Epilepsy Lecture Flashcards
Epilepsy
• A chronic neurologic disorder manifesting by repeated seizures (fits) which result from paroxysmal uncontrolled discharges of neurons within the CNS (grey matter disease).
• The clinical manifestations range from a major motor
convulsion to a brief period of lack of awareness.
– altered consciousness
– altered motor activity
– altered sensory phenomenon
– unusual behaviour
• Epilepsy usually presents in childhood or adolescence but may occur for the first time at any age.
• 5% population suffer a single sz at some time,
• 0.5-1% of the population have recurrent sz = EPILEPSY
Epilepsy - Classification
• Partial (Focal seizures)
- account for 80% of adult epilepsies
- Simple partial seizures
- Complex partial seizures
- Partial seizures secondarily generalised
• Generalised seizures
- Tonic-Clonic (grand mal)
- Absence (petit mal)
- Myoclonic
- Status
- Atonic
Partial (Focal) Seizures
• Seizure begins locally, often resulting from focal structural lesion in the brain, may remain localised or progress to generalised seizures (spread to entire cortex);
- Simple partial seizures:
Motor, somatosensory or psychic symptoms; Usually no loss of consciousness
-Complex partial seizures:
Temporal lobe, psychomotor, Loss of consciousness
Generalised Seizures
• Affect whole brain with loss of consciousness;
-Tonic-Clonic seizures (Grand Mal):
Initial rigid extensor spasm, respiration stops, defecation,
micturition and salivation occur (tonic phase, ~1min), Violent synchronous jerks (clonic phase, 2-4 min)
- Absence seizures (Petit Mal): Briefly loss of awareness (10-30s) No loss of posture tone May occur 100+ times a day Primarily paediatric problem Often described as daydream, not paying attention Usually disappear as child matures
- Myoclonic: Seizures of a muscle or group of muscles
- Atonic: Loss of muscle tone / strength
-Status: A condition when consciousness does not return between seizures for more than 30 min.
This state may be life-threatening with the development of pyrexia, deepening coma and circullatory collapse.
Death occurs in 5-10%
Pathogenesis
• Unbalance of excitatory and inhibitory neurotransmission:
Excitation (too much) Ionic—inward Na+, Ca++ currents
Neurotransmitter—glutamate, aspartate Inhibition (too little) Ionic—inward CI-, outward K+ currents Neurotransmitter—GABA
• Abnormal electrical properties of the affected cells,
causing sudden excessive & asynchronized neuronal
firing;
• May have no obvious stimulus or may be due to trauma,
hypoglycemia, infection
Spread of seizure
Spread facilitated by repeated firing:
a) ↑ [K+]out→ ↓K+ efflux
b) ↑ [Ca2+] in →↑ neurotransmitter release
c) excitory nt release (glu) promotes further depolarization
inhibition by surrounding GABAergic neurons
Na+ channel refractory period inhibits spread
Antiepileptic drugs (AED)
• Aim to inhibit the abnormal neuronal discharge
rather than to correct the underlying one
- Inhibition of Sodium channel function:
- carbamazepine
- phenytoin - Neuronal calcium channel blocker:
- ethosuximide - Neuronal potassium channel opener:
- retigabine - Enhancement of GABA action
i. GABA receptor agonists
- benzodiazepines
- barbiturates
ii. GABA reuptake inhibitor
- tiagabine
iii. GABA transaminase inhibitor
- vigabatrin - Glutamate receptor antagonist:
- topiramate - Others:
- valproic acid
- GABApentin
- levetiracetam
(1). Na+ channel inhibitors • Mechanism
– use dependant - inhibit cells that are firing repeatedly
(i.e those involved in seizure)
– bind preferentially to Na+ channel in refractory state
– slow channel return to resting state
– may have additional mechanisms
(1). Na+ channel inhibitors • drugs
– Carbamazepine
» may also potentiate opening of K+ channels
– Phenytoin
– Lamotrigine
(1). Na+ channel inhibitors • indications
– Carbamazepine – anticonvulsant, neuralgia, bipolar disease
– phenytoin
» long term (po) and rapid (i.v.) control of epilepsy
» arrhythmia –blocks cardiac Na+ channel
– lamotrigene –epilepsy
(1). Na+ channel inhibitors • PK
– Carbamazepine
» metabolized by and induces cytP450 3A4 (induces its own metabolism)
» t1/2 falls (65h →20 h) on repeated use & takes 2 weeks to reach new plasma conc
» measurement of plasma conc helpful after 2 weeks
» may take several months to titrate, may need b.i.d,
– Phenytoin
» also induces its own metabolism by Cyp 3A4
» metabolism is saturable in normal dose range
– small increase in dose can cause large increase in plasma conc
– increase dose slowly
» highly bound to plasma protein
– may be affeced by or affect other drugs bound to plasma protein
– Lamotrigene
» eliminated by glucoronidation and excretion in urine
(1). Na+ channel inhibitors • caution
– Carbamazepine
» makes myoclonic and absence seizures worse!
» risk of foetal neural tube defects during pregnancy
– Phenytoin
» risk of foetal neural tube defects in pregnancy (folate antagonism)
(1). Na+ channel inhibitors • CI
– Carbamazepine in patients with AV conduction abnormalities
(1). Na+ channel inhibitors • ADR
– Carbamazepine
» rash – may be transient but may be intolerable
» blurred vision
» causes ADH secretion and hence water retention
» CNS effects – drowsiness & loss of balance
– Phenytoin
» immediate – CNS effects- tremor, ataxia, lethargy, coma
» after long term therapy-– altered facial features due to collagen deposition, hirsutism, acne, rash, anaemia
– Lamotrigene
» rash (refer to doctor –possible hypersensitivity)
» CNS effects- dizziness, nervousness, tremor, confusion
» GI effects – nausea, vomiting
- Calcium channel inhibitors • Mechanism
– Inhibit “T-type” Ca2+ channel
- Calcium channel inhibitors • drugs
– Ethosuximide
- Calcium channel inhibitors • indications
– Absence seizures: brief interruption of consciousness, blank state
– Not effective against other generalized seizures (thought not to involve T-type Ca2+ channel)
- Calcium channel inhibitors • pk
– Absorption from the gut is almost complete
– Metabolism in the liver is extensive
– Half-life is long at 2-3 days
- Calcium channel inhibitors • ADR
– Nausea, vomiting, anorexia
– Drowsiness, dizziness, ataxia
3(i). GABA receptor agonists
• Benzodiazepines
– Enhance GABA binding to GABAR
– promote Cl- channel opening frequency
• Drugs – diazepam – lorazepam – midazolam – clonazepam
3(ii). GABA receptor agonists
• Barbiturates increase GABA Cl- channel open duration • not widely used: – significant sedation – respiratory depression – significant hypotension
Phenobarbital • Affects duration & intensity of seizures • Rather than seizure threshold • Well absorbed • 50% bound to protein • T1/2: 50-140h • 25% is excreted unchanged in urine • The remaining 75% is metabolised by hepatic microsomal enzymes
- Glutamate receptor antagonist • mechanism
– Antagonist activity at AMPA / Kainite glutamate receptor
– Blockade of neuronal sodium channel
– Enhancement of action of GABA at GABAA receptors
- Glutamate receptor antagonist • drugs
– Topiramate
- Glutamate receptor antagonist • indications
– Seizures
– Migraine
