Overview

Definitions

• Seizure: an acute change in neurological function produced by abnormal synchronous activity in the cerebral cortex
• Epilepsy: a predisposition to having seizures

Seizures can be classified in several ways:

• In terms of underlying cause:
• In terms of semiology (clinical picture)
• In terms of which parts of the cortex are involved

Types of seizure by cortical origin:

• Focal seizure with retained consciousness: a seizure originating from a single region which does not spread and does not cause any impairment of consciousness.
• Focal seizure with impairment of consciousness: a seizure which originated from a localised region of cortex but spreads and leads to impairment of consciousness.
• Generalised seizure: a seizure originating from bilateral cerebral hemispheres which usually produces loss of consciousness at its onset

Pathogenesis

Causes of seizures

Acute symptomatic seizures are seizures which occur in the context of an acute CNS illness. Common causes include:

Infection

• Meningitis
• Encephalitis
• Cerebral abscess

Vascular

• Stroke
  • Arterial
    • SAH
    • Ischaemic
    • Haemorrhagic
  • Venous thrombosis
• Subdural haematoma

Trauma

• TBI

Endocrine/metabolic

• Hypoglycaemia
• Hypocalcaemia
• Hypomagnasaemia
• Uraemia
• Hyper/hypothyroidism

Toxic

• Alcohol
  • Intoxication
  • Withdrawal
• BDZ withdrawal
• Most recreational drugs

Causes of epilepsy

Some people diagnosed with epilepsy have a clear underlying factor promoting epileptogenesis. In others, epilepsy is presumed to multifactorial. In the majority there is no obvious inciting factor causing the epilepsy. The list of likely causes depends mainly on the patient’s age: genetic and metabolic conditions mainly present in childhood, whereas space-occupying lesions, neurodegenerative disorders, and other causes are more likely causes in people who present with adult-onset epilepsy. Causes can be classified as follows:

• Structural
  • Neurodevelopmental abnormalities
  • Space-occupying lesions
  • Neurodegenerative disease
  • Post-infarction
  • Hippocampal sclerosis
• Genetic
  • ‘Idiopathic’ generalised epilepsies of childhood
  • Channelopathies
• Metabolic
  • Mitochondrial disorders
  • Enzyme deficiencies
• Immune
  • NMDA encephalitis
  • Paraneoplastic encephalitis
• Infectious
  • Neurocysticercosis
  • TB
  • HIV

Clinical presentation

Focal seizures without impaired consciousness

• Manifestations depend on
  • Initial Location
  • Spread
• Locations
  • Most common site: temporal lobes
  • Also frontal lobes
  • More rarely, parietal or occipital lobes
• Characteristics
  • Brief
  • Intense
• Specific manifestations
  • Focal motor signs
  • Autonomic signs (flushing, sweating, vomiting)
  • Sensory signs (flashing lights, unpleasant odours, tastes, vertigo, paraesthesiae, pain)
  • Psychic symptoms (déjà vu, depersonalisation, fear, illusions, hallucinations)

Focal seizures with impaired consciousness

• Definition : impairment of consciousness
• Can either start with impaired consciousness or progress from a simple partial seizure
• Characteristics
  • Automatic behaviours
    • plucking at clothes, fiddling, lip smacking, chewing, grimacing, undressing, purposeless activities
  • Last for minutes
  • Post-ictal
    • confusion
    • amnesia

Focal and generalised seizures

• Definition: generalised seizures which originate as partial seizures
• Can be difficult to diagnose as the initial, localised onset can progress rapidly
• Usually >> generalised tonic-clonic but can also lead to
  • Unilateral tonic-clonic
  • Tonic
  • Atonic

Generalised seizures

• Definition: a seizure arising bilaterally in the cortex which involves loss of consciousness at the onset à there is usually no warning
• Classification:
  • Generalised tonic-clonic
  • Absence
  • Myoclonic
  • Atonic
  • Tonic
  • clonic

Type	Aura	During	Post-ictal
GTCS	No warning	Tonic phase: ‘all-over’ rigidity, +/- apnoea, unilateral tongue-biting Clonic phase: rhythmic jerking of all 4 limbs Relaxation phase	Drowsiness Confusion Headache Myalgia Incontinence
Absence	No warning	Blank appearance Eyelid fluttering Head flopping	Mild confusion
Myoclonic	No warning Occur in morning	Brief, involuntary jerky movement	None
Atonic	No warning	‘Drop attack’: sudden loss of tone	None
Tonic	No warning	Sudden rigidity >> fall	Rapid recovery

DIAGNOSIS

General points

• Epilepsy is primarily a clinical diagnosis
• It is a diagnosis with implications e.g. driving, so be careful
• Investigations and symptoms may be entirely normal/absent between attacks
• Main differential diagnosis in an adult
  • Syncope
  • Migraine
  • Panic attack
  • TIA
  • NEAD
• Main differential diagnoses in a child
  • Breath-holding attacks
  • Pavor nocturnis – night terrors

Key differentials and how to rule them out

• Syncope
  • Prodrome: can be a bit like an aura. Prodrome in vasovagal syncope is usually very clear.
    • Hot/flush
    • Dizzy
    • Vision becomes grey
  • Situation: rarely when sitting (unless cardiogenic)
  • Precipitant: usually there is a precipitant
  • The attack: some limb jerking may occur especially if they are propped up as this compromises cerebral blood flow. Very rare to have proper tonic-clonic jerking.
  • Recovery: post-syncope it is rare to be confused. Usual to feel shaky and sick.
• Migraine
  • Especially basilar migraine, but this will usually occur in tandem with other brainstem symptoms e.g. vertigo, nausea
  • Seizures are often followed by headache, so this can be confusing
  • Migraine can also show paroxysmal EEG phenomena
• Hyperventilation
  • Paraesthesiae
  • Carpopedal spasm
• Vertebrobasilar TIA
  • Young women
  • Associated with vertigo and bilateral visual symptoms
  • Possibly tetraparesis
• Transient Global Amnesia
  • Middle-age à older people
  • Alert & communicative
  • Patient may repeat the same question
  • Recovery is complete
  • Residual amnesia of episode
• Pseudoseizures
  • Prolactin levels are increased

NB in partial seizures there may be an ‘autonomic prodrome’ which mimic presyncope.

	Epilepsy	NEAD
Stereotypy	Stereotyped	Variable
Cyanosis	Possible	Rare
Incontinence
Tongue biting
Burns, other injuries
Plantars	Extensor after tonic-clonic	Flexor
Eyes	Easily opened	Hard to open
Duration	Seconds-minutes	Variable. Possibly up to 1h
Ictal EEG	Abnormal	Normal
Post-ictal EEG	Abnormal	Normal
Prolactin level post-ictal	Very high after tonic-clonic	Slightly raised
Association with psychological event	Often	Very often
Response to AEDs	Excellent	Short-lived

 

INVESTIGATIONS

• Bloods (rule out reversible causes)
  • Infection
  • Metabolic
    • Hyponatraemia
    • Hypocalcaemia
    • Hypoglycaemia
    • Hypothyroidism
    • Hepatic failure
    • Renal failure
• EEG
  • Interictal EEG has about 50% sensitivity and 99% specificity
  • Repeat EEG improves these stats
  • Sleep EEG is even better (80% sensitivity)
  • Routine EEG can be improved using
    • Photic stimulation
    • Hyperventilation
  • If these are unsuccessful, consider
    • Video telemetry
      • Useful pre-surgery
      • ?NEAD
      • Unusual events during sleep
    • Ambulatory EEG
      • Artefacts
      • Lack of video
    • Certain epileptic foci are invisible to scalp EEG:
      • Simple partial seizures (if small)
      • Orbitofrontal cortex
• MRI
  • Indications
    • Epilepsy + focal neurological signs
    • New epilepsy after the age of 20
    • New epilepsy in the neonatal period
  • MRI is especially useful in diagnosing hippocampal sclerosis

Management

~50% of patients with newly diagnosed epilepsy will become seizure-free with the first anti-epileptic drug (AED) prescribed [ref]

Choice of medications is tailored to individual taking into account complex web of:

• efficacy
• tolerability
• drug/comorbidity interactions
  • Remember, many AEDs including phenytoin, carbamazepine & topiramate are inducers of the P450 enzyme system
  • Caution when co-prescribing warfarin, or oral contraceptive pill
• pregnancy considerations

Monotherapy is generally preferable and increases the probability of compliance. “Start low and go slow” tactics used in titration to reach dose that is both tolerable to efficacious.

In terms of which is the best initial monotherapy, there have been a bunch of head-to-head shortish RCTs, all of which seem to suggest most of the AEDs have comparable efficacy. The largest randomised trial (the SANAD trial) was unblinded but mean follow up was >3 years. SANAD concluded that lamotrigine is best for focal seizures, and valproate is best for generalised, however as above, the choice is also dependent on other patient-specific factors. Specific medications are discussed below:

	Simple	Complex	Tonic-clonic	Absence	Mechanism	Side effects	Teratogenicity
Carbamazepine	1	1	1		Blocks Na channels	P450 inducer, diplopia, ataxia, blood dyscrasia, SJS	High
Phenytoin	1	1	1		Blocks Na channels	Cerebellar syndrome, sedation, peripheral neuropathy, hirsuitism, gum hyperplasia, megaloblastic anaemia	High
Lamotrigine	1	1	1	1	Blocks voltage-gated Na channels	SJS	Low
Valproate	1	1	1	1	Inactivates Na channels, increases GABA	Hepatotoxicity, pancreatitis, tremor, weight gain	High
Topiramate	1	1	1		Blocks Na channels, increases GABA	Sedation, weight loss
Levetiracetam	1	1	1		Unknown

What does NICE (CG137) say?

• Focal
  • New diagnosis: Carbamazepine or lamotrigine
  • Add in: clobazam, gabapentin, levetiracetam, valproate or topiramate
• Generalised
  • New diagnosis: Valproate or lamotrigine
  • Add in: clobazam, levetiracetam, valproate or topiramate
• Absence
  • New diagnosis: Ethosuximide or valproate
  • Add in: Lamtorigine
  • Avoid: carbamazepine, gabapentin, phenytoin, pregabalin …
• Myoclonic or juvenile myoclonic seizures
  • New diagnosis: Valproate
  • Add in: levetiracetam or topiramate
  • Avoid: lamotrigine and carbamazepine