Epilepsy Causes and Treatments (O'Donoghue M DR) Flashcards
What goes wrong in a seizure?
Hyper-synchronised activity within a neural network
What varies between different types of seizure?
Pattern of epileptic discharges, circuits involved, likely cause, drugs for treatment, chance of cure (also varies between patients).
Why are some people prone to seizures?
Brain lesions and disorders of channels or receptors
How do anti-epileptic drugs work?
They target neuronal channels and neurotransmitter receptors: Na+ K+ Ca++ GABA and Glutamate SV2a Cannabinergic mechanisms
What is a ‘seizure’?
Clinical manifestation of a disordered and hyper-synchronised discharge in a network of cerebral neurons
How do we study seizures clinically?
Careful history from patient and witness
Home videos of seizure
Combined video-EEG
Result > Classification of seizures
What determines the type of seizure?
Location of onset
Type of discharge
Patter of spread
Where does a generalised seizure start?
Both hemispheres simultaneously
Where does a focal seizure start?
Seizure starts in a focus and then spreads
What three types of generalised seizures are there?
Typical absence
Myoclonic
Tonic-Clonic
When is the onset of Absence Seizures? How do they manifest?
Onset in childhood mainly Frequent, brief attacks (1-30s) Sudden loss and return of consciousness No aura or post-ictal state Some involuntary movements
What is the presentation of a Myoclonus Seizure?
Sudden, bried, shock-like muscle contraction
Usually bilateral arm jerks
Often worse in the morning
Precipitated by sleep deprivation and alcohol
Occurs in Epilepsy syndromes and certain non-epileptic causes
What are tonic-clonic seizures?
Sudden onset, gasp, fall
Tonic phase (stiff) with cyanosis (blueish discolouration)
Clonic phase
Post-ictal phase - confusion, exhaustion, disorrientation
Tongue bitten and incontinence
Noisy breathing
Headache and muscle pain afterwards
What three sub groups are there to Uncommon Generalised Seizures?
Atypical absence
Tonic - stiff
Atonic a.k.a drop seizure
Usually associated with severe epilepsy
What are the features of Focal (Partial) Seizures?
Focal onset means there is often an aura (warning to the beginning)
As seizures spread, a ‘complex partial seizure’ develops with loss of awareness and automatisms
In a ‘simple partial’, awareness is maintained, but in a ‘complex partial’ when the seizure spreads, alertness and awareness is lost.
In Focal Seizures the location of onset determines the seizure symptoms - which zones are potential sites?
Temporal lobe
Frontal lobe
Occipital lobe
Parietal lobe
What presents in a temporal lobe seizure?
Aura
-epigastric rising sensation, olfactory and gustatory (smell and taste)
-De ja vu
In a complex partial seizure starting in the temporal lobe; arrest reaction and blank stare, oral automatisms (lip smacking) and manual automatisms.
What is the hallmark EEG of generalised seizures?
Bilateral activity spike in waves
Are tonic clonic seizures ever seen in focal epilepsy?
Yes, the final culmination of a focal seizure
What are the key regulators in neuronal activity? Channels
Non-gated
Voltage-gated
Ligad-gated
Which receptors are key regulators in neuronal activity?
Metabotropic receptors (second messenger role)
Which cells have a role in neuronal activity?
Glia (astrocytes)
What is Ictogenesis?
The generation of a seizure
The inter-ictal spike; a short burst of epileptiform activity lasting 200ms
What is an inter-ictal spike?
A burst of activity by Na+ activity
An abnormal process / phenomenom
How does neuronal firing differ in seizures compared to normal?
Burst firing behaviour of neurons
When the firing becomes hyper-synchronised this leads to a seizure.
In absence seizures what is cut off?
Sensory input and inter-neurons are lost
What are the two modes of firing of thalamic neurons?
Burst mode or tonic mode
What happens if you make the cortex hyper-excitable?
Causes spike and wave - absence seizure like events / discharges.
What happens if you stimulate the frontal cortex or intra-laminar thalamic nucleus?
Causes spike and wave - absence seizure like events / discharges.
During human spike and wave discharges, where can these be measured?
Thalamus - (in absence seizures).
What is the pathophysiology of absence seizures?
There are connections between thalamus - cortex and the thalamus itself also contains loops. The membrane and synaptic nature of these neurons in loops causes oscillations. disturbances to these oscillations may cause spike wave firing.
What goes wrong in absence seizures?
Primary abnormality may be bursts of abnormal activity from the cortex to the thalamus
Thalamus may have a role in synchronising
The reticular nucleus inhibits TC relay cells which may underlie the “absence”.
What parts of the brain are involved in tonic-clonic seizures?
Basal ganglia / brain stem involved. Substantia nigra has gating function for severity of seizure.
What is the function of the basal ganglia?
The substantia nigra is the source of the striatal input of the neurotransmitter dopamine, which plays an important role in basal ganglia function.
What is Epileptogenesis? How does it develop?
Changes occur to :
Neuronal channels, receptors (play a role in pathophysiology)
Gap junctions
Glia: buffering of extracellular environment
BBB and inflammation
Loss and reorganisation of synapses
Cell loss inhibitory neurons
Inherited channel defects can cause epilepst (Dravet syndrome)
Some acquired epilepsies show changes in dendritic channel functions
What is Dravet syndrome?
Lost inhibitory neurons therefore increased neuronal firing
What is one of the main drug targets in epilepsy and why?
Sodium channels
They are use and voltage dependent
Prolongs the inactivated state of channel
The strength of the block increases with repetitive activation
Reduces burst firing
What properties are needed to block Na+ channels for therapeutic effect?
Drugs bind poorly to resting Na channels Fast inactivation (normal) is not affected Binding with prolonged depolarisations Main action is to stop the spread of the seizure (the onset of block is slow, can't stop all spikes but can prevent spread)
How does Lacosamide work?
Binds to Nap selectively in order to stop persistent sodium current
What kind of sodium channel mutation can lead to epilepsy?
Some mutations in sodium channels give increased function to Na p –> this can lead to persistent sodium current
Some brain lesions may also have increased Na p channels “acquired channelopathy”
How can Lamotrigine worsen some epilepsy?
Patients with a mutation that results in loss of function in sodium channels might have epilepsy worsened by Lamotrigine because inhibitory neurons are inhibited further.
How is GABA manipulated by AEDs?
Enhancing Cl current at GABA receptors promotes inhibition of neuronal firings
Reducing GABA degradation or reuptake to maximise amount at synaptic cleft.
How do Benzodiazepines, Barbiturates and Topiramate work as anti-epileptics?
Enhance Cl current at GABA receptors = inhibition
How does Vigabatrin and Tiagabine act as AED?
Vigabatrin is a GABA transaminase inhibitor
Tiagabine is a GABA reuptake inhibitor
These higher GABA levels prevent the fading of inhibition.
How does Retigabine work? (WITHDRAWN)
Augments potassium channel
Currently withdrawn due to possible retinal side effects
How does Perampanel work?
Highly selective non-competitive AMPA antagonist
Inhibits excitatory transmission
Side effect = patients can become violent as a result
Which AEDs are particularly poorly understood?
Valproate NA K CA GABA NMDA?
Gabapentin and Pregabalin Ca, GABA, NMDA?
Levetiracetam SV2a?
What are the key points to epilepsy management?
Ensuring correct diagnosis
Determining the cause
Deciding on treatment
Advising on life-style issues
What are some of the non-epileptic causes of seizures and ‘black outs’?
Epilepsy Fainting Cardiac causes Attacks with psychological causes Rarities
The epilepsy is then classified by what factors?
Seizure type EEG MRI Family history Associated causes Treatment and prognosis determined from this
What is idiopathic epilepsy?
No neurological damage
Often responds well to treatment
Genetic component suspected
What is symptomatic epilepsy?
Seizures are the symptoms of lesion, tumor, stroke etc
Focal and harder to treat, more resistant to treatment an d have associated neurological defects.
What are the causes of symptomatic epilepsy?
Cortical malformations (from birth due to hypoxia)
Cerebral palsy
Genetic and metabolic disorders
Hippocampal sclerosis (convulsions as an infant)
Trauma and Infection
What are the principles of treatment with reference to
The disorder
The patient
The drug
The disorder - diagnosis must be certain
The patient - wants treatment and is counselled about it
The drug - is appropriate for the syndrome, low dose initially, side effects and interactions are explained
Initial treatment options fro generalised epilepsy?
Sodium valproate
(child-bearing) Lamotrigine
Initial treatment for focal epilepsy?
Lamotrigine
What are the benefits to using Lamotrigine?
Broad spectrum
1st line
Focal and generalised
Well tolerated, safer for women of a child-bearing age
How does Carbamazepine work?
Acts on sodium channels to suppress burst activity and spread of seizures Not helpful (makes worse), for myoclonus or absences.
How does Valproate work?
Unknown action
GABA, inhibits excitatory transmission via Ca or K?
1st line for partial and generalised seizures
Important for myoclonus, absences and photosensitive seizures also
How does Phenytoin wok?
Acts on sodium channels
Suppresses burst activity and spread of seizures
Not helpful for myoclonus and absences
Useful in emergencies
Which AED is helpful for myoclonus or absence seizures?
Valproate
Topiramate
What is a problem in the administration of phenytoin?
Zero order kinetics, metabolism is not linear
How does Levetiracetam work?
Potent broad spectrum agent, targets synaptic vesicle protein 2a, well tolerated
What are the problems associated with enzyme inducing drugs?
Reduced combined oral contraceptive, antimicrobials, anti-virals, analgesics, oncology drugs, warfarin
What is Status Epilepticus?
A medical emergency
Rapid treatment: IV Benzodiazepine and phenytoin
IV levetiracetam or valproate or lacosamide
General anesthesia
Which non-pharmacological treatments can be recommended for epilepsy?
Vagal nerve stimulation
Resection of epileptic focus
Ketogenic diet
What are the potential future treatments for epilepsy?
Gene therapy
Deep brain stimulation
Optogenetics; harnessing the power of light!
What are the consequences of epilepsy?
Loss of employment, driving license Stigmatisation and anxiety Needing AED Problems with contraception and conception Injuries and mortality
Overview of Drug Use
Absence: valproate, ethosuximide, lamotrigine, benzos
Myoclonus: valproate, benzos, levetiracetam
GTC; CBZ, LTG, valproate, phenytoin, topiramate
Focal: carbamazepine, lamotrigine, topiramate, levetiracetam
