Estimates of epilepsy prevalence, psychiatric co-morbidity and cost

Christensen, Jakob; Dreier, Julie Werenberg; Sun, Yuelian; Linehan, Christine; Tomson, Torbjörn; Marson, Anthony G; Forsgren, Lars; Granbichler, Claudia A.; Trinka, Eugen; Illiescu, Catrinel; Malmgren, Kristina; Kjellberg, Jakob; Ibsen, Rikke; Jennum, Poul

doi:10.1016/j.seizure.2022.06.010

Cited by 14 publications

(9 citation statements)

References 38 publications

(61 reference statements)

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“…Additionally, we expect that almost all patients with epilepsy are treated at hospitals. 31 Patients with stroke are in close contact with the hospital system and, therefore, more likely than people without stroke to be captured and diagnosed with epilepsy. This differential misclassification potentially results in overestimation of the risk of epilepsy after stroke and is a problem relevant in most studies of poststroke epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Stroke and Risk of Epilepsy: A Danish Nationwide Register-Based Study

Ebbesen,

Dreier,

Andersen

et al. 2024

Stroke

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BACKGROUND: Stroke is associated with a risk of epilepsy, but associations with age, sex, stroke type and severity, time trends, and mortality are uncertain. We studied the risk of epilepsy after stroke while accounting for sex, age, stroke types and severity, calendar time, and death. METHODS: This was a prospective nationwide register-based, matched cohort study of patients admitted with a validated first stroke in Denmark from April 1, 2004, to December 16, 2018, excluding those with prior epilepsy. Patients with stroke were matched 10:1 on age, sex, and calendar time with reference people without prior epilepsy or stroke. We estimated the cumulative incidence of an epilepsy diagnosis in the Danish National Patient Registry ( International Classification of Diseases Tenth Revision : G40) with death as a competing risk using competing risk regression and estimated adjusted hazard ratios by Cox regression models. RESULTS: We identified 101 034 patients with stroke (46.5% female; mean age, 70.4 years) who survived 14 days after stroke along with 1 010 333 matched reference people. Two years after the stroke, the cumulative incidence of epilepsy was 3.0% (95% CI, 2.9–3.2) after ischemic stroke and 8.6% (95% CI, 8.0–9.2) after intracerebral hemorrhage versus 0.7% (95% CI, 0.7–0.7) in the matched references. Compared with the reference population, the 2-year hazard ratio of epilepsy was 21.7 (95% CI, 20.3–23.2) after ischemic stroke and 61.3 (95% CI, 51.1–73.4) after intracerebral hemorrhage. The risk of epilepsy increased with stroke severity; the 2-year cumulative incidence of epilepsy was 10.5% (95% CI, 9.5–11.4) for very severe ischemic stroke and 13.1% (95% CI, 11.1–15.1) after very severe intracerebral hemorrhage. CONCLUSIONS: In this population-based study of patients with validated stroke, the absolute and relative risk estimates of poststroke epilepsy were lower compared with previous studies. Reasons for the lower risk estimates include accounting for the high mortality associated with stroke, which had a significant impact on risk especially for severe stroke.

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Section: Discussionmentioning

confidence: 99%

Stroke and Risk of Epilepsy: A Danish Nationwide Register-Based Study

Ebbesen,

Dreier,

Andersen

et al. 2024

Stroke

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“…[1][2][3][4] Although many patients achieve seizure freedom with existing antiseizure medications (ASMs), most require long-term (often lifelong) treatment, adding to the serious impact of chronic epilepsy on their physical and psychosocial wellbeing, and also resulting in a substantial burden on the healthcare system. 2,[5][6][7][8] There is a pressing need for new therapies that can prevent the development of chronic epilepsy or modify its course after it presents. 2,9,10 Stroke accounts for up to 11% of all epilepsy cases and is the leading cause in the elderly population, responsible for approximately 50% of newly diagnosed epilepsy cases in those aged >60 years.…”

Section: Introductionmentioning

confidence: 99%

“…Available drug therapies suppress seizures, targeting the symptoms rather than causes of epilepsy, and none modifies the course or prevents the onset of the disease 1–4 . Although many patients achieve seizure freedom with existing antiseizure medications (ASMs), most require long‐term (often lifelong) treatment, adding to the serious impact of chronic epilepsy on their physical and psychosocial wellbeing, and also resulting in a substantial burden on the healthcare system 2,5–8 . There is a pressing need for new therapies that can prevent the development of chronic epilepsy or modify its course after it presents 2,9,10 …”

Section: Introductionmentioning

confidence: 99%

Antiepileptogenesis after stroke—trials and tribulations: Methodological challenges and recruitment results of a Phase II study with eslicarbazepine acetate

et al. 2023

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There is currently no evidence to support the use of antiseizure medications to prevent unprovoked seizures following stroke. Experimental animal models suggested a potential antiepileptogenic effect for eslicarbazepine acetate (ESL), and a Phase II, multicenter, randomized, double‐blind, placebo‐controlled study was designed to test this hypothesis and assess whether ESL treatment for 1 month can prevent unprovoked seizures following stroke. We outline the design and status of this antiepileptogenesis study, and discuss the challenges encountered in its execution to date. Patients at high risk of developing unprovoked seizures after acute intracerebral hemorrhage or acute ischemic stroke were randomized to receive ESL 800 mg/d or placebo, initiated within 120 hours after primary stroke occurrence. Treatment continued until Day 30, then tapered off. Patients could receive all necessary therapies for stroke treatment according to clinical practice guidelines and standard of care, and are being followed up for 18 months. The primary efficacy endpoint is the occurrence of a first unprovoked seizure within 6 months after randomization (“failure rate”). Secondary efficacy assessments include the occurrence of a first unprovoked seizure during 12 months after randomization and during the entire study; functional outcomes (Barthel Index original 10‐item version; National Institutes of Health Stroke Scale); post‐stroke depression (Patient Health Questionnaire‐9; PHQ‐9); and overall survival. Safety assessments include the evaluation of treatment‐emergent adverse events; laboratory parameters; vital signs; electrocardiogram; suicidal ideation and behavior (PHQ‐9 question 9). The protocol aimed to randomize approximately 200 patients (1:1), recruited from 21 sites in seven European countries and Israel. Despite the challenges encountered, particularly during the COVID‐19 pandemic, the study progressed and included a remarkable number of patients, with 129 screened and 125 randomized. Recruitment was stopped after 30 months, the first patient entered in May 2019, and the study is ongoing and following up on patients according to the Clinical Trial Protocol.

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Section: Introductionmentioning

confidence: 99%

“…Epilepsy is a neurological disorder characterized by recurrent and spontaneous seizures (Christensen et al, 2023); when left uncontrolled, it can lead to neuronal damage (Sun et al, 2022), cognitive deficits (Chai et al, 2023), and even sudden unexpected death (SUDEP) (Whitney et al, 2023). A prominent feature of epileptic seizures is hyperexcitability and excessive abnormal neural activity, which in some cases could be attributed to genetic changes in ion channels (Oyrer et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation

Que,

Olivero-Acosta,

Chen

et al. 2023

Preprint

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Neuronal hyperexcitability is a hallmark of seizures. It has been recently shown in rodent models of seizures that microglia, the brain’s resident immune cells, can respond to and modulate neuronal excitability. However, how human microglia interacts with human neurons to regulate hyperexcitability mediated by epilepsy-causing genetic mutation found in human patients remains unknown. TheSCN2Agenetic locus is responsible for encoding the voltage-gated sodium channel Nav1.2, recognized as one of the leading contributors to monogenic epilepsies. Previously, we demonstrated that the recurring Nav1.2-L1342P mutation identified in patients with epilepsy leads to hyperexcitability in a hiPSC-derived cortical neuron model from a male donor. While microglia play an important role in the brain, these cells originate from a different lineage (yolk sac) and thus are not naturally present in hiPSCs-derived neuronal culture. To study how microglia respond to diseased neurons and influence neuronal excitability, we established a co-culture model comprising hiPSC-derived neurons and microglia. We found that microglia display altered morphology with increased branch length and enhanced calcium signal when co-cultured with neurons carrying the Nav1.2-L1342P mutation. Moreover, the presence of microglia significantly lowers the action potential firing of neurons carrying the mutation. Interestingly, we further demonstrated that the current density of sodium channels in neurons carrying the epilepsy-associated mutation was reduced in the presence of microglia. Taken together, our work reveals a critical role of human iPSCs-derived microglia in sensing and dampening hyperexcitability mediated by an epilepsy-causing mutation present in human neurons, highlighting the importance of neuron-microglia interactions in human pathophysiology.Significance StatementSeizure studies in mouse models have highlighted the role of microglia in modulating neuronal activity, particularly in the promotion or suppression of seizures. However, a gap persists in comprehending the influence of human microglia on intrinsically hyperexcitable neurons carrying epilepsy-associated pathogenic mutations. This research addresses this gap by investigating human microglia and their impact on neuronal functions. Our findings demonstrate that microglia exhibit dynamic morphological alterations and calcium fluctuations in the presence of neurons carrying an epilepsy-associated SCN2A mutation. Furthermore, microglia suppressed the excitability of diseased hyperexcitable neurons, suggesting a potential beneficial role. This study underscores the role of microglia in the regulation of abnormal neuronal activity, providing insights into therapeutic strategies for neurological conditions associated with hyperexcitability.

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Estimates of epilepsy prevalence, psychiatric co-morbidity and cost

Cited by 14 publications

References 38 publications

Stroke and Risk of Epilepsy: A Danish Nationwide Register-Based Study

Stroke and Risk of Epilepsy: A Danish Nationwide Register-Based Study

Antiepileptogenesis after stroke—trials and tribulations: Methodological challenges and recruitment results of a Phase II study with eslicarbazepine acetate

Human iPSC-derived microglia sense and dampen hyperexcitability of cortical neurons carrying the epilepsy-associated SCN2A-L1342P mutation

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