Epilepsy Pathophysiology: Study Notes for General Biology

Epilepsy Pathophysiology

Introduction

Epilepsy is a neurological disorder characterized by a chronic predisposition to recurrent, unprovoked seizures. Seizures result from abnormal, excessive, or synchronous neuronal activity in the brain. Understanding epilepsy involves exploring its classification, underlying mechanisms, clinical presentation, and associated syndromes.

Defining Epilepsy

Clinical Definition and Criteria

• Epilepsy is defined as a clinical phenomenon where a person has a risk of recurrent seizures due to a chronic, underlying process.

• Diagnosis requires at least one of the following:

  • At least two unprovoked (or reflex) seizures occurring >24 hours apart.

  • One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years.

  • Diagnosis of an epilepsy syndrome.

• Epilepsy is considered resolved for:

  • Individuals who had an age-dependent epilepsy syndrome but are now past the applicable age.

  • Those who have remained seizure-free for the last 10 years, with no seizure medicines for the last 5 years.

Epilepsy Classification Framework

Types and Etiology

Epilepsy is classified based on seizure types, epilepsy types, and underlying etiology. Comorbidities may also be present.

• Seizure Types:

  • Focal

  • Generalized

  • Unknown

• Epilepsy Types:

  • Focal

  • Generalized

  • Combined Generalized & Focal

  • Unknown

• Etiology:

  • Structural

  • Genetic

  • Infectious

  • Metabolic

  • Immune

  • Unknown

Epilepsy syndromes are defined by clusters of features such as seizure type(s), EEG patterns, imaging features, age at onset/remission, triggers, and comorbidities.

Electroencephalogram (EEG) in Epilepsy

EEG Patterns and Seizure Types

EEG is a key diagnostic tool for epilepsy, recording electrical activity from different brain regions.

• Normal EEG: Shows regular, organized waveforms across frontal, temporal, and occipital sites.

• Generalized Seizure EEG (Tonic-Clonic Type): Displays widespread, synchronous discharges across multiple regions.

• Generalized Seizure EEG (Absence Type): Characterized by spike-and-wave discharges, often at 3 Hz.

EEG Type	Features
Normal	Regular, organized waveforms
Tonic-Clonic Seizure	Widespread, synchronous discharges
Absence Seizure	Spike-and-wave discharges (3 Hz)

Pathophysiology of Seizures

Neuronal Ion Concentration and Signal Propagation

• Excitatory Signal Propagation:

  • Presynaptic release of glutamate opens postsynaptic sodium (Na+) or calcium (Ca2+) channels, causing depolarization.

  • Key receptors: AMPA and NMDA.

• Inhibitory Signal Propagation:

  • GABAergic transmission facilitates chloride (Cl-) influx, hyperpolarizing the neuron and inhibiting firing.

• Normal vs. Abnormal Neuronal Firing:

  • Normal firing is controlled and asynchronous.

  • Abnormal firing (paroxysmal depolarizing shift) leads to synchronous, excessive activity, seen in seizures.

Prolonged seizures can cause neuronal injury, permanent changes in neuronal circuitry, and functional deficits (e.g., memory loss).

Epileptogenesis

Development of Chronic Seizure Susceptibility

• Epileptogenesis refers to the transformation of a normal neuronal network into one that is chronically hyper-excitable.

• Key features:

  • Formation of an epileptic focus (often in the hippocampus).

  • Neuronal injury and rewiring of networks.

  • Enhanced susceptibility to seizures.

Seizure Precipitating Factors

Common Triggers

• Metabolic and electrolyte imbalances (e.g., low glucose, sodium, calcium, magnesium)

• Reduction or inadequate antiepileptic drug (AED) treatment

• Herbal remedies

• Hormonal changes (menses, puberty, pregnancy)

• Sleep deprivation, sensory stimuli, emotional stress

• Fever, systemic infection, concussion, intracranial bleeding, hypoxia

• Genetic predisposition (e.g., Juvenile Myoclonic Epilepsy)

• Psychogenic factors (“pseudoseizures”)

• Hyperventilation (absence seizures)

Drug and Substance Causes of Seizures

Examples of Seizure-Inducing Agents

• Alkylating agents (e.g., busulfan)

• Antimalarials (e.g., chloroquine, mefloquine)

• Antimicrobials/antivirals

• Quinolones

• Psychotropics

• Anesthetics and analgesics

• Sedative-hypnotic drug withdrawal

• Dietary supplements

• Drugs of abuse

• Contrast agents

• Theophylline

• Flumazenil (in benzodiazepine-dependent patients)

Seizure Types and Clinical Presentation

Focal Onset Seizures

• Originate in a localized network (may be subcortical).

• May be discretely localized or more widely distributed.

• Awareness:

  • Focal aware: consciousness fully preserved.

  • Focal impaired awareness: consciousness impaired during seizure.

• Clinical manifestations vary with site of origin and degree of spread.

• Duration typically <2 minutes; postictal confusion may occur.

Focal to Bilateral Tonic-Clonic Seizures

• Begin as focal seizures and spread diffusely throughout the cortex.

• Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases.

• Typical duration: 1-3 minutes; postictal confusion and somnolence may follow.

Generalized Seizures

• Originate at some point within, and rapidly engage, bilaterally distributed networks.

• Involve both hemispheres; loss of consciousness is common.

• Awareness is usually impaired; not used as a classifier.

Types of Generalized Seizures

• Absence Seizures:

  • Sudden cessation of activity and awareness; brief staring spells.

  • Lasts 3-20 seconds; alert/attentive afterwards.

  • Can be provoked by hyperventilation; onset typically between 4 and 14 years of age.

  • Normal development and intelligence.

• Tonic-Clonic Seizures:

  • Loss of consciousness and postictal confusion/lethargy.

  • Duration: 30-120 seconds.

  • Tonic phase: muscle stiffening and fall.

  • Clonic phase: rhythmic extremity jerking.

• Tonic Seizures:

  • Symmetric, tonic muscle contraction of extremities with flexion of waist and neck.

  • Duration: 2-20 seconds.

• Atonic Seizures:

  • Sudden loss of postural tone; may result in falls.

  • Awareness usually impaired; duration usually seconds.

• Myoclonic Seizures:

  • Brief, shock-like jerk of a muscle or group of muscles; usually bilateral and synchronous.

  • Consciousness not usually impaired; short duration (<1 sec).

  • Several in succession may be termed a clonic seizure.

Epilepsy Syndromes

Key Syndromes and Features

• Juvenile Myoclonic Epilepsy:

  • Generalized seizure disorder of unknown cause; appears in early adolescence.

  • Bilateral myoclonic jerks, single or repetitive; may also have generalized tonic-clonic and absence seizures.

  • Most frequent in morning upon awakening; provoked by sleep deprivation.

  • Consciousness preserved unless myoclonus is severe; complete remission is uncommon.

  • Responds well to appropriate anticonvulsant therapy.

• Dravet Syndrome:

  • Develops around 6-15 months of age; usually febrile status epilepticus, hemiclonic or generalized.

  • Other seizure types develop from 1-4 years; may include absence and myoclonic seizures.

  • Triggers: fever, fatigue, photic stimulation, excitement.

  • Intellectual disability (severe in 50%) and ongoing seizures common.

• Lennox-Gastaut Syndrome:

  • Tonic and atonic drop attacks; common in preschool children.

  • Often occurs in children with history of encephalopathy.

  • Unfavorable prognosis; associated with mental retardation and behavioral problems.

• Mesial Temporal Lobe Epilepsy Syndrome (MTLE):

  • Most common syndrome associated with focal impaired awareness seizures.

  • Clinical, EEG, and pathologic features; may include fear, olfactory sensations, and dysphasia.

  • MRI can detect characteristic hippocampal sclerosis.

General First Aid for Seizures

Basic Principles

• Always stay with the person until the seizure is over.

• Pay attention to the length of the seizure.

• Stay calm; most seizures last only a few minutes.

• Prevent injury by moving nearby objects out of the way.

• Make the person as comfortable as possible.

• Keep onlookers away.

• Do not forcibly hold the person down or put anything in their mouth.

• Ensure breathing is okay; do not give water, pills, or food by mouth unless fully alert.

• If necessary, call for emergency medical help.

• Be sensitive and supportive; ask others to do the same.

Summary Table: Seizure Types and Features

Seizure Type	Consciousness	Duration	Main Features
Focal Aware	Preserved	<2 min	Localized symptoms
Focal Impaired Awareness	Impaired	<2 min	Automatisms, confusion
Focal to Bilateral Tonic-Clonic	Impaired	1-3 min	Tonic and clonic phases
Absence	Impaired	3-20 sec	Staring, sudden cessation
Tonic-Clonic	Impaired	30-120 sec	Stiffening, jerking, confusion
Tonic	Impaired	2-20 sec	Muscle stiffening
Atonic	Impaired	Seconds	Loss of tone, falls
Myoclonic	Usually preserved	<1 sec	Brief muscle jerks

Key Terms and Concepts

• Seizure: Transient occurrence of signs/symptoms due to abnormal neuronal activity.

• Epileptogenesis: Process by which a normal brain develops chronic seizure susceptibility.

• EEG: Electroencephalogram, a tool for recording brain electrical activity.

• Automatisms: Involuntary, repetitive movements during seizures.

• Postictal: Period following a seizure, often with confusion or lethargy.

Relevant Equations

• Action Potential Propagation:

$V_m = V_{rest} + rac{g_{Na^+}(E_{Na^+} - V_m) + g_{K^+}(E_{K^+} - V_m) + g_{Cl^-}(E_{Cl^-} - V_m)}{g_{total}}$

• EEG Frequency (Absence Seizure):

$f_{spike-wave} \approx 3 \text{ Hz}$

Additional info: These notes expand on the original slides by providing definitions, context, and structured tables for clarity. The equations are standard for neuronal membrane potential and EEG frequency in absence seizures.