Epilepsy

Epilepsy is a chronic neurological disorder, which is characterised by recurrent seizures.

Epilepsy is characterised by development of multiple seizures.

A seizure refers to a transient neurological change due to synchronous, hyperexcited neuronal activity in the brain. Clinically, this manifests as a transient occurrence of seizure-like activity. This ‘activity’ may refer to a disturbance of consciousness, motor function, emotion, behaviour, cognition or sensation.

Epilepsy is a common neurological disorder that affects > 70 million people globally. The lifetime risk of having a single seizure is 1 in 10, whereas the lifetime risk of having epilepsy is 3%.

The cause of epilepsy is unknown in up to one third of patients.

Seizures are common and often occur secondary to an acute insult. These types of ‘provoked’ seizures usually occur at the time of acute illness (e.g. acute stroke, head trauma, hypoglycaemia) or in temporal relationship with the insult. 

An acute symptomatic seizure secondary to a defined cause needs to be differentiated from the recurrent, unprovoked seizures that occur in epilepsy. 

The cause of epilepsy can be broadly divided into six groups:

• Genetic: known or presumed genetic mutation that predisposes to recurrent seizures. 
• Structural: visible neurological abnormalities that predispose to seizures (e.g. chronic cerebrovascular disease, congenital malformation)
• Metabolic: known or presumed metabolic disorder that predisposes to seizures
• Immune: underlying immune disorder that predisposes to recurrent seizures
• Infectious: chronic infection predisposing to seizures (e.g. HIV). This must be differentiated from seizures associated with an acute infection (e.g. meningitis)
• Unknown: up to one third of patients.

Seizures develop due to an imbalance between inhibitory and excitatory signals in the brain.

A seizure may initiate due to high-frequency bursts of excitatory action potentials in neurons. This leads to synchronous, hyperexcitable activity within a neuronal population. If this activity is propagated to other neuronal populations it can lead to clinically apparent seizures. The seizure phenotypes (i.e. clinical features) relate to the location and function off the neuronal network that have been recruited into this abnormal synchronous activity. 

In epilepsy, acquired or genetic factors effect the balance between inhibitory (i.e. gabanergic) and excitatory (i.e. glutamatergic) signals.

• Gabanergic: inhibitory, characterised by gamma-aminobutyric acid (GABA) receptors. Ligand-gated ion channel that allows flow of chloride ions. GABA is the main inhibitory neurotransmitter that binds to these receptors.
• Glutamatergic: excitatory, characterised by glutamate receptors (multiple types: ion-channels and G-coupled protein). Glutamate is a small neurotransmitter that can active these receptors.

Overtime, there is transformation within neural networks that promote excitability. This is associated with long-lasting structural and/or biochemical changes that promotes development of epilepsy. 

Several known factors increase the risk of developing epilepsy.

• Cerebrovascular disease
• Head trauma
• Cerebral infections
• Family history: epilepsy or neurological illness
• Premature birth
• Congenital malformations of the brain
• Genetics conditions associated with epilepsy

The classification of epilepsy is based on recommendations by the International League Against Epilepsy (ILAE).

There are many types of seizures and associated syndromes. The ILAE has a very useful website for helping us classify epilepsy.

Classification is based on:

• Seizure type
• Epilepsy type
• Epilepsy syndrome. 

This refers to the exact type of seizure that occurs.

Seizure type can be determined using a three step process that focuses on the area of onset, presence of awareness and associated clinical features. 

Area of onset

• Focal: localised to a network of neurons in one hemisphere of the brain. 
• Generalised: affecting both hemispheres of the brain and associated neuronal networks 
• Focal to bilateral tonic-clonic: a focal seizure may spread to affect a wider network of neurons involving both hemispheres.Traditionally termed a secondary generalised seizure.

Awareness

• Awareness: fully aware of themselves and their environment throughout seizure. 
• Impaired awareness: any impairment of awareness during course of seizure. Complex partial seizures was the old term for focal onset impaired awareness seizures. 

NOTE: important for focal seizures. All generalised seizures affect awareness in some way. 

Clinical features

• Motor:
  • Tonic (generalised muscle stiffening)
  • Clonic (rhythmic muscle jerking)
  • Myoclonic (brief, ‘shock-like’ involuntary jerks)
  • Atonic (loss of motor tone)
  • Spasms (sudden flexion and/or extension movements).
• Non-motor:
  • Focal onset associated with sensory, cognitive, emotional, autonomic or behavioural changes.
  • Generalised onset with symptoms typical of an absence seizure.

Following diagnosis, the actual type of epilepsy can be determined.

The development of recurrent seizure types may lead to the diagnosis of epilepsy. Diagnosis is based on one of three criteria (see chapter on diagnosis). If one of these criteria is met, epilepsy can be classified to a particularly type. 

• Focal epilepsy: any focal seizure types. 
• Generalised epilepsy: generalised seizure types.
• Generalised and focal epilepsy: combination of both. 
• Unknown epilepsy: insufficient evidence to conclude whether focal, generalised or both. 

Epilepsy may be organised into a specific syndrome.

An epilepsy syndrome is characterised by the recurrent propensity to a specific seizure type or series of seizure types. Determining an epilepsy syndrome is important to guide medical therapy with anti-epileptic drugs (AEDs). Classic epilepsy syndromes include West syndrome, Lennox Gastaut syndrome and juvenile myoclonic epilepsy among many others.

Epilepsy syndromes usually have important characteristics:

• Typical age of onset
• Specific seizure types
• Specific electroencephalogram (EEG) features
• Additional clinical or radiological features

Epilepsy is characterised clinically by seizures, which can manifest in numerous ways.

The clinical features associated with a seizure depend on the affected location and function of the brain. This is covered in the chapter on classification.

Each individual seizure is composed into four distinct stages: prodromal, early-ictal, ictal, post-ictal.

Prodromal

This describes a period of subjective feeling or sensation that occurs before the onset of a seizure. It only occurs in some patients and may present with features such as confusion, irritability or mood disturbances.

Early-ictal

This phase is characterised by aura. An aura is the earliest sign of seizure activity and refers to subjective symptoms experienced by the patient. These can include sensory, cognitive, emotional or behaviour changes. Not all patients will experience an aura (e.g. generalised seizure onset).

An aura is suggestive of focal epilepsy (occurring in one part of the brain) and may progress to affect a wider area, or develop into a focal to bilateral tonic-clonic seizure.

Ictal

The ictal phase is highly variable depending on seizure type. 

In layman terms, ‘seizure’ usually refers to a generalised tonic-clonic seizure. This is characterised by stiffening and subsequent rhythmic jerking of the limbs. It may be associated with urinary incontinence and tongue biting, and normally lasts 1-2 minutes.

When a single seizure lasts > 30 minutes in duration, or two seizures occur without regaining consciousness after the first, it is termed status epilepticus or ‘status’. Status is broadly divided into convulsive (i.e. movement) and non-convulsive (i.e. no movement). This is a medical emergency and discussed further in our notes on status epilepticus. 

Post-ictal

This is the recovery period, when the seizure has abated. There may be an extended recovery period, which is dependent on seizure type. During the period of recovery there may be altered consciousness, confusion, memory loss, drowsiness or general malaise. 

This period may last hours, particularly with tonic-clonic seizures. 

The diagnosis of epilepsy is based on one of three criteria.

A diagnosis of epilepsy is made if any of the following three criteria apply:

• Criteria 1: ≥2 unprovoked (or reflex) seizures occurring more than 24 hours apart 
• Criteria 2: 1 unprovoked (or reflex) seizure with a probability of further seizures felt to be at a similar recurrence risk to patients with ≥2 unprovoked seizures over the next 10 years.
• Criteria 3: A diagnosed epilepsy syndrome

Differential diagnosis

There are numerous epilepsy mimics, which can be grouped into several categories:

• Syncope and anoxic seizures: transient loss of consciousness from impaired cerebral blood flow. 
• Behavioural, psychological and psychiatric: non-epileptic seizures (i.e. pseudoseizures)
• Sleep-related conditions
• Paroxysmal movement disorders
• Migraine associated disorders
• Other

NOTE: non-epileptic seizures resemble epileptic seizures but with no electrophysiological correlation or clinical evidence for epilepsy.

Neuroimaging and an EEG can help support the diagnosis of epilepsy.

Following a seizure, baseline investigations should be used to look for a precipitating cause. In adults, a series of baseline investigations including an ECG and bloods is essential. 

• ECG
• Bloods: FBC, U&E, LFT, Glucose, Bone profile
• Other: depending on suspected aetiology and age of presentation. 

EEG

A non-invasive method of assessing and recording the electrical activity of the brain. Epilepsy, or the propensity towards seizures, is associated with particular waveform activity on an EEG. They are usually analysed by neurophysiologists. 

Main uses:

• Support a diagnosis of epilepsy
• Assess risk of seizure recurrence
• Determine seizure type of epilepsy syndrome

It is not used as a sole diagnostic tool and cannot be used to exclude epilepsy, particularly if the clinical presentation supports a diagnosis of epilepsy. 

Neuroimaging

Typically involves magnetic resonance imaging (MRI), but computed tomography (CT) can be used where MRI is not available or suitable. Able to look for structural abnormalities that cause certain epilepsies. 

MRI essential in patients who develop epilepsy before two years old, there is a suggestion of focal onset seizures or poor seizure control with anti-epileptics. 

Management of epilepsy is broadly divided into acute control of seizures and long-term prevention of seizures with AEDs.

The overall goal for managing a patient with epilepsy should be for no seizures and no side-effects from medications. This will not be possible in every patient due to the complexity of epilepsy.

The key aspects of management are education and safety, treating acute seizures, role of the first fit clinic and long-term treatment with AEDs.

Education and safety

It is vital to educate patients, family and carers about epilepsy, provide information regarding safety precautions and how to provide pre-hospital care for seizures. This may be in the form of a formal first-aid course or guidance on epilepsy society websites.

Safety precautions:

• Driving: see the section below on driving rules
• Water safety: a seizure whilst in water can be life-threatening. Use a buddy system. Showers instead of baths.
• Fire safety: be careful with heat or flames, particularly with frequent seizures.
• Environmental safety: arranging the home or work environment to be safe in case of seizures
• Other: care with heights, high risk recreational activities, contraception for certain mediations, etc.

Acute seizures

For management of an acute seizure see our notes on status epilepticus.

First fit clinic

After initial presentation and management of a suspected epileptic seizure, patients should be referred to a ‘first fit’ clinic where they will be seen by a specialist who manages patients with epilepsy (i.e. neurologist).

The clinic involves formal assessment (history and examination) and organisation of relevant investigations (e.g. MRI, EEG) to determine whether the seizure is likely to represent epilepsy. If the diagnosis of epilepsy is made, patients are given education and started on AEDs.

As a general rule, following a single seizure patients are not routinely started on AEDs unless there is felt to be considerable risk for another seizure.

Anti-epileptic drug choices

AEDs are the hallmark of long-term treatment of epilepsy. They reduce the risk of developing seizures. There are different choices, which depend on the type of epilepsy, patient demographics, side-effect profiles and patient choice.

Common AEDs:

• Sodium valproate: unclear mechanism. Teratogenic. Key side-effects: drug-induced liver injury, pancreatitis, increased suicide risk.
• Carbamazepine: sodium channel antagonist. Increased teratogenic risk. Key side-effects: agranulocytosis, SIADH.
• Lamotrigine: sodium channel antagonist. Increased teratogenic risk (but low). Key side-effects: severe skin reactions
• Levetiracetam: unclear mechanism. Not enough evidence re. teratogenicity. Key side-effects: CNS disturbance (somnolence, decreased energy, headache), neuropsychiatric disturbance.
• Phenytoin: sodium channel antagonist. Teratogenic. Key side-effects: multiple. Arrhythmia with parenteral use. Classic cause of gum hypertrophy and cerebellar atrophy.

Anti-epileptic drugs and pregnancy

The Medicines and Healthcare products Regulatory Agency (MHRA) provide information on the safety of AEDs and pregnancy.

Most importantly, sodium valproate is highly teratogenic (30-40% developmental disorder / 10% congenital malformation) and should NOT be given to women and girls of childbearing potential. This includes girls who are likely to need treatment into their childbearing years. They provide recommendations for other AEDs. A clear risk/benefit discussion of these AEDs should always be discussed with the patient.

Anti-epileptic drug indications

The NICE CG137 guidelines (last updated May 2021, last accessed November 2021) provide guidance on the first-line and adjuvant medications that can be used for different types of epilepsy. The general rule is the initiation of monotherapy at the lowest possible dose to control seizures. Doses can be increased, and if ineffective, can be weaned down and a new medication introduced. Combination (i.e. adjunctive) therapy may be needed.

Common recommendations:

• Focal seizures:
  • 1st line – Lamotrigine (if childbearing potential), alternative carbamazepine (if no childbearing potential)
  • 2nd line – Levetiracetam, oxcarbazepine or sodium valproate*
• Generalised tonic-clonic seizures:
  • 1st line – sodium valproate* or lamotrigine.
  • 2nd line – clobazam, lamotrigine, levetiracetam or topiramate.
• Absence seizures:
  • 1st line – ethosuximide or sodium valproate*.
  • 2nd line – lamotrigine.
• Myoclonic seizures:
  • 1st line – sodium valproate.
  • 2nd line – levetiracetam or topiramate.
• Juvenile myoclonic epilepsy:
  • 1st line – sodium valproate*.
  • 2nd line – lamotrigine , levetiracetam or topiramate.

*NOTE: only offered to boys, men, and women who are not of childbearing potential

Contraception

Patients should be advised that oxcarbazepine and topiramate can impair the effectiveness of hormonal contraceptives.

The two major complications of epilepsy are status epilepticus and sudden unexpected death in epilepsy (SUDEP).

Several complications may develop due to seizures including trauma, drowning, road traffic accidents and falls. A sustained seizure > 30 minutes or recurrent seizures without regaining consciouses describes status epilepticus. This is a life-threatening medical emergency. For more details see our notes on status epilepticus. 

SUDEP

Sudden unexplained death in epilepsy is the result of sudden death in a patient with epilepsy with no identifiable cause. It is the most common cause of death in young adults with epilepsy. SUDEP has been linked to uncontrolled epilepsy and nocturnal seizures. Seizure control is pivotal to reduce risk. 

Following a seizure, patients need to stop driving and inform the DVLA.

There are certain rules to driving in the context of having a seizure. These depend on the timing of the seizure(s) (i.e. day or night) and whether the person has a group 1 (cars, motorcycles) or 2 (large lorries, buses) license. Always consult the DVLA for further advice.

In general:

• First seizure – impaired consciousness (group 1): do not drive for six months, reapply
• Epileptic seizure – impaired consciousness (group 1): do not drive for one year, reapply
• Seizures – no loss of consciousness (group 1): seek DVLA advice
• Nocturnal seizures: seek DVLA advice
• First seizure (group 2): do not drive for 5 years, but seek DVLA advice (depends on type)
• ≥1 seizure (group 2): do not drive for 10 years, but seek DVLA advice (depends on type)