Seizures and Epilepsy Overview

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Questions and Answers

What is a significant risk factor associated with epilepsy in young adults?

History of head trauma

Frequent medication changes

Lack of neurological symptoms

Young adult age (20-40 years) (correct)

Which of the following is NOT a consequence of seizures on neurotransmitter function in the short term?

Massive release of neurotransmitters

Increased neurotransmitter receptor density (correct)

Changes in receptor sensitivity

Transient energy depletion

Which short-term effect of seizures is related to ionic shifts?

Increased metabolic demand

Neurotransmitter release

Risk of neuronal injury

Ionic imbalance (correct)

What long-term structural change in the brain is associated with frequent seizures?

Hippocampal sclerosis Signup and view all the answers

Chronic epilepsy can lead to which of the following long-term effects?

Brain atrophy Signup and view all the answers

Which of the following statements about gliosis is true?

It leads to scar tissue formation. Signup and view all the answers

Which of these factors contributes to neurocognitive impairment in epilepsy?

Regular seizures without medication Signup and view all the answers

What can commonly occur due to frequent seizures that disrupt the blood-brain barrier?

Increased inflammation in the brain Signup and view all the answers

What is often a structural cause of focal seizures?

A localized organic lesion in the brain Signup and view all the answers

What pathological finding is most common in temporal lobe epilepsy?

Hippocampal sclerosis Signup and view all the answers

Which neurotransmitter is associated with the inhibitory function that can be disrupted during seizures?

GABA Signup and view all the answers

What effect do extrinsic or intrinsic factors have during seizures?

They disrupt the balance of excitation and inhibition Signup and view all the answers

What is hypersynchronization in the context of seizure activity?

A discrete region of cortex generating excessive synchronous discharges Signup and view all the answers

What can cause damage to GABAergic neurons, leading to seizure activity?

Exposure to neurotoxins or drugs Signup and view all the answers

How does scar tissue in the brain influence seizure activity?

It makes surrounding neurons more excitable Signup and view all the answers

What phenomenon occurs when seizure activity spreads within the brain?

Seizure propagation Signup and view all the answers

What characterizes a seizure based on its definition?

An abnormal excessive or hyper-synchronous neuronal activity in the brain Signup and view all the answers

Which of the following best describes partial seizures?

Seizures that originate in networks limited to one hemisphere Signup and view all the answers

What is a common clinical feature of seizures?

Disordered thought and temporary confusion Signup and view all the answers

How can EEG be used in the context of epilepsy?

To differentiate between common seizure types Signup and view all the answers

What mechanism do anti-epileptic drugs primarily target?

Modulating voltage-gated sodium, calcium, and potassium channels Signup and view all the answers

Which of these seizure types occurs with motor symptoms such as jerking of a limb?

Partial seizures with motor symptoms Signup and view all the answers

What is NOT a focus when outlining the pharmacological treatment of epilepsy?

Reinforcing immune responses in the body Signup and view all the answers

Which aspect of brain activity is likely disrupted during a seizure?

Normal neuronal communication and synchronization Signup and view all the answers

What is the effect of activating the GABA system?

Sleep and drowsiness Signup and view all the answers

What effect can inhibition of the GABA system lead to?

Increased risk of seizures Signup and view all the answers

What role do benzodiazepines play in relation to GABA?

They are channel modulators that enhance GABA activity Signup and view all the answers

What is a common adverse effect associated with the use of benzodiazepines?

Withdrawal syndrome upon abrupt cessation Signup and view all the answers

How do benzodiazepines compare to other antiepileptic drugs in treating status epilepticus?

They act very rapidly compared to other medications Signup and view all the answers

What is the initial outcome of increasing GABA activity?

Activation of GABA receptors leading to Cl− influx Signup and view all the answers

What could happen if sedation from benzodiazepines becomes pronounced?

Exacerbation of seizure activity upon abrupt withdrawal Signup and view all the answers

Where is diazepam often administered for acute seizures, particularly in children?

Rectally Signup and view all the answers

What effect does increasing potassium conductance have on neurons?

Hyperpolarizes them, making them less excitable Signup and view all the answers

What is a primary use of Retigabine?

As an adjunctive treatment for focal seizures Signup and view all the answers

In what way does Retigabine activate potassium channels?

It interferes with the voltage sensor of potassium channels Signup and view all the answers

What is a known side effect of Retigabine?

Cognitive impairment Signup and view all the answers

How do Gabapentin and Pregabalin affect voltage-gated calcium channels?

They partially block voltage-gated calcium channels Signup and view all the answers

Which of the following seizures can Lamotrigine treat?

Partial, absence, and myoclonic seizures Signup and view all the answers

What mechanism does Lamotrigine primarily utilize?

Prolongs deactivation of voltage-gated sodium channels Signup and view all the answers

Which statement about Pregabalin is correct?

Is mainly used for partial seizures Signup and view all the answers

What is a characteristic of high voltage activated calcium channels?

They regulate neurotransmitter release by controlling calcium entry Signup and view all the answers

Why was Retigabine withdrawn from use?

Because of cognitive side effects Signup and view all the answers

What is the primary mechanism of action of vigabatrin?

Inhibition of GABA transaminase Signup and view all the answers

Which of the following side effects is associated with long-term use of vigabatrin?

Peripheral visual field defects Signup and view all the answers

Which condition is NOT treated by clonazepam?

Tonic-clonic seizures Signup and view all the answers

What type of seizures is topiramate primarily used to treat?

Both B and C Signup and view all the answers

Which drug acts primarily by enhancing the action of GABA?

Diazepam Signup and view all the answers

Which of the following agents is a GABA reuptake inhibitor?

Tiagabine Signup and view all the answers

Which drug is indicated for status epilepticus?

Clonazepam Signup and view all the answers

What is a notable characteristic of topiramate compared to phenytoin?

It blocks sodium and calcium channels Signup and view all the answers

What is the primary mechanism by which drugs like carbamazepine and phenytoin exert their effects in epilepsy treatment?

Inhibiting voltage-dependent sodium channels Signup and view all the answers

Which characteristic of sodium channel blockers is crucial for their efficacy in treating seizures?

They preferentially block channels during high-frequency neuronal firing. Signup and view all the answers

Why is it undesirable to use a general voltage-gated sodium channel blocker in epilepsy treatment?

It would indiscriminately affect both high-frequency and low-frequency firing. Signup and view all the answers

Which of these drugs primarily utilizes an action on sodium channels to control seizures?

Lamotrigine Signup and view all the answers

In the context of antiepileptic drugs, what is a significant consequence of blocking sodium channels?

Reduced number of functional channels available for action potentials Signup and view all the answers

Which of the following antiepileptic drugs is effective against both partial and generalized seizures, including absence seizures?

Valproate Signup and view all the answers

What is one of the common adverse effects associated with long-term use of phenytoin?

Peripheral neuropathy Signup and view all the answers

Which mechanism primarily describes how carbamazepine functions in the treatment of epilepsy?

Stabilizing deactivated sodium channels Signup and view all the answers

Which of the following antiepileptic drugs is recognized as non-sedative within its usual therapeutic range?

Carbamazepine Signup and view all the answers

Which adverse effect is specifically associated with valproate when used during pregnancy?

Neural tube defects Signup and view all the answers

Which antiepileptic drug's main feature is that it acts as a GABA receptor agonist while also affecting sodium channels?

Carbamazepine Signup and view all the answers

What differentiates primidone from phenytoin in terms of efficacy?

Primidone leads to sedation unlike phenytoin Signup and view all the answers

Which adverse effect is NOT commonly associated with long-term phenytoin use?

Hypertension Signup and view all the answers

Which antiepileptic drugs are most difficult to withdraw from?

Barbiturates and Benzodiazepines Signup and view all the answers

What is a common outcome when drugs used for partial or generalized tonic-clonic seizures are discontinued?

Increased risk of seizures during withdrawal Signup and view all the answers

What is the recommended practice for a patient who has been seizure-free for 3 or 4 years?

Gradual discontinuance trial is often warranted Signup and view all the answers

Which teratogenic effect is specifically associated with Valproate?

Neural tube defects Signup and view all the answers

What must be considered regarding the exposure to antiepileptic drugs (AEDs) during perinatal periods?

There's a risk of major congenital malformations associated with AED exposure Signup and view all the answers

How long may withdrawal from certain drugs needed for seizures take?

Weeks or months with gradual dosage decrements Signup and view all the answers

What phenomenon is associated with the gradual discontinuance of antiepileptic drugs?

Monitoring for the occurrence of seizures Signup and view all the answers

Which malformation is linked to Carbamazepine use?

Spina bifida and hypospadias Signup and view all the answers

What is a significant characteristic of Perampanel in relation to AMPA receptors?

It is a potent noncompetitive antagonist of AMPA receptors. Signup and view all the answers

Which condition is notably included in the black box warning for Perampanel?

Serious psychiatric and behavioral changes. Signup and view all the answers

What effect does Levetiracetam have in neuronal functioning?

It reduces neuronal hyperactivity. Signup and view all the answers

Which mechanism does Levetiracetam utilize that remains not fully understood?

Modulating SV2A proteins. Signup and view all the answers

Which of the following statements about Brivaracetam is accurate?

It is similar in action to Levetiracetam. Signup and view all the answers

Which of the following describes an advantage of Levetiracetam's pharmacological profile?

Minimal risk of serious side effects. Signup and view all the answers

Which statement correctly identifies a characteristic of Levetiracetam in regards to its therapeutic use?

It can be used as both monotherapy and adjunctive therapy. Signup and view all the answers

What type of drug interaction risk is associated with Levetiracetam?

Low risk of significant interactions. Signup and view all the answers

What characterizes status epilepticus?

Prolonged seizures lasting longer than 5 minutes Signup and view all the answers

How does the postictal phase typically manifest?

Physical and mental exhaustion Signup and view all the answers

What is the incidence rate of SUDEP in individuals with epilepsy?

1 in 1,000 Signup and view all the answers

Which consequence is NOT associated with prolonged seizures in status epilepticus?

Increased energy levels Signup and view all the answers

What is a typical neurological symptom experienced during the postictal phase?

Agitation or irritability Signup and view all the answers

What best describes the nature of SUDEP?

Sudden death with no toxicological or anatomical cause Signup and view all the answers

Which factor contributes to the morbidity associated with status epilepticus?

Failure of normal seizure self-termination mechanisms Signup and view all the answers

What common cognitive effect may follow a seizure event?

Confusion and disorientation Signup and view all the answers

What is one of the primary therapeutic uses of phenobarbital?

Partial seizures Signup and view all the answers

Which enzyme acts as a coenzyme in the synthesis of GABA?

Glutamic acid decarboxylase (GAD) Signup and view all the answers

What is the mechanism of action for tiagabine as it relates to GABA levels?

Inhibition of GAT-1 Signup and view all the answers

What is the role of GABA transaminase (GABA-T) in the context of GABA function?

Metabolically inactivate GABA Signup and view all the answers

Which voltage-gated channels are affected by barbiturates aside from GABAA receptors?

Voltage gated calcium channels Signup and view all the answers

Which of the following best characterizes the reuptake of GABA into presynaptic terminals?

Reuptake involves specific transporters that promote GABA reabsorption. Signup and view all the answers

What is the effect of long-term glutamate conversion in glial cells?

Conversion into glutamine for recycling Signup and view all the answers

Which statement accurately reflects the pharmacological action of barbiturates?

Barbiturates act on multiple neuronal systems with diverse effects. Signup and view all the answers

Study Notes

Seizures and Epilepsy: Pathophysiological and Pharmacological Perspectives

Human brain has approximately 90 billion neurons.
A typical neocortical neuron has about 7,000 synapses.
The total number of synapses in the human brain is approximately 0.15 x 10^15, or 0.15 quadrillion.
Cultured cortical neurons with a fluorescent reporter of Ca2+ are shown in a video at the provided link.

Learning Objectives

Describe the pathophysiological processes that contribute to hyperexcitability in the brain.
Outline the classification of seizure types.
Explain how EEG can be used to differentiate common seizure types and how other investigations are used.
Describe the mechanism of action and adverse effects of drugs used in the treatment of epilepsy.
Describe the principles, risks, and considerations underlying other therapies employed in the treatment of epilepsy.
List the antiepileptic drugs that are safe in pregnancy.

Seizure

Clinical features depend on location and extent of affected neurons.
Seizures can range from disordered thought to temporary confusion, staring spells, clonic-tonic convulsions, and loss of consciousness.
A seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or hyper-synchronous neuronal activity in the brain (ILAE).

Important Definitions

Seizure: Characterized by uncontrolled excessive activity of either part or all of the central nervous system.
Epilepsy: A tendency toward recurrent seizures, unprovoked by any systemic or acute neurologic insults.
Epileptogenesis: A sequence of events that converts a normal neuronal network into a hyperexcitable network.

Classification of Seizure Types

Focal Onset: Seizure originates in networks limited to one hemisphere (partial).
Generalized Onset: Seizure begins simultaneously in both hemispheres (bilaterally distributed networks).
Unknown Onset: The onset of the seizure is unclear.
Subtypes include aware/impaired awareness, motor/nonmotor onset, focal to bilateral tonic-clinic.
Types of seizures include tonic, clonic, tonic-clonic, myoclonic, and atonic seizures.

Post-Ictal Phase

Symptoms include altered consciousness (confusion, disorientation), neurological symptoms (headache, aphasia, motor deficits, visual disturbances), mood and behavioral changes (agitation, irritability, feelings of depression or anxiety), general fatigue, and duration (lasting from several minutes to hours).

Status Epilepticus

A condition characterized by continuous seizures that persist for more than 5 minutes without recovery or the occurrence of repeated seizures without the person regaining consciousness between seizures.
Symptoms include severe, continuous seizures without recovery (more than 5 minutes), normal seizure self-termination mechanisms failure.
Medical emergency requiring aggressive treatment with anticonvulsants.
Significant morbidity and mortality due to excitotoxicity and brain damage.

SUDEP - Sudden Unexpected Death in Epilepsy

Sudden, unexpected, non-traumatic, and non-drowning death in a person with epilepsy, with no toxicological or anatomical cause of death found.
Affects approximately 1 in 1,000 people with epilepsy annually.
Risk factors include poorly controlled seizures (especially generalized tonic-clonic), high seizure frequency, young adult age (20-40 years), early onset of epilepsy, duration of epilepsy, and medication non-adherence.

Effects of Seizures on the Brain (Short Term)

Increased release of neurotransmitters.
Increased metabolic demand for oxygen and glucose.
Ionic imbalance (shifts).
Risk of neuronal injury.

Effects of Seizures on the Brain (Long Term)

Epileptogenesis (changes in brain structure and function).
Hippocampal sclerosis (loss of neurons).
Neurocognitive impairment.
Brain atrophy.

Effects of Seizures on the Brain (Molecular and Cellular Changes)

Gliosis (increased astrocytes).
Inflammatory responses.
Changes in gene expression.
Blood-brain barrier disruption.

Seizures Can Have Multiple Causes

Acute electrolyte disorders
Meningitis
Hypoglycemia
Drugs

Epilepsy

Chronic condition involving recurrent seizures.
Not a single disease; symptoms and pathophysiological mechanisms are heterogeneous.
Caused by various factors, including trauma, infection, tumors, and degenerative changes. (Idiopathic epilepsy)

Classification of Epilepsy

Includes mutations in sodium channel subunits, calcium channel subunits, GABA channel subunits.
Includes Genetic linkage and Non-receptor-based mutations.

Epileptogenesis - Terms and Definitions

Epileptogenic: Drugs or pathological factors increasing neuronal excitation or impairing inhibition tend to be epileptogenic, causing epilepsy development.
Epileptogenesis: The process by which normal brain development leads to epilepsy.
Hyperexcitability: A feature of epileptogenesis, where the likelihood of activating neural networks increases.

Epilepsy vs. Seizures

Recognising the distinction between seizures and epilepsy is essential.
Epilepsy requires chronic treatment, and isolated seizures do not.

Types of Neuron Affected in Epilepsy, Context

Projection neurons (e.g., pyramidal neurons) projecting information to distant brain regions and forming excitatory synapses on postsynaptic neurons.
Interneurons (e.g., basket cells) locally influencing activity of nearby neurons and forming inhibitory synapses.
Both types use glutamate (projection) and GABA (interneurons) as neurotransmitters.

Signal Isolation Through Surround Inhibition

Discrete signals, maintained within limited neuronal circuits within a defined area.
Neural networks, ensuring a signal specificity.
Surround inhibition, restricting action potentials to adjacent neurons.

Hyper-excitability

A hyper-excitable state can result from drugs or toxins that increase excitatory synaptic neurotransmission or decrease inhibitory neurotransmission.
It can also result from altered structure of voltage-gated ion channels due to genetic mutations (e.g., Dravet syndrome), prolonged opening of specific ion channels by drugs, or toxins, like aconitine.

Cellular Causes of Focal (Partial) Seizures

A decrease in GABA-mediated inhibition can promote the synchronisation of a seizure focus.
Possible causes include congenitally deranged local circuitry, degeneration of GABAergic neurons, and changes at receptor level due to drugs or toxins.

Epileptogenesis - How Seizure Activity Spreads

Extrinsic or intrinsic factors alter excitation/inhibition balance, leading to a breakdown of the inhibitory surround.
Further spread of seizure activity occurs throughout the brain.

Structural Causes of Focal (Partial) Seizures

Scar tissue impacts adjacent tissue.
Tumors compress brain areas, causing damage to brain tissue.

Mechanisms: Damage to the Hippocampus and Hypersynchronization

Damage to hippocampus leads to hyper-excitable networks
Hypersynchronous discharges (synchronous neuronal activity) begin in discrete areas, leading to spread to neighboring regions.
Spread of seizure activity due to loss of surrounding inhibition and recruitment of surrounding neurons, involving pathways in the corpus callosum.

###EEG (Electroencephalogram)

Measures electrical activity in the brain.
Important tool for diagnosis, recording electrical activity generated by currents from neuronal activity passing across extracellular spaces.
Usually recorded from the scalp, reflecting cortical activity.
Good temporal resolution but poor spatial resolution.

EEG: Focal Onset Seizure; EEG: Generalized Onset Seizure

Focal Onset: Seizure originates in one or more foci, capable of spreading to involve the entire brain and leading to bilateral tonic-clonic seizures.
Generalized Onset: Seizure begins simultaneously in both hemispheres and lacks a clear focal origin.

Interictal EEG Abnormalities in Epilepsy

EEG assessment between seizures, indicative of seizure predisposition.
Key features: spikes, sharp waves, and background abnormalities.

Brain Imaging in Neurological Assessment

Structural Imaging: Detects physical anomalies in brain tissue (MRI, CT scan).
Functional Imaging: Visualizes brain activity/metabolism (fMRI, PET).

Clinical Scenario: What Looks Like a Seizure but Isn't?

Psychogenic non-epileptic seizures (pseudo seizures) are non-epileptic attack disorder (NEAD) often related to psychiatric disturbance.

Pharmacological Targets

Drugs that enhance sodium channel inhibition
Drugs that inhibit calcium channels
Drugs that enhance GABA-mediated inhibition
Drugs that inhibit glutamate receptors

Anti-epileptic Drugs

Mechanisms are related to the modulation of specific ion channels, especially sodium, calcium, and potassium channels, as well as glutamate, and GABA (gamma-aminobutyric acid) receptors.
Multiple targets and types of drugs exist.

Potassium Channel Openers

Drugs like retigabine treat focal seizures.
Increasing potassium conductance hyperpolarizes neurons, reducing excitability.

High Voltage Activated Calcium Channels

Regulate neurotransmitter release by controlling calcium entry into the presynaptic terminal.

Calcium Channel Blockers

Drugs like gabapentin and pregabalin can treat generalized tonic-clonic and partial seizures.
They partially block voltage-gated calcium channels and prevent vesicle release of neurotransmitters.

Mixed Sodium and High Voltage Calcium Channel Blockers

Lamotrigine

Acts as a blocker of voltage-gated sodium channels.
Also used to block glutamate release.
Used in partial and absence seizures.

Absence Seizures

Brief and sudden impairment of consciousness.
Characterized by a specific EEG pattern.
Caused by abnormal activation of the T-type calcium channels.

Drugs Used to Treat Absence Seizures

Medications like ethosuximide, succinimide, and valproate block thalamic T-type calcium channels.

Glutamate

Major excitatory neurotransmitter in the central nervous system.
Multiple subtypes exist for glutamate receptors.

NMDA Receptors

Set apart by physiological properties from other receptors.
Magnesium ion blockers when the channel is closed.
Sodium ion influx required for AMPA receptor activation.

AMPA Receptors

Activated by glutamate.
Permitted entry of sodium ions, and depolarization.

Functional Importance of Glutamate in Epileptogenesis

Plays a critical role in the initiation and spread of seizure activity and epileptogenesis.
Dependent on activation of NMDA receptors.

Drugs Targeting NMDA Receptors

Felbamate is a widely used drug to block NMDA receptors at open channels.
It is approved by the FDA in the U.S. for intractable partial seizures and Lennox-Gastaut syndrome.

Perampanel

First selective AMPA receptor antagonist for epilepsy treatment.
It does not affect NMDA receptor responses.
Effective at low brain concentrations, and has a boxed warning due to potential psychiatric effects.

Levetiracetam

Inhibits glutamate and, therefore, reduces neuronal hyperactivity

GABA Modulators

Increase GABA action to improve inhibition at the receptor

Drugs Acting at Multiple Receptors

Topiramate has multiple mechanisms.
May block sodium channels
Enhance GABA action
Block AMPA receptors

Basis of Combination Treatment

Combination of newer antiepileptic drugs with different mechanisms of action can be more effective.

Cannabidiols in Epilepsy

Cannabidiol (CBD) can be used as an add-on therapy.

The Ketogenic Diet

High-fat, low-carbohydrate, controlled protein diet for epilepsy treatment.
A medical treatment when other medications have failed.

Common Adverse Effects

Somnolence, sedation, dizziness, and ataxia are frequently observed as adverse effects during medication use.

Overdose and Antiepileptic Drugs

Respiratory depression represents the most critical consequence of overdose.
Supports treatment approach with medical supervision.

Withdrawal from Antiepileptic Drugs

Withdrawal of some medications can cause significant increase in seizure frequency/severity.
Withdrawal of anti-absence drugs is easier than those for other forms of seizures.

Discontinuation

A gradual dose tapering is recommended in patients who are seizure-free, allowing for monitoring.

Teratogenic Side Effects

Potential for adverse pregnancy effects for fetuses including neural tube defects (e.g. spina bifida), cleft lip/palate, hypospadias.
Higher risks from VPA compared to lamotrigine.

Pregnant Women with Epilepsy

Minimizing antiseizure drug exposure and carefully monitoring maternal seizures are crucial aspects of treatment.
Medication substitution to a lower-risk category, even if less effective, might be necessary for pregnant women.

Suggested Treatment Timeline for Women with Epilepsy Planning Pregnancy

Includes monitoring and early planning.

Summary

Various known mechanisms of action for anticonvulsant drugs.

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Description

This quiz explores seizures and epilepsy from both pathophysiological and pharmacological viewpoints. It covers the underlying mechanisms of hyperexcitability, seizure classification, and the use of EEG in diagnosis. Additionally, it addresses the antiepileptic drugs, their safety in pregnancy, and alternative treatment therapies.