NS7 – PATHOPHYSIOLOGY OF EXCITATION & INHIBITION
NS7 – PATHOPHYSIOLOGY OF EXCITATION AND INHIBITION - EPILEPSY
I. OVERVIEW
A. Seizure:
1. Definition: The clinical manifestation of an imbalance between excitatory and inhibitory signaling
causing overexcitation of neurons which results in abnormal, synchronous neuronal firing. Either too much
glutamate (excitatory) is released or too little GABA (inhibitory) is released.
2. Causes
a. brain damage during birth
b. head injuries
c. stroke
d. brain tumours
e. alcoholism & drug use
f. hypoglycemia
g. genetics
h. flickering lights (photosensitive epilepsy) http://en.wikipedia.org/wiki/Photosensitive_epilepsy
3. Incidence: 5%
B. Epilepsy:
1. Definition: a chronic neurological syndrome of recurrent unprovoked seizures.
http://www.epilepsy.com/web/animation.php?swf=what_is
2. Causes: unknown
3. Incidence: 1% (children and adults)
4. Symptoms:
a. involuntary changes in muscle activity, sensory awareness, autonomic function, emotion, cognition
b. may last from seconds to continuous (status epilepticus; requires intervention)
5. Types
a. Partial: initiated in one part of the brain and may spread to other regions
i. Simple:
• abnormal motor activity
• abnormal sensory activity
• abnormal autonomic signs and symptoms
• altered states of consciousness
ii. Complex:
• impairment of consciousness
• automatisms
b. General: simultaneously occurs in many regions resulting in loss of consciousness.
i. Tonic-clonic (grand mal): Detectable loss of consciousness. First increased muscle tone or
rigidity (tonic) followed by jerking motions (clonic); may also display autonomic symptoms.
ii. Absence (petit mal): Brief loss of consciousness (10 seconds or less); usually occurs in children
between 5-12 yrs and spontaneously stops.
iii. Myoclonic: brief muscle contractions that are often mistaken for tics; associated with epileptic
syndromes.
c. Syndrome- associated Epilepsy (infants & children): West syndrome (infantile spasm) and
Lennox-Gastaut syndrome.
1

NS7 – PATHOPHYSIOLOGY OF EXCITATION & INHIBITION
6. Diagnosis
a. medical history
b. EEG: identification of brain regions with abnormal brain wave patterns; but usually the patterns are
normal between seizures
c. CT or MRI: identification of contributing structural lesions; but usually there are no detectable le-
sions.
7. Treatment
a. Medication: administered with gradually increasing dose until seizures stop; effective dose must be
maintained until slowly withdrawn; non-compliance biggest problem with effectiveness.
Table 1: Selection of Anti-Epileptic Drugs (AED) with known targets
Drugs Drug target
-
primidone GABA-receptor agonist (activates Cl channel)
(Mysoline)
produces phenobarbital and PEMA as metabolites
-
diazepam GABA-receptor agonist (activates Cl channel)
(Valium)
lorazepam benzodiazepine derivative
-
clobazam GABA-receptor agonist (activates Cl channel)
clonazepam
flurazepam benzodiazepine derivative
-
pentobarbital GABA-receptor agonist (activates Cl channel)
(Nembutal)
barbiturate
selective GABA reuptake blocker
tigabine
(Gabitril)
GABA catabolism blocker
vigabatrin
(Sabril)
stabilizes inactivated state of Na+ channel
carbamazepine
(Tegretol)
oxcarbazepine
Na+ channel blocker
lamotrigine
(Lamictal)
voltage-gated Ca++ channel blocker
gabapentin
pregabalin
structurally similar to GABA
Ca++ channel blocker
ethosuximide
GABA-receptor activator
topiramate
glutamate receptor inhibitor
(Topamax)
sulfamate substituted monosaccharide
b. Surgery (for drug resistant cases):
i. palliative surgery (to reduce size and frequency of epilepsy)
• removal of scarred tissue
• callosotomy: severing anterior corpus callosum to prevention of seizures from generalizing
• vagal nerve stimulation
ii. resective surgery (to eliminate seizures)
• anterior temporal lobectomy: removal of frontal part of right or left temporal lobe
• hemispherectomy: removal of all or half of the cerebral cortex; young patients (<5yrs) may
recover some motor control of the ipsilateral body (same side as excised brain)
2

NS7 – PATHOPHYSIOLOGY OF EXCITATION & INHIBITION
c. Diet: ketogenic diet (high fat, low carb, limited fluid intake); difficult to maintain
d. Epilepsy alert Dog http://www.abc.net.au/science/news/stories/s1137619.htm
II. BRAIN REGIONS INVOLVED IN SEIZURE ACTIVITY
Table 2: Epileptic symptoms and implicated brain regions
SYMPTOMS BRAIN REGION LOBE
sudden involuntary muscle contraction (partial simple) motor cortex
eye movements (partial simple) premotor cortex
asymmetrical limb posturing (partial simple) frontal eye field (voluntary eye frontal
muscular rigidity (partial simple) movement)
muscle jerkiness(partial simple)
loss of speech (partial complex) Broca’s area frontal
impairment of consciousness (unable to respond; un-
aware of surroundings; partial complex) frontal
loss of consciousness (general)
automatism (chewing, repetitive gestural motions, wan- temporal or
dering, repetition of phrases; partial complex) frontal
altered consciousness: loss of memory, emergence of amygdala
old memories, unprovoked fear, displeasure, happiness hippocampus temporal
(partial simple)
temporal
smelling unpleasant odors (partial simple) olfactory cortex
frontal
hearing buzzing sounds (partial simple) auditory cortex temporal
tingling sensation, sensation of pain, absence or pres- somatosensory cortex
parietal
ence of limbs (partial simple)
seeing flashes of light, or illusions visual cortex occipital
generalized seizures (tonic-clonic) thalamus complex
(relay center for ascending senso-
ry, motor, emotional, visceral in-
formation)
abnormal autonomic signs brain stem (seizures do not
originate here
but may spread
to these regions)
loss of balance coordination cerebellum
3

NS7 – PATHOPHYSIOLOGY OF EXCITATION & INHIBITION
III. PATHOPHYSIOLOGY OF EPILEPSY
A. MECHANISMS CONTRIBUTING TO DECREASED INHIBITION
1. Mutations or alterations of GABA receptor function
2. Reduced activation of GABA cells
B. MECHANISMS CONTRIBUTING TO INCREASED EXCITATION
1. Increased activation of glutamate receptors
2. Increased synchrony between neurons by non-synaptic means via
a. an increase in extracellular ion concentration
b. gap junctions
3. Increased synchrony between neurons synaptically
C. EXAMINATION OF TWO SPECIFIC CASES OF EPILEPSY
Case Clinical Level of ab- Brain Region Main mechanism Epilepsy syn- Prognosis
syndrome normal ex- of abnormal ex- drome classifi-
citability citability cation
partial Variable; of-
1 Temporal Large-scale hippocampus, Hippocampal ten good with
lobe epilepsy (limbic) neu- temporal lobe sclerosis, axonal resection
ronal circuit sprouting
2 Childhood Thalamo-corti- thalamus Abnormal T-type general Good
absence cal circuits cortex calcium channel
epilepsy and HCN channel
1. TEMPORAL LOBE EPILEPSY & EPILEPTOGENESIS
a. The risk of developing TLE is great following severe traumatic brain injury.
b. TLE is the result of epileptogenesis which is characterized by
i. selective loss of vunerable neurons in the hippocampus
ii. sprouting – formation of new synaptic connections
iii. neurogenesis, migration, formation of a new layer of neurons
iv. change in receptor expression and function
v. astrogliosis – abnormal increase in astrocytes in response to injury
2. CHILDHOOD ABSENCE EPILEPSY & CHANNEL MUTATIONS
a. Aberrant activity in the thalamocortical circuit contributes to CAE.
b. Thalamus relay neurons have oscillations in their membrane potentials.
c. Oscillations of TR neuron potentials
i. increases synchronization of cortical neurons during depolarization
ii. decreases activation of cortical neurons during hyperpolarization
d. Oscillation of membrane potential is regulated by the T-type calcium channels in the TR neuron
i. T-type calcium channels are voltage-gated and have an open, closed and inactive state;
inactivated channels must be hyperpolarized in order to become active again.
ii. NRT (nucleus reticulus of the thalamus neurons) hyperpolarizes TR neurons and resets the
inactivated T-channels.
iii. Hyperpolarization is mediated by the HCN (Hyperpolarizing cation ) channel
e. Mutations in T- calcium channels and HCN channels are implicated in CAE
4

NS7 – PATHOPHYSIOLOGY OF EXCITATION & INHIBITION
5