Epilepsy

General considerations

Definitions:

Seizure – clinical manifestation of an abnormal, excessive, hypersynchronous discharge of a population of cortical neurons
Epilepsy – disorder of the CNS with recurrent seizures unprovoked by an acute systemic or neurologic insult
Epileptogenesis – sequence of events that turns a normal neural network into a hyperexcitable network
Intractability – failure of 2 AEDs, >1sz/mo for 18 mo, <3mo sz-free
Idiopathic or cryptogenic
Focal or generalized
Status epilepticus – seizure lasting >30min or recurrent seizures for 30 minutes without return to baseline LOC
Refractory status epilepticus – seizure lasting >1h or refractory to 2 appropriate AEDs

Engel classification

Axis 1 – ictal phenomenology
Axis 2 – seizure type, focal origin, precipitating stimuli
Axis 3 – epilepsy syndrome
Axis 4 – etiology
Axis 5 – impairment

Incidence

40 in 100,000 per year in children <16 years
120 in 100,000 per year in children <1 year
75% GTC or partial, 15% absence, 10% secondary generalized

Recurrence

40% after 1 seizure, 80% after 2 seizures
75% recurrences in first 6 months
Delaying treatment until 10 seizures does not affect outcome
No evidence that multiple seizures facilitates additional seizures

Outcome

80% respond to 1 AED, 10% intractable
In adults – 50% respond to 1 AED, 15% to 2^nd, <5% to 3^rd, 35% uncontrolled
50% children outgrow epilepsy
70% children can successfully stop treatment at 2 years
Positive predictors:

Normal intelligence and neuro exam
Few seizures, generalized seizures
Age <12 years at first seizure
Resolution of interictal discharges

Seizure neurophysiology:

Paroxysmal depolarizing shift

Sudden, large (20-40mV), long-lasting (50-200ms) depolarization triggering a train of action potentials, normally followed by an after-hyperpolarization.
Epileptic spike is a result of hypersynchrony in a local population of neurons induced by a paroxysmal depolarizing shift occurring in the focus.
Failure of hyperpolarization leads to propagation of high frequency action potentials, recruiting surrounding cells, causing seizure.

AAN practice guidelines

Evaluating first nonfebrile seizure:

Electrolytes, tox screen, lumbar puncture only if clinically indicated
EEG is recommended
Neuroimaging

Urgent if prolonged Todd’s paresis or prolonged decreased LOC
Non-urgent if cognitive or motor deficits, focality, non-benign EEG, or age <1y
MRI preferred

Evaluating status epilepticus:

Check AED levels
Consider tox screen if cannot find etiology
Blood cultures, LP, metabolics, genetics, EEG, imaging only if clinically indicated

Acute treatment

Lorazepam 0.1mg/kg, max 4mg x2
For children <18mo consider pyridoxine 100mg IV
For adults consider thiamine 100mg IV
Phenytoin 20mg/kg, max 1g, over 20 min
Phenobarbital 20mg/kg, max 1g, over 5-10 min
Fosphenytoin 30mg/kg (20mg/kg PE), over 5-10 min
Paraldehyde 0.4mL/kg PR, max 10mL in 1:1 olive oil
Valproate 60-70mg/kg
Midazolam

0.15mg/kg bolus, then 2mcg/kg/min infusion
Increase by 2mcg/kg/min q5min to 24mcg/kg/min or 20mg/hr (0.15mg/kg boluses as needed)
Wean by 1mcg/kg/min q15min

Thiopental

Bolus 2-4mg/kg, then 2-4mg/kg/hr infusion
Discontinue midazolam and phenobarbital, maintain phenytoin
Extra 2mg/kg bolus then increase rate by 1mg/kg/hr q30min to 6mg/kg/hr
Target EEG suppression
Wean over 12hr by 25% decrements (restart phenobarbital)

Propofol 2mg/kg bolus then 150mcg/kg/min infusion

Propofol infusion syndrome – metabolic acidosis, rhabdomyolysis, renal failure, cardiac failure

Epilepsy syndromes (2001 ILAE classification)

Localization-related epilepsies and syndromes

Idiopathic

Benign childhood epilepsy with centrotemporal spikes
Early-onset benign childhood occipital epilepsy (Panayiotopoulos type)
Late-onset childhood occipital epilepsy (Gastaut type)
Idiopathic photosensitive occipital lobe epilepsy
Autosomal dominant nocturnal frontal lobe epilepsy
Reflex epilepsies

Primary reading epilepsy
Other visual sensitive epilepsies
Startle epilepsy

Symptomatic/cryptogenic

Limbic epilepsies

Mesial temporal lobe epilepsy with hippocampal sclerosis
Mesial termporal lobe epilepsy defined by specific causes
Other types defined by location and cause

Neocortical epilepsies

Rasmussen’s syndrome
Hemiconvulsion-hemiplegia syndrome
Migrating partial seizures of infancy

Other types defined by location and cause

Familial temporal lobe epilepsies
Familial focal epilepsy with variable foci

Generalized epilepsies and syndromes

Idiopathic

Benign familial neonatal seizures
Benign neonatal convulsions (not epilepsy)
Benign myoclonic epilepsy of infancy
Benign familial infantile seizures
Benign infantile seizures (nonfamilial)
Childhood absence epilepsy
Juvenile absence epilepsy
Juvenile myoclonic epilepsy
Epilepsy with generalized tonic-clonic seizures only
Other undetermined epilepsies not defined above
Juvenile myoclonic epilepsy
Landau-Kleffner syndrome
Epilepsy with continuous spike and waves during slow-wave sleep (other than LKS)
Progressive myoclonic epilepsies
Generalized epilepsies with febrile seizures plus

Cryptogenic/symptomatic

West’s syndrome
Lennox-Gastaut syndrome
Epilepsy with myoclonic-astatic seizures (Doose’s syndrome)
Dravet’s syndrome (severe myoclonic epilepsy of infancy)
Epilepsy with myoclonic absences
Ohtahara’s syndrome (early infantile epileptic encephalopathy with suppression burst)
Early myoclonic encephalopathy
Myoclonic status in non-progressive encephalopathies

Special syndromes

Febrile seizures
Drug or other chemically-induced seizures
Alcohol-withdrawal seizures
Single seizures or isolated cluster of seizures
Rarely repeated seizures (oligoepilepsy)
Immediate or early post-traumatic seizures

Idiopathic localization-related epilepsies

Benign childhood epilepsy with centrotemporal spikes

15-25% of childhood epilepsy
Age 3-13 years, peak 8-9 years
Linked to chr 15q14, autosomal dominant, age-dependent penetrance
Seizure-types:

75% seizures during SWS or drowsiness
Oro-phayngo-laryngeal seizures
Unilateral sensory / motor symptoms

EEG features:

Broad centrotemporal spikes with anterior-posterior dipole
2-5x more frequent during slow wave sleep

Prognosis:

Remission after age 15 years, often within 5 years of diagnosis

Syndrome	Gene locus	Gene
Autosomal dominant nocturnal frontal lobe epilepsy	20q 1q 15q	CHRNA4 CHRNB2 ?
Autosomal dominant partial epilepsy with auditory features	10q	LGI1
Familial partial epilepsy with variable foci	22q	?
Benign rolandic epilepsy of childhood	15q	?
Benign familial infantile convulsions	19q	?

Early-onset benign childhood occipital epilepsy (Panayiotopoulos type)

Half as frequent as BECTS, excellent prognosis
Age 1-14 years (typical 5 years)
Seizure-types:

Autonomic/behavioral disturbances with vomiting, gaze deviation, impaired consciousness
Can progress to convulsions
45% last >30 minutes (mean 2 hours)
2/3 occur during sleep

EEG features:

High voltage, sharp wave discharges over one or both occipital regions
Attenuated by eye opening, activated by sleep

Prognosis:

1/3 have only one seizure

Late-onset childhood occipital epilepsy (Gastaut type)

2-7% benign childhood epilepsies
Age 3-16 years (typical 8 years)
Seizure-types:

Elementary visual hallucinations, ictal blindness, eyelid fluttering
1-3 minute seizures
No ictal vomiting, but may have migraine after seizure
Can occur at any time of day

EEG features:

Low amplitude, high frequency rhythmic occipital spikes
Fixation-off sensitivity

Prognosis:

50-60% remit in 2-4 years, some require continued AED therapy

Autosomal dominant nocturnal frontal lobe epilepsy

Childhood onset, lifelong disorder
Autosomal dominant:

CHRNA4 (chr20), CHRNB2 (chr1) – nicotinic cholinergic receptor subunits

Clinical features:

Clusters of brief hypermotor and tonic seizures with sleep predominance

EEG findings:

Normal background, ictal bilateral anterior discharges

Symptomatic localization-related epilepsies

Mesial temporal sclerosis

Pathologic changes in the mesial temporal region
Common cause of refractory temporal lobe seizures in adults
Controversial if link with prolonged febrile seizures early in life
Seizure-types:

Rising epigastric aura, alterations in consciousness
Ipsilateral picking automatism, contralateral dystonic posture
Secondary generalization with contralateral head/eye version and clonus

EEG features:

Interictal epileptiform discharges in anterior to midtemporal region, esp subtemporal leads
Ictal rhythmic theta-alpha pattern

Epilepsy surgery superior to medical therapy

Rasmussen’s syndrome

Onset before age 10, often preceded by infectious/inflammatory illness
Evidence for anti-GluR3 antibodies ?autoimmune process
Seizure-types and presentation:

Epilepsia partialis continua
Slow neurologic deterioration and hemiparesis, hemianopia

EEG features:

Dysrhythmic or rhythmic delta activity over contralateral hemisphere
Increasing pleomorphic spike and sharp waves, poor correlation with jerks

Hemispherectomy is of benefit

Migrating partial epilepsy of infancy

Onset from 13 days to 7 months
Clinical features:

Motor and autonomic seizures, polymorphic and variable, with secondary generalization
Seizures can be very subtle (eye deviation, eye jerks, eyelid twitching, limb jerks, chewing, apnea, flushing, salivation)
Myoclonus and spasms are rare
Seizures become almost continuous by 12 months
Developmental deterioration during seizure clustering, improves with seizure control
Progressive microcephaly

Outcome poor due to poor ability to attain seizure control

Idiopathic generalized epilepsies

Benign familial neonatal convulsions

Seizures from DOL#2-3
Excellent developmental outcome
5% have febrile seizures, 11% have epilepsy later
Genetics: KCNQ2 (chr20) and KCNQ3 (chr8) potassium-channel subunit genes, autosomal dominant
Seizure-types: From awakening, often tonic with apneas

Benign familial neonatal-infantile seizures

Seizure onset from 2 days – 6 months (mean 11 weeks)
Excellent outcome, no later epilepsy
Genetics: SCN3A neuronal sodium channel mutation, autosomal dominant

Benign familial infantile seizures

Onset between 2-20 months (mean 4-8 months)
Head and eye deviation seizures to either side, clonic, tonic
EEG – parieto-occipital discharges
Autosomal dominant
Sometimes associated with:

paroxysmal kinesogenic choreoathetosis (chr16)
familial hemiplegic migraine (ATP1A2, chr1)
Chr19

Benign myoclonic epilepsy of infancy

Onset 4 mo – 3 years
Positive family history in 30%
Rare, brief seizures, normal EEG background
Randomly or reflexively (photosensitive, startle), exaggerated by drowsiness and SWS
Photoparoxysmal response can be seen years after seizures resolved
Outcome favorable with early treatment (valproate)

Childhood absence epilepsy (pyknolepsy)

Onset 3-10 years (peak 6-7 years)
Neurologically normal, 15-45% family history, incomplete penetrance
Frequent, typical absence seizures
Genetics:

ECA1 – chr8
ECA2 – chr5 – GABRG2 GABA-A receptor
ECA3 – chr3 – CLCN2 chloride channel
More seen in girls

EEG findings:

Normal background
2.5-3Hz spike-and-wave discharge

Outcome:

Remits in adolescence, GTC may develop
Up to 40% are resistant to treatment
Associated cognitive/learning problems
15% develop JME

Juvenile absence epilepsy

Onset 9-13 years, less frequent seizures
GTC and myoclonic seizures on awakening
EEG 3.5-4.5Hz spike-and-wave, elicited by hyperventilation

Juvenile myoclonic epilepsy

Onset 8-24 years
Starts with absence seizures, then 1-9 years later myoclonus starts, then GTC seizures
Genetics: EJM1 (chr6) and EJM2 (chr15)
EEG findings:

4-6 Hz polyspike and slow wave complexes
Photoparoxysmal response
Increased epileptiform discharges in sleep state transitions

Vaproate and levetiracetam good (lamotrigine can exacerbate myoclonus) – lifelong therapy

Generalized epilepsy with febrile seizures plus (GEFS+)

Onset from first few months of life to early childhood
Genetics:

SCN1A (chr2) sodium channel
SCN1B (chr19) sodium channel
SCN2A (chr2) sodium channel
GABRG2 (chr5) GABA-A receptor

Clinical features: 75% have febrile seizures only, 25% also GTC, absence, myoclonic, tonic
EEG findings: normal background, ictal changes depend on seizure type
Outcome: seizures remit usually by age 12 years

Landau-Kleffner Syndrome

Acquired epileptic aphasia
Partially reversible epileptic encephalopathy of childhood
M:F = 2:1
Onset 2-8 years
Auditory verbal agnosia, progressing to pure word deafness or nonlanguage sound agnosia
Impaired expressive language, progressing to mutism
Associated with ADHD, psychosis, seizures
EEG findings:

Spikes, sharps, or spike-and-wave discharges bilaterally over temporal/parietal regions
Present in slow wave sleep > awake, disappears with REM
CSWS – temporally predominant

Epilepsy with continuous spike-wave in slow wave sleep (ECSWS)

Onset 2 mo-12 years (peak 4-5 years) – older than LKS
Partially reversible epileptic encephalopathy of childhood
Triad:

CSWS – frontally predominant for >85% slow wave sleep
Seizures
Neuropsychological/behavioral impairment

Acquired epileptiform opercular syndrome – oral motor dysfunction, drooling, dysarthria, speech arrest

Progressive myoclonic epilepsies

Myoclonic jerks, mental retardation, cerebellar dysfunction
EEG slow background, generalized epileptiforn discharges
SSEP giant cortical responses
Associated conditions:

Neuronal ceroid lipofuscinosis
Lafora disease
Unverricht-Lundborg disease
Sialidosis type I (cherry red spot myoclonus)
Gaucher type 3
MERRF
DRPLA

Neuronal ceroid lipofuscinosis

Autosomal recessive disorders (9 known subtypes) with accumulation of autofluorescent lipopigment
Clinical features:

Triad: cognitive/motor decline, visual loss, progressive myoclonic seizures

Subtypes:

Infantile NCL – Santavuori-Haltia disease

CLN1 (1p32) – palmitoyl protein thioesterase
Onset 6 months to 2 years
Visual loss can be later
Acquired microcephaly
Granular osmiophilic deposits (GRODs) on EM
“vanishing” EEG
Death in 5-10 years

Late infantile NCL – Jansky-Bielschowsky disease

CLN2 (11p15) – tripeptidyl peptidase
Onset 2-4 years
Present with seizures first à regression à visual loss
Curvilinear bodies on EM
EEG occipital spikes at low-frequency photic stimulation
Death by 8-12 years

Juvenile NCL – Batten disease, Spielmeyer-Sjogren disease

CLN3 (16p12) – unknown lysosomal transmembrane protein
Onset 4-10 years
Presents with visual loss first à regression à seizures
Optic atrophy and macular degeneration
Fingerprint bodies on EM
EEG nonspecific
Death in 3^rd-4^th decade

Adult-onset NCL

Kufs disease

Autosomal recessive – CLN1, 3, 4 – before age 40 years
Type A – progressive myoclonic epilepsy, ataxia, dementia
Type B – dementia, ataxia, dystonia, chorea
EEG fast spike and wave with photosensitivity
Death after 10 years of onset

Parry disease

Autosomal dominant with retinal degeneration

Unverricht-Lundborg disease

Baltic myoclonus
Genetics: EPM1 – chr21q22 – cystatin B (cysteine protease inhibitor) – Autosomal recessive
Clinical features:

Onset 6-15 years
Stimulus-sensitive myoclonus
GTC seizures, absence seizures
Mental retardation, ataxia, dysarthria

MRI – normal or atrophy of pons, medulla, cerebellum
EEG findings:

Diffusely slow background
Irregular generalized spike or polyspike and slow wave complexes
Photosensitive, decreased during sleep

Prognosis: Slow progression, may live to 60s

Lafora Disease

Genetics:

EPM2A – chr6 – laforin (intracellular phosphatase)
EPM2B – chr6 – malin (NHLRC1)
? 3^rd mutation

Lafora bodies – PAS positive cytoplasmic inclusions in dendrites and amacrine cells
Clinical features:

Triad of epilepsy, myoclonus, dementia
Seizure types – GTC, partial visual seizures, atypical absence, atonic, complex focal
Cognitive decline, emotional disturbance, dysarthria, ataxia

EEG findings:

MISF developing into slowing with fast generalized spike or polyspike and slow waves
Occipital spikes
Discharges decrease during sleep

Prognosis: death by 10 years of diagnosis

MERRF

Mitochondrial A8344G mutation (tRNA^lys), maternal inheritance
Onset by age 20 years
Clinical features:

Early – progressive myoclonic epilepsy, GTC seizures, ataxia, action-induced polymyoclonus
Late – progressive muscle weakness, hypertrophic cardiomyopathy, dementia, deafness, multiple lipomata, short stature

Pathological features:

Ragged-red fibers
Lesions of dentate and inferior olives
Degeneration of cerebellum, brainstem, and spinal cord
Astrocytosis, demyelination

Symptomatic generalized epilepsies

Infantile spasms

Mostly within the first year of life (peak 4-6 months) and cease by 5 years of age

West syndrome

Triad: infantile spasms, hypsarrhythmia, mental retardation
Hypsarrhythmia

chaotic background with high amplitude asynchronous slow waves and spikes
not always present (e.g. Aicardi)

Modified hysarrhythmia
Electrodecremental discharges
Etiologies:

Prenatal – infections, malformation, neurocutaneous syndromes, metabolic disorders
Perinatal – HIE, perinatal asphyxia
Postnatal – infections, trauma, HIE, tumours
Cryptogenic

Management:

Vigabatrin

30% response by 2 weeks
Especially in TS (90-100% response)
Adverse effects: concentric visual field deficits, irritability, insomnia, hypotonia
Follow with ERG

ACTH

75 U/m² IM bid x2wks, then taper
50-90% response by 7-10 days
Especially if cryptogenic
Adverse effects: irritability, cerebral atrophy, hypertension, sepsis and death

Prednisone

2mg/kg/d x 4-7 weeks
30-40% response

Valproate

Aicardi syndrome

X-linked dominant, male lethal
Clinical features:

Neuronal migration defects – polymicrogyria, periventricular heterotopia, choroids plexus cyst
Hemispheric asymmetry
Triad:

Agenesis of the corpus callosum
Infantile spasms
Chorioretinal lacunae

Spastic hemiplegia
Acquired microcephaly
Unilateral optic disc coloboma, microphthalmia
Rib, vertebral anomalies

Prognosis:

Intractible epilepsy, mental retardation, few walk

Lennox-Gastaut Syndrome

Onset 2-8 years (peak 3-5 years)
EME à IS à LGS
Clinical triad:

Multiple seizure types – tonic, atonic, GTC, atypical absence, myoclonic
Bursts of generalized <2.5Hz slow spike-wave activity
Cognitive deficits

Abnormal imaging in 2/3, cryptogenic in 1/3
EEG findings: Slow generalized spike-and-wave discharges (1-2 Hz)
AEDs of choice:

Valproate, clonazepam, ethosuximide, levetiracetam, topiramate, (vigabatrin)
Ketogenic diet

Outcome: 80-90% intractable seizures, 90% cognitive impairment, 5% death

Severe epilepsy with MISF

In spectrum of IS and LGS
Onset 4-7 years
EEG shows MISF
Mostly intractable seizures, especially tonic seizures

Epilepsy with myoclonic-astatic seizures (Doose syndrome)

Onset between 1-8 years (mean 2-4 years)
Clinical features:

Developmentally normal prior to seizures
Present with febrile or afebrile GTC seizure
Myoclonic-astatic (atonic) seizures – myoclonic jerk followed by loss of tone for 1-4 seconds
50% have absence seizures

EEG findings:

Rhythmic parasagittal theta
2.5-3Hz generalized spike or polyspike-wave discharges (myoclonus) interrupted by slow wave paroxysmal bursts (atonia)

AEDs of choice: Valproate, levetiracetam, lamotrigine, topiramate
Outcome: 50% resolve, 50% continue to have GTC seizures

Epilepsy with myoclonic absence

Onset 7 years
Absence with rhythmic jerks
Poorer prognosis, resistant to therapy, 60% develop other seizure types
EEG 3 Hz spike-and-wave

Early myoclonic epilepsy

Onset first month (often first week) of life
Etiologies: often inborn errors of metabolism (nonketotic hyperglycinemia, PA, MMA, Menkes, Zellweger)
Clinical features:

Triad:

Myoclonic jerks

Erratic, fragmented, random, asynchronous, asymmetric
Massive axial bilateral myoclonus

Focal seizures
Tonic seizures

Encephalopathy, global developmental delay, hypotonia, progressive microcephaly

EEG findings:

Burst-suppression pattern
Myoclonic jerks do not correlate with EEG changes

Management considerations: try pyridoxine, look for inborn errors of metabolism
Outcome: 50% die, 50% severe neurological deficits

Ohtahara syndrome (early infantile epileptic encephalopathy with suppression burst)

Onset intrauterine to 3 months (average DOL#10)
Associated with cerebral dysgenesis (hemimegalencephaly, porencephaly, Aicardi syndrome, agenesis of mammilary bodies), linear sebaceous nevus syndrome
Clinical features:

Tonic spasms, partial seizures, rare myoclonic seizures
Severe psychomotor retardation

EEG findings: Suppression burst pattern in wake and sleep
Outcome:

Frequent death during infancy
If survive, frequent progression to West syndrome

Dravet syndrome (severe myoclonic epilepsy of infancy, SMEI)

Onset in 1^st year of life, progressive epileptic encephalopathy
Genetics (like GEFS+):

SCN1A sodium channel mutation
GABRG2 GABA-A receptor mutation

Clinical features:

Early onset simple febrile seizures
Myoclonic jerks
Atypical absences
Complex focal seizures
Pre-seismic period with febrile seizures, followed by seismic period until age 11-12 years
Improvement of seizures in post-seismic period, although seizures still persist
Fever is always a trigger
Severe cognitive impairment
High mortality rate

No effective management

Febrile seizures

Simple febrile seizures

Lasts <15 minutes
Not recurring within 24 hrs
No post-ictal neuro deficits

Complex febrile seizures

Lasts >15 minutes
Recurrent within 24 hrs
Focal seizure
Todd’s paresis

Epidemiology

Most commonly between 3 months – 5 years
1/3 recurrence – risks:

young age at onset
family history
low temperature
persistent neurological deficits
complex febrile seizure

Risk for epilepsy:

General population = 0.5%
Single febrile seizure = 1%
Complex (repeated) = 4%
Complex (focal) = 30%
Risk factors:

Complex
Developmental delay
Family history of epilepsy
1 (3-4% risk), 2+ (13% risk)

Association with mesial temporal sclerosis controversial

Retrospective review of MTS shows association with prolonged febrile seizures
Prospective studies on febrile seizures not showing MTS

Updated: December 17, 2007

Disclaimer: These are personal study notes. No promises for accuracy or originality.