injury (LFPI) or sham surgery. Rats were assessed for acute injury indicators and neuromotor performance, and blood was serially collected. At 7 days post-injury, brains were collected for quantification of tissue atrophy by cresyl violet (CV) histology, and immunofluorescent staining of activated inflammatory cells. FAST rats showed an exacerbated physiological response acutely post-injury, with a 100% seizure rate and mortality within 24 h. Conversely, SLOW rats showed no acute seizures and a more rapid neuromotor recovery compared with controls. Brains from SLOW rats also showed only modest immunoreactivity for microglia/macrophages and astrocytes in the injured hemisphere compared with controls. Further, group differences were apparent between the control strains, with greater neuromotor deficits observed in Long Evans rats compared with Wistars post-TBI. Brain-injured Long Evans rats also showed the most pronounced inflammatory response to TBI across multiple brain regions, whereas Wistar rats showed the greatest extent of regional brain atrophy. These findings indicate that differential genetic predisposition to develop acquired epilepsy (i.e., FAST vs. SLOW rat strains) determines acute responses after experimental TBI. Differences in the neuropathological response to TBI between commonly used control rat strains is also a novel finding, and an important consideration for future study design. Our results support further investigation into whether genetic predisposition to acute seizures predicts the chronic outcomes after TBI, including the development of post-traumatic epilepsy.
The sulfonadyns: a class of aryl sulfonamides inhibiting dynamin I GTPase and clathrin mediated endocytosis are anti-seizure in animal models

Odell, LRR ; Jones, NCC ; Chau, N ; Robertson, MJJ ; Ambrus, JII ; Deane, FMM ; Young, KAA ; Whiting, A ; Xue, J ; Prichard, K ; Daniel, JAA ; Gorgani, NNN ; O'Brien, TJJ ; Robinson, PJJ ; McCluskey, A (ROYAL SOC CHEMISTRY, 2023-08-16)

We show that dansylcadaverine (1) a known in-cell inhibitor of clathrin mediated endocytosis (CME), moderately inhibits dynamin I (dynI) GTPase activity (IC50 45 μM) and transferrin (Tfn) endocytosis in U2OS cells (IC50 205 μM). Synthesis gave a new class of GTP-competitive dynamin inhibitors, the Sulfonadyns™. The introduction of a terminal cinnamyl moiety greatly enhanced dynI inhibition. Rigid diamine or amide links between the dansyl and cinnamyl moieties were detrimental to dynI inhibition. Compounds with in vitro inhibition of dynI activity <10 μM were tested in-cell for inhibition of CME. These data unveiled a number of compounds, e.g. analogues 33 ((E)-N-(6-{[(3-(4-bromophenyl)-2-propen-1-yl]amino}hexyl)-5-isoquinolinesulfonamide)) and 47 ((E)-N-(3-{[3-(4-bromophenyl)-2-propen-1-yl]amino}propyl)-1-naphthalenesulfonamide)isomers that showed dyn IC50 <4 μM, IC50(CME) <30 μM and IC50(SVE) from 12-265 μM. Both analogues (33 and 47) are at least 10 times more potent that the initial lead, dansylcadaverine (1). Enzyme kinetics revealed these sulfonamide analogues as being GTP competitive inhibitors of dynI. Sulfonadyn-47, the most potent SVE inhibitor observed (IC50(SVE) = 12.3 μM), significantly increased seizure threshold in a 6 Hz mouse psychomotor seizure test at 30 (p = 0.003) and 100 mg kg-1 ip (p < 0.0001), with similar anti-seizure efficacy to the established anti-seizure medication, sodium valproate (400 mg kg-1). The Sulfonadyn™ class of drugs target dynamin and show promise as novel leads for future anti-seizure medications.
EEG based automated seizure detection - A survey of medical professionals

Wong, S ; Simmons, A ; Rivera-Villicana, J ; Barnett, S ; Sivathamboo, S ; Perucca, P ; Kwan, P ; Kuhlmann, L ; Vasa, R ; O'Brien, TJ (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-12)

Diagnosing and managing seizures presents substantial challenges for clinicians caring for patients with epilepsy. Although machine learning (ML) has been proposed for automated seizure detection using EEG data, there is little evidence of these technologies being broadly adopted in clinical practice. Moreover, there is a noticeable lack of surveys investigating this topic from the perspective of medical practitioners, which limits the understanding of the obstacles for the development of effective automated seizure detection. Besides the issue of generalisability and replicability seen in a small amount of studies, obstacles to the adoption of automated seizure detection remain largely unknown. To understand the obstacles preventing the application of seizure detection tools in clinical practice, we conducted a survey targeting medical professionals involved in the management of epilepsy. Our study aimed to gather insights on various factors such as the clinical utility, professional sentiment, benchmark requirements, and perceived barriers associated with the use of automated seizure detection tools. Our key findings are: I) The minimum acceptable sensitivity reported by most of our respondents (80%) seems achievable based on studies reported from most currently available ML-based EEG seizure detection algorithms, but replication studies often fail to meet this minimum. II) Respondents are receptive to the adoption of ML seizure detection tools and willing to spend time in training. III) The top three barriers for usage of such tools in clinical practice are related to availability, lack of training, and the blackbox nature of ML algorithms. Based on our findings, we developed a guide that can serve as a basis for developing ML-based seizure detection tools that meet the requirements of medical professionals, and foster the integration of these tools into clinical practice.
Changes over 24 years in a pregnancy register - Teratogenicity and epileptic seizure control

Vajda, F ; O'Brien, T ; Graham, J ; Hitchcock, A ; Perucca, P ; Lander, C ; Eadie, M (Elsevier, 2023-11)

OBJECTIVES: To trace (i) changes in Australian Pregnancy Register (APR) records concerning antiseizure medications (ASMs) prescribed for women with epilepsy (WWE) over the course of 24 years and correlate the changes with (ii) rates of occurrence of pregnancies involving foetal malformations, (iii) the body organs involved in the malformations, and (iv) freedom from epileptic seizures. RESULTS: Use of valproate and carbamazepine decreased progressively, use of lamotrigine remained relatively static, and the use of levetiracetam increased progressively, whereas the use of topiramate first increased and then fell again, associated with a temporary increase in malformation-associated pregnancy rate. More serious malformations, such as spina bifida, became less frequent, whereas more trivial ones tended to increase, whereas epileptic seizure freedom rates improved. CONCLUSIONS: The increasing use of newer ASMs in pregnant women has been associated with overall advantages in relation to the frequency and severity of foetal malformation and with advantages in relation to freedom from epileptic seizures.
Effects of the T-type calcium channel CaV3.2 R1584P mutation on absence seizure susceptibility in GAERS and NEC congenic rats models

Casillas-Espinosa, PM ; Lin, R ; Li, R ; Nandakumar, NM ; Dawson, G ; Braine, EL ; Martin, B ; Powell, KL ; O'Brien, TJ (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2023-08)

RATIONALE: Low-voltage-activated or T-type Ca2+ channels play a key role in the generation of seizures in absence epilepsy. We have described a homozygous, gain of function substitution mutation (R1584P) in the CaV3.2 T-type Ca2+ channel gene (Cacna1h) in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS). The non-epileptic control (NEC) rats, derived from the same original Wistar strains as GAERS but selectively in-breed not to express seizures, are null for the R1584P mutation. To study the effects of this mutation in rats who otherwise have a GAERS or NEC genetic background, we bred congenic GAERS-Cacna1hNEC (GAERS null for R1584P mutation) and congenic NEC-Cacna1hGAERS (NEC homozygous for R1584P mutation) and evaluated the seizure and behavioral phenotype of these strains in comparison to the original GAERS and NEC strains. METHODS: To evaluate seizure expression in the congenic strains, EEG electrodes were implanted in NEC, GAERS, GAERS-Cacna1hNEC without the R1584P mutation, and NEC-Cacna1hGAERS with the R1584P mutation rats. In the first study, continuous EEG recordings were acquired from week 4 (when seizures begin to develop in GAERS) to week 14 of age (when GAERS display hundreds of seizures per day). In the second study, the seizure and behavioral phenotype of GAERS and NEC-Cacna1hGAERS strains were evaluated during young age (6 weeks of age) and adulthood (16 weeks of age) of GAERS, NEC, GAERS-Cacna1hNEC and NEC-Cacna1hGAERS. The Open field test (OFT) and sucrose preference test (SPT) were performed to evaluate anxiety-like and depressive-like behavior, respectively. This was followed by EEG recordings at 18 weeks of age to quantify the seizures, and spike-wave discharge (SWD) cycle frequency. At the end of the study, the whole thalamus was collected for T-type calcium channel mRNA expression analysis. RESULTS: GAERS had a significantly shorter latency to first seizures and an increased number of seizures per day compared to GAERS-Cacna1hNEC. On the other hand, the presence of the R1584P mutation in the NEC-Cacna1hGAERS was not enough to generate spontaneous seizures in their seizure-resistant background. 6 and 16-week-old GAERS and GAERS-Cacna1hNEC rats showed anxiety-like behavior in the OFT, in contrast to NEC and NEC-Cacna1hGAERS. Results from the SPT showed that the GAERS developed depressive-like in the SPT compared to GAERS-Cacna1hNEC, NEC, and NEC-Cacna1hGAERS. Analysis of the EEG at 18 weeks of age showed that the GAERS had an increased number of seizures per day, increased total seizure duration and a higher cycle frequency of SWD relative to GAERS-Cacna1hNEC. However, the average seizure duration was not significantly different between strains. Quantitative real-time PCR showed that the T-type Ca2+ channel isoform CaV3.2 channel expression was significantly increased in GAERS compared to NEC, GAERS-Cacna1hNEC and NEC-Cacna1hGAERS. The presence of the R1584P mutation increased the total ratio of CaV3.2 + 25/-25 splice variants in GAERS and NEC-Cacna1hGAERS compared to NEC and GAERS-Cacna1hNEC. DISCUSSION: The data from this study demonstrate that the R1584P mutation in isolation on a seizure-resistant NEC genetic background was insufficient to generate absence seizures, and that a GAERS genetic background can cause seizures even without the mutation. However, the study provides evidence that the R1584P mutation acts as a modulator of seizures development and expression, and depressive-like behavior in the SPT, but not the anxiety phenotype of the GAERS model of absence epilepsy.
Development and validation of a peripheral cell ratio and lactate score for differentiating status epilepticus from prolonged psychogenic nonepileptic seizures

Tan, THL ; Sanfilippo, P ; Colman, B ; Perucca, P ; Kwan, P ; O'Brien, TJ ; Monif, M (WILEY, 2023-12)

OBJECTIVE: Differentiating status epilepticus (SE) from prolonged psychogenic nonepileptic seizures (pPNES) can be difficult clinically. We aimed to define the utility of peripheral cell counts, cell ratios, and lactate levels in distinguishing SE from pPNES. METHODS: Retrospective two-center study investigating the sensitivity and specificity of acute (≤12 h of event offset) peripheral cell counts, cell ratios (neutrophil-lymphocyte ratio, neutrophil-monocyte ratio, monocyte-lymphocyte ratio, platelet-lymphocyte ratio, systemic immune-inflammatory index [SII], systemic inflammatory response index [SIRI]), and lactate levels in differentiating SE from pPNES. Patients were identified from two tertiary hospitals, with one forming the development cohort and the other the validation cohort. Using generalized additive models to generate biomarker vs time curves, optimal blood collection times were defined for set parameters. Three diagnostic scores combining neutrophil count, SII, or SIRI with lactate levels were developed and validated in separate cohorts. RESULTS: For the development cohort, 1262 seizure-like events were reviewed and 79 SE and 44 pPNES events were included. For the validation cohort, 241 events were reviewed and 20 SE and 11 pPNES events were included. Individually, the biomarkers generally had low sensitivity and reasonable specificity for differentiating SE from pPNES, with the neutrophil count, SIRI, and SII performing best with sensitivities of 0.65-0.84, specificities of 0.64-0.89, and ROC AUCs of 0.78-0.79. Lactate levels peaked at 60 min, while cell counts and ratios peaked after 240 min. Combining early peaking lactate levels and later peaking neutrophil count, SIRI or SII resulted in three scores that improved predictive potential with sensitivities of between 0.75 and 0.79, specificities between 0.93 and 1.00, and ROC AUCs of 0.89-0.91. SIGNIFICANCE: Lactate levels peak early post-SE, whereas cell counts and ratios do so later. The differing post-event time profiles of lactate levels vs neutrophil count, SIRI, and SII allow incorporation into three separate scores which can assist in differentiating SE from pPNES.

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