Lecture 46 - Pathophysiology of Seizure Disorders Flashcards

1
Q

Epilepsy Statistics

A

> 80% of all patients with epilepsy will experience their first seizure by the age of 20
Chance of recurrence:
– After a single seizure: 20%
– After a second seizure: 60%
– After a third seizure: 75%

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2
Q

Generalized seizures (non-absence types)

A

myoclonic
tonic
clonic
atonic
tonic-clonic

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3
Q

Myoclonic

A
  • shock-like contraction of muscles
  • isolated jerking of head, trunk, body
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4
Q

Tonic

A
  • these seizures occur in children
  • involve rigidity as a result of
    increased tone in extensor muscles
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5
Q

Clonic

A
  • these seizures occur in
    babies and young children
  • involve rapid, repetitive motor activity
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6
Q

Atonic

A
  • sudden loss of muscle tone
  • patients fall if standing (‘drop attacks’)
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7
Q

Tonic-Clonic

A
  • tonic phase immediately followed by clonic phase
  • referred to as ‘grand mal’, characteristic of epilepsy
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8
Q

Seizure

A

paroxysmal disorder of the CNS characterized by abnormal cerebral neuronal discharges with or without loss of consciousness.

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9
Q

Paroxysm

A

sudden attack or outburst

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10
Q

Convulsion

A

specific seizure type where the attack is manifested by involuntary muscle contractions (this term is de-emphasized in the 2017 classification system).

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11
Q

Epilepsy

A

Repeated seizures due to damage, irritation, and/or chemical imbalance in the brain which leads to a sudden, excessive, synchronous electrical discharge.

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12
Q

Seizures involve

A

the anomalous firing of a population of neurons in the brain.

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13
Q

A seizure originates from

A

the gray matter of any cortical or subcortical area of the brain.

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14
Q

Seizures are a result of

A

disordered, synchronous, and rhythmic firing of a population of brain neurons (synchronized hyperexcitability).
Neurons recruit adjoining neurons to do the same.
* The clinical manifestations depend on the site of the focus, on the degree of irritability of the surrounding area of the brain, and on the intensity of the impulse.
* During a seizure, the brain uses more energy than it can manufacture (and more O2), and thus prolonged seizures can result in cell ischemia.

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15
Q

Seizure classifications

A

focal onset
generalized onset
unknown onset

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16
Q

Focal onset

A

classified either: aware, impaired awareness; motor onset, non-motor onset
may progress to: focal to bilateral tonic-clonic

17
Q

Generalized onset

A

classified to either: motor - tonic clonic, other motor; non-motor (absence seizures)

18
Q

Unknown onset

A

classifoed to either: motor - tonic clonic, other motor; non-motor
unclassified

19
Q

Focal

A

~60% of seizures
* only part of the brain affected
* begin focally in cortical region (e.g. temporal lobe)
* usually due to a lesion (e.g., head trauma, tumor, stroke, hypoxia at birth, metabolic disorder, infection, malformations)
* frequently progress to generalized seizure (‘focal to bilateral’)

20
Q

Generalized

A

~40% of seizures
* loss of consciousness
* both brain hemispheres involved
* referred to as ‘primary’ or ‘idiopathic’ (i.e. not due to a lesion as in the case of focal seizures)
* most are presumed to be
genetic

21
Q

Pathways for the propagation of focal seizures

A

Seizure activity spreads from a focus in one part of the brain (red area of neocortex). This is a focal seizure.
Focal seizures frequently progress to secondary generalized seizures via projections to the thalamus (latest classification: ‘focal to bilateral’ seizure).

22
Q

Pathways for the propagation of generalized seizures

A

Primary generalized seizures
propagate via diffuse interconnections between the thalamus and cortex (no discrete focus). The earliest clinical signs show involvement of both brain hemispheres.

23
Q

Focal seizures can be of the ‘AWARE’ type or involve impaired awareness.

A
  • ‘Aware’ type (previously referred to as ‘simple partial’)
    – ~25% of focal seizures
    – limited convulsions (e.g., jerking of a single limb or body part)
    – limited sensory disturbance
    – no loss of consciousness
    – subjective experiences (auras) also occur
  • abdominal discomfort
  • sense of fear
  • unpleasantsmell
  • result of abnormal electrical activity
24
Q

Focal seizures can be of the ‘aware’ type or involve
IMPAIRED AWARENESS.

A
  • Impaired Awareness (previously referred to as ‘complex partial’)
    – most common among focal seizures
    – clouding of consciousness
    – staring
    – repetitive motor behaviors (automatisms, for which patients have no memory)
  • swallowing
  • chewing
  • lip smacking
    – disturbances of visceral, emotional, and autonomic systems (e.g., visceral: diarrhea, vomiting)
    – seizure followed by confusion, fatigue, and throbbing headache
    – aura is common
    – Postictal state due to impaired awareness
25
Q

Postictal state

A
  • After a seizure, a patient will not recover a normal level of consciousness immediately.
  • Postictal state may last for seconds to hours depending on:
    – area of the brain affected
    – length of seizure
    – use of anti-epileptic drugs (AEDs) – age
  • Symptoms
    – confusion
    – disorientation
    – anterograde amnesia
25
Q

Generalized seizures (absence type)

A
  • Absence: typical or atypical
    Typical, also referred to as ‘petit-mal’
    – brief loss of consciousness (10-45 seconds)
    – staring or eye flickering
    – begin abruptly
    – often repetitive
    – May not realize it after the seizures
    – no convulsions, aura, or postictal period
    Atypical
    – slower onset than typical
    – more difficult to control pharmacologically than typical
26
Q

Generalized tonic-clonic (grand mal) seizure

A
  • Most dramatic of all epileptic seizures
  • First phase: tonic phase
  • begins abruptly, often with diaphragm contraction (no aura)
  • tonic rigidity in all extremities (lasts 15-30 seconds)
  • tonus is interrupted by a tremor that corresponds to relaxation
  • Second phase: clonic phase
  • begins as relaxation periods become more prolonged
  • involves violent jerking of the body that lasts 1-2 minutes
  • After the jerking period, patients are usually in a stuporous state.
  • Tongue or cheek may be bitten
  • Urinary incontinence is common
  • Primary generalized tonic-clonic seizures show no evidence of localized onset.
  • Focal-to-bilateral tonic-clonic seizures start out as a focal seizure (this type of seizure was previously referred to as a ‘secondarily
    generalized attack’). In this case there can be a brief aura.
27
Q

Status Epilepticus

A
  • Generalized convulsive status epileptic (GCSE)
  • repetitive seizure activity in which the patient does not regain consciousness between seizures OR
  • a continuous, single seizure episode lasting ≥30 minutes
  • Could be life-threatening
  • A more practical definition…
  • ≥5 minutes of continuous seizure activity OR
  • recurrent seizure activity without an appropriate return to baseline
  • Therapeutic goal is to bring seizures under control within 60 minutes
    to minimize neurologic and cardiovascular complications, including:
    – abnormal glucose utilization
    – compromised CNS blood flow (oxygen)
    – lactic acid accumulation
    – cardiovascular collapse (arrhythmia)
    – long term impact on cognitive function
    – worsening of seizure disorder
28
Q

Epilepsy statistics

A
  • Incidence of epilepsy is between 1% and 2% of the population.
  • 1 in 5 individuals will experience some type of seizure activity sometime during their lifetime.
  • “One seizure does not make an epilepsy”
  • 50 – 75% of patients with epilepsy are successfully treated with therapeutic agents.
  • Drug therapy can be gradually withdrawn in patients who have been clinically-free of seizures for 2-5 years.
  • Sudden unexpected death in epilepsy (SUDEP) could happy and is receiving great attention
29
Q

Which of the following types of convulsions can be preceded by an aura phase?

A

focal to bilateral (secondary generalized) tonic-clonic

30
Q

Paroxysmal depolarizing shift (PDS)

A
  • The PDS consists of a large depolarization that triggers a burst of action potentials.
  • Depolarization involves the activation of (i) AMPA and NMDA channels by the excitatory neurotransmitter glutamate, and (ii) voltage-gated calcium channels (gCa), leading to an influx of cation e.g., Ca2+ ions (panel A).
  • Depolarization is followed by hyperpolarization involving the activation of GABA receptors (influx of chloride ions) and voltage- and calcium-dependent K+ channels (gK), leading to an efflux of K+.
  • Neuronal signaling (depolarization) is normally dampened by feed- forward and feedback inhibition – involving GABAergic neurons – in a typical cortical neuron circuit.
  • Disrupted excitation/inhibitory (E/I) balance
  • excitatory pyramidal neurons (glutamatergic)
  • inhibitory interneuron (GABAergic)
31
Q

Seizure focus and inhibitory surround

A
  • Electrical discharge spreads through the seizure focus but is contained as a result of inhibition in a neighboring zone called the ‘inhibitory surround’ (panel A).
  • Panel B shows an excitatory pyramidal neuron ‘a’ activating another pyramidal neuron ‘b’, whereas neuron ‘c’ in the surround inhibited
    region is hyperpolarized because of GABAergic inhibition.
32
Q

Electrophysiological basis for the tonic and clonic phases of a generalized tonic-clonic seizure

A
  • The evolution of a focal seizure to a generalized (bilateral) seizure involves a loss of hyperpolarization and surround inhibition.
  • In the tonic phase, GABA-mediated inhibition disappears, whereas glutamate-mediated AMPA and NMDA receptor (via the influx of cation ions) activity increases.
  • In the clonic phase, GABA-mediated inhibition (via the influx of Cl− ions) gradually returns, leading to a period of oscillation.
  • As GABA-mediated inhibition breaks down during the tonic phase, action potentials propagate to distant neurons, leading to a spread of seizure activity from the focus to distant sites in the brain.
33
Q

Potential triggers of status epilepticus

A

Underlying conditions in the brain:
* prenatal injury
* cerebrovascular disease
* brain tumors
* head trauma
* infection
* hemorrhage
* anoxia
* drugs
More general perturbations:
* metabolic disturbances
Ø hyperventilation
Ø blood gas, pH
Ø hypoglycemia
* sleep deprivation
* stress
* alcohol withdrawal
* withdrawal from AEDs
Ø especially sudden discontinuation
* repetitive light stimulation (e.g., strobe light)

34
Q

Drugs that aggravate or increase the risk of seizures

A
  • alcohol
  • theophylline
  • CNS stimulants
  • bupropion
  • oral contraceptives
  • withdrawal from depressants
  • clozapine (converted to norclozapine via Cyp1A2 – and norclozapine is responsible for increasing seizure risk)
35
Q

Which of the following occurs during the hyperpolarization phase of a PDS?

A

influx of Cl- ions resulting from GABAA receptor activation