Case 13- Epilepsy Flashcards
Epileptic seizures
They tend to be transient in nature and present with a variety of signs and symptoms. The symptoms depend on what part of the brain is being affected. The type of epilepsy is based on the age of onset, type of seizure, specific EEG characteristics. This has implications for treatment, management and prognosis
Categories of epileptic seizures
1) 3 main types: focal onset, generalised onset and unknown onset.
2) Generalised onset seizures are classified into 2 major categories: motor and non-motor. Generalised seizures affect both hemispheres of the brain.
Non-motor generalised seizures
Main type is Absence seizures. Brief episodes of impaired consciousness with no aura or postictal confusion. They last up to 20 seconds and are accompanied by few or no automatisms. Of the automatisms that develop, the facial ones are common, with repetitive blinking. Hyperventilation or photic stimulation frequently precipitates these seizures, which typically begin during childhood or adolescence and may persist into adulthood. Absences seizures can be typical, atypical, myoclonic or with eyelid myoclonia. No physical convulsions.
Main types of generalised motor seizures
1) Tonic-clonic seizures
2) Myoclonic tonic-clonic seizures
3) Myoclonic-atonic seizures
4) Clonic seizures
5) Tonic seizures
6) Atonic seizures
Generalised motor seizures= Tonic-clonic seizures
Known as grand mal seizures. They consist of several motor behaviours - generalized tonic extension of the extremities lasting for few seconds, followed by clonic rhythmic movements and prolonged postictal confusion. Most common motor form of seizure, whole body stiffness followed by rhythmic movement. Loss of consciousness.
Generalised motor seizures= Myoclonic tonic clonic seizures
Begins with a few myoclonic jerks followed by tonic–clonic activity. The initial jerks can be considered to be either a brief period of clonus or myoclonus. These seizures are commonly seen in patients with juvenile myoclonic epilepsy and occasionally with other generalized epilepsies.
Myoclonus
Spasmodic jerky contractions of a group of muscles
Clonus
A rhythmic, oscillating, stretch reflex,
Generalised motor seizures= Myoclonic atonic seizures
Involves brief jerking of limbs or trunk (myoclonic jerk) due to muscle contractions, followed by a limp drop (atonic component). These seizures, previously called myoclonic-astatic seizures, are most commonly seen in Doose syndrome but can also be encountered in Lennox-Gastaut and other syndromes.
Clonic seizures
Consists of rhythmic jerking motor movements with or without impairment of consciousness. They can have a focal origin too.
Tonic seizures
Sudden-onset tonic extension or flexion of the head, trunk and/or extremities for several seconds. These seizures typically occur in relation to drowsiness, shortly after patients fall asleep, or just after they awaken. Tonic seizures are often associated with other neurologic abnormalities. Brief loss of consciousness, body stiffens
Atonic seizures
Also called “drop attacks.” These seizures occur in people with clinically significant neurologic abnormalities and consist of brief loss of postural tone, often resulting in falls and injuries. Brief loss of consciousness, become limp.
Focal seizures
Where a burst of activity is limited to one part of the brain
Classification of focal seizures
Can be classified into with preserved or impaired awareness. These can further be spilt into motor and non-motor. Motor includes automatisms, atonic, clonic, myoclonic, tonic and hyper kinetic and epileptic spasms. Non-motor examples are autonomic, behavioural, cognitive, emotional and sensory.
Simple focal seizure
Muscular jerks or altered sensation in one arm/leg. Odd taste, do not lose consciousness or awareness.
Complex focal seizures
Often starts in the temporal lobe. May behave oddly- mumble, wander, handle objects. May have odd emotions, fear, visions or sensations.
Link between focal seizures and generalised seizures
Focal seizures may develop into generalised seizures
Categorisation of unknown onset seizures
Can be classified into motor, non-motor and unclassified
Causes of epilepsy
Tend to be unknown, may have a genetic component, there doesn’t tend to be any other neurological conditions associated with it. Unknown/idiopathic epilepsy tends to respond well with treatment.
Symptomatic epilepsy
Tends to present from birth or develop later. Can be caused by scar tissue, neoplasia, infarction or heat in the brain. Causes abnormal depolarisation in the brain
Epileptic triggers
Dont cause epilepsy but make seizures more likely. Triggers- stress, drugs, tiredness, low blood glucose, alcohol and flickering lights.
Pathology of epilepsy
Na+ channel inactivated state helps prevent repetitive firing during a seizure. Depolarisation and Na+ entry causes a seizure. Abnormalities in Na+ channels (excessively stimulated or open for a long time) can cause seizures.
Epilepsy- Neuronal signalling
Balance between excitatory (glutamate) and inhibitory (GABA) control.
Surround inhibition
Prevents spread of activity (GABA) but also amplifies local signal. Abnormal activation will not spread to further sites. The surround inhibition is made of GABA neurons, when activated they release chlorine into the cell stopping the depolarisation by increasing the negative charge. The activated circuit in the centre will amplify signals but it is surrounded by an inhibitory surrounding which decreases signals.
Cause of all seizures
Caused by abnormal synchronous discharge due to a failure of protective mechanisms
Causes of focal seizures
Due to a sudden depolarisation ‘Paroxysmal Depolarising shift’ in a group of neurons. Depolarised for a long period of time (200ms). Causes a sustained level of abnormal depolarisation. Surround inhibition may limit spread, you will still be able to see it on an EEG. If the surround inhibition is not effective the depolarisation will travel to different parts of the brain causing a seizure.
What may cause a focal seizure to spread
- Increase in intracellular K+
- Activation of NMDA channels (depolarisation)
- Decrease in GABA inhibition
Cause of generalised seizures
The seizure will focus in one part of the brain, due to a lack of surround inhibition the wave of depolarisation will spread across the hemisphere to the thalamus. The thalamus then passes the signals into both hemispheres. Depolarising neuronal networks will be turned on in both hemispheres causing a secondary generalised seizure. The whole brain does not have to be affected just significant parts of both hemispheres.
Steps of tonic-clonic seizures
- A loss of GABA neurones- causes contraction of muscles (tonic)
- GABA is restored but there is AMPA/NMDA excitation which is associated with the clonic phase.
- GABA recovers- the body becomes flaccid.
More information about the steps in tonic-clonic seizures
1) Tonic phase
2) Clonic phase
3) Postictal
Tonic phase
Sustained muscular contractions, the body becomes stiff. Sodium channels get switched on in the neurone, GABA neurons (Cl-) get switched off. Sustained depolarisation in the skeletal muscle.
Clonic phase
GABA neurones recover intermittently. When switched on they produce a hyperpolarising effect and dampen the Na+ channels The GABA neurons then dampen because it has not fully recovered and the Na+ channel will turn on. There will be periods of depolarisation and hyperpolarisation. Jerky movement due to skeletal muscles contracting and then relaxing.
Postictal phase
GABA is restored. The Na+ channels turn off, there is no more depolarisation
Primary generalised seizures
Seizures originate centrally in the Thymus and spreads to both hemispheres
Absence seizures
Tonic-clonic seizures are dependent on the activation of Na+ channels. Absence seizures are due to an activation of T-type Ca+2 channels. Requires the neurones to originally be hyperpolarised, at the start there will be an increase in GABA and then Ca+2 channels.
Effectiveness of epileptic medication
Majority of people with epilepsy can be seizure free if they receive the right type of medication for their seizure. Prognosis depends on the type of epilepsy. Might stop medication if they are seizure free for 2-3 years
When to start treatment for epilepsy
Treatment starts with a low dose after the second seizure but this varies. Standby medication can be administered when someone is in a seizure to limit its progression.
Principals of drug treatment for epilepsy
Use a monotherapy approach when possible. If the initial treatment fails a second drug should be started, it may be an alternative first or second line drug. Combination therapy should only be considered when monotherapy does not result in seizure freedom.
Treatment for childhood absence epilepsy
- First-line treatment- ethosuximide or sodium valproate
- If high risk of GTC seizures - sodium valproate
- Lamotrigine if ethosuximide/sodium valproate not suitable
Treatment for epilepsy with newly diagnosed generalised tonic-clonic seizures
- First-line treatment - sodium valproate
- Lamotrigine if sodium valproate not suitable
- Lamotrigine/sodium valproate if proven epilepsy syndrome
First line treatment for tonic or atonic seizures
Sodium valproate
First line treatment for myoclonic seizures
Sodium valproate
First line treatment for focal seizures
Carbamzepine or lamotrigine
Drug targets for epileptic treatment
- Na+ channel- inhibition
- Ca+2 channel- inhibition
- GABA receptor- activation
- Glutamate receptors- inhibition
When to use Sodium Valproate
- Infantile epilepsy= low toxicity, reduced sedative effect
* Adolescents with tonic–clonic, myoclonic or absence seizures
Sodium Valproate
Chemically unrelated to other epileptic drugs
o Increase in GABA by blocking GABA transaminase, stops depolarisation
o Inhibits sodium channels
o Inhibits T-type calcium channels
Sodium Valproate PK and PD
Well absorbed orally. Renal excretion – glucuronidation, another group is added to the drug in order to package it for excretion. Plasma half-life being about 15 h.
Sodium Valproate side effects
Thinning and curling of the hair, Hepatotoxicity, Teratogen - spina bifida, Thrombocytopenia.
Ethosuximide
Effective in absence seizures, little or no effect in other types of epilepsy. Mechanism of action is inhibition of T-type calcium channels.
Ethosuximide- PK and PD
Orally well absorbed, renal excretion, plasma half life 60h
Ethosuximide side effects
Nausea, anorexia, lethargy and dizziness, may precipitate tonic-clonic seizures in susceptible patients.
Types of sodium channel blockers
Used in focal and secondary generalised seizures
1) Phenytoin
2) Carbamazepine
3) Lamotrigine
Phenytoin
Slows recovery from Na+ inactivated state to closed state. Use dependent effect on blocking Na+ channels. Prevents repetitive firing of neurones, prevents the paroxysmal depolarising shift.
Phenytoin PK
95% plasma protein bound, half life 20h. Saturation kinetics so possible dosage problems, enzymes become saturated so difficult to predict plasma population. Hepatic enzyme inducer. Cytochrome P450 metabolism. Narrow therapeutic range.
Phenytoin side effects and interaction
Side effects= ataxia, nystagmus, confusion, incoordination, megaloblastic anaemia, coarse facial appearance and acne, hirsutism, gingival hyperplasia.
Interactions= cimetidine, isoniazid, chloramphenicol.
Carbamazepine
Chemically related to the TCA antidepressant. Similar pharmacology to phenytoin, metabolites may have antiepileptic properties. May use a slow releasing preparation. Requires therapeutic drug monitoring. Most widely used antiepileptic drug, particularly good for partial seizures.
Carbamazepine side effects and interactions
Side effects= Drowsiness, hyponatraemia, confusion, incoordination, ataxia, neutropenia.
Interactions= Powerful inducer of hepatic microsomal enzymes so may reduce concentration of other drugs such as Phenytoin, oral contraceptives, warfarin and corticosteroids.
Lamotrigine
Pharmocologicaly similar to phenytoin but with broader therapeutic actions so less likely to overdose. Effective against absence seizures.
Lamotrigine side effects
Nausea, dizziness and ataxia, hypersensitivity reaction
Activation of GABAa
Enhance GABA mediated surround inhibition. Response varies due to GABA subtypes and distribution, Prevent spread of seizure focus.
Drugs which activate GABAa
1) Benzodiazepines
2) Clonazepam
3) Vigabatrin
4) Gabapenin, pregabalin
5) Felbamate
Benzodiazepines
Benzodiazepines (diazepam, lorazepam, midazolam, Clonazepam)- Increases affinity of GABAa receptor to GABA. Increased Cl- influx (Hyperpolarisation). Neuronal action potential threshold more difficult to reach.
Side effects= ataxia, sedation and dizziness
Clonazepam
Has a T-type Ca channel effect
Phenobarbital
Increases duration of channel opneing
Vigabratrin
Inhibits GABA breakdown via GABA transaminase. Useful in resistant forms of epilepsy. Side effects are peripheral visual field defects, these are relatively common.
Gabapentin, pregabalin
Blocks HVA Ca+2 channels, reduces neurotransmitter release. Fewer adverse drug effects. Not generally 1st line treatment but may be useful in focal seizures.
Felbamate
Inhibits NMDA receptors (glutamate), use limited to unresponsive epilepsy due to risk of aplastic anaemia and liver failure.
