Lecture 46 - Pathophysiology of Seizure Disorders

Question 1

Epilepsy Statistics

Answer 1

> 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%

Question 2

Generalized seizures (non-absence types)

Answer 2

myoclonic
tonic
clonic
atonic
tonic-clonic

Question 3

Myoclonic

Answer 3

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

Question 4

Tonic

Answer 4

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

Question 5

Clonic

Answer 5

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

Question 6

Atonic

Answer 6

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

Question 7

Tonic-Clonic

Answer 7

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

Question 8

Seizure

Answer 8

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

Question 9

Paroxysm

Answer 9

sudden attack or outburst

Question 10

Convulsion

Answer 10

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

Question 11

Epilepsy

Answer 11

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

Question 12

Seizures involve

Answer 12

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

Question 13

A seizure originates from

Answer 13

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

Question 14

Seizures are a result of

Answer 14

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.

Question 15

Seizure classifications

Answer 15

focal onset
generalized onset
unknown onset

Question 16

Focal onset

Answer 16

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

Question 17

Generalized onset

Answer 17

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

Question 18

Unknown onset

Answer 18

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

Question 19

Focal

Answer 19

~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’)

Question 20

Generalized

Answer 20

~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

Question 21

Pathways for the propagation of focal seizures

Answer 21

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).

Question 22

Pathways for the propagation of generalized seizures

Answer 22

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.

Question 23

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

Answer 23

• ‘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

Question 24

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

Answer 24

• 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

Question 25

Postictal state

Answer 25

* 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

Question 25

Generalized seizures (absence type)

Answer 25

* 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

Question 26

Generalized tonic-clonic (grand mal) seizure

Answer 26

* 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.

Question 27

Status Epilepticus

Answer 27

* 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

Question 28

Epilepsy statistics

Answer 28

* 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

Question 29

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

Answer 29

focal to bilateral (secondary generalized) tonic-clonic

Question 30

Paroxysmal depolarizing shift (PDS)

Answer 30

- 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)

Question 31

Seizure focus and inhibitory surround

Answer 31

- 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.

Question 32

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

Answer 32

- 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.

Question 33

Potential triggers of status epilepticus

Answer 33

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)

Question 34

Drugs that aggravate or increase the risk of seizures

Answer 34

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

Question 35

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

Answer 35

influx of Cl- ions resulting from GABAA receptor activation