Lecture 46 - Pathophysiology of Seizure Disorders Flashcards
Epilepsy Statistics
> 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%
Generalized seizures (non-absence types)
myoclonic
tonic
clonic
atonic
tonic-clonic
Myoclonic
- shock-like contraction of muscles
- isolated jerking of head, trunk, body
Tonic
- these seizures occur in children
- involve rigidity as a result of
increased tone in extensor muscles
Clonic
- these seizures occur in
babies and young children - involve rapid, repetitive motor activity
Atonic
- sudden loss of muscle tone
- patients fall if standing (‘drop attacks’)
Tonic-Clonic
- tonic phase immediately followed by clonic phase
- referred to as ‘grand mal’, characteristic of epilepsy
Seizure
paroxysmal disorder of the CNS characterized by abnormal cerebral neuronal discharges with or without loss of consciousness.
Paroxysm
sudden attack or outburst
Convulsion
specific seizure type where the attack is manifested by involuntary muscle contractions (this term is de-emphasized in the 2017 classification system).
Epilepsy
Repeated seizures due to damage, irritation, and/or chemical imbalance in the brain which leads to a sudden, excessive, synchronous electrical discharge.
Seizures involve
the anomalous firing of a population of neurons in the brain.
A seizure originates from
the gray matter of any cortical or subcortical area of the brain.
Seizures are a result of
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.
Seizure classifications
focal onset
generalized onset
unknown onset
Focal onset
classified either: aware, impaired awareness; motor onset, non-motor onset
may progress to: focal to bilateral tonic-clonic
Generalized onset
classified to either: motor - tonic clonic, other motor; non-motor (absence seizures)
Unknown onset
classifoed to either: motor - tonic clonic, other motor; non-motor
unclassified
Focal
~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’)
Generalized
~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
Pathways for the propagation of focal seizures
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).
Pathways for the propagation of generalized seizures
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.
Focal seizures can be of the ‘AWARE’ type or involve impaired awareness.
- ‘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
Focal seizures can be of the ‘aware’ type or involve
IMPAIRED AWARENESS.
- 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
Postictal state
- 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
Generalized seizures (absence type)
- 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
Generalized tonic-clonic (grand mal) seizure
- 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.
Status Epilepticus
- 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
Epilepsy statistics
- 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
Which of the following types of convulsions can be preceded by an aura phase?
focal to bilateral (secondary generalized) tonic-clonic
Paroxysmal depolarizing shift (PDS)
- 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)
Seizure focus and inhibitory surround
- 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.
Electrophysiological basis for the tonic and clonic phases of a generalized tonic-clonic seizure
- 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.
Potential triggers of status epilepticus
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)
Drugs that aggravate or increase the risk of seizures
- alcohol
- theophylline
- CNS stimulants
- bupropion
- oral contraceptives
- withdrawal from depressants
- clozapine (converted to norclozapine via Cyp1A2 – and norclozapine is responsible for increasing seizure risk)
Which of the following occurs during the hyperpolarization phase of a PDS?
influx of Cl- ions resulting from GABAA receptor activation
