21st June 2023

Seizure Disorders

Classification of epilepsy

Aetiology of epilepsy

Definitions

The National Institute of Health and Care Excellence (NICE) defines a seizure as a transient acute change in neurological function produced by abnormal excessive or synchronous activity in the brain. Therefore, epilepsy is a predisposition to having recurrent seizures and can only be definitively diagnosed after a person has had two or more seizures.

Causes of Epilepsy

The causes of epilepsy are heterogenous. The table below summarises the main causes of epilepsy:

Classification of Seizures

Seizures are classified by the origin of the seizure within the brain.

Focal seizures

Focal seizures originate from a single region within the brain.

There are two types of focal seizures:

• Focal seizure with retained consciousness – a seizure originating from a single region, which does not spread and does not cause impairment of consciousness
• Focal seizure with impairment of consciousness – a seizure which originates from a localised region of the cortex but then spreads generally; associated with impairment of consciousness.

Generalised seizures

Generalised seizures affect both hemispheres of the brain and cause impaired consciousness at its onset. Generalised seizures include:

• Absence seizure – a seizure lasting seconds where the individual suddenly becomes unaware and usually involves a blank appearance and clonic (rhythmic jerking) movements, occurring at 3Hz, of the face – commonly the eyelids, the perioral region or the chin. EEG classically shows regular 3Hz generalised spike-and-wave patterns. Post-ictally, there is more likely to be confusion. If it lasts more than 45 seconds, it is more likely to be a focal seizure. Focal seizures are more common in children.
• Atonic seizure – sudden loss of muscle tone lasting seconds, typically involving the head, trunk or limbs. EEG shows slow waves during atonia.
• Tonic-clonic seizures – a seizure that starts with a tonic phase, presenting as bilateral increased tone, followed by a clonic phase, presenting as bilateral repetitive rhythmic jerking of the whole body. EEG in the tonic phase may show generalised fast rhythmic spikes, and in the clonic phase, bursts of spikes followed by synchronous slow waves may be seen. The post-ictal phase commonly presents as drowsiness, headache, confusion, and incontinence.

Features of seizures

The features that result from the seizure depend on the region affected; this is usually sub-classified as motor features and non-motor features. These features can be seen in focal and generalised seizures.

Seizures with motor features:

• Clonic seizure – rhythmic jerking of one body part.
• Myoclonic seizure – a cluster of muscle contractions or jerks lasting milliseconds. On EEG, a myoclonic jerk correlates with a generalised spike-and-wave or polyspike-and-wave.
• Tonic seizure – increased muscle tone in one body part. This usually recovers quickly. EEG shows generalised and accelerating low amplitude paroxysmal activity.
• Hyperkinetic seizure – irregular large movements of a group of muscles, such as thrusting, rocking or jumping.
• Automatism seizure – repetitive activity, which mimics voluntary movement, such as lip smacking, head nodding, walking or grunting.
• Commonly after focal motor seizures, patients develop Todd’s paresis, which is characterised by post-ictal weakness or paralysis of the contralateral limb or contralateral side of the body.

Seizures with non-motor features:

• Sensory seizures – involve a sensory experience, such as sensation, visual, olfactory, auditory, vestibular, and gustatory.
• Cognitive seizures – involve change to a cognitive function, such as expressive dysphasia, dyslexia, déjà vu or jamais vu (feeling of unfamiliarity).
• Autonomic seizures – involve autonomic symptoms, such as palpitations, nausea, pallor, altered respiration, etc.
• Emotional seizures – involve changes in mood or emotion, such as anxiety, crying, anger, etc.

Status epilepticus

NICE defines status epilepticus as a seizure that lasts for more than 5 minutes or recurrent seizures, one after the other, without recovery in between. Status epilepticus can be convulsive or non-convulsive. Non-convulsive status epilepticus causes a change in mental status or behaviour. Status epilepticus can cause disability or death.

Treatment of epilepsy

63.7% of patients with newly diagnosed epilepsy will become seizure-free within the first year. 86.6% of these patients gained seizure control with a single anti-epileptic drug (AED).

Some antiepileptics are inducers of the cytochrome P450 enzyme, which can increase the metabolism (and therefore alter effectiveness) of certain drugs, such as warfarin and the oral contraceptive pill. This should be taken into consideration when choosing an AED.

Treatment for each seizure type

Absence Seizures

NICE advises the following treatment for absence seizures:

Focal seizures

NICE advises the following treatment for focal seizures:

Generalised Tonic-Clonic Seizures

NICE advises the following treatment for generalised tonic-clonic seizures:

Myoclonic seizures

NICE advises the following treatment for myoclonic seizures:

Status Epilepticus

It is essential that status epilepticus is recognised and treated quickly. Initial management in a healthcare setting should include the following:

• A – secure airway
• B – give high-flow oxygen and assess respiratory function
• C – assess cardiac function and secure IV access with a cannula in a large vein.
• D – check blood glucose levels

Pharmacological management in the community:

• Buccal midazolam 10mg
• Rectal diazepam at 10-20mg

Another dose can be given after 15 minutes.

Pharmacological management in hospital:

• First line treatment – IV lorazepam 0.1 mg/kg. Repeat after 10-20 minutes.
• Second line – IV diazepam.

If no IV access – buccal midazolam.

If seizures continue, IV phenytoin can be used, and in refractory cases, intensive care will likely be required for treatment with propofol or thiopental sodium.

Side Effects

Cytochrome P450 Enzyme

Cytochrome P (CYP) enzymes are haemoproteins that are key in drug metabolism. AEDs are known to either induce or inhibit Cytochrome P450. When a medication induces cytochrome P450, there is an increase in the metabolisation of the medication, which means the medication has less of an effect. When a medication inhibits cytochrome P450, there is reduced metabolisation of the medication and an increased risk of toxicity. Dose of these AEDs might have to be titrated accordingly.

Sodium valproate

Sodium valproate works by increasing GABA activity by decreasing its degradation and by blocking sodium, potassium, and calcium channels.

The severe side effects of sodium valproate, according to the British National Formulary (BNF), include teratogenicity, agranulocytosis, rhabdomyolysis, systemic lupus erythematosus (SLE), and severe cutaneous adverse reactions such as Stevens-Johnson Syndrome, DRESS syndrome, Toxic Epidermal Necrolysis.

Levetiracetam

The mechanism of action of levetiracetam has not been fully elucidated. So far, it has been found that it inhibits presynaptic calcium channels.

The severe side effects of levetiracetam include psychosis, suicidality agranulocytosis, and severe cutaneous adverse reactions.

Lamotrigine

Lamotrigine acts by inhibiting sodium channels and inhibits glutamate release.

The severe side effects of lamotrigine include suicidality, disseminated intravascular coagulation, haemolytic anaemia, and severe cutaneous adverse reactions.

Ethosuximide

Ethosuximide works by inhibiting T-type calcium channels that act in the hyperactive thalamocortical neuronal circuit.

The severe side effects of ethosuximide include suicidality, agranulocytosis, cytopaenia, SLE, and severe cutaneous skin reactions.

Topiramate

Topiramate acts on multiple targets. It acts on voltage-gated sodium channels, voltage-gated calcium channels, GABA receptors, and AMPA glutamate receptors.

The severe side effects of topiramate include facial oedema, glaucoma, neutropaenia severe cutaneous adverse reactions.

Phenytoin

Phenytoin is a voltage-gated sodium channel blocker.

The severe side effects of phenytoin include teratogenicity, agranulocytosis, pancytopaenia, SLE, and severe cutaneous adverse reactions.

Phenytoin toxicity can present with nystagmus, diplopia, slurred speech, ataxia, confusion, and hyperglycaemia.

The signs and symptoms of chronic phenytoin use are hirsutism, acne, coarsening of the facial features, gingival hyperplasia, and megaloblastic anaemia

Clobazam

Clobazam is a benzodiazepine that works by being a partial agonist of GABA-A receptors.

The severe side effects of clobazam include respiratory depression, drowsiness, ataxia, nystagmus, and coma.

DVLA Guidance

Be aware of the Driver and Vehicle Licensing Agency (DVLA) guidance, as patients must be informed of any driving restrictions.

The DVLA guidance for Group 1 licences (cars and motorcycles) for seizures or epilepsy are:

• First unprovoked epileptic seizure or a single isolated seizure – must not drive for 6 months.
• Established epilepsy – must be seizure-free for at least 1 year and have no history of unprovoked seizures.

Contraception

AEDs can affect the effectiveness of contraception or vice versa, so women with epilepsy should be counselled regarding this when prescribing AEDs and/or contraception.

Enzyme-inducing AEDs (see the subsection on Cytochrome P450 under Side Effects) and contraception:

Lamotrigine and contraception:

If a woman with epilepsy plans to get pregnant, she should be referred to an epilepsy specialist for pre-conception counselling and remain on contraception until she has seen that specialist. NICE recommends starting all these women on high dose (5mg) folic acid.

Pregnancy

In those with epilepsy who are pregnant, there is a huge and understandable concern about AEDs harming the unborn baby. Therefore, it is essential to be aware of the potential harms and the rates of harmful effects for each of the common AEDs, so one can counsel a woman on the risks and come to a joint decision on which AED to prescribe. A change in AED might need to be made. Overall, it is essential to emphasise the importance of compliance during pregnancy, as the risk of harm to baby from an epileptic seizure is more likely than the risk of harm from taking the AED.
The Medicines and Healthcare products Regulatory Agency has produced updated advice on AEDs in pregnancy following a comprehensive safety review based on all evidence of the effects of AEDs on the mother and the baby.

The following AEDs have evidence-based harmful effects according to the table below. If the AED is not listed in the table, then either the evidence shows the AED does not increase the risk of the harmful effect, or there is not enough evidence to draw a conclusion either way.

The table below summarises the effect of pregnancy on serum levels of the AED according to studies.

Non-epileptic seizures

One fifth of those referred to epilepsy specialist centres do not have epilepsy. The majority of these patients have non-epileptic seizures (NES), which are also known as dissociative seizures or attacks. NES is not due to aberrant electrical activity seen in epilepsy or any other neurological cause.

Risk factors

The risk factors for developing NES are:

• Female – 75% of patients with NES are women
• Trauma or acute stress, such as the loss of a loved one, bullying, a history of abuse, or adverse experiences in childhood or adolescence, etc.
• Family history of epilepsy or psychiatric diagnoses
• Comorbid disorders:
  • Another functional disorder – a history of previous medically unexplained symptoms is present in 80% of patients
  • Epilepsy – 10-30% of those with non-epileptic seizures also have epilepsy.
  • Head injury
  • Sleep disorders
  • Cognitive problems
  • Migraine
  • Asthma
  • Depression – the most common psychiatric comorbidity in children and adolescents
  • Anxiety
  • Post-traumatic stress disorder
  • Personality disorder

Features of non-epileptic seizures

When giving the diagnosis of NES to a patient and their carer, the following are key points to discuss :

1. Reasons for concluding they do not have epilepsy – results of tests and what they mean, etc.
2. What they do have (describe what dissociation is and why it can develop)
3. Validating their experiences and reassurance that they are not ‘putting it on’ – one of the primary fears/judgments of patients with dissociative or functional disorders feel
4. The triggering “stress(es)” might not be clear
5. The aetiological factors in their case
6. Maintaining factors
7. Caution that if on an AED that its withdrawal should be done gradually
8. Describe psychological treatment

Treatment

The mainstay of current NES treatment is cognitive behavioural therapy (CBT). This will allow one to learn coping techniques to deal with the NES and hopefully improve them over time. Part of treatment is learning the warning sign of an attack, as this will help the patient regain control of the attacks. One way to regain control and avert an attack is by the patient challenging and answering their anxious thoughts, such as will they injure themself, will it be embarrassing, or will they die. Another way is for the patient to distract themselves, by doing things like counting, talking to someone or playing a game, or by grounding where they pay attention to each of their senses and what they are experiencing in the present. The indications that the treatment is working are that the patient will start to have more warnings, the warnings will be less anxiety-provoking for them, the warning symptoms will be longer, they will be conscious and aware during some of their episodes, and eventually they can avert some of the attacks.