Immunity and Inflammation in Epilepsy

Vezzani, Annamaria; Lang, Bethan; Aronica, Eleonora

doi:10.1101/cshperspect.a022699

Cited by 173 publications

(148 citation statements)

References 177 publications

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“…At this point, genetic testing is available for several single genes, as well as complex genetic disorders (see Coulter and Steinhäuser 2015;Vezzani et al 2015). A basic karyotype can be performed to evaluate for a chromosomal anomaly, especially in a patient with dysmorphic features.…”

Section: Genetic Testingmentioning

confidence: 99%

Seizures and Epilepsy: An Overview for Neuroscientists

Stafstrom

Carmant²

2015

Cold Spring Harbor Perspectives in Medicine

562

387

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Epilepsy is one of the most common and disabling neurologic conditions, yet we have an incomplete understanding of the detailed pathophysiology and, thus, treatment rationale for much of epilepsy. This article reviews the clinical aspects of seizures and epilepsy with the goal of providing neuroscientists an introduction to aspects that might be amenable to scientific investigation. Seizures and epilepsy are defined, diagnostic methods are reviewed, various clinical syndromes are discussed, and aspects of differential diagnosis, treatment, and prognosis are considered to enable neuroscientists to formulate basic and translational research questions.T his article provides an overview of seizures and epilepsy for neuroscientists. We focus on broad concepts, rather than clinical details, and raise questions related to mechanisms, epileptogenesis, and therapeutic approaches that might generate interest among basic researchers. Further information about differential diagnosis, drug doses, and clinical management are available from numerous resources (Engel and Pedley 2008;Duchowny et al. 2012;Engel 2013).We first define seizures and epilepsy and summarize their classification, pathophysiology, and genetics. Diagnostic methods are then considered, including the importance of an accurate historical description of an event suspected to be a seizure and the appropriate use of ancillary/confirmative tests, such as electroencephalogram (EEG), neuroimaging, and genetic studies. These modalities enable the clinician to differentiate epilepsy from numerous clinical conditions that mimic seizures, but have a nonepileptic pathophysiological basis. Examples of epilepsy syndromes are then described, selected based on their frequency in the population or because they embody scientific questions that warrant elucidation. Finally, we provide an overview of treatment options and prognosis, including a consideration of conditions that accompany epilepsy (comorbidities) and complicate the daily lives of people with epilepsy. Subsequent articles in this collection explore the scientific basis of many of the clinical concepts introduced here. DEFINITIONS AND EPIDEMIOLOGYA "seizure" is a paroxysmal alteration of neurologic function caused by the excessive, hyper-

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Section: Genetic Testingmentioning

confidence: 99%

Seizures and Epilepsy: An Overview for Neuroscientists

Stafstrom

Carmant²

2015

Cold Spring Harbor Perspectives in Medicine

562

387

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“…Additionally, using chimeric mice and cell ablation techniques, these investigators showed that HCA2 receptors were present on bone marrow-derived monocytes and macrophages that infiltrated the brain, and that the neuroprotective effect of BHB required HCA2 receptor activation on these immune cells, and further, involved prostaglandin synthesis. This study was the first clear demonstration that BHB can exert a profound anti-inflammatory effect, something that has been clearly recognized to reduce seizure activity [60]. …”

Section: Hca2 Receptors and The Nrlp3 Inflammasomementioning

confidence: 99%

Ketone Bodies as Anti-Seizure Agents

Simeone

Rho

2017

Neurochem Res

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There is growing evidence that ketone bodies (KB)—derived from fatty acid oxidation and produced during fasting or consumption of high-fat diets—can exert broad neuroprotective effects. With respect to epilepsy, KB (such as β-hydroxybutyrate or BHB, acetoacetate and acetone) have been shown to block acutely induced and spontaneous recurrent seizures in various animal models. Although the mechanisms underlying the anti-seizure effects of KB have not been fully elucidated, recent experimental studies have invoked ketone-mediated effects on both inhibitory (e.g., GABAergic, purinergic and ATP-sensitive potassium channels) and excitatory (e.g., vesicular glutamate transporters) neurotransmission, as well as mitochondrial targets (e.g., respiratory chain and mitochondrial permeability transition). Moreover, BHB appears to exert both epigenetic (i.e., inhibition of histone deacetylases or HDACs) and anti-inflammatory (i.e., peripheral modulation of hydroxycarboxylic acid receptor and inhibition of the NOD-like receptor protein 3 or NRLP3 inflammasome) activity. While the latter two effects of BHB have yet to be directly linked to ictogenesis and/or epileptogenesis, parallel lines of evidence indicate that HDAC inhibition and a reduction in neuroinflammation alone or collectively can block seizure activity. Nevertheless, the notion that KB are themselves anti-seizure agents requires clinical validation, as prior studies have not revealed a clear correlation between blood ketone levels and seizure control. Notwithstanding this limitation, there is growing evidence that KB are more than just cellular fuels, and can exert profound biochemical, cellular and epigenetic changes favoring an overall attenuation in brain network excitability.

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“…Recent studies have introduced the neurological sequelae, in which pro-inflammatory cytokines with proictogenic properties (such as IL-1β, high-mobility group box 1 [HMGB1], cyclooxygenase-2 [COX-2], prostaglandin E2 [PGE2], IL-6, TNF-α and nicotinamide adenine dinucleotide phosphate-oxidase [NOX2]) play an important role in seizure generation and exacerbation (Vezzani, Auvin, Ravizza & Aronica 2012, Wu & Huang 2015, Dey, Kang, Qiu, Du & Jiang 2016). IL-1β and HMGB1 induce the proinflammatory innate immunity IL-1 receptor type 1 (IL-1R1)/toll-like receptor 4 (TLR4) signaling (Ravizza, Kostoula & Vezzani 2013, Vezzani, Lang & Aronica 2016) leading to neuroinflammation, its perpetuation and thus modulating seizure susceptibility, lowering seizure threshold and epileptogenesis (Maroso, Balosso, Ravizza, Liu, Aronica, Iyer et al 2010, Riazi, Galic & Pittman 2010, Vitaliti, Pavone, Mahmood, Nunnari & Falsaperla 2014, Vezzani, Lang & Aronica 2016). …”

Section: Inflammation and Neuroinflammation: Definitions Targets mentioning

confidence: 99%

Inflammation in Epileptic Encephalopathies

Shandra

Moshé

Galanopoulou

2017

Stress and Inflammation in Disorders

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West syndrome (WS) is an infantile epileptic encephalopathy (EE) that manifests with infantile spasms, hypsarrhythmia (in ~60% of infants) and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12–15%) or of unknown origin. The current treatment options include hormonal treatment [adrenocorticotropic hormone (ACTH) and high dose steroids], the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate pro-inflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of West syndrome? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox-Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?

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Immunity and Inflammation in Epilepsy

Cited by 173 publications

References 177 publications

Seizures and Epilepsy: An Overview for Neuroscientists

Seizures and Epilepsy: An Overview for Neuroscientists

Ketone Bodies as Anti-Seizure Agents

Inflammation in Epileptic Encephalopathies

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