Overview
This lecture covers epilepsy from definition through to management. It starts with what a seizure and epilepsy are and the clinical operational definition, then works through the ILAE 2017 classification of seizure types (and the older 1981 scheme), the signs and symptoms used to classify, and the rules for applying the classification. It then covers the diagnostic tools (EEG patterns, investigations), the differential diagnosis including non-epileptic seizures, aetiology and precipitants, and finally management: when to start and stop drugs, drug mechanisms and efficacy spectrum, recurrence risk, driving, pregnancy, status epilepticus, SUDEP and surgery.
Scale of the problem
- 65 million people worldwide have epilepsy.
- 20 to 30% are resistant to medication.
- 15 new drugs have been licensed in the last 20 years, yet the percentage of drug-resistant cases is unchanged.
Definitions
- A seizure is a convulsion or transient abnormal event resulting from a paroxysmal discharge of cerebral neurons.
- Epilepsy is the continuing tendency to have seizures.
Clinical operational definition (Fisher et al., ILAE). Epilepsy is diagnosed by any one of:
- At least two unprovoked seizures occurring more than 24 hours apart.
- One unprovoked seizure plus a probability of further seizures similar to the general recurrence risk after two unprovoked seizures (approximately 75% or more).
- At least two seizures in a setting of reflex epilepsy.
ILAE 2017 classification of seizure types
Three onset categories: focal onset, generalized onset, unknown onset.
Basic version:
- Focal onset: aware or impaired awareness; motor or non-motor; and focal to bilateral tonic-clonic.
- Generalized onset: motor (tonic-clonic, other motor) or non-motor (absence).
- Unknown onset: motor (tonic-clonic, other motor), non-motor, or unclassified (due to inadequate information or inability to place in other categories).
Expanded version:
- Focal onset, classified as aware or impaired awareness, then by:
- Motor onset: automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic.
- Non-motor onset: autonomic, behavior arrest, cognitive, emotional, sensory.
- Plus focal to bilateral tonic-clonic.
- Generalized onset:
- Motor: tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms.
- Non-motor (absence): typical, atypical, myoclonic, eyelid myoclonia.
- Unknown onset:
- Motor: tonic-clonic, epileptic spasms.
- Non-motor: behavior arrest.
- Unclassified.
Atonic seizures and epileptic spasms could be either focal or generalized, with or without alteration of awareness.
The older 1981 classification
- Partial seizures (start in one place):
- Simple (no loss of consciousness or memory): sensory, motor, sensory-motor, psychic (abnormal thoughts or perceptions), autonomic (heat, nausea, flushing).
- Complex (consciousness or memory impaired): with or without aura (warning), with or without automatisms.
- Secondarily generalized.
- Generalized seizures (apparent start over wide areas of brain): absence (petit mal), tonic-clonic (grand mal), atonic (drop seizures), myoclonic, other.
- Unclassifiable seizures.
Seizure signs and symptoms, and their terms
| Symptom | Medical term |
|---|---|
| automatic behaviors | automatisms |
| emotions or appearance of emotions | emotions |
| extension or flexion postures | tonic |
| flushing, sweating, piloerection | autonomic |
| jerking arrhythmically | myoclonus |
| jerking rhythmically | clonus |
| language or thinking problems, deja vu | cognitive |
| lid jerks | eyelid myoclonia |
| limp | atonic |
| numbness or tingling, sounds, smells, tastes, visions, vertigo | sensations |
| pausing, freezing, activity arrest | behavior arrest |
| thrashing, pedaling | hyperkinetic |
| trunk flexion | spasm |
Further descriptors (not seizure types, just suggested descriptive words; free text description is also encouraged):
- Cognitive: acalculia, aphasia, attention impairment, deja vu or jamais vu, dissociation, dysphasia, hallucinations, illusions, memory impairment, neglect, forced thinking, responsiveness impairment.
- Emotional or affective: agitation, anger, anxiety, crying (dacrystic), fear, laughing (gelastic), paranoia, pleasure.
- Autonomic: asystole, bradycardia, erection, flushing, gastrointestinal, hyper or hypoventilation, nausea or vomiting, pallor, palpitations, piloerection, respiratory changes, tachycardia.
- Automatisms: aggression, eye-blinking, head-nodding, manual, oral-facial, pedaling, pelvic thrusting, perseveration, running (cursive), sexual, undressing, vocalization or speech, walking.
- Motor: dysarthria, dystonic, fencer’s posture (figure-4), incoordination, Jacksonian, paralysis, paresis, versive.
- Sensory: auditory, gustatory, hot-cold sensations, olfactory, somatosensory, vestibular, visual.
- Laterality: left, right, bilateral.
Impaired consciousness and why it matters
Among the many possible behaviors during a seizure, impairment of consciousness has always had a key role in classifying seizures, because of practical importance for:
- Driving
- Safety during seizures
- Employability
- Interference with schooling and learning
Two types of seizure carry loss of consciousness: the generalized tonic-clonic seizure and the complex partial seizure. The lecture raises the question of how well the public understands loss of consciousness during a complex partial seizure.
Rules for classifying seizures
- Onset: decide whether seizure onset is focal or generalized, using an 80% confidence level.
- Awareness: for focal seizures, decide whether to classify by degree of awareness or to omit awareness as a classifier.
- Impaired awareness at any point: a focal seizure is a focal impaired awareness seizure if awareness is impaired at any point during the seizure.
- Onset predominates: classify a focal seizure by its first prominent sign or symptom, and do not count transient behavior arrest.
- Behavior arrest: a focal behavior arrest seizure shows arrest of behavior as the prominent feature of the entire seizure.
- Motor / non-motor: a focal aware or impaired awareness seizure may be further sub-classified by motor or non-motor characteristics. Alternatively a focal seizure can be characterized by motor or non-motor characteristics without specifying level of awareness, for example a focal tonic seizure.
Supportive information
Seizures are usually classified by symptoms and signs, but supportive information may help when available:
- Videos brought in by family
- EEG patterns
- Lesions detected by neuroimaging
- Laboratory results such as detection of anti-neuronal antibodies
- Gene mutations
- Diagnosis of an epilepsy syndrome
From seizure type to syndrome
The diagnostic framework runs in three levels: seizure type (focal onset, generalized onset, unknown onset) leads to epilepsy type (focal, generalized, combined generalized and focal, unknown), which leads to an epilepsy syndrome diagnosis. Two things sit alongside all three levels:
- Etiology: structural, genetic, infectious, metabolic, immune, unknown.
- Co-morbidities, which relate across all levels.
EEG
- The electroencephalogram uses scalp electrodes to detect cortical activity. Electrodes are placed at standard positions: Fz, Cz and Pz along the midline, and Fp1, F3, C3, P3, F7, T3, T5, O1 laterally (mirrored on the other side), referenced anatomically to the nasion and inion, over the frontal, parietal, occipital and temporal lobes.
- A normal recording is shown as an eight-channel bipolar montage (FP1-F3, F3-C3, C3-P3, P3-O1, Fp2-F4, F4-C4, C4-P4, P4-O2) with normal background rhythms of varying frequency and amplitude.
Paroxysmal abnormalities:
- Spike: less than 70 msec.
- Sharp wave: 70 to 200 msec.
- Spike and slow wave activity.
- Polyspike activity.
- Paroxysmal slow waves.
- Activity can be diffuse or focal. Note diffuse equals generalised, focal equals partial.
Waveform types illustrated: single spikes, spike-wave complexes, polyspikes and polyspike waves, periodic polyspikes, sequential sharp waves, broad sharp waves, and high frequency muscle activity.
Warning
The bottom label row of the spikes-and-sharp-waves EEG figure is cut off at the edge of the slide image, so the final waveform label is only partially readable.
Characteristic patterns:
- Absence seizure: generalized 3 Hz spike and wave, appearing across all channels.
- Partial (focal) seizure: a focal, localised rhythmic discharge that builds up over the recording.
- Rolandic epilepsy: repeated spike discharges concentrated in the centrotemporal channels (centrotemporal spikes).
Distinguishing generalised from focal to bilateral tonic-clonic seizures
Features pointing to a focal onset that has secondarily spread:
- Aura
- Focal onset to the seizure
- Postictal focal signs, for example Todd’s paresis
- Focal changes in the EEG
Differential diagnosis
- Syncope
- Migraine
- TIA
- Hypoglycaemia
- Panic attacks
- Breath holding attacks
- Psychogenic non-epileptic seizures
Features suggesting non-epileptic seizures:
- Gradual onset
- Eye closure
- Asymmetrical thrashing movements
- Side-to-side head movements
- Pelvic thrusting
- Opisthotonic posturing
- Lack of stereotypic pattern
- Talking or screaming
- Long duration
- Prolonged bilateral involvement without impairment of consciousness
- Sudden return to consciousness
- Waxing and waning
Aetiology and precipitants
- Genetic predisposition
- Developmental, for example hamartomas, neuronal migration abnormalities
- Trauma and surgery
- Pyrexia
- Intracranial mass lesions: tumour
- Vascular: cerebral infarction, arteriovenous malformation
- Drugs and drug withdrawal
- Encephalitis and inflammatory conditions
- Metabolic abnormalities, for example hypocalcaemia
- Neural degenerative disorders
- Provoked seizures: photosensitivity and sleep deprivation
Investigations
- Blood tests: FBC, urea and electrolytes, calcium, glucose, CRP, toxin screen
- Chest X-ray
- ECG
- EEG
- Neuroimaging: CT or MRI
- Lumbar puncture if CNS infection is a possibility
Pharmacological management
Licensed antiepileptic drugs have accumulated steadily since 1912: phenobarbital 1912, phenytoin 1938, primidone 1954, ethosuximide 1958, diazepam 1963, carbamazepine 1965, valproate 1967, clonazepam 1968, vigabatrin 1989, oxcarbazepine 1990, lamotrigine 1990, felbamate 1993, gabapentin 1994, topiramate 1995, tiagabine 1996, levetiracetam 1999, zonisamide 2002, pregabalin 2004, stiripentol 2007, rufinamide 2007, lacosamide 2008.
Starting treatment
- Treat after 2 or more seizures.
- Consider treating a single seizure if risk factors are present: structural lesion, EEG abnormality, partial seizure, family history of seizures.
- Immediate treatment increases time to a second seizure and reduces the time to 2 year remission.
Mechanisms of action
| Na channels | Glutamate receptors | GABA | Other |
|---|---|---|---|
| Phenytoin, Carbamazepine, Oxcarbazepine, Lamotrigine, Lacosamide, Rufinamide, Eslicarbazepine | Topiramate, Zonisamide, Perampanel, Felbamate | Benzodiazepines, Barbiturates, Valproic acid, Vigabatrin, Tiagabine, Neurosteroids | Levetiracetam, Ezogabine, Gabapentin, Pregabalin, Ethosuximide |
Efficacy spectrum
- Focal seizures and most generalised seizures: valproate, lamotrigine, levetiracetam, topiramate, benzodiazepines, barbiturates.
- Primarily effective against focal seizures: carbamazepine, phenytoin, gabapentin, lacosamide, pregabalin, vigabatrin.
- Absences only: ethosuximide.
- Choice also considers tolerability, and interactions or enzyme induction.
Stopping therapy
- Consider stopping after 2 years.
- Risk of recurrence is 25% with no risk factors, and greater than 50% in patients with risk factors.
- Withdraw gradually.
Recurrence risk after a seizure
- After a single seizure with immediate treatment: risk of a seizure in the following 12 months is 14% (CL 10 to 18) after a 6 month seizure-free period, and 7% (CL 4 to 11) after a 12 month seizure-free period (Bonnett et al.).
- Without treatment the risk is 18% after a seizure-free period of 6 months.
- The National General Practice Study of Epilepsy suggested a higher overall risk of 35% over a year following 6 months seizure-free. This is because it was a population-based study that included patients who had already had further seizures.
- Risk varies with aetiology, seizure type, age, and elapsed time from the first attack.
Driving and epilepsy
- Class 1 or 6: must be seizure free 12 months, compliant, and not undertaking activities such as excess drinking that increase seizure risk. The period can be reduced if there is a favourable specialist report.
- Class 2, 3, 4 or 5, and/or P, V, I or O endorsement: permanently unfit, but NZTA may consider a licence if a neurologist supports the application and the person has been seizure free 5 years without medication.
Pregnancy and epilepsy
- Seizures may increase, in about 1 in 3.
- AED levels may fall.
- Seizures may harm the foetus.
- Birth defects are increased if either parent has epilepsy.
- Risk of birth defects is doubled in patients on AEDs.
- Foetal anticonvulsant syndrome: facial abnormalities, transverse palmar creases, skeletal abnormalities.
- Neural tube defects: especially with valproate; reduce with folic acid; detect with ultrasound.
- Obstetric complications are increased, seizures can occur during labour, and breast feeding is usually okay but watch for sedation.
Rates of major congenital malformations at 1 year after birth by AED monotherapy and dose (EURAP data, Tomson 2012, Lancet Neurology): high-dose valproate (at or above 1500 mg/day) and phenobarbital (at or above 150 mg/day) bands carry the highest malformation rates with the widest confidence intervals, while lamotrigine bands (at or above 300 mg/day, and below 300 mg/day) carry the lowest. Carbamazepine bands sit between. Rates rise with dose within each drug.
Important
Valproate carries the highest congenital malformation risk of the AEDs shown, is specifically implicated in neural tube defects, and the risk is dose-dependent.
Status epilepticus
If seizures recur without recovery, or a single seizure continues for more than 5 minutes, treat as status epilepticus. Escalate stepwise:
- Benzodiazepines
- AEDs / barbiturates
- Anaesthetic, intubate, ICU
SUDEP
Sudden Unexplained Death in Epilepsy.
- Rates are low with drug-responsive epilepsy.
- Mean age 35 years, probably related to un-witnessed seizure activity.
- The association with AED polytherapy is likely confounded with refractory seizures.
Epilepsy surgery
20 to 30% of patients do not respond to medication. Surgical options:
- Focal resections: anterior temporal lobectomy, amygdalohippocampectomy, extratemporal resection, lesionectomy
- Hemispherectomy
- Large multilobar resections
- Corpus callosotomy
- Vagal nerve stimulation
Self-test
- Define a seizure and define epilepsy.
- State the three criteria of the clinical operational definition of epilepsy, any one of which is sufficient for diagnosis.
- List the three onset categories of the ILAE 2017 classification and the subdivisions immediately under each in the basic version.
- List the motor and non-motor subtypes of focal onset seizures in the expanded ILAE 2017 classification.
- Distinguish simple partial from complex partial seizures in the 1981 classification.
- Give the medical term for each of: jerking rhythmically, jerking arrhythmically, limp, pausing or freezing, trunk flexion, thrashing or pedaling.
- Why has impairment of consciousness always had a key role in seizure classification? Give the four practical reasons.
- State the rule for deciding whether a focal seizure is a focal impaired awareness seizure, and the rule for which feature you classify a focal seizure by.
- What confidence level does the ILAE rule specify for deciding focal versus generalized onset?
- A patient’s focal seizure begins with a brief behavior arrest and then a prominent versive head turn. How should it be classified, and why?
- List the three levels of the diagnostic framework running from seizure type to syndrome, and the six etiology categories that apply across them.
- Give the duration cut-offs distinguishing a spike from a sharp wave on EEG.
- Describe the EEG pattern of an absence seizure and contrast it with that of a partial seizure.
- What is the characteristic EEG finding of Rolandic epilepsy?
- List the features that suggest a tonic-clonic seizure was focal to bilateral rather than generalised from onset.
- List the differential diagnosis of seizures.
- A 24 year old has an episode with gradual onset, eye closure, side-to-side head movements, waxing and waning intensity over 20 minutes with talking throughout, and a sudden return to consciousness. What is the likely diagnosis and which features support it?
- List the aetiologies and precipitants of seizures.
- List the investigations for a first seizure.
- When should treatment be started, and which risk factors justify treating after a single seizure?
- Classify the following by main mechanism of action: phenytoin, topiramate, vigabatrin, levetiracetam, ethosuximide.
- Which AEDs are effective against both focal and most generalised seizures, which are primarily effective against focal seizures only, and which is effective only against absences?
- When can stopping therapy be considered, and what is the recurrence risk with and without risk factors?
- After a single treated seizure, what is the risk of a further seizure in the next 12 months if the patient has been seizure free for 6 months, and for 12 months? How does the untreated 6 month figure compare?
- Why did the National General Practice Study of Epilepsy report a higher recurrence risk of 35%?
- What are the driving requirements for a Class 1 or 6 licence, and for Class 2 to 5 or a P, V, I or O endorsement?
- Describe the effects of pregnancy on epilepsy and of epilepsy and its treatment on the foetus.
- Which AED carries the highest rate of major congenital malformations, and what is the relationship with dose?
- Define status epilepticus and describe the escalation of treatment.
- What is SUDEP, and what is known about its rate, age distribution and association with polytherapy?
- List the surgical options for epilepsy, and state the proportion of patients who do not respond to medication.
- A patient with focal seizures arising from one temporal lobe has failed several drugs and is planning a pregnancy. Explain how seizure classification, EEG, drug choice and surgical options come together in her management.
Answers
Reveal answers
- A seizure is a convulsion or transient abnormal event resulting from a paroxysmal discharge of cerebral neurons. Epilepsy is the continuing tendency to have seizures.
- At least two unprovoked seizures more than 24 hours apart; one unprovoked seizure with a probability of further seizures similar to the general recurrence risk after two unprovoked seizures (approximately 75% or more); or at least two seizures in a setting of reflex epilepsy.
- Focal onset (aware or impaired awareness; motor or non-motor; plus focal to bilateral tonic-clonic), generalized onset (motor: tonic-clonic or other motor; non-motor: absence), unknown onset (motor: tonic-clonic or other motor; non-motor; unclassified).
- Motor onset: automatisms, atonic, clonic, epileptic spasms, hyperkinetic, myoclonic, tonic. Non-motor onset: autonomic, behavior arrest, cognitive, emotional, sensory.
- Simple partial seizures have no loss of consciousness or memory (sensory, motor, sensory-motor, psychic, autonomic subtypes). Complex partial seizures have consciousness or memory impaired, with or without aura and with or without automatisms.
- Clonus; myoclonus; atonic; behavior arrest; spasm; hyperkinetic.
- Because of practical importance for driving, safety during seizures, employability, and interference with schooling and learning.
- A focal seizure is a focal impaired awareness seizure if awareness is impaired at any point during the seizure. Classify a focal seizure by its first prominent sign or symptom, not counting transient behavior arrest.
- An 80% confidence level.
- As a focal seizure classified by the versive motor feature. Transient behavior arrest is explicitly not counted when identifying the first prominent sign; behavior arrest only defines the seizure if it is the prominent feature of the entire seizure.
- Seizure type, then epilepsy type (focal, generalized, combined generalized and focal, unknown), then epilepsy syndrome. Etiology categories: structural, genetic, infectious, metabolic, immune, unknown. Co-morbidities also apply across all levels.
- A spike is less than 70 msec; a sharp wave is 70 to 200 msec.
- Absence seizure: generalized 3 Hz spike and wave appearing across all channels. Partial seizure: a focal, localised rhythmic discharge that builds up over the recording, confined to some channels.
- Centrotemporal spikes, that is repeated spike discharges concentrated in the centrotemporal channels.
- Aura, focal onset to the seizure, postictal focal signs such as Todd’s paresis, and focal changes in the EEG.
- Syncope, migraine, TIA, hypoglycaemia, panic attacks, breath holding attacks, psychogenic non-epileptic seizures.
- Psychogenic non-epileptic seizures. Supporting features: gradual onset, eye closure, side-to-side head movements, waxing and waning, talking or screaming, long duration, and sudden return to consciousness.
- Genetic predisposition; developmental causes such as hamartomas and neuronal migration abnormalities; trauma and surgery; pyrexia; intracranial mass lesions such as tumour; vascular causes such as cerebral infarction and arteriovenous malformation; drugs and drug withdrawal; encephalitis and inflammatory conditions; metabolic abnormalities such as hypocalcaemia; neural degenerative disorders; and provoked seizures from photosensitivity and sleep deprivation.
- Blood tests (FBC, urea and electrolytes, calcium, glucose, CRP, toxin screen), chest X-ray, ECG, EEG, neuroimaging with CT or MRI, and lumbar puncture if CNS infection is a possibility.
- Start after 2 or more seizures. Consider treating a single seizure if there is a structural lesion, an EEG abnormality, a partial seizure, or a family history of seizures. Immediate treatment increases time to a second seizure and reduces time to 2 year remission.
- Phenytoin: Na channels. Topiramate: glutamate receptors. Vigabatrin: GABA. Levetiracetam: other. Ethosuximide: other.
- Focal and most generalised: valproate, lamotrigine, levetiracetam, topiramate, benzodiazepines, barbiturates. Primarily focal: carbamazepine, phenytoin, gabapentin, lacosamide, pregabalin, vigabatrin. Absences only: ethosuximide.
- Consider after 2 years. Recurrence risk is 25% with no risk factors and greater than 50% with risk factors. Withdraw gradually.
- 14% (CL 10 to 18) after 6 months seizure free, and 7% (CL 4 to 11) after 12 months seizure free. Without treatment the 6 month figure is 18%.
- It was a population-based study that included patients who had already had further seizures, which raises the observed recurrence rate.
- Class 1 or 6: seizure free 12 months, compliant and not undertaking activities such as excess drinking that increase seizure risk, though this can be reduced with a favourable specialist report. Class 2 to 5 or P, V, I or O endorsement: permanently unfit, but NZTA may consider a licence if a neurologist supports the application and the person is seizure free 5 years without medication.
- Seizures may increase in about a third of pregnancies and AED levels may fall; seizures may harm the foetus; birth defects are increased if either parent has epilepsy and doubled on AEDs; foetal anticonvulsant syndrome gives facial abnormalities, transverse palmar creases and skeletal abnormalities; neural tube defects occur especially with valproate, are reduced by folic acid and detected by ultrasound; obstetric complications are increased, seizures can occur in labour, and breast feeding is usually okay but watch for sedation.
- Valproate, particularly at doses of 1500 mg/day or above. Malformation rates rise with dose within each drug; lamotrigine has the lowest rates and phenobarbital at 150 mg/day or above is also high.
- Seizures recurring without recovery, or a single seizure continuing more than 5 minutes. Treat with benzodiazepines first, then AEDs or barbiturates, then anaesthetic with intubation and ICU care.
- Sudden Unexplained Death in Epilepsy. Rates are low with drug-responsive epilepsy; mean age is 35 years and it is probably related to un-witnessed seizure activity; the association with AED polytherapy is likely confounded with refractory seizures.
- 20 to 30% do not respond to medication. Options: focal resections (anterior temporal lobectomy, amygdalohippocampectomy, extratemporal resection, lesionectomy), hemispherectomy, large multilobar resections, corpus callosotomy, and vagal nerve stimulation.
- Classification as focal onset (confirmed by aura, focal EEG changes and any postictal focal signs) directs drug choice towards agents effective in focal seizures, but pregnancy planning argues against valproate given its high dose-dependent malformation rate and neural tube defect risk, favouring lamotrigine, which has the lowest malformation rates and covers focal seizures. Folic acid should be given and ultrasound used for detection. Because she has failed several drugs she falls in the 20 to 30% drug-resistant group, so surgical assessment for anterior temporal lobectomy or amygdalohippocampectomy is appropriate, and AED levels should be monitored in pregnancy since they may fall.