Etiology and Mechanisms of Epilepsy

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Questions and Answers

What role do pro-inflammatory cytokines play in the epileptic brain?

They inhibit the activation of glia and neurons.

They facilitate the formation of new synapses.

They enhance neurotransmitter release.

They lead to blood-brain barrier leakage. (correct)

Which signaling pathway is primarily activated in response to inflammatory triggers in the epileptic brain?

Wnt/β-catenin signaling pathway.

IL-1 receptor/toll-like receptor signaling pathway. (correct)

Notch signaling pathway.

MAPK/ERK signaling pathway.

What is a potential consequence of peripheral inflammation in the context of epilepsy?

Inhibition of leukocyte migration.

Enhanced excitability of cortical neurons. (correct)

Decreased glutamate levels in the CNS.

Formation of new vascular pathways.

What initiates the inflammatory cascade linked to seizure events?

Trauma, stroke, or febrile seizures. Signup and view all the answers

Which molecules are most likely released by activated glia and endothelial cells in response to neuroinflammation?

Proinflammatory cytokines and danger signals. Signup and view all the answers

What mechanism primarily distinguishes the balance of excitation and inhibition in seizures and epilepsy?

Altered GABA-ergic activity Signup and view all the answers

Which of the following describes the structural etiology of epilepsy?

Is inferred from neuroimaging that shows abnormalities Signup and view all the answers

Hippocampal sclerosis frequently involves a loss of which type of neurons?

GABA-ergic neurons Signup and view all the answers

What term describes the reorganization phenomena observed in the granule cell layer following hippocampal sclerosis?

Mossy fiber sprouting Signup and view all the answers

Which of the following best represents acquired structural causes of epilepsy?

Hypoxic-ischemic encephalopathy and trauma Signup and view all the answers

What is a potential consequence of elevated granule cell neurogenesis post-epileptogenic insult?

Increased excitatory feedback loops Signup and view all the answers

What type of genetic changes are involved in structural etiologies of epilepsy?

Single-nucleotide mutations and chromosomal abnormalities Signup and view all the answers

Which subregions of the hippocampus primarily exhibit pathological changes in hippocampal sclerosis?

CA1 and CA4 subregions Signup and view all the answers

What is a primary characteristic of genetic generalized epilepsy (GGE)?

It is characterized by generalized seizures involving both sides of the brain Signup and view all the answers

Which gene is associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)?

CHRNA4 Signup and view all the answers

What outcome is associated with the mutation in the CHRNA4 gene in ADNFLE patients?

Reduced AChR function Signup and view all the answers

Which type of epilepsy is often characterized by developmental delay and poor prognosis?

Epileptic encephalopathy Signup and view all the answers

Which gene is linked to benign familial neonatal seizures?

KCNQ2 Signup and view all the answers

What effect does the dysfunction of NaV1.1 channels have in patients with Dravet syndrome?

Decreased excitability of GABA-ergic neurons Signup and view all the answers

Which of the following best describes reactive gliosis?

A downregulation of gap junction connexins and potassium channels Signup and view all the answers

Which deletion on chromosomes is associated with juvenile myoclonic epilepsy?

15q13.3 Signup and view all the answers

Which of these syndromes does not typically involve autonomic seizures?

Juvenile myoclonic epilepsy Signup and view all the answers

What is the main consequence of downregulated aquaporin 4 channels in astrocytes?

Reduced cell permeability to water Signup and view all the answers

How many genes were associated with epilepsy in the study referenced?

977 Signup and view all the answers

What mutation is primarily linked to the familial mesial temporal lobe epilepsy (FMTLE)?

LGI1 gene mutation Signup and view all the answers

What type of epilepsy is primarily characterized by auditory ictal manifestations?

Focal epilepsy Signup and view all the answers

What is the relationship between large recurrent deletions at chromosome 15 and autism?

They are positively correlated with autism and schizophrenia. Signup and view all the answers

Which characteristic is typical of mutations resulting in epileptic encephalopathies?

Refractory seizures with developmental regression Signup and view all the answers

What is the proposed underlying mechanism of the “channelopathy” hypothesis regarding epilepsy syndromes?

Dysregulation of ion channels. Signup and view all the answers

Which specific mutation is exemplified as a Nav-based channelopathy and how does it affect channel activity?

F1449V mutation increases channel activity by enlarging the diameter. Signup and view all the answers

What are common infectious agents that can lead to an infectious etiology of epilepsy?

Cysticercus and human immunodeficiency virus. Signup and view all the answers

What percentage range of survivors of CNS infections may experience unprovoked seizures in developed countries?

6.8 to 8.3% Signup and view all the answers

Which condition is not classified as a metabolic disorder leading to seizures?

Autoimmune encephalitis. Signup and view all the answers

What type of response might lead to persistent neuronal hyperexcitability in the brain?

Proinflammatory cytokine activity. Signup and view all the answers

In the context of immune etiology of epilepsy, which antibody is associated with disrupting synaptic functions?

IgG anti-LGI1. Signup and view all the answers

What characterizes metabolic epilepsies compared to symptomatic seizures?

They are related to known metabolic derangements. Signup and view all the answers

Which of the following does not directly induce seizures but contributes to epileptogenesis?

Acute CNS infection. Signup and view all the answers

Which autoimmune-related mechanism is associated with neuronophagia in epilepsy?

Cytotoxic T cell activity. Signup and view all the answers

What type of treatments are preferred for autoimmune epilepsies?

Immunotherapies. Signup and view all the answers

Which disorder represents an example of a large-molecule metabolic disorder?

Lysosomal storage disorders. Signup and view all the answers

What is a key consideration for classifying epilepsy patients with an infectious etiology?

Evidence of antibody presence. Signup and view all the answers

Study Notes

Etiology of Epilepsy

Epilepsy is a neurological disorder characterized by recurrent seizures, caused by an imbalance between excitation and inhibition in the CNS.
Six etiologic categories:
- Genetic: Inherited or de novo mutations leading to epilepsy syndromes.
- Structural: Abnormal brain structures like hippocampal sclerosis or lesions caused by trauma or infection.
- Metabolic: Disorders affecting neuronal function, such as amino acidopathies, mitochondrial disorders, or leukodystrophies.
- Infectious: CNS infections, like neurocysticercosis or encephalitis, can cause brain damage and epilepsy.
- Immune: Autoimmune encephalitis, where antibodies attack brain components, leading to seizures.
- Unknown: Cause remains unidentified.

Pathophysiological Mechanisms

Hippocampal Sclerosis (HS):
- Common structural cause of epilepsy found mainly in temporal lobe seizures.
- Characterized by neuronal loss, gliosis, and mossy fiber sprouting in the hippocampus.
- Loss of inhibitory GABAergic neurons leads to increased excitability in the hippocampus.
Genetic Epilepsy:
- Over 977 genes associated with epilepsy categorized into 4 groups:
  - Epilepsy genes
  - Neurodevelopment-associated epilepsy genes
  - Epilepsy-related genes
  - Putatively associated genes.
- Classified into three major classes:
  - Genetic Generalized Epilepsy (GGE): Begins in childhood/adolescence, involving both brain hemispheres. Examples: juvenile myoclonic epilepsy, childhood absence epilepsy.
  - Focal Epilepsy (FE): Originates in one hemisphere, involving only a specific brain region. Examples: familial mesial temporal lobe epilepsy, autosomal dominant nocturnal frontal lobe epilepsy, autosomal dominant lateral temporal epilepsy.
  - Epileptic Encephalopathy: Severe, early-onset condition with refractory seizures, developmental delay, and poor prognosis. Examples: Dravet syndrome, benign familial neonatal seizures, benign familial infantile epilepsy.
Ion Channel Disorders:
- KCNQ2: Encodes potassium channels responsible for M current, reducing excitability. Loss of function can lead to increased neuronal hyperexcitability in benign familial neonatal seizures.
- SCN1A: Encodes NaV1.1 sodium channels, predominantly in GABAergic neurons. Mutations disrupt GABAergic neuron function, increasing excitability in Dravet syndrome.
- SCN2A: Encodes sodium channels. Mutations can lead to benign familial infantile epilepsy.
Infectious Epilepsy:
- CNS infections are a leading cause of epilepsy in some regions.
- Different infections cause specific types of brain damage, leading to epilepsy.
- Immune response to infections can also contribute to epilepsy.
Metabolic Epilepsy:
- Seizures are often a core symptom of metabolic disorders.
- Small molecule disorders: Amino acidopathies, organic acidemias, demyelinating conditions, GABA metabolism disorders, mitochondrial disorders.
- Large molecule disorders: Lysosomal storage, peroxisomal and glycosylation disorders, leukodystrophies.
Immune Epilepsy:
- Autoimmune encephalitis: Antibodies attack brain structures, leading to seizures.
- Antibodies against neuronal surface antigens (LGI1, NMDA-R, AMPA, GABA-B, mGluR5).
- Antibodies against neuronal intracellular antigens (GAD65, ANNA-1, Ma).
Neuroinflammation in Epilepsy:
- Both innate and adaptive immune responses contribute to epileptogenesis.
- Proinflammatory cytokines (IL-1β, TNF-α) and danger signals (HMGB1) contribute to BBB leakage and neuronal hyperexcitability.
- Immune response triggered by infections, trauma, febrile seizures, or stroke can lead to epilepsy development.

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Description

This quiz explores the various etiological categories of epilepsy, including genetic, structural, metabolic, infectious, immune, and unknown causes. It also highlights the pathophysiological mechanisms, particularly focusing on hippocampal sclerosis. Test your knowledge on this complex neurological disorder.