Epilepsy

Epilepsy is a disorder characterised by recurrent seizures due to abnormal electrical activity occurring in the brain.

We can define epilepsy as any of the following:

2 or more unprovoked or provoked (reflex) seizures more than 24 hours apart.
One unprovoked or provoked seizure + a probability of recurrence of at least 60% over the next 10 years.
Diagnosis of an epilepsy syndrome (more on these later).

A reflex seizure is a seizure provoked by external stimuli or (less frequently) internal stimuli:

External stimuli - light patterns (photosensitive epilepsy), sounds (musicogenic), reading, bathing etc.
Internal stimuli - mental processes such as decision making, abstract reasoning, calculations can be the cause of seizures in certain instances).

🔢 Classification

We can classify epilepsy based on 3 things:

1. Seizure classification

Generalised onset seizure
Focal onset seizure
Unknown onset seizure

2. Epilepsy classification

Generalised epilepsy
Focal epilepsy
Combined (generalised and focal) epilepsy
Unknown epilepsy

3. Epilepsy syndromes

Epilepsies with common clinical and electrical manifestations.

Myoclonic-atonic - technically it is also known as Doose syndrome.

[COMPLETE SYNDROMES SUCH AS LENNOX-GASTAUT, JANZ SYNDROME ETC.]

🔢

Seizure classification

Generalised onset seizure

Seizure originating in a certain point in the brain but then spreads to both hemispheres.

They can be further sub-classified as motor or non-motor:

Motor

Tonic:

Bilateral hypertonia (stiffness) of limbs that lasts between 3 seconds - 2 minutes + total loss of consciousness.

Tonic-clonic (grand mal seizures):

Consists of the tonic phase (hypertonia) followed by a clonic phase (bilateral sustained rhythmic stiffening and relaxing of the muscle) and once again accompanied by total loss of consciousness.

Atonic:

Sudden hypotonia (without a preceding myoclonic or tonic phase). They are very brief (less than 2 seconds) and involved the head, trunk or limbs.

Myoclonic:

Rapidly alternating stiffening and relaxing of a muscle or muscle group. They usually last milliseconds. Myoclonic jerks can occur in non-epileptics too, for example, a jerk that we make as we are falling asleep that can wake us up sometimes.

Epileptic spasms:

Sudden flexion, extension or both of the proximal and truncal muscles that lasts longer than a myoclonic jerk but not as long as a tonic seizure (i.e. 1-2 seconds long).

Non-motor

Absence seizure (petit mal seizure):

Generalised seizure with altered awareness. It is typically an abrupt onset and offset but atypically is less abrupt. They may be triggered often by a period of hyperventilation.

Absence seizure with eyelid myoclonia:

Absence seizure + myoclonic jerks of the eyelids with simultaneous upward deviation of the eyeballs and extension of the head.

Myoclonic absence seizure:

Myoclonic jerks of the shoulders and arms with

Focal onset seizure (partial seizure)

Seizures that remain limited to one hemisphere. As it is not as widespread, we can determine the lobe(s) involved based on the symptoms.

These focal seizures may subsequently spread to wider areas of the brain, leading to a secondary generalised seizure, which is nowadays referred to as a focal to bilateral tonic-clonic seizure. In these instances, consciousness will be impaired.

Focal seizures can be sub-classified based on 2 things:

Level of awareness

Aware
Impaired awareness

Initial feature at onset of seizure - depending on whether it is initially a motor feature or non-motor.

a. Motor onset

Focal clonic seizure - sustained rhythmic jerking of a distal limb, on one side of the body. This jerking may spread to other regions of the motor cortex leading to a shift in the limb(s) involved. This can be identified through the homunculus and is known as a Jacksonian March.
Focal tonic seizure
Focal myoclonic seizure

b. Non-motor onset

Focal sensory seizure - sensation experienced at seizure onset. It may be somatosensory (tingling, numbness, pain), visual, auditory, olfactory, gustatory, vestibular etc.
Focal cognitive seizure - alterations in cognitive function at seizure onset. This may mean deficits in cognition but also may include forced thoughts
Focal emotional seizure - alterations in mood or emotion. This may include seizures with fear/anxiety/panic, laughing, crying, pleasure or anger.
Focal autonomic seizure - characterised by alterations in systems controlled by the autonomic nervous system at seizure onset, such as palpitations, hypo or hyperventilation, pallor/flushing, pupillary dilatation/constriction, altered respiration.
Focal behavioural arrest seizure - this is characterised by stopping of movement and changes to other non-motor areas.

Unknown onset seizure

An unclassified seizure based on an inadequacy in the information meaning that we are unable to determine if the seizure is generalised or focal. Inadequacies may be due to the seizure being unwitnessed at onset or investigation results being unavailable yet.

🔢

Epilepsy classification

Generalised epilepsy - these patients have generalised seizures.
Focal epilepsy - these patients have focal seizures.
Combined (generalised and focal) epilepsy - these patients may have both generalised and focal seizures. Patients with epilepsy syndromes such as Dravet syndrome or Lennox-Gastaut syndrome may have combined epilepsy.
Unknown epilepsy - when the patient is known to have epilepsy but it is uncertain whether it is generalised, focal or combined. It is usually due to insufficient information for us to classify the epilepsy.

🔢

Epilepsy syndromes

We’ll discuss this at the end in more detail…

[REMINDER TO DISCUSS MORE]

Pathophysiology

The definitive pathophysiology of epilepsy is not clear. It does relate to hyperexcitability of neurons and hypersynchrony (neurons firing action potentials in unison). A commonality across different seizure types is an imbalance between glutamatergic signalling (excitatory) and GABAergic signalling (inhibitory). The imabalance is as a result of deficits in the GABAergic signalling (i.e. decreased inhibition) or due to overloads in the glutamatergic signalling (i.e. hyperexcitation).

The aetiology of the hyperexcitability and hypersyhnchrony may be broken down into the following:

Infectious aetiology

The most common aetiology worldwide. This may be due to:

Tuberculosis
HIV
HSV
Malaria
Toxoplasmosis
Neurocysticercosis - parasitic infection due to taenia solium found in pigs (also known as pork tapeworm).
Measles - which becomes complicated and leads to subacute sclerosing panencephalitis.

Genetic aetiology

The genetic mutations may be inherited (both autosomal dominant or recessive) or may be de novo. The de novo mutations only affect a percentage of cells (known as mosaicism).

Germline mutations (if gonadal cells are affected) may make it heritable.

Structural aetiology

This is when there is a distinct structural abnormality within the brain that may predispose one to seizures. This may be due to trauma, infection, stroke, or it may be a genetic structural abnormality.

Metabolic aetiology

Another form of inherited epilepsy in which normal metabolic processes are impaired as a result of mutations or deficiencies of certain enzymes or metabolites.

Immune aetiology

Autoimmune epilepsy may be due to antibodies against neural receptors such as NMDA receptor, LGI1 receptor, or GAD65.

The antibodies may sometimes occur as a paraneoplastic syndrome.

Rasmussen’s syndrome is a progressive autoimmune encephalitis that can lead to epilepsies.

😷 Presentation

The presentation of the seizure is totally dependent on the region of the brain that is affected as well as the level of awareness. We will look at the symptoms that can help identify the focus in a focal seizures.

Before we look at the symptoms that occur, let’s clarify that there are 3 seizure phases (especially with generalised seizures):

Prodromal phase

This is a sensation felt hours or days prior to the seizure itself. It is a subjective feeling that is felt in about 20% of epileptics. It is not a phase of the seizure itself but is still important to note.

Prodromal symptoms may include:

Confusion
Anxiety
Irritability and mood swings
Headache

Early ictal (aura) phase

Seen in 2/3rds of epileptic patients. The symptoms also depend on the region affected, the seizure type, the severity of the seizure.

Aura symptoms may include:

Deja vu
Jamais vu
Dizziness
Visual disturbances
Paraesthesias
Headache
Anxiety
Sadness or happiness
Muscle twitching

Ictal phase

This is the more identifiable phase of the seizure. The symptoms involved are dependent once again on the region affected, seizure type and severity.

Ictal symptoms may include:

Impaired awareness
Convulsions
Confusion
Sensory changes
Lip smacking or chewing
Palpitations
Respiratory difficulties
Pallor/flushing of skin
Tongue biting
Urinary incontinence

Post-ictal phase

This is considered the “recovery” phase of the seizure. Some people immediately recover while others may take a while (up to days) to feel totally recovered.

Fatigue
Unconsciousness
Headache
Anxiety
Embarrassment
Myalgia
Nausea

The absence of a post-ictal phase is highly suggestive of an alternative diagnosis to epilepsy.

Anatomical distribution of symptoms

In focal seizures, the features that present correspond to the anatomical location involved. Let’s take a look at the relevant lobes and the symptoms that may present accordingly:

🧠

Frontal lobe:

The frontal lobe is the region containing the motor cortex. It is the largest lobe and therefore many seizure types may occur.

They often have a brief aura and awareness may/may not be impiared. However, if it is a frontal focal impaired awareness seizure then it may be difficult to distinguish from absence seizures.

The seizures are usually brief.

Other symptoms of frontal lobe seizures include:

Head and eye deviation
Explosive prominent vocalisation - such as screaming, laughing, profanities.
Altered language expression
Strange behaviour
Urinary incontinence
Motor symptoms

Asymmetrical tonic posturing - one arm flexed while the other extended (as if fencing).
Bipedal kicking (kicking with both legs)
Pelvic thrusting
Jacksonian march

🧠

Parietal lobe:

The parietal lobe is the lobe responsible for sensory activity in the body. As sensations are subjective to the individual experiencing them and not outwardly visible, it makes these seizures difficult to diagnose (especially in children who are unable to express themselves as well).

Parietal focal seizures may present with:

Paraesthesias
Hyper-sensitivity or hypo-sensitivity to sensory stimuli.
Disorientation
Illusions and hallucinations

🧠

Temporal lobe:

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy.

TLE that is an aware seizure often begins with an aura of:

Rising epigastric sensation
It may then be followed by deja vu or jamais vu.
Sometimes there may be an auditory, gustatory (taste), or olfactory hallucination of sorts.
Lip smacking, grabbing, plucking are all “automatisms” that may be present with TLE seizures.

It is important to be aware that an olfactory hallucination may raise suspicion of a tumour/lesion within the hippocampus region.

It may also be a focal impaired awareness seizure.

🧠

Occipital lobe:

Our occipital lobe is the region of the visual cortex. Hence, focal visual seizures originate here. Visual seizures are experienced differently from person-to-person, therefore they can be difficult to diagnose (especially in kids).

These seizures often do not remain in the occipital lobe and spread to other lobes of the brain.

Features of occipital lobe focal seizures include:

Forced eye closing
Eyelid fluttering
Eye deviation
Nystagmus
Floaters and/or flashes

🔍 Investigations

A comprehensive history is necessary to understand the nature of the seizures. We can then carry out some investigations, such as:

Electroencephalogram (EEG) - this is an electrogram of the electrical activity of the brain. It should be carried out after the patient’s first seizure.
Neuroimaging - this also needs to be carried out after an EEG. It is usually an MRI that is performed.

EEG and imaging may be all normal in epilepsy sometimes, and other times non-specific signs may be interpreted as epilepsy. A method that may be used to differentiate between epileptic and non-epileptic seizures is to elevate the individual’s arm above their head. If the arms fall laterally, then it is non-epileptic. If the arms fall on the head then it is more likely to be epileptic.

🧰 Management

We will look at the management of epilepsy in the acute setting, followed by long-term management of different seizure types.

Acute seizure management

🧰

Acute management of seizures:

Most seizures spontaneously terminate, however, if a seizure does not terminate within 5 minutes, then the patient is deemed to be in status epilepticus.

🚨 Managing convulsive status epilepticus in adults

Managing convulsive status epilepticus of course requires anticonvulsant medications. The choice of anticonvulsant used is dependent of the setting in which we are in/the ability to gain IV access:

🥇 Community setting (no IV access) - buccal midazolam or rectal diazepam.
🥇 Hospital setting (IV access) - IV lorazepam.

A maximum of 2 doses of benzodiazepines should be given.

🥈 The patient should be reassessed after 5-10 minutes, and if they are found to still have a seizure → leviteracetam OR phenobarbital OR phenytoin. The anaesthetist should also be called.

🥉 After 5 minutes after giving the second-line agent we should reassess. If the patient is still seizing, then a general anaesthetic should be administered, such as thiopental or propofol.

🚨 Managing convulsive status epilepticus in children

The RESUS council has provided the algorithm for children. The algorithm is very similar to that of adults. The only change is that in the community setting intraosseous lorazepam can also be considered instead of rectal diazepam.

If there are 3 or more self-terminating seizures within 24 hours this is referred to as cluster seizures. Cluster seizures are a medical emergency and require immediate attention.

🚨 Managing cluster seizures

🥇 Follow the patient’s individualised emergency management plan if it is available.

🥈 If unavailable, give a benzodiazepine immediately.

Clobazam or midazolam are some options that may be used.

Long-term epilepsy management

Antiepileptic drugs (AEDs) are generally started following a second epileptic seizure. NICE does have certain instances in which an AED should be started following the first epileptic seizure. This includes any of the following criteria:

Patient has any neurological deficit
Patient has any structural brain abnormality present
EEG shows unequivocal epileptic activity
Patient, family or carers do not accept the risk of a further seizure

AEDs are the mainstay of epilepsy management. Other options may include:

Ketogenic diet - it is not entirely understood, but t has been shown that chronic ketosis elevates the brain energy reserve by reducing excitability of synapses and their stabilisation.
Resective epilepsy surgery - this involves removing tumours, abscesses or other damage in the brain that has been causing seizures.
Vagus nerve stimulation - a pulse generator is connected to the left vagus nerve in the neck which stimulates it to reduce brain excitability.

Let’s now look at which AED’s are indicated in specific types of epilepsies:

🧰

Choosing antiepileptic drugs:

Generalised tonic-clonic seizures (grand mal seizures):

🥇 Monotherapy:

Males

🥇 Sodium valproate
🥈 Lamotrigine/leviteracetam - if sodium valproate is not successful or intolerable.

Females

🥇 If unable to conceive or <10 years old and not deemed likely to need treatment when of childbearing age - sodium valproate
🥇 If of childbearing age or if <10 years old and deemed likely to continue needing medication when of childbearing age - lamotrigine/leviteracetam

🥈 First-line add-ons:

Clobazam
Lamotrigine
Leviteracetam
Perampanel
Sodium valproate
Topiramate

🥉 Second-line add-ons

Brivaracetam
Lacosamide
Phenobarbital
Primidone
Zonisamide

Focal seizures:

🥇 Lamotrigine OR leviteracetam
🥈 Carbamazepine OR oxcarbazepine zonisamide

Absence seizures:

Ethosuxamide
Sodium valproate - in males
Lamotrigine or leviteracetam - in females

Myoclonic seizures:

Sodium valproate - if male.
Lamotrigine - if female (can also be second-line option in males).

A ketogenic diet can also be trialled in children.

Idiopathic generalised epilepsies

Males

🥇 Sodium valproate
🥈 Lamotrigine/leviteracetam - if sodium valproate is not successful or intolerable.

Females

🥇 If unable to conceive or <10 years old and not deemed likely to need treatment when of childbearing age - sodium valproate
🥇 If of childbearing age or if <10 years old and deemed likely to continue needing medication when of childbearing age - lamotrigine/leviteracetam

Let’s take a look quickly at some special scenarios:

🤰

Epilepsy in pregnancy:

Many AEDs have a risk of teratogenicity and pose a risk to the foetus. However, the risk of uncontrolled epilepsy throughout pregnancy poses a greater risk and for this reason pregnant women are advised to manage their epilepsy. Congenital defects are present in approximately 1-2% of non-epileptic pregnancies. in epileptics, this rises to 3-4%.

It is important to come to a shared decision with the mother.

The risks of uncontrolled epilepsy during pregnancy generally outweigh the risks of medication to the fetus. All women thinking about becoming pregnant should be advised to take folic acid 5mg per day well before pregnancy to minimise the risk of neural tube defects. Around 1-2% of newborns born to non-epileptic mothers have congenital defects. This rises to 3-4% if the mother takes antiepileptic medication.

Monotherapy is preferred and should be aimed for. Breastfeeding is also generally considered safe, except if the mother uses barbiturates.

Let’s discuss some specific AEDs and their risks:

Sodium valproate - associated with neural tube defects and neurodevelopmental delay. it should not be used in pregnancy or in women of childbearing age.
Leviteracetam and lamotrigine - preferred in pregnancy and women of childbearing age. Lamotrigine dosage needs to be increased in pregnancy too.
Phenytoin - associated with cleft palate. If taking phenytoin during pregnancy, vitamin K is advised during the last month of pregnancy to prevent any clotting disorders in the neonate.

🛻

Driving:

After a seizure, patients are not allowed to drive for 6 months. If they get a diagnosis of epilepsy, the patient has to be seziure-free for 12 months before driving. The DVLA ahas to be informed, however.

💊

Drug interactions:

AEDs can inhibit or induce the cytochrome P450 enzymes and this can increase or decrease the effect of certain medications. For example, warfarin activity increases with carbamazepine or phenytoin for example.