Lecture 16: Epilepsy Flashcards
Define Epilepsy and Epileptic seizures
Epilepsy is a condition in which patients have r_ecurrent, unprovoked epileptic seizures_.
An epileptic seizure comprises an abnormal and excessive electrical discharge from neurons in the c_erebral cortex_ (often associated with loss of consciousness)
It is important to realise that: a) Epilepsy does not always produce loss of consciousness, and b) Loss of consciousness may result from other pathological processes
Does Epilepsy always produce loss of consciousness?
No. but Loss of consciousness may result from other pathological processes
What are some ‘causes’ of epilepsy?
Epilepsy is a syndrome (symptom of brain dysfunction) for which there are many possible causes, rather than a specific diagnosis.
- Structural
- Genetic
- Metabolic/functional
Epilepsy is __________-
A symptom of brain dysfunction
Seziures may be propagated via……
Seizures occur as a results of abnormal synchronous activation of large numbers of hyper-excitable neurons which hare connected in networks.
- Seizures may be propagated via both normal and abnormal pathways
- Seizures spread through synaptic and non synaptic (e.g. gap junctions) pathways
Everyone has neuronal circulatory that can generate seizures, e.g. ECT and drugs can induce seizures
How are seizures classified?
The most important distinction is between focal (partial) and generalised seizures.
- Focal (partial) seizure i_nvolves neurones in a part of the brain_ only (manifestations depend on which part of brain involved)
- Generalised seizure i_nvolves all the neuronal networks_ so extensive regions of both hemispheres (manifestations vary greatly)
Note that a seizure may start as a focal seizure and secondarily generalize.
Briefly describe some generalised seizures
Major motor manifestations- convulsions
- Tonic: Body goes stiff sustained bilateral contraction of axial and limb muscles
- Clonic: Jerking regular repeated bilateral contractions of axial and limb muscles
- Tonic/clonic: tonic (sustained) contraction followed by clonic motor movements
- Myoclonic: sudden jolt sudden brief jerks of axial and limb muscles
- Epileptic spasms: initial myoclonic component then brief tonic contractions of bilateral axial and limb muscles (last 2-10s and occur in a cluster)
No or Minor Motor Manifestations
- Absence: (light-switch goes off) abrupt onset and end (relatively brief), patients continue their movements but loss of consciousness, EEG shows generalised spike and slow wave discharge at 3-4Hz
- Atypical absence: more gradual onset and finish (longer duration), may be followed by confusion, EEG shows slower generalised spike and slow wave discharge at ~2.5Hz.
- Atonic: sudden loss of muscle tone causing a collapse of the head or trunk
- Myoclonic-astatic: epileptic falls when the seizure type (tonic, myoclonic, atonic) is unknown
Describe the different types of focal seizures
1) Focal Aware Seizures (simple partial)
Symptoms are determined by the part of the brain involved in the discharge:
- Visual: typically bright or dark spots
- Somatosensory: typically parasthesiae
- Auditory: buzzing or ringing sounds
- Psychic: sensation that internal or external environment is experienced in a distorted manner, an object or situation may be perceived as familiar or foreign (deja vu, jamais vu) or remote or small
2) Focal impaired awareness seizures (Complex partial)
* Patient is unresponsive with loss of consciousness.
Describe the types and pyhsiology of ligand gated ion channels
It involves binding of neurotransmitter (ligand) produces conformational change in ion channel. Generally permit transit of wider range of ions than voltage gated channels.
1. Excitatory Neurotransmission
Major excitatory neurotransmitter is glutamate (Glu)
There are 3 types of glutamate receptors, and different subtypes for all, both high and low affinity.
Non-NMDA Receptors (Ionotropic Amino Acid Receptors)
These are activated by AMPA and kainic acid (2 major types), not activated by NMDA
Channel is permeable to Na+ and K+ causing partial depolarization, but relatively impermeable to Ca2+
Rapidly activated and inactivated (much faster than NMDA receptors).
NMDA (N-methyl-D-aspartate) Receptors (Ionotropic Amino Acid Receptors)
These are activated by NMDA, absolute requirement for glycine as co-agonist.
When receptor occupied, channel is relatively selective to Ca2+, also permeable to Na+ and K+.
Activation is much slower than non-NMDA receptors.
- When membrane hyperpolarized, Mg2+ blocks channel;
- When membrane partially depolarized, Mg2+ expelled, results in positive feedback, produces further Ca2+ entry.
Note that hypomagnesium in serum predispose to seizures.
2. Inhibitory Neurotransmission
GABA (gamma amino butyric acid) Receptors
GABA receptors is involved in ~70% of synapses
- GABAa receptors linked to ion channel; binds 2 molecules of GABA
- Opens Cl- channels and hyperpolarize neurones
- GABA mediated inhibition promotes neuronal synchronization
- Allosteric binding sites which modulate Cl- channel, e.g. benzodiazepines and barbiturates to treat epilepsy
Compare NMDA and non-NMBDA receptors
Both NMDA and non-NMDA receptors are co-localized at most excitatory glutamatergic synapses
- · Depolarization of presynaptic terminal results in entry of Ca2+
- · Fusion of vesicles with specialized regions of presynaptic membrane
- · Exocytosis of contents into synaptic cleft
Non-NMDA channels open quickly, produce partial depolarization
NMDA channels’ partial depolarization results in expulsion of Mg2+, produces further Ca2+ entry, further depolarization
Do ion channels stay the same?
No. There is substantial plasticity. Channels are not permanent!
Ion channels demonstrate f_requency dependent changes in synaptic efficiency_
- Excitatory synapses are potentiated when fire repetitively
- Inhibitory synapses decrease in efficacy when fire repetitively
NMDA receptors are important in l_ong term potentiation_
- Stimulation lowers threshold for further activation
- Important in memory, and may be important in generating seizures
Provide some evidence of involvement of ion channels in epileptogenesis
Which channels are implicated in epileptogenesis?
1. Mutations In Voltage Gated K+ Channels
Benign familial neonatal epilepsy (2 different autosomal dominant mutations)
- Ongoing frequent epilepsy for first 3-4 days of life in neonates, then stop and perfectly healthy
- This is because the expression of mutated channel only occurs in first week of life, then replaced by other channels.
2. Mutations In Voltage Gated Na+ Channels
Severe myoclonic epilepsy of infancy (Dravet’s syndrome) - SCN1A (onset ~6 months of age, can cause intellectual impairment and abnormal gait)
Benign familial neonatal epilepsy - SCN2A
Generalized epilepsy with febrile seizures plus - SCN1A, SCN1B, SCN2A
Early onset absence seizures - SCN1B
3. Absence Seizures and Ca2+ Channels
Absence seizures due to abnormal activation of T-type Ca2+ channels in the thalamus.
Hyperpolarization of thalamic relay neurones produces synchronous depolarization of the cortex via excitatory neurones
Mutations of T-type Ca2+ channels induced in GAERS rats
4. Mutations In Genes Encoding Ligand Gated Ion Channels
- Autosomal dominant nocturnal frontal lobe epilepsy (mutation of nicotinic ACh receptor) - mutation is found everywhere, but seizure is only in frontal lobe typically during sleep
- Generalized epilepsy with febrile seizures plus (mutations of GABAa receptor)
- Angelman’s syndrome (deletion of part of chromosome 15 contains genes for several GABAa receptor subunits) – mutation causes mental retardation and motor disorder
Severe myoclonic epilepsy can be caused my mutations in the ______–
Voltage gated sodium channels
Absence seziures can be caused by mutations in the ___________
Voltage gated Ca2+ channels
What are the effects of some drugs that can cause seizures?
Blockade of GABAa receptors (suppress inhibition)
- Bicuculline (competitive antagonist)
- Picrotoxin (non-competitive antagonist)
- Penicillin (enters open GABA channels and occludes them)
Activation of Glu receptors (increase excitation)
- Kainate, domoic acid (shellfish poisoning)
Unblocking of NMDA receptors by low Mg2+
Blockade of K currents with 4-aminopyridine (variant used to treat multiple sclerosis)
