Showing papers by "Josemir W. Sander published in 2022"

The burden of epilepsy and unmet need in people with focal seizures

Abstract: Epilepsy is one of the most common neurological conditions worldwide. As a chronic condition, epilepsy imposes a significant burden on people with epilepsy and society. We aimed to assess the burden and unmet need of individuals with epilepsy and their caregivers, focusing on focal seizures, the main type of seizure in adults and children.

A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

Abstract: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%–20% of people treated with LEV report psychiatric side‐effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV.

Effect of Anti-seizure Medications on Functional Anatomy of Language: A Perspective From Language Functional Magnetic Resonance Imaging

Abstract: Background In epilepsy, cognitive difficulties are common, partly a consequence of anti-seizure medications (ASM), and cognitive side-effects are often considered to be more disabling than seizures and significantly affect quality of life. Functional MRI during verbal fluency tasks demonstrated impaired frontal activation patterns and failed default mode network deactivation in people taking ASM with unfavourable cognitive profiles. The cognitive effect of ASMs given at different dosages in monotherapy, or in different combinations, remains to be determined. Methods Here, we compared the effects of different drug loads on verbal fluency functional MRI (fMRI) in people (i) taking dual therapy of ASMs either considered to be associated with moderate (levetiracetam, lamotrigine, lacosamide, carbamazepine/oxcarbazepine, eslicarbazepine, valproic acid; n = 119, 56 females) or severe (topiramate, zonisamide) side-effects; n = 119, 56 females), (ii) taking moderate ASMs in either mono-, dual- or triple-therapy (60 subjects in each group), or (iii) taking different dosages of ASMs with moderate side-effect profiles (n = 180). “Drug load” was defined as a composite value of numbers and dosages of medications, normalised to account for the highest and lowest dose of each specific prescribed medication. Results In people taking “moderate” ASMs (n = 119), we observed higher verbal-fluency related to left inferior frontal gyrus and right inferior parietal fMRI activations than in people taking “severe” ASMs (n = 119). Irrespective of the specific ASM, people on monotherapy (n = 60), showed greater frontal activations than people taking two (n = 60), or three ASMs (n = 60). People on two ASMs showed less default mode (precuneus) deactivation than those on monotherapy. In people treated with “moderate” ASMs (n = 180), increased drug load correlated with reduced activation of language-related regions and the right piriform cortex. Conclusion Our study delineates the effects of polytherapy and high doses of ASMs when given in monotherapy on the functional anatomy of language. Irrespective of the cognitive profile of individual ASMs, each additional ASM results in additional alterations of cognitive activation patterns. Selection of ASMs with moderate cognitive side effects, and low doses of ASMs when given in polytherapy, could reduce the cognitive effect.

A cluster‐randomized trial comparing home‐based primary health care and usual clinic care for epilepsy in a resource‐limited country

Abstract: To ascertain whether home‐based care with community and primary healthcare workers' support improves adherence to antiseizure medications, seizure control, and quality of life over routine clinic‐based care in community samples of people with epilepsy in a resource‐poor country.

Sudden Death and Cardiac Arrythmia With Lamotrigine

Abstract: Background and Objectives A recent Food and Drug Administration warning concerning an arrhythmogenic potential of lamotrigine created concern in the neurologic community. This warning was based on in vitro studies, but no clinically relevant risk was considered. This rapid systematic review aims to elucidate the risk of lamotrigine on sudden death or ECG abnormalities. Methods We conducted a systematic search of Ovid Medline and Ovid Embase, including randomized controlled trials and observational studies and studies of people with or without epilepsy, with the outcome measures sudden unexpected death in epilepsy (SUDEP) or sudden cardiac death as well as the development or worsening of ECG abnormalities. We evaluated the sudden death definitions used in all included studies, as some could have used unclear or overlapping definitions. We used the American Academy of Neurology risk of bias tool to evaluate the class of evidence and the GRADE approach to evaluate our confidence in the evidence. Results We included 26 studies with 24,962 participants, of whom 2,326 used lamotrigine. Twelve studies showed no significant risk of SUDEP for lamotrigine users. One study reporting on sudden cardiac death and 3 studies with unclear sudden death definitions did not report an elevated risk of death in lamotrigine users compared to controls. In 10 studies reporting on ECG measures, there was no statistically significant increased risk among lamotrigine users except in 2 studies. These 2 studies reported either “slight increases” in PR interval or an increased PQ interval that the primary study authors believed to be related to structural cardiac differences rather than an effect of lamotrigine. One study was rated Class II; all others were Class III or IV. We had very low confidence in the evidence following the GRADE assessment. None of the studies examined the risk of lamotrigine in people with preexisting cardiac conditions. Discussion There is insufficient evidence to support or refute that lamotrigine is associated with sudden death or ECG changes in people with or without epilepsy as compared to antiseizure medication or placebo, due to the high risk of bias in most studies and low precision and inconsistency in the reported results.

Risk of seizure recurrence in people with single seizures and early epilepsy - Model development and external validation.

Abstract: Purpose Following a single seizure, or recent epilepsy diagnosis, it is difficult to balance risk of medication side effects with the potential to prevent seizure recurrence. A prediction model was developed and validated enabling risk stratification which in turn informs treatment decisions and individualises counselling. Methods Data from a randomised controlled trial was used to develop a prediction model for risk of seizure recurrence following a first seizure or diagnosis of epilepsy. Time-to-event data was modelled via Cox's proportional hazards regression. Model validity was assessed via discrimination and calibration using the original dataset and also using three external datasets - National General Practice Survey of Epilepsy (NGPSE), Western Australian first seizure database (WA) and FIRST (Italian dataset of people with first tonic-clonic seizures). Results People with neurological deficit, focal seizures, abnormal EEG, not indicated for CT/MRI scan, or not immediately treated have a significantly higher risk of seizure recurrence. Discrimination was fair and consistent across the datasets (c-statistics: 0.555 (NGPSE); 0.558 (WA); 0.597 (FIRST)). Calibration plots showed good agreement between observed and predicted probabilities in NGPSE at one and three years. Plots for WA and FIRST showed poorer agreement with the model underpredicting risk in WA, and over-predicting in FIRST. This was resolved following model recalibration. Conclusion The model performs well in independent data especially when recalibrated. It should now be used in clinical practice as it can improve the lives of people with single seizures and early epilepsy by enabling targeted treatment choices and more informed patient counselling.

Verbal fluency functional magnetic resonance imaging detects anti‐seizure effects and affective side effects of perampanel in people with focal epilepsy

Abstract: Perampanel, a noncompetitive antagonist of the postsynaptic a‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic (AMPA) receptor, is effective for controlling focal to bilateral tonic–clonic seizures but is also known to increase feelings of anger. Using statistical parametric mapping–derived measures of activation and task‐modulated functional connectivity (psychophysiologic interaction), we investigated 14 people with focal epilepsy who had verbal fluency functional magnetic resonance imaging (fMRI) twice, before and after the add‐on treatment of perampanel. For comparison, we included 28 people with epilepsy, propensity‐matched for clinical characteristics, who had two scans but no change in anti‐seizure medication (ASM) regimen in‐between. After commencing perampanel, individuals had higher task‐related activations in left orbitofrontal cortex (OFC), fewer task‐related activations in the subcortical regions including the left thalamus and left caudate, and lower task‐related thalamocaudate and caudate‐subtantial nigra connectivity. Decreased task‐related connectivity is observed between the left OFC and precuneus and left medial frontal lobe. Our results highlight the brain regions associated with the beneficiary therapeutic effects on focal to bilateral tonic–clonic seizures (thalamus and caudate) but also the undesired affective side effects of perampanel with increased anger and aggression (OFC).

Somatic symptoms and related disorders in a large cohort of people with epilepsy: A cohort study

Abstract: This study was undertaken to characterize somatic symptoms and related disorders (SSD) in epilepsy.

Artificial intelligence and MRI: the source of a new epilepsy taxonomy

Abstract: Artificial intelligence (AI)-based tools are widely employed, but their use for diagnosis and prognosis of neurological disorders is still evolving. We capitalise on a large-scale, cross-sectional structural MRI dataset of 814 people with epilepsy. We use a recently developed machine-learning algorithm, Subtype and Stage Inference (SuStaIn), to develop a novel data-driven disease taxonomy based on distinct patterns of spatiotemporal progression of brain atrophy. We identify two subtypes common to focal and idiopathic generalised epilepsies, characterised by neocortical-driven or basal ganglia-driven progression, and a third subtype, only detected in focal epilepsies, characterised by hippocampus-driven progression. We corroborate external validity via an independent cohort of 254 people and decode associations between progression subtypes and clinical measures of epilepsy severity. Our findings suggest fundamental processes underlying the progression of epilepsy-related brain atrophy. We deliver a novel MRI- and AI-guided epilepsy taxonomy, which could be used for individualised prognostics and targeted therapeutics.

Yield and risk associated with prolonged presurgical video-EEG monitoring: a systematic review

Abstract: Objective Presurgical long-term video-EEG monitoring (LT-VEEG) is an important part of the presurgical evaluation in patients with focal epilepsy. Multiple seizures need to be recorded, often in limited time and with the need to taper anti-seizure medication (ASM). The aim of this study was to systematically study the yield – in terms of success – and risks associated with presurgical LT-VEEG, and to identify all previously reported contributing variables. Methods A systematic review of the databases of PubMed Medline, Embase, Cochrane Central, and the Cochrane Database of Systematic Reviews were searched following the Preferred Reporting Items for Systematic Reviews (PRISMA) guideline. Publications about presurgical LT-VEEG reporting on variables contributing to yield and risk were included. Study characteristics of all included studies were extracted following a standardized template. Within these articles, studies presenting multivariable analyses of factors contributing to the risk of adverse events or the success of LT-VEEG were identified. Results We found 36 articles reporting on LT-VEEG, including 4,703 presurgical patients, both children and adults. Presurgical LT-VEEG monitoring led to an average yield of 85%. Adverse events occurred with an averaged total event rate of 17%, but the type of included events was variable among studies. Factors reported to independently contribute to successful LT-VEEG were: baseline seizure frequency, a shorter interval from the most recent seizure, extratemporal lobe epilepsy, and no requirement for ASM reduction. Factors independently contributing to the occurrence of adverse events were: ASM tapering, a history of status epilepticus, a history of focal to bilateral tonic-clonic seizures, psychiatric comorbidity, and ASM taper rate. Significance This study reveals that the data on factors contributing to yield and risk of adverse events is significant and variable, and often reported with inadequate statistics. Future research is warranted to develop guidelines for ASM withdrawal during presurgical video-EEG monitoring, taking predefined factors for success and risks of adverse events into account.

The need for a pragmatic seizure classification in clinical trials

Abstract: To the Editors: We read with interest the report by Steriade et al.1 of a pragmatic seizure classification based on the International League Against Epilepsy (ILAE) scheme for use in clinical trials. The authors sought to shift the focus to outcome measures that are reliable, interpretable by various stakeholders, and clinically relevant to the development of new antiseizure medications.1 This is a welcome practical proposal and expands on the importance of pragmatic seizure classification. The utility of seizure classification categories is critical. Previously, we have noted the limitations of existing seizure classifications based on semantics, syntax, and semiotics of seizures.2 For example, “dialeptic seizures” are unnecessarily broad. Steriade et al. recommended utilizing “focal aware with or without observable signs” instead of “focal aware with or without motor signs” and not distinguishing focal unaware with or without motor signs. This modified epilepsy classification will place clinically relevant outcomes at the forefront of randomized controlled trials. The precision of seizure classification categories must be addressed. Utilizing precise language when describing seizure types is essential for localizing and managing epilepsy medically or surgically and facilitating communication to specific groups.2,3 Steriade et al.1 recommended avoiding the term “drop attacks,” noting that multiple seizure types produce falls. In contrast, the term “tonic– clonic” has a specific definition and does not refer to all seizures with motor activity.3 When classifying seizures, utilizing additional terms appended to standard categories in an extended classification, such as cognitive effects or automatisms, may render diagnosis more specific.3 Incorporating factors such as comorbidities, the changing demographics of epilepsy, brain age, genetic etiologies, and environmental triggers will provide further granularity.2,4 Additionally, existing and emerging technologies should be used to increase the granularity and utility of epilepsy classification. The first ILAE seizure classification was published in 1981 following the development of video electroencephalography (EEG).5 It was recommended to integrate complementary surrogate markers such as shortand longterm EEG data into seizure types with poor selfreport reliability.1 EEG findings may be useful for all seizure types, rather than simply those with poor selfreport reliability. Technologies likely to impact future classifications include 7T magnetic resonance imaging, genome sequencing, and artificial intelligence.2 Additional factors are essential to consider. Epilepsy classification schema must be sufficiently flexible to allow clinically useful classification in a variety of social, political, economic, and cultural contexts in addition to the clinical trial settings proposed by Steriades et al.2,4 The classification must be helpful for a variety of stakeholders.1 Incorporating the epilepsy classification into a comprehensive teambased approach to clinical trials with the input of clinical and nonclinical stakeholders may enhance the clinical relevance of the outcomes under study.2,4 In aggregate, these modifications will increase the patientcenteredness of research and empower people with epilepsy.