Jasper's Basic Mechanisms of the Epilepsies

by Jeffrey L. Noebels, Massimo Avoli, Michael A. Rogawski, Annamaria Vezzani, Antonio V. Delgado-Escueta

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Cod produs/ISBN: 9780197549469

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Autor: Jeffrey L. Noebels, Massimo Avoli, Michael A. Rogawski, Annamaria Vezzani, Antonio V. Delgado-Escueta

Editura: Oxford University Press

Limba: Engleza

Nr. pagini: 1752

Coperta: Hardcover

Dimensiuni: 188 x 274 x 74 mm

An aparitie: 6 iunie 2024

Descriere
Comentarii / Reviews

This is an open access title available under the terms of a CC BY-NC-ND 4.0 International licence. It is free to read at Oxford Academic and offered as a free PDF download from OUP and selected open access locations.Jasper's Basic Mechanisms of the Epilepsies has served as the definitive reference in the field of basic research in the epilepsies for five decades through four well-regarded editions. Since its inception, the book has been an indispensable must-read and belongs in the hands of every experimental epilepsy investigator, practicing epileptologist, clinical neuroscientist, and student for both clinical and basic science reference, doctoral and board exam preparation.This fifth edition is the most ambitious yet and remains the definitive reference in the field, providing encyclopedic and updated coverage of the current understanding of basic research in the epilepsies, while also mapping new research directions for the next decade, and reviewing how molecular laboratory evidence is now being translated into new therapeutics. In 79 chapters, the book considers the role of interactions between neurons, synapses, and glia in the initiation, spread, and arrest of seizures. It examines mechanisms of excitability, synchronization, seizure susceptibility and, ultimately, their contributions to epileptogenesis. It provides a framework for expanding the monogenic epilepsy genome and understanding the complex heredity responsible for common epilepsies. It explores the molecular and cellular disease mechanisms of ion channelopathies, developmental epilepsy genes, and progressive myoclonic epilepsies. It considers newly emerging mechanisms of epilepsy comorbidities. And, for the first time, it describes current efforts to identify biomarkers of disease progression and translate discoveries of epilepsy disease mechanisms into new therapeutic strategies at the frontier of molecular medicine.

Table of Contents:

Section 1 Evolving Concepts
1. The Paroxysmal Depolarizing Shift: The First Cellular Marker of Focal Epileptogenesis
Introduction
Neuronal Networks, Synaptic and Intrinsic Membrane Currents, and PDS Generation
Intrinsic Neuronal Properties and PDS Generation
Role of Dendritic Ca2+ Spikes in PDS Generation
Dendritic Abnormalities in Models of Epilepsy
Concluding Remarks
2. Hippocampal Sclerosis in Temporal Lobe Epilepsy: New Views and Challenges
Introduction
What Are the Patterns of Cell Loss in Hippocampal Sclerosis?
What Neurons Remain and How Are They Altered?
Alterations in Dentate Granule Cells
Alterations in CA2
Alterations in the Subiculum
What Is the Circuitry among Remaining Neurons?
Future Directions
3. Cerebral Cortical Dysplasia or Dysgenesis: Keratan Sulfate Proteoglycan for Fetal Axonal Guidance and Excitatory/Inhibitory Synaptic Targets That Influence Epileptogenesis
Introduction
Developmental Principles of Neuroembryology and Cerebral Dysgenesis
Semantics
Timing during Ontogenesis
Developmental Processes
Neuroblast Maturation
Keratan Sulfate in Fetal Axonal Guidance
Keratan Sulfate at Glutamatergic and GABAergic Synaptic Membranes
Examples of Epileptogenic Dysplasias Influenced by Keratan Sulfate
Polymicrogyria and Schizencephaly
Focal Cortical Dysplasia Type Ia
Examples of Less Epileptogenic or Non-Epileptogenic Disorders Influenced by Keratan Sulfate
Holoprosencephaly, Alobar, and Semi-Lobar Forms
Down Syndrome
Congenital Hydrocephalus
Atrophic Cerebral Cortex
Conclusions
4. mTOR in Acquired and Genetic Models of Epilepsy
The mTOR Signaling Pathway
Clinical Disorders Caused by mTOR Pathway Mutations
mTORopathy Genes
Tuberous Sclerosis Complex and Related Malformations of Cortical Development
Other Syndromes Associated with mTOR
Clinical Treatment of mTORopathies with mTOR Inhibitors
Genetic Models of mTORopathies
An Overview of Models
General Lessons from Animal Models
Molecular Mechanisms of Epileptogenesis due to mTOR Hyperactivation
Ion Channel/Neurotransmitter Regulation
Inflammatory Mechanisms
Metabolism and Autophagy
Morphological and Pathological Effects of mTOR Hyperactivation on Cell Structure
Genetic Effects: Not All mTORopathy Genes Are Equal
mTOR Hyperactivation in Acquired Epilepsy
Challenges and Opportunities
5. Epilepsy Genomics: Disease-Causing Sequence Variants
Introduction
History of Curating the Epilepsy Genome: The First Ten Years of Epilepsy Variants
Benefits of Curating the Epilepsy Genome
Genetic Testing for Epilepsy Variants Improves Diagnosis Treatment and Prognosis
Novel Molecular Concepts of Epileptogenesis in Genetic Epilepsy Syndromes
Epilepsy Genomics: At Last A Road to Halting and Reversing Disease Progression and Possible Cures
Key Elements in the Genetic and Clinical Platform Needed in the Quest to Cure Each Epilepsy
Key Turning Points
Remaining Challenges and Trends in the Next Ten Years
Ex Vivo HSPC Transduction Gene Therapy Can Cure MLD
Genome Editing in Hurler Mucopolysaccharidosis I
Lafora Type Progressive Myoclonic Epilepsy: The Key Elements and Critical Genetic and Clinical Ingredients Necessary for a Quest to Cure Are Already Available
Developmental and Epileptic Encephalopathies
Focal Epilepsies
Vigilance for Unexpected Adverse Effects of ASOs and GRT
Key Social and Ethical Issues in the Quest to Cure the Epilepsies
Section 2 Seizures, Networks, and Systems
6. GABA-Receptor Signaling and Ionic Plasticity in the Generation and Spread of Seizures
Introduction
Network Patterns of Focal Seizures
Interneurons and Epileptiform Events: A Prelude
Focal Seizure Patterns: From Epilepsy Patients to Animal Models In Vivo and In Vitro
Activity-Dependent Ionic Mechanisms Underlying Fast Transformation from Inhibitory to Excitatory GABAR Signaling
Ionic Basis of the Reversal Potential and Driving Force of GABAR-Mediated Currents
High-Frequency Activity of Interneurons Leads to GABAR-Mediated Excitation
Recurrent Epileptiform Events Driven by GABARs in the Absence of Glutamatergic Transmission
Ionic Avalanches in the Generation and Spread of Seizures
Glutamate-Induced Depolarization Enhances Neuronal GABAR-Mediated Cl− Loading
Positive Feedback Loops Involving Ion Shifts and Epileptiform Activity
Cellular and Molecular Sources of K+ Contributing to Activity-Dependent K+ Transients
Chronic Epilepsy and Long-Term Ionic Plasticity
Conclusions
7. Connexins, Pannexins, and Epilepsy
Introduction
Fundamental Biology of Gap Junctions, Connexins, and Pannexins
Gap Junctions and Connexins
Pannexin Channels
Connexin-36 and Pannexin-1 in Neurons
Connexins and Pannexins in Glia
Connexins and Pannexins in the Neuro-Glial-Vascular Unit
Gap Junctions and Epilepsy
Gap Junctional Function and Seizures
Alterations of Gap Junction Coupling in Brain Specimens of Epileptic Patients and Relevant Animal Models
Glial-Based Gap-Junctional-Mediated Extracellular Potassium Homeostasis and Seizures
Pannexins and Seizures
Conclusions
8. Mechanisms Leading to Initiation, Development, and Termination of Focal Seizures
Introduction
Focal Seizure Patterns in Humans
Focal Seizure Patterns in Animal Models
Chronic Animal Models of Focal Epilepsy In Vivo
In Vitro Models of Focal Seizures
Focal Seizure Onset
Progression of a Focal Seizure Discharge
Focal Seizure Termination
The Relationship between Focal Seizure Termination and Postictal Suppression
Conclusions
9. Transition to Seizure from Cellular, Network, and Dynamical Perspectives
Introduction
Seizure Initiation
Cellular and Network Mechanisms of Seizure Initiation
Transition to the Seizure and Preictal State
The Phenomenon of Critical Slowing and Loss of Resilience
Experimental and Empirical Evidence for a Critical Slowing and Loss of Stability in the Epileptic Brain
Empirical Evidence for a Preictal Critical Slowing and Loss of Stability in Humans
Proictal States, Seizure Probability Fluctuation, and Markers of Resilience
Conclusions and Future Research
10. Role of the Subiculum in Focal Epilepsy
Introduction
Subiculum: Anatomy, Local Networks, and Cellular Properties
Anatomy within the Brain and Links with Temporal Lobe Cortices
Subiculum Substructures
Local Neuronal Networks
Neuron Subtypes: Morphology and Electrophysiological Properties
Subiculum Physiology: More Than a Hippocampal Output
Subiculum Local Oscillatory Rhythms
Memory
Spatial Orientation
Stress Response
Role of the Subiculum in Rodent Models of Epilepsy
In Vivo Involvement of the Subiculum in Focal Epilepsy
In Vitro Indication of the Role of the Subiculum in Focal Epilepsy
Role of the Subiculum in Human Focal Epilepsy
Ex Vivo Experimental Data from Human Epileptic Postoperative Tissues
In Vivo Evidence of the Subicular Role in Temporal Lobe Epilepsy
Conclusions
11. Optogenetic Modulation of Focal Seizures
Introduction
Optogenetic Stimulation in In Vitro Models of Epileptiform Synchronization
Optogenetic Stimulation in In Vivo Models of Mesial Temporal Lobe Epilepsy
Acute Seizures
Spontaneous Seizures
Limitations and Clinical Translation of Optogenetic Procedures
Concluding Remarks
12. Balancing Seizure Control with Cognitive Side Effects Using Changes in Theta
Introduction
Network Approach to Epileptic Seizures
Pathological Theta and Relationship to Interneurons Preictally
Pathological Theta-Related Decrease in Neuronal Activity Interictally
Pathological Theta and Reduced Cognitive Performance
Stimulation of Theta Reduces Ictogenesis and Attenuates Cognitive Dysfunction
Impact of an Inclusive Framework on Treatment
13. High-Frequency Oscillations
Definitions
Recording Methods
Separating Physiological from Pathological HFOs
Basic Mechanisms of Generation
Are There Different Mechanisms in Neocortex?
Visual Analysis and Automatic Detection in Clinical Settings
Relationships to the Epileptogenic Zone
Fast Ripples and the Underlying Anatomopathological Entities
Biomarker of Epilepsy
Conclusion
14. Seizures and Sleep
Neuronal Activity during Sleep Oscillations and Epileptic Activity
Bidirectional Interactions between Epileptic Activity and Sleep
Relationship between Epileptic Activity and Sleep
Distribution of Seizures across the Sleep-Wake Cycle
High-Frequency Oscillations are Modulated by Sleep
Sleep-Related Hypermotor Epilepsy as an Example of a Sleep-Related Epilepsy Syndrome
Sleep Microstructure and Epileptic Activity
Link between Sleep Fragmentation and Epileptic Activity
Localizing Value of Sleep for Seizure Focus Identification and Outcome Prediction
Effects of Sleep Homeostasis and Circadian, Multidien, and Circannual Rhythms of Epileptic Activity
Effects of Sleep-Related Epileptic Activity on Sleep Structure and Function
SUDEP, Seizures, and Sleep
Future Directions
15. Cycles in Epilepsy
Introduction
Historical Perspective
Ancient Beliefs
Epilepsy Colonies
The Invention of the EEG
Chronic Recordings in Animals
Methodological Advances
Digital Seizure Diaries
Ambulatory Recording Devices
Computational Advances
Sleep-Wake and Circadian Seizure Cycles
Sleep-Wake Seizure Cycles
Circadian Seizure Cycles
Circadian Seizure Networks
Circadian Seizure Timing in Animal Models
Combined Circadian and Sleep-Wake Modulations
Putative Mechanisms
Multidien Seizure Cycles
Multidien Cycles of Seizures
Multidien Cycles of Epileptic Brain Activity
The Relationship between Seizures and IEA
Free-Running Rhythms
Putative Mechanisms
Circannual Seizure Cycles
Putative Mechanisms
Impact and Future Challenges
16. Human Single-Neuron Recordings in Epilepsy
Introduction
Devices for Recording Single Neurons in Humans
Behnke-Fried Hybrid Depth Electrodes
“Utah” Microelectrode Arrays
Recording Methodology and Technical Considerations
Ethical Considerations
Recording Techniques
Single- and Multi-Unit Discrimination and Analyses
Multi-Unit Activity and Spike-Sorting Single Units
Cell-Type Subclassification
Insights into Ictal Dynamics from Human Single-Neuron Recordings
Spatiotemporal Activity of Human Neurons during Seizures
Tracking Single-Unit Activity during Seizures: Special Considerations
Correlating Single-Neuron Data with Clinical Recordings
Cell-Type-Specific Activity during the Ictal Transition
Translating Animal Studies to Human Single-Unit Recordings
Human Single-Neuron Activity in the Interictal Period
Single-Neuron Neurocognitive Studies in Epilepsy Patients
Future Considerations
17. Role of Ion Concentration Dynamics in Epileptic Seizures
Introduction
Potassium Ions and the K+ Accumulation Hypothesis
Sodium Ions and the Na+/K+ Pump
Chloride
Calcium and Magnesium
Conclusion
18. A Classification of Seizures Based on Dynamics
Introduction
A Taxonomy of Seizure Dynamics
Prelude
Seizures and Bifurcations
The Dynamotypes
Application to Clinical Data
Summary of Observed Dynamotypes
Noise and Complex Dynamics
Coexistence of Dynamotypes
Implications for the Clinic
Conclusion
19. Computational EEG Analysis of Human Epileptogenic Networks
Introduction
Scalp EEG
Intracranial Stereo-EEG
Epileptogenicity Index
Statistical Parametric Mapping of Epileptogenicity Index
Quantified Frequency Analysis Index
Nonlinear Structure Index
High-Frequency Oscillations
Ultra-Long-Term EEG
The Next Ten Years
20. Excitation-Inhibition Balance in Absence Seizure Ictogenesis
Intrinsic Mechanisms
T-Type Ca2+ Channels
HCN Channels
Summary
Network/Synaptic Mechanisms
Summary
SWD Frequency in Animal Models and Humans
Conclusions
21. Cortical and Thalamic PV+ Interneuron Dysfunction in the Pathogenesis of Absence Epilepsy
The Corticothalamic Circuit Involved with Absence Epilepsy
Brief History of Thalamocortical Inhibition in Absence Epilepsy
Evolution of Available Models of Absence Epilepsy
Debate on the Thalamic versus Cortical Onset of Seizures
Genetic and Molecular Insights into Cell-Type-Specific Contributions to Absence Epilepsy
Insights from Drug-Induced Models of Absence Seizures
Insights from Monogenic Models
Further Insight from Inbred Rat Models of Absence Epilepsy
A Working Model of Absence Epileptogenesis
Insights into Network Mechanisms from Recent In Vivo Imaging and Minimally Invasive Manipulation Studies
In Vivo Imaging Studies
Optogenetic/DREADD Studies
New Directions and Treatment Considerations
Conclusions
22. Convergence of Thalamic Mechanisms in Genetic Epilepsies
Introduction
Thalamic Organization and Rhythmogenesis
Structural Elements of Thalamic and Thalamocortical Circuits: From Gross Anatomy to Cell Types
Thalamic Firing
Calcium Channels and Thalamic Firing
Calcium Channels
Spotlight on T-Type Calcium Channels and Burst Firing
Spatial Distribution of T-Type Calcium Channel Subunits
Rhythmogenesis in the Thalamus: Strengths and Weaknesses
Delta Oscillations
Spindle Oscillations
Slow Oscillations
The Thalamus in Absence Epilepsy and Beyond
Insights from Human Genetic Studies of Absence Epilepsy
T-Type Calcium Channels in Genetic Models of Absence Epilepsy
R-Type and P/Q-Type Channels in Genetic Models of Absence Epilepsy
SK Channels and Thalamic Bursting in Dravet Syndrome
The Emerging Role of the Thalamus in Acquired Epilepsies
Conclusions
Section 3 Epileptogenesis: Molecular Mechanism and Treatments
23. The Diverse Roles of Mossy Cells in the Normal Brain, Epileptogenesis, and Chronic Epilepsy
Introduction: Defining Mossy Cells
Thorny Excrescences as a Defining Feature—With a Caveat
Somatic and Dendritic Characteristics
Axon
Neurotransmitter
Cell-Specific Markers of MCs
Electrophysiology
Dorsal and Ventral MCs
Summary
Functional Role of MCs in the Normal DG
Inputs and Outputs of MCs in the Normal DG
Are MCs Excitatory or Inhibitory to GCs?
Plasticity
Hippocampal EEG
Behavior
MCs in Epileptogenesis and Epilepsy
How Studies of MCs in Epilepsy Led to Predictions about Their Role in the Disease
How Studies of the Normal Brain Suggested Additional Ways MCs Influence Epileptogenesis and Epilepsy
Advent of New Methods Using Mice Expressing Cre in MCs and AAV
The Era of Mouse Models of Epilepsy: What It Has Suggested about the Role of MCs
Caveats and Open Questions
24. Temporal Lobe Epileptogenesis: A Focus on Etiology, Neuron Loss, the Latent Period, and Dentate Granule Cell Disinhibition
Introduction
Three Steps to Refractory Temporal Lobe Epilepsy When Prolonged Febrile Seizures Are an Antecedent Factor
Excitotoxicity, Neuron Loss, Disinhibition, and Temporal Lobe Epileptogenesis
The Etiology of Hippocampal Sclerosis
Prolonged Excitation Can Damage the Normal Brain; No Preexisting Defect Is Needed
The Conundrum of Granule Cell Disinhibition without Dentate Basket Cell Degeneration
The “Dormant Basket Cell” Hypothesis
Extending the “Dormant Basket Cell” Hypothesis; Lateral Inhibition in the Normal and Injured Dentate Gyrus
The Latent Period; When after Injury Do Self-Generated Epileptic Seizures Begin?
The Definition of “Epileptogenesis” and the Notion of the “Gestational” Latent Period
Is Neuron Loss Immediately Epileptogenic or Does Epilepsy Require Time, Reactive Gliosis, and Tissue Shrinkage (Sclerosis)?
Is the Latent Period after Nonconvulsive Status Epilepticus a State of Clinically Subtle Seizures or of No Seizures at All?
Is Dentate Gyrus Disinhibition a Directly Epileptogenic Mechanism?
GABAergic Disinhibition Instantly Triggers Acute “Nonepileptic” Seizures, but Could Disinhibition Also Cause Spontaneous “Epileptic” Seizures?
Can GABA Neuron Ablation Cause Prolonged Seizures, Hippocampal Sclerosis, and Epilepsy?
A Unifying Theory of Inherited and Acquired TLE Epileptogenesis
Step One: Initiation of Epileptogenesis
Step Two: Injury, When It Occurs
Step Three: Epileptogenesis; What Is It and When Does It Occur?
Unaddressed and Unanswered Questions
Synopsis
25. Adult Neurogenesis in Epileptogenesis and Comorbidities
Concept of Epileptogenesis
Morphological Changes of Adult-Born Granule Cells in Epilepsy
Molecular Regulators of Aberrant Neurogenesis in Epilepsy
Glial Control of Aberrant Neurogenesis in Epilepsy
Functional Roles of Adult Hippocampal Neurogenesis in Acute and Chronic Phase of Epilepsy
The Role of Normal Newborn Granule Neurons in Generation of Acute Seizures
The Role of Newborn Granule Neurons in Epileptogenesis
Role of Aberrant Neurogenesis in Epilepsy-Associated Comorbidities
Conclusions and Future Perspectives
26. A Crucial Role for Astrocytes in Epileptogenesis: Gap Junctions and Glutamate Receptors
Introduction
Gap Junction Channels
The Astroglial Network and Its Potential Role in Epilepsy
Connexin Expression and Gap Junctional Coupling in Human and Experimental Epilepsy
Impact of Genetic and Pharmacological Modulation of Gap Junctions on Neuronal Excitability and Epileptogenesis
Glutamate Receptors
Glutamate Uptake Dysregulation in Epileptogenesis
Regulation of Metabotropic Glutamate Receptors in Epileptogenesis
Targeting Astrocyte Glutamate Receptors as a Therapy for Refractory Epilepsies
Conclusions
27. Adenosine Kinase: Cytoplasmic and Nuclear Isoforms
Introduction
The Biochemistry of Adenosine: Role in Epilepsy
ADK-S Regulates Extracellular/Synaptic Adenosine
ADK-S Regulates Cytoplasmic Adenosine Levels and Transmethylation Reactions
Nuclear ADK-L Regulates Epigenetic Mechanisms
Adenosine Kinase Hypothesis of Epileptogenesis
Targeting ADK for Epilepsy Treatment
Targeting ADK-S and Elevating Extracellular Adenosine for Seizure Suppression
Targeting ADK-L for Epilepsy Prevention
Conclusions and Therapeutic Perspective
28. Inflammatory Astrocytic TGFβ Signaling Induced by Blood–Brain Barrier Dysfunction Drives Epileptogenesis
Introduction
The Blood–Brain Barrier
Physiological BBB Function
Dysfunctional BBB
BBBD in Epileptogenesis
BBBD Induces Inflammatory TGFβ Signaling
Astrocytic TGFβ Activation Induces Functional Network Modifications, ECM Remodeling, and Pathological Synaptic Plasticity
Translational Impact—Therapeutic Approaches to BBB Dysfunction in Epilepsy
Diagnostics: Detecting BBBD as a Biomarker in Epileptogenesis
BBBD and TGFβR as Targets for Antiepileptogenic Interventions
Conclusions
29. Pericytes and Microglia: Neurovascular and Immune Regulatory Cells in Seizure Disorders
Introduction: Neuro-Glio-Vascular Regulatory Cells in Seizure Networks
What Is a Pericyte?
Perivascular Inflammatory Cell Reactivity during Seizures: Focus on Pericytes
What Are Microglial Cells?
Microglia Surveillance and Neuronal Interactions
Microglial Pro- and Anti-inflammatory Molecular Equilibriums in Experimental Epilepsy
Microglia-Pericytes Perivascular Assembly and Reactivity during Seizures: Experimental and Clinical Evidence
Microglial Profiles in Human Drug-Resistant Epilepsies
Pharmacological Entry Points: Focus on Pericytes and Microglia
Conclusion: Refining Timing and Targets for Pharmacological Interventions
30. Neuroinflammation in Epilepsy: Cellular and Molecular Mechanisms
Introduction
Evidence for Neuroinflammation as a Risk Factor and Intensifying Influence for Epilepsy
Neuroinflammatory Pathways Relevant to Epilepsy
Cytokines
Cytokine Mechanisms Underlying Hyperexcitability and Neurotoxicity
Interleukin-1β
Direct Neuronal Effects Relevant for Seizures
Indirect Effects on Neuronal Excitability Mediated by Glia and Brain Endothelium
Tumor Necrosis Factor
Interaction with Glutamatergic and GABAergic Neurotransmission
Other Neuromodulatory Effects
Effects Mediated by Glial Cells
IL-6
Inflammation-Induced Channelopathies: Impact on Neuronal Excitability and Comorbidities
Lipopolysaccharide
Polyinosinic:Polycytidylic Acid
COX-2 Signaling Pathways
EP1 Receptors Mediate P-glycoprotein Induction in the Blood–Brain Barrier
EP2 Receptors Exacerbate Neuroinflammation
Chemokines
CXCL1
CCL2-CCR2
Complement Pathway
Mechanisms Underlying Complement Effects
Variants in Immune-Related Genes
Conclusions
31. Role of Reactive Oxygen Species in Epilepsy
Introduction
Neuron-Glial Interactions and Their Role in Metabolic Dysfunction Associated with Seizures
Role of Oxidative and Nitrosative Stress in Epilepsy
Redox Homeostasis
Sources of Reactive Oxygen Species Production
Redox-Mediated Cellular Pathway Disruption in Epilepsy
Redox Regulation of Nrf2 in Epilepsy
Biomarkers
Therapeutic Strategies
Conclusions
32. BDNF/TrkB Signaling and Epileptogenesis
Introduction
BDNF and TrkB Biology
BDNF/TrkB Signaling: Epileptogenesis Caused by Trauma
BDNF/TrkB Signaling: Development of Epilepsy Caused by Hypoxic/Ischemic Insults
BDNF/TrkB Signaling: Development of Epilepsy Caused by Seizures
BDNF/TrkB Signaling: A Role in Neuronal Survival
Summary and Perspective
33. Clinical Features and Molecular Mechanisms Underlying Autoantibody-Mediated Seizures
Introduction
Clinical Features of Antibody-Mediated CNS Disorders
NMDA Receptor Antibody Encephalitis
LGI1-Antibody Encephalitis
Other Autoantibody-Mediated Syndromes
An Enduring Tendency to Seizure?
Immunopathogenesis
Neuropathogenesis
Mechanisms of Autoantibodies Directed against Synaptic Receptors
Mechanisms of Antibodies Directed against Other Extracellular Proteins
Conclusions
34. Transcriptomic Alterations in Epileptogenesis: Transcription Factors in the Spotlight
Introduction
Transcriptional Control by FOS and JUN
Transcriptional Control by Early Growth Response Genes
Transcriptional Control by Serum Response Factor
Transcriptional Control by the CREB Signaling Pathway
Transcriptional Control Mechanisms by SP1
Inflammation-Associated Transcriptional Regulation by NF-kB
The JAK/STAT Signaling Cascade
Zn2+-Induced Transcriptional Control
Circadian Clock-Controlled Transcription
NRF2-Mediated Control of Antioxidant Defenses
Transcriptional Repression by RE1-Silencing Transcription Factor
Genetic Variants and Transcriptional Control Mechanisms
Differential Transcriptional Regulation by Alternative Promoters
Summary and Future Course
35. Epigenetics
Introduction
Basic Concepts
Genomes Are Nonrandomly Spatially Organized in 3D
Readers, Writers, and Erasers
Cellular Memory
Key Epigenetic Mechanisms
DNA Methylation
Histone Modifications
Noncoding RNAs
Chromatin Remodeling
On the Epigenetic Origin of Epilepsy
Epigenetics in Epileptic Encephalopathies
DNA Methylation in Focal Epilepsy
Noncoding RNAs in Focal Epilepsy
Histone Methylation in Focal Epilepsy
Histone Acetylation in Focal Epilepsy
A Key Role for Metabolism
Epigenetic Biomarkers in Epilepsy
Outlook
Section 4 Biomarkers of Epileptogenesis
36. EEG Biomarkers of Epileptogenesis
The Electroencephalogram
EEG as a Biomarker for Epileptogenesis
EEG Signatures of Epileptogenesis
Interictal Spikes
High-Frequency Oscillations
Theta-Wave Dynamics
Nonlinear Dynamics
Future Challenges and Potential Mitigation Strategies
Epilepsy Is Not One Disorder
Translating Animal Findings into Clinical Tools
Future Opportunities
More Efficient Clinical Trials
More Effective Treatments
Wearable EEG
Conclusions
37. Blood Biomarkers: Noncoding RNAs and Proteins
Introduction
The Challenge of Diagnosis and Prognosis
What Is a Biomarker and Why Are Circulating Blood Molecules Sought?
Practical Uses of a Circulating Biomarker
Why Should Circulating Biofluids Contain Molecular Biomarkers of Epilepsy?
Other Criteria That Must Be Met for Circulating Molecular Biomarkers
What Type of Molecules Should We Be Looking for?
How Would a Molecular Biomarker Be Used?
miRNAs as Epilepsy Biomarkers
miRNAs—An Overview
miRNAs as Biomarkers
Presence of miRNAs in Blood in Epilepsy—Clinical Findings
Presence of miRNAs in Blood in Epilepsy—Preclinical Model Findings
Practical Issues—How Will miRNA Biomarkers Be Detected?
Other Circulating Noncoding RNAs as Biomarkers of Epilepsy
Circulating Protein Biomarkers of Epilepsy
Circulating Structural Protein Biomarkers of Epilepsy
Circulating Inflammation-Related Protein Biomarkers of Epilepsy
Current Gaps—What We Know We Don’t Know
Summary and Conclusions
38. Behavioral Biomarkers of Epileptogenesis and Epilepsy Severity
Introduction
Neurobehavioral Comorbidities of Epilepsy: Bidirectional Relationship
Shared Neuropathological Mechanisms between Epilepsy and Comorbidities
Behavioral Comorbidities as Biomarkers of Epileptogenesis
Behavioral Comorbidities as Biomarkers of Epilepsy Severity
Conclusions and Future Directions
39. Genetic and Imaging Biomarkers of Epileptogenesis
Introduction
Biomarker Types
Genetic Biomarkers
Genetic Risk Biomarkers
Diagnostic Genetic Biomarkers
Prognostic Genetic Biomarkers
Predictive Genetic Biomarkers
Imaging Biomarkers
Imaging Risk Biomarkers
Human Studies
Diagnostic Imaging Biomarkers
Prognostic Imaging Biomarkers
Predictive Imaging Biomarkers
Conclusions
40. Machine-Learning Approach to Discover Novel Biomarkers for Posttraumatic Epilepsy
Introduction
Materials and Methods
Animals and Experimental Procedures
Data Preprocessing and Feature Engineering
Exploratory Data Analysis and Statistical Hypothesis Testing
Machine Learning
Model Training and Evaluation
Cohort Similarity Assessment
Implementation
Results
Exploratory Data Analysis and Hypothesis Tests
Classification
Subcohort Similarity
Discussion
Section 5 Genes and Network Development
41. Human Epilepsy Gene Discovery: The Next Decade
Genetic Contributions to Epilepsy: Current Knowledge
Genetic Generalized Epilepsy
Focal Epilepsy
Developmental and Epileptic Encephalopathy
What’s Next?
Genome Sequencing
Long-Read Sequencing
Epigenetics
Multiomics
Mosaicism
Oligogenic and Polygenic Risk
The Importance of Collaboration
Summary
42. Functional Exploration of Epilepsy Genes in Patient-Derived Cells
Introduction
Generating iPSCs
Gene Editing of iPSCs
Methods of 2D Neuronal Differentiation
Physiological Assays for hPSC-Derived Neurons
Genetic Epilepsy Modeling Using 2D hPSC Cultures
Dravet Syndrome
STXBP1-Related DEE
Tuberous Sclerosis Complex
Rett Syndrome
Studying SUDEP Using hPSCs
Brain Organoid Models
Modeling Genetic Epilepsies and Their Effects on Cortical Network Function With Brain Organoids
Challenges and Future Directions
Conclusions
43. Brain Mosaicism in Epileptogenic Cortical Malformations
Introduction
Somatic Mutations in mTOR Pathway Genes in Focal Cortical Dysplasia
Brain Somatic Mutations in the N-Glycosylation Pathway in MOGHE
Modeling of Brain Somatic Mutations in Rodents
In Utero Electroporation to Model Somatic Mosaicism
Genetic Hyperactivation of mTOR to Model FCDII
Cellular and Circuit Features Underlying Focal Cortical Dysplasia
Human Studies
Mouse Studies
Disease Modeling Using Human Stem Cell Models
Precision Medicine and Perspectives
44. Sodium Channelopathies in Human and Animal Models of Epilepsy and Neurodevelopmental Disorders
Introduction
SCN1A
SCN1A Variants in Patients with Epilepsy and Neurodevelopmental Disorders
In Vitro Analyses of Nav1.1 Mutant Channels
Nav1.1 Distribution in Brain
SCN1A Animal/Human Cell Models and Disease Pathogenesis
Precision Therapies for Diseases with Nav1.1 Deficiency
SCN2A
SCN2A Variants in Patients with Epilepsy and Neurodevelopmental Disorders
In Vitro Analyses on Nav1.2 Mutant Channels
Nav1.2 Distribution in Brain
SCN2A Animal Models and Disease Pathogenesis
SCN8A
SCN8A Variants in Patients with Epilepsy and Neurodevelopmental Disorders
In Vitro Analyses of Nav1.6 Mutant Channels
Nav1.6 Distribution in Brain
Scn8a Animal Models and Disease Pathogenesis
SCN1B
SCN1B Variants in Patients with Epilepsy and Neurodevelopmental Disorders
In Vitro Analyses of β1 and β1B Wild-Type and Mutant Channels
SCN1B Expression in Brain
SCN1B Animal Models and Disease Cascade
Mechanisms of SUDEP in SCN1B Animal Models
Concluding Remarks
45. Potassium Channels in Genetic Epilepsy: A Functional Perspective
Introduction
Brief Summary of Potassium Channel Classification
Characterization and Classification of Potassium Channel Variants
Types of Potassium Currents in Neurons
IA-Related Channelopathies and Epilepsy (KCND2, KCND3)
ID-Related Channelopathies and Epilepsy (KCNA1, KCNA2)
IK-Related Channelopathies and Epilepsy (KCNB1, KCNC1)
IM and ImAHP-Related Channelopathies and Epilepsy (KCNQ2, KCNQ3, KCNQ5)
IfAHP-Related Channelopathies and Epilepsy (KCNMA1, KCNB2)
Slow Afterhyperpolarization (sAHP)-Related Channelopathies and Epilepsy (KCNT1, KCNT2, KCNQ2, KCNQ3, KCNJ11)
Ikir-Related Channelopathies and Epilepsy (KCNJ10, KCNJ11)
Ileak-Related Channelopathies and Epilepsy (KCNK4)
KCNH1-Related Channelopathies and Epilepsy
New Concepts, Gaps in Our Knowledge, and Novel Approaches
Potassium Channels, Developmental Expression, and Homeostasis
Potassium Channels as Signaling Hubs
Potassium Channels—Cotransporter Complexes
Large-Scale Approaches to Bridge the Gap between Potassium Channel Dysfunction and Seizures
Conclusion
46. High-Voltage-Activated Calcium Channels in Epilepsy: Lessons from Humans and Rodents
Introduction
Voltage-Gated Calcium Channels: An Overview
L-Type VGCCs in Epilepsy
L-Type Ca1.2 Channels: CACNA1C-Associated Disorders in Humans
L-Type Ca1.3 Channels: CACNA1D-Associated Disorders in Humans
Mechanisms of L-Type VGCC-Associated Epilepsy: Dendritic Calcium Transients, Afterhyperpolarization, and Paroxysmal Depolarization Shifts
P/Q-Type Ca2.1 VGCC and Epilepsy
P/Q-Type Ca2.1 Channels: CACNA1A-Associated Disorders in Humans
Physiological Roles of P/Q-Type Ca2.1 Channels
Cellular and Circuit Mechanisms of Cacna1a-Associated Epilepsy
R-Type Ca2.3 Channels: CACNA1E-Associated Epilepsy
CACNA1E-Associated Disorders in Humans
Mechanisms of CACNA1E-Related Epilepsies: Ca2.3-Mediated R-Type Currents Regulate Firing Mode, Plateau Potentials, and Afterhyperpolarization
Conclusions
47. Transcriptional Regulation of Cortical Interneuron Development
Introduction
Subpallial Progenitor Domain Subdivisions
Medial Ganglionic Eminence
Caudal Ganglionic Eminence
Lateral Ganglionic Eminence
Pre-Optic Area
Septum
Regional Specification of IN-Generating Progenitor Zones
MGE Specification and LGE/CGE Identity Repression
Roles of Gsx1 and Gsx2 in Establishing LGE and CGE
Ventral and Rostral Patterning Centers Together Induce Nkx2.1 and the MGE through SHH and FGF8 Signaling
IN Fate Mapping
Identification of MGE-Derived Descendants
Identification of CGE-Derived Descendants
POA-Derived INs
Pallial Progenitors Contribute to Olfactory Bulb IN Diversity
Shh Fate Mapping
Fgf8 and Fgf17 Fate Mapping
Progenitor Zones/Stem Cell Biology in the Ganglionic Eminences
GE Ventricular Zone
GE Subventricular Zones
Mechanisms Proposed for the Generation of SST and PV CIN
Functions of TFs Expressed in Migratory and Post-Migratory Immature INs
Postmitotic Roles of Dlx TFs in IN Survival, Morphogenesis, and Synapse Formation and Function
Nr2f1/Nr2f2 Promotes CGE Fate Specification and MGE Generation of SST CIN
Role of Arx in MGE-Derived IN Migration and PV IN Fate Specification
Opposing Roles of Npas1 and Npas3 in the MGE/CGE-Derived IN Generation and Differentiation
Roles of the Mafb and c-Maf TFs in PV/SST IN Fate Specification, Migration, and Maturation
Activity-Dependent Expression of Satb1 Drives SST CIN Maturation
Mef2c Controls PV CIN Differentiation
Genomic Approaches to Understand Transcriptional Control of IN Development
Forebrain Enhancer Identification and Functional Characterization
Epigenetic Functions of Dlx1/2/5, Gsx2, Lhx6, Nkx2.1, and Otx2 during GE Development
Molecular and Genetic Tools Utilizing Enhancer
Interneuron Classification and New Marker Discovery through Single-Cell RNA Sequencing
Conclusion
48. GABA Receptors, Seizures, and Epilepsy
GABA Receptors in Epilepsy and as Therapeutic Targets
GABAR Structure
GABAR Subtypes
Targeting GABAR Subtypes for Epilepsy Therapy
Tolerance
Treatment of Epilepsy Comorbidities
EtOH-Induced Plasticity of GABAR-Mediated Inhibition at the Gene Expression and Protein Levels
Synaptic Matrix Tethering with Neuroligin-2, Gephyrin, and Collybistin; Role of LHFPL4
Activation of Extrasynaptic δ-GABAR Induces Spike-Wave Seizures
Advances in GABAR Structural Pharmacology Relevant to Pentobarbital, Propofol, and Etomidate
Neuroactive Steroids
Benzodiazepines
Stiripentol
Optogenetics and Chemogenetics
Conclusion and Future Directions
49. Gene–Genome Interactions: Understanding Complex Molecular Traits in Epilepsy
Complex Molecular Networks in Epilepsy
The Growing Epilepsy Genome
Studying the “Multiome”
Single-Cell Analysis
Single-Cell Genomics
Single-Cell Transcriptomics
3D Genome Conformation
Genetics 3.0—Artificial Intelligence and Deep Learning
Better Phenotypes, Faster
A Normative Framework for Complex Data––From Computer Vision to Genomic Sequence
New Phenotypes from Neural Networks
The Next Ten Years
Section 6 Progressive Myoclonus Epilepsies
50. The Neuronal Ceroid Lipofuscinoses
Introduction
Genetics
Epidemiology
Clinical Features
Neuroimaging and EEG Findings
Pathology
Morphology
Molecular Basis of Disease
NCL Proteins
Diagnosis
Laboratory Diagnosis
Prenatal Diagnosis
Care Management
Therapy
Enzyme Replacement Therapy for CLN2 Disease
Experimental Therapies
Conclusions and Future Directions
51. Progressive Myoclonus Epilepsy: Unverricht-Lundborg Disease
Introduction
Clinical Features
Genotype-Phenotype Correlations
Differential Diagnosis
The Cystatin B Gene and Protein
Disease-Associated CSTB Mutations
Cystatin B–Deficient Mouse Model for EPM1
Disease Mechanisms
Regulation of Histone Cleavage, Cell Cycle, and Neurogenesis
GABAergic Signaling and Synapse Physiology
Microglial Dysfunction and Inflammation
Oxidative Stress and Apoptotic Cell Death
52. Strategies on Gene Therapy in Progressive Myoclonus Epilepsies
Introduction
Molecular/Genetic Markers
Gene Therapy with Particularities to Progressive Myoclonus Epilepsy
Unverricht-Lundborg Disease
Lafora Disease
Neuronal Ceroid Lipofuscinoses
Gene Replacement Therapy for NCLs
Conclusion
53. Therapeutic Window for the Treatment of Lafora Disease
Brain Glycogen
Lafora Disease
Pathological Contribution of Glycogen in the LD Brain
Targeting Glycogen to Treat LD
Malin Gene Replacement Therapy to Treat LD
New Challenges and Perspectives Using MGS-Based Suppression or Malin-Restoration Approaches
Conclusions
54. Progressive Myoclonus Epilepsy of Lafora: Treatment with Metformin
Introduction
Proposed Mechanism of Action of Metformin
Inhibition of Mitochondrial Glycerol-3-Phosphate Dehydrogenase
Inhibition of the Lysosomal Proton Pump v-ATPase
Inhibition of Mitochondrial Complex I of the Respiratory Chain and Activation of AMP-Activated Protein Kinase
Metformin Ameliorates Oxidative Stress
Metformin and Neuroinflammation
Metformin as a Neuroprotective Agent in Epilepsy
Metformin in Lafora Disease
Clinical Aspects of Lafora Disease
Animal Models of Lafora Disease
Pharmacological Interventions in Animal Models of Lafora Disease
55. Treating Lafora Disease with an Antibody-Enzyme Fusion
The Problem: Lafora Bodies Drive Epilepsy, Neurodegeneration, and Inflammation
Glycogen
Synthesis and Degradation
Glycogen: Architecture
Glycogen and LBs in the Brain
The Solution: Novel Antibody-Enzyme Fusions Clear LBs
Enzymatic Degradation of LBs
The 3E10 Targeting Platform
VAL-0417 Activity in Cells and Systemic Administration
CNS Administration of VAL-0417
VAL-0417 Ablates Brain LBs
Assessing Brain Function via Metabolomics
Metabolic Profiles to Assess Target Engagement
Brain Glycogen: Glucose and Glucosamine
Next Steps
56. Antisense Oligonucleotide Therapy for Progressive Myoclonus Epilepsies
Progressive Myoclonus Epilepsies—A Brief Overview
Antisense Oligonucleotides and Their Different Modes of Action
ASO Strategies to Treat PME Disorders
ASOs That Modulate Splicing
ASOs Targeting mRNA for Degradation via RNase H
Upregulation of Gene Expression through ASOs
Combination of ASOs with Readthrough Drugs to Target Nonsense Mutations
Conclusions and Future Perspectives
Section 7 Comorbidities of Epileptic Networks
57. Dissecting Epileptic and Cognitive Network Dysfunction in Epilepsy
Introduction
Memory Processes
Measuring the Functional Integrity of Neuronal Networks
The Output: Behavioral Assays
Probing Brain Functions through Single-Unit Activity
Brain Rhythms: Networks in Motion
Functional Mechanisms of Cognitive Impairment in Epilepsy
Epilepsy Models
Neuronal Dynamics and Coding in Epilepsy
Development of Neural Coding and Oscillations
GABAergic Neurons: Coordinators of Complex Systems
Dissecting Epileptic and Cognitive Network Dysfunction
Conclusion and Perspectives
58. Attention-Deficit Disorders and Epilepsy
Epilepsy and ADHD—Clinical Background and Genetics
Epidemiology of Comorbid ADHD and Epilepsy
Genetics of ADHD and Epilepsy
Pathophysiologic Insights from Rodent Models of Epilepsy and ADHD
Testing Attention Deficits in Rodents
Rodent Models of ADHD and Epilepsy/Seizures
Insights into Current and Future Treatment of Attention Disorders in Epilepsy
The Effect of Pharmacotherapy for ADHD on Seizures
Treatment of Concurrent Seizures and Attention Disorders
Future Screening of Antiseizure Drugs
Conclusion
59. What Rodent Models Teach Us about the Association of Autism and Epilepsy
The Association of Autism and Epilepsy
The Role of Animal Models for Studying Autism/Epilepsy Syndromes
Dravet Syndrome: An Ion Channelopathy Causing Refractory Seizures, Cognitive Deficits, and Autism
Calcium Channelopathies
Potassium Channels: Kv4.2 and Kv7.2
CNTNAP2
Do Seizures during Development Cause Impairments in Social Behavior?
Future Directions
60. Artificial Intelligence–Guided Behavioral Phenotyping in Epilepsy
Introduction
Why Do We Care about Behavior in Epilepsy?
What Kind of Behavioral Readout and Expertise Is Required to Phenotype Animal Models of Epilepsies?
Analyzing Behavior Starts with Tracking
Machine Learning and Deep Learning Revolutionized Animal Motion Tracking
With Machine Learning Toward Marker-less Animal Tracking
Basics of Deep Learning
State-of-the-Art Animal Motion Capture with Deep Learning
Quantifying Behavior
Reference Coordinates
Decomposing the Temporal Structure of Behavior
Conclusion and Future Directions for Basic Epilepsy Research
AI-Guided Phenotyping in Epilepsy for Screening at Scale
Linking Brain to Behavior in Epilepsy with AI-Guided Phenotyping
61. Mechanisms of Depression in the Epileptic Brain
Epilepsy and Depression Comorbidity
Phenomenology
Management and Treatment
Depression and Vulnerability to Epilepsy
Epilepsy and Vulnerability to Depression
Mechanisms of Depression
Potential Mechanisms Mediating Comorbid Depression and Epilepsy
Network/Structural Abnormalities
HPA Axis
Altered Neurotransmission
Summary
62. Heterogeneous Mechanisms of Spreading Depolarization and Seizures
Introduction
SD Initiation/Propagation
SD Contributors and Pharmacosensitivity
Roles of Astrocytes
Neuronal Structural Alteration and Injuries in SD
Physiological and Pathological SD Repolarization
Neurovascular Responses in SD and Seizure
Anatomical Susceptibility of SD
SD and Seizure Generation in Acute, Subacute, and Chronic Conditions
Hypoxia/Ischemia/Hypoglycemia
Brain Trauma/Mechanical Stress
Hyperthermia/Fever
SD Generation/Inhibition by Seizure Activities
Clinical Associations between Seizure and SD
SD Recording in Human Epilepsy Patients
Summary
63. Genetic and Cellular Mechanisms Underlying SUDEP Risk
Introduction
The MORTEMUS Study Defines a Common Temporal Framework for Nocturnal Sudden Death
The MORTEMUS Pattern and Timetable Have Mechanistic Implications
Ictal Asystoles, Ictal Apneas, and Postictal Cortical EEG Suppression Are Unreliable SUDEP Biomarkers
Ictal Asystoles
Ictal Apneas
Postictal Generalized EEG Suppression
Atypical SUDEP Patterns: Parallels with SCD, SIDS, and SUDY
Monogenic SUDEP Risk
The Neurocardiac Gene Hypothesis for SUDEP
Potassium Channels
KCNQ1
KCNA1
SENP2
Other
Sodium Channels
SCN1A
SCN1B, 2A, 8A
Ryanodine Receptor
RYR2
SUDEP Gene Diversity
Monogenic Neurorespiratory Syndromes
Gene-Specific Longevity Profiles: SD50
Epistatic Interactions among SUDEP Genes Impact Survival
Conditional Genetic Dissection of Critical SUDEP Pathways
Heart versus Brain
Forebrain versus Brainstem
Excitatory versus Inhibitory Networks
Progressive Central and Cardiac Pathology and SUDEP Risk
Forebrain
Brainstem
Cardiac
Diurnal Rhythm and SUDEP
Brainstem Spreading Depolarization
Brainstem SD Is Linked to Postictal Cardiorespiratory Collapse in Mouse SUDEP Models
In Vivo SD Imaging
Seizure-SD Coupling
The Perilous Genetic Landscape of SUDEP
SUDEP: Gene-Guided Research and Interventions
Circuitry
Modifier Genes
Pharmacology
Gene Therapy
Summary
Section 8 Epilepsy Therapeutics
64. New Models for Assessment of Antiseizure Activity
Introduction
Zebrafish and Other Model Organisms
Drosophila melanogaster Models of Epilepsy
Mouse Models of Genetic Epilepsy and Therapy Development
Theiler’s Murine Encephalomyelitis Virus Mouse Model
Intra-Amygdala Kainate and Intra-Hippocampal Kainate Mouse Models
Induced Pluripotent Stem Cells and the Future
Summary and Conclusions
65. Disease Biology Factors Accounting for Epilepsy Severity: An Updated Conceptual Framework for New Drug Discovery
Call for Paradigm Shift Toward Treating Disease Biology
Drug-Resistant Epilepsy: Time to Break with Traditional Views
Concept of Intrinsic Epilepsy Severity Index
Contribution of the Epileptic Perturbation to the Intrinsic Epilepsy Severity Index
Contribution of Mitigating and Propagating Factors to Intrinsic Epilepsy Severity
Contribution of Recurrent Seizures to Intrinsic Epilepsy Severity
Future Technologies Will Drive Better Understanding of Neurobiological Factors Contributing to the Epilepsy Severity Index
Intrinsic Disease Severity Concept Provides a Holistic View to Drug Resistance
Targeting Intrinsic Epilepsy Severity as an Approach to Achieve Disease Control
Conclusion
66. Animal Models of Pharmacoresistant Epilepsy
Introduction
6 Hz Psychomotor Seizure Model
Lamotrigine-Resistant Kindled Rodent Model
Phenytoin-Resistant Kindled Rat Model
Post–Status Epilepticus Models of Spontaneous Recurrent Seizures
Intra-Amygdala and Intra-Hippocampal Kainate SE
Systemic Kainate- and Pilocarpine-Induced-SE Model
Electrical Stimulation Induced-SE Model
Conclusion
67. Drug Combinations for Antiepileptogenesis
Introduction
Single Drug versus Drug Combinations for Antiepileptogenesis
Efficacy of Drug Combination to Prevent or Modify the Development of Epilepsy
Systematic Evaluation of Drug Combinations for Antiepileptogenesis
Three Drug Combinations Stand Out in Their Antiepileptogenic Efficacy
Potential Mechanisms of Effective Drug Combinations
Effects on Diverse versus Similar Targets for Antiepileptogenesis
Top-Down versus Bottom-Up Target-Based Approaches in Identifying New Antiepileptogenic Therapies
Future Advancements in the Search for Synergistic Antiepileptogenic Drug Combinations
Conclusions and Outlook
68. Prophylaxis of Epileptogenesis in Injury and Genetic Epilepsy Models
Gabapentinoids, Excitatory Synapse Formation, and Antiepileptogenesis
Antiepileptogenesis in a Genetic, Noninjury Model of Epilepsy with Enhanced Excitatory Connectivity
Antiepileptogenesis in Posttraumatic Epilepsy and a Genetic Epilepsy Model with Reduced Inhibitory Interneuronal Function
Unresolved Issues
69. Management of Febrile Status Epilepticus: Past, Present, and Future
Introduction
Outcomes Following Febrile Status Epilepticus: Risk of Epilepsy
Outcomes Following Febrile Status Epilepticus: Cognitive Deficits
Pharmacologic Management of FSE: Past and Present
Neuroimaging after FSE to Predict Clinical Outcomes
Future Treatments to Prevent Long-Term Neurological Changes Following FSE
The Future of FSE and Its Treatment
70. Excitatory Transmission in Status Epilepticus
Introduction
Cholinergic Agents and Glutamate Analogs Induce Status Epilepticus
Glutamate Receptors
Glutamate Receptor Expression in the Brain
Glutamate Receptor Plasticity during SE
Glutamate Receptor Antagonists in the Treatment of SE: Studies in Experimental Animals
Glutamate Excitotoxicity and Cell Death
NMDA Receptors Regulate the Plasticity of GABA-A and AMPA Receptors during SE
NMDA Receptors Regulate Epileptogenesis
Glutamate Receptor Antagonists in the Treatment of SE
Conclusions
71. Ionic Mechanisms of Ictogenic Disinhibition: All GABA Signaling Is Local
Introduction
Physiology
The GABA Reversal Potential
E versus RMP
When Are GABA Currents Excitatory?
Is E a Monolithic Number?
What Determines E?
The Role of Transporters in Chloride Homeostasis
All GABA Signaling Is Local
Cytoplasmic Chloride Microdomains
Role of Transporters in the Chloride Distribution by Displacement Model
Experimental Analysis of Chloride Distribution by Displacement
Pathology
Seizures Associated with Acute Brain Injury
Salt Flux Associated with Neuronal Injury
Other Mechanisms of Salt Influx
Bumetanide Trials for Neonatal Seizures
Human Bumetanide Trials
Temporal Variance in E
Spatial Variance in E
Chronic Epilepsy
72. Epileptogenic Channelopathies Guide Design of NBI-921352, a Highly Isoform-Selective Inhibitor of Na1.6
Introduction
Na Cellular and Subcellular Distribution
Central Nervous System
Peripheral Tissues
Genetic Channelopathies Guide a Preferred Selectivity Profile for Antiseizure Medications
Peripheral Nas
Na1.1
Na1.6
Designing a New Class of Isoform-Selective Sodium Channel Inhibitors
NBI-921352, the First Isoform-Selective Inhibitor of Na1.6
Like Nonselective Na Inhibitor ASMs That Bind the Pore Domain, NBI-921352 Is a State-Dependent Inhibitor
NBI-921352 Inhibits Persistent and Resurgent Currents from Mutant Na1.6 Channels
NBI-921352 Inhibits Electrically Induced Seizures in Scn8aN1768D/+ Mice
Concentration Dependence of NBI-921352 in Comparison to Common ASMs
NBI-921352 Inhibits Electrically Induced Seizures in Wild-Type Mice and Rats
Efficacious Concentrations of NBI-921352 Are Well Separated from Concentrations That Provoke Behavioral Signs
In Vitro Na1.6 Inhibition Predicts In Vivo Efficacy
Conclusions
73. Purinergic Signaling in Epilepsy
Purinergic Signaling in the Brain
ATP Receptors
Adenosine Receptors
Interconversion of Endogenous Purinergic Ligands
Sources and Release
Targeting Purinergic Receptors for Seizure Control and the Treatment of Epilepsy
ATP Release during Seizures and Epilepsy
Targeting Adenosine and P1 Receptors
P2 Receptors
P2 Receptor–Mediated Molecular Mechanisms Contributing to Seizures and Epilepsy
Purines as Diagnostics for Epilepsy
Conclusion
74. Anti-inflammatory Strategies for Disease Modification: Focus on Therapies Close to Clinical Translation
Introduction
The Need for Biomarkers
Anti-inflammatory Treatments in Clinical Practice
Interference with the IL-1beta-IL-1R1 Axis
IL-1beta-IL-1R1 Axis Activation in Epilepsy
Clinical Studies with Anti-IL-1beta Treatments
Arachidonic Acid and COX-2 Signaling Pathways
Timing of Intervention
Disease Modification as Clinical Target
Dexamethasone
Interference with Leukocyte-Endothelial Cell Interaction by Natalizumab
Statins
Combinatorial Anti-inflammatory Therapy
Summary and Conclusions
75. Targeted Augmentation of Nuclear Gene Output (TANGO)
Dravet Syndrome: An Intractable Developmental and Epileptic Encephalopathy
Identification of Nonsense-Mediated Decay, or Poison, Exons, in SCN1A
TANGO: A Therapeutic Strategy That Takes Advantage of NMD Exons
Noncoding Sequences in SCN1A
Other Therapeutic Strategies on the Horizon
SCN8A ASO
Viral Approaches
Rett Syndrome and Angelman Syndrome—Other DEEs with Unique Challenges
Rett Syndrome
Angelman Syndrome
Pros and Cons of Gene Regulation Therapy
Timing of Treatment
Concerns with Viral Vectors
Concerns with ASO Treatment
GOF Variants
Administration of Treatment
Study Planning
Health Economics
Conclusion
76. Gene Therapy for Epilepsy
Introduction
Genetic Epilepsy
Clinical Trials in Genetic Epilepsy
Gene Therapy
Overview of Gene Therapy
Types of Gene Therapy
Viral Vectors
Current Limitations of Gene Therapy
Gene Therapy in Epilepsy
Gene Replacement
Gene Editing and Manipulation
Delivery of Neuroactive Substances
Conclusion
Key Points
77. Gene Therapy for Refractory Epilepsy
Introduction
Viral Vectors
Promoters
Transgenes: Manipulation of the Excitation/Inhibition (E/I) Balance
Regulated Gene Therapy
Upregulation of Endogenous Gene Expression
Neurotrophic Factors
Monogenic Epilepsies
Clinical Translation
Conclusions
78. Cell Therapy for Treatment of Epilepsy
Introduction
The Route to Clinical Studies
Proof-of-Concept Studies
Delivering GABA: Cell Resources and Progress
Initial Studies to Engineer Cells for GABA Release
Animal Sources of Inhibitory Neurons
Human Stem Cells
Clinical Considerations
Functional Properties of IN
Preclinical Studies with Cell Transplantation
Antiseizure Efficacy in Experimental Models of Epilepsy
Functional Integration into the Host Brain
Histology
Other Disease-Modifying Effects
Safety
Where Are We Now?
Conclusion
79. Mechanisms of Ketogenic Diet Action
Introduction
Historical and Clinical Perspectives
Early Animal Models
Mechanistic Studies in the Early Renaissance Era
Ketone Bodies and Glucose
Neurotransmitters and Neuromodulators
Fatty Acids
Mitochondria, Anaplerosis, Oxidative Stress, and Redox Imbalance
Insights at the Close of the First Century of Use
Neuroinflammation
Gut Microbiome
Epigenetic Regulation
Beyond Epilepsy
2021 National Institutes of Health Ketogenic Diet Workshop
Conclusions
Index

An aparitie	6 iunie 2024
Autor	Jeffrey L. Noebels, Massimo Avoli, Michael A. Rogawski, Annamaria Vezzani, Antonio V. Delgado-Escueta
Dimensiuni	188 x 274 x 74 mm
Editura	Oxford University Press
Format	Hardcover
ISBN	9780197549469
Limba	Engleza
Nr pag	1752