Epilepsy

Andrew Bleaselandrew.bleasel@sydney.edu.au

Westmead Hospital,Children’s Hospital at Westmead

Seizures

An epileptic seizure is a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

Fischer RS et al., Epileptic Seizures and Epilepsy. Epilepsia, 46(4):470–472, 2005

Epilepsy

Epilepsy is a disorder of the brain characterized by an enduring predisposition to generate epileptic

seizures and by the neurobiologic, cognitive, psychological, and social consequences of this

condition. Epilepsy is not a singular disease entity but a variety of disorders reflecting underlying brain dysfunction

that may result from many different causes.

Fischer RS et al., Epileptic Seizures and Epilepsy. Epilepsia, 46(4):470–472, 2005

EpilepsyChronic disorder intermittent expressionno obvious physical signshistory is everything

– correct diagnosis of seizure– classification of seizure– epilepsy syndrome– management, titration of medication

EpidemiologySeizures; lifetime cumulative risk, of 1 seizure,

5-9% – 1/3 children, febrile seizures– 1/3 patients single seizure – 1/3 epilepsy

Epilepsy; at least 2 seizures, on more than 1 occasion– prevalence, number of cases at a given time– approximately 6 per 1,000, 0.5-1.0%

Diagnosis of EpilepsyEpilepsy is a disease of the brain defined by

any of the following conditionsAt least two unprovoked (or reflex) seizures

occurring >24 h apartOne unprovoked (or reflex) seizure and a

probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years

Diagnosis of an epilepsy syndrome

Fischer RS et al., A practical clinical definition of Epilepsy. Epilepsia, 55(4):475-485, 2014

Classification of seizures

International League Against Epilepsy Classification of Epileptic Seizures, 1981– based upon clinical seizure, interictal EEG and

ictal EEGPathophysiology

– Partial seizures– Generalised seizures– Unclassified

– Display of fluctuations in voltage which occur over the scalp generated by postsynaptic potentials in cortical neurones.

– To record at the scalp, there must be summation of synchronous potentials generated by many synapses.

ElectroencephalographyEEG

Revision of classification scheme

Epilepsia, 51(4):676–685, 2010

Generalized seizures

"those in which the first clinical changes indicate initial involvement of both hemispheres"– Tonic-clonic seizures – Absence seizures, "petit mal" – Myoclonic– Tonic seizures– Atonic seizures

Generalized epileptic seizures are thought to originate within bilaterally distributed networks. These include cortical and subcortical structures, but not necessarily the entire cortex. They can arise from focal lesions.

Ingrid Scheffer with permission, 2013

200uV

Rhythmical voltage fluctuations as a result of interaction between the cortex and thalamus.

Rhythmical voltage fluctuations as a result of interaction between the cortex and thalamus.

Generalised tonic clonic seizure

Convulsion, Grand mal seizure, “fit”Sudden onset no warning for patientMay see myoclonic jerks firstTonic phase with tremor Interupted by brief atonia = clonic phaseUnconscious afterward, confused

Focal (Partial) seizures

"the first clinical and EEG changes indicate initial activation of a system of neurons limited to part of one cerebral hemisphere" – ? consciousness is preserved or lost during the

seizures. » Simple partial seizures » Complex partial seizure, automatisms are

semipurposeful movements

Focal epileptic seizures originate within networks limited to one hemisphere.  These may be discretely localized or more widely distributed.…

Ingrid Scheffer with permission, 2013

15 year old girl

Seizures started at age 10 years– abnormal movements of the right arm– followed by weakness

Second daily seizures despite medication trials– carbamazepine, increasing doses– carbamazepine and levetiracetam

Normal motor and sensory function

•Axial T1 MRI images•post central encephalomalcia

27 year old male, seizures since 11 yrs

Seizures begin in right frontal lobe– spread to frontal eye field– patient aware of head &

eye deviation to left – then loss of awareness– secondarily generalised

tonic clonic seizure

Seizure onset

footleg

hand

facetongue

Frontal eye field

Examination of the seizure evolution

Head and eye version

Key features in Seizures

Focal onset– Aura?– Consciousness lost?– May progress to generalised seizure

Generalised – with in a rapidly engaged network– Non-convulsive, absence– Generalised tonic clonic seizures

Aetiology of Epilepsy Infancy & childhood

– Birth injury– Inborn error metabolism– Congenital malformn.

Childhood & adolescence– Genetic syndromes– CNS infection

Adolescence & young adult– Head trauma

Older adult– Stroke– Brain tumor

Proportion of incidence cases of epilepsy by aetiology in Rochester, Minnesota, 1935–1984

Aetiology of epilepsy25-30% have an identifiable neurological or

systemic disorder» Stroke 12%, head injury 4%, infection 2.5%» brain tumour 3.5-5%, neurodegenerative 2%» birth trauma, developmental malformations of brain

– Age related incidence60-70% will not have an identifiable cause

for the epilepsy– epileptic syndromes can be defined

Epilepsy syndrome

Classification of the epilepsies and epileptic syndromes, 1989

describes the patient’s illness– history and examination, aetiology– family history– seizure type(s)– electroencephalography– structural neuroimaging

Mesial temporal sclerosis on MRI scan of the brainComplex partial seizures

loss of awareness, amnesia for events, automatisms

Mesial temporal lobe epilepsy

Childhood absence epilepsy

peak onset 6-7 years, girls > boys – family history of epilepsy– Absences very frequent

EEG, 3Hz spike and wave complexes, » clinical seizures produced by hyperventilation

remission in approx. 80% by adolescence – generalised tonic clonic seizures, 20-40%– ethosuximide, valproate, lamotrogine

Juvenile myoclonic epilepsy– age of onset, 12-16 years

» myoclonic seizures, early morning occurrence» generalized (clonic-)tonic-clonic seizures, 90-95%» absence seizures occur in 10-33% of cases

– genetic etiology, » ?chr 6, ?dominant pattern, ?autosomal recessive

– interictal EEG, normal background activities» generalised spike-wave discharges 4-6 Hz» photoparoxysmal responses, 30%

– Prognosis good, with 86-90% responding VPA

Epilepsy Syndromes

Describe the patients epilepsy– Seizure types, aetiology, prognosis

Many epilepsy syndromes exist without a known aetiology– Idiopathic or Genetic epilepsy– Ion channel disorders

IdiopathicGeneralized

IdiopathicPartial

Symptomatic Generalized

Symptomatic Partial

1989 Classification

But many patients could not be classified

The Epilepsies (2014)Generalized Focal

Genetic GeneticStructural StructuralMetabolic MetabolicImmune Immune

Infectious InfectiousUnknown Unknown

Genetic contribution to epilepsy Relatives of probands with epilepsy > controls

– prevalence studies 4.8% vs 1.9%

Risks are greater for generalised than focal epilepsies

– Generalised epilepsies: risk to sibs ~ 10%

– Focal epilepsies: risk to sibs < 5%

– Febrile seizures: risk to sibs ~ 8%

Genetic contribution to epilepsy

– Twin studies» “idiopathic” epilepsy syndromes (genetic);

eg. Childhood Absence Epilepsy

» monozygotic 70.2%, dizygotic 7.5%» Structural focal epilepsy (acquired);

eg. Head injury, encephalitis, tumour » monozygotic 10.8%, dizygotic 5.6%

Epilepsy with Mendelian inheritance

Autosomal dominant– eg. tuberous sclerosis, Familial cavernous angiomas

Autosomal recessive– eg . phenylketonuria, pyridoxine dependency, Lissencephaly

X linked– eg. Subcortical band heterotopia

Epilepsies with Simple Inheritance Voltage-gated Channelopathies

– Benign Familial Neonatal Seizures; Potassium channel genes– Benign Familial Neonatal-Infantile Seizures; Sodium channel gene– Generalized Epilepsy with Febrile Seizures Plus, Sodium channel

Ligand-gated Channelopathies– Autosomal Dominant Nocturnal Frontal Lobe Epilepsy; Nicotinic

receptor subunit genes– Idiopathic Generalized Epilepsy /GEFS+; GABA receptor subunit

gene– Juvenile myoclonic epilepsy; GABA receptor subunit gene

Non-Channel genes– Autosomal Dominant Partial Epilepsy with Auditory Features;

?Tumour suppressor gene

Genetic epilepsy syndrome with heterogeneous phenotypes

Common phenotypes– Typical febrile seizures

– Febrile seizures outside 3m to 6yr ± afebrile seizures (FS+)

Less common phenotypes– FS+ and absences, FS+ and myoclonus, FS+ and atonic seizures

– FS+ and focal (esp. temporal) epilepsy

– Myoclonic-astatic epilepsy, Severe myoclonic epilepsy infancyScheffer & Berkovic 1997; Singh et al 1999

Generalised Epilepsy with Febrile Seizures Plus (GEFS+)

Berkovic and Scheffer, 2003

Majority of Idiopathic Epilepsies have complex inheritance

Simple inheritance

GA, 56 year old woman

Husband was woken from sleep by his wife having a seizure

He found GA stiff and unresponsive, jerking

She was unconscious when CDA arrivedShe next recalls waking in the hospital, c/o headache and back pain, laceration

lateral margin of tongue

Questions with a First SeizureSeizure or not?Seizure type?

– focal onset, postictal deficitsEvidence of CNS dysfunction?

– school, work, hemiparesis, PMHAny precipitating factors?What investigations to order?Do we start an AED?What precautions to advise?

Seizure Precipitants

Low (less often, high) blood glucose

Low sodium, calcium, magnesium

Stimulant/other proconvulsant intoxication

Sedative withdrawal

Severe sleep deprivation

Evaluation of a First Seizure

History, physicalBlood tests: FBC, electrolytes, glucose, Ca,

Mg, hepatic and renal functionLumbar puncture only if meningitis or

encephalitis suspected (CT scan)Urine drug screenElectroencephalogramCT or MR brain scan

EEG studies interictal epileptiform abnormalities

– increased risk for seizure occurrence » normal EEG does not exclude epilepsy» presence of an epileptiform abnormality does not

prove epilepsy

– interictal epileptiform, partial or generalized if normal,

» repeat after sleep deprivation» >3 normal, rare to be diagnostically useful

Seizure recurrence after 1st seizure

wide range from studies, pooled data 51%most recurrences in 1st year, usually 3-6moPredictive factors

– idiopathic (32%) vs remote symptomatic (57%)» abnormal exam, structural lesion on CT/MRI

– abnormal EEG, epileptiform (58%)– partial seizures, especially remote symptomatic

Relapse rate is reduced by AED treatment

Paroxysmal nonepileptic eventeg. syncope

Acute symptomatic seizureeg. Febrile convulsion

Single seizure

Idiopathic

Temporal Extratemporal

Symptomatic

Partial

Idiopathic Symptomatic

Generalised

Recurrent unprovoked seizures. Epilepsy

Unprovoked seizureIs it the first seizure?

SeizureWas there an intercurrent illness?

Was it provoked?

Paroxysmal clinical eventWas it a seizure?

Aims of AED treatment

Choose appropriate medication– valproate for generalised seizures

Use a single drug, monotherapy – simplifies treatment, reduces adverse effects

Make the patient seizure free– without dose related side effects

if seizures recur, increase dose– maximal tolerated dose– need to observe for 2-3x usual seizure interval

Prognosis

70% have a good prognosis for control of seizures and remission– better for idiopathic than symptomatic– better for generalised than partial

20% need regular medication and may have breakthrough seizures

5-10% poorly controlled

Clinical practice

First Seizures– Are they isolated?– Is this the onset of epilepsy?

Epilepsy– Investigation, aetiology– Treatment with AED– Titrattion against seizures

Paroxysmal nonepileptic eventeg. syncope

Acute symptomatic seizureeg. Febrile convulsion

Single seizure

Idiopathic

Temporal Extratemporal

Symptomatic

Partial

Idiopathic Symptomatic

Generalised

Recurrent unprovoked seizures. Epilepsy

Unprovoked seizureIs it the first seizure?

SeizureWas there an intercurrent illness?

Was it provoked?

Paroxysmal clinical eventWas it a seizure?

MR, 16 year old boy

Several witnessed generalised seizures– during the day

about to go on trip to Japan

Would you start medication?Which AED to use?

Syncope Precipitating factors Light-headed, tinnitus limp fall, convulsive

movements brief rapid recovery no incontinence or

tongue bite Normal EEG

Seizures

Supine, sleep Aura, CPS tonic clonic evolution duration minutes postictal confusionmuscle soreness, injury,

lateral margin tongue bite Abnormal EEG

Syncope vs Seizures

Precipitating factors Light-headed, tinnitus limp fall, convulsive

movements brief rapid recovery no incontinence or tongue

bite Normal EEG

Supine, sleep Aura, CPS tonic clonic evolution duration minutes postictal confusionmuscle soreness, injury,

lateral margin tongue bite Abnormal EEG

Differential diagnosis of seizures

SeizureSyncopeMigraineCerebral ischaemiaMovement disorderSleep disorderMetabolic disturbancePsychiatric disturbance

Refractory seizure disorder

Review the diagnosis– are the seizures epileptic?

Review the medical therapy– compliance with medication?– adequate trials of AEDs?

Consider alternatives to medical therapy– epilepsy surgery in partial seizure disorders

Refractory seizure disorder

Review the diagnosis– are the seizures epileptic?

Review the medical therapy– compliance with medication?– adequate trials of AEDs?

Consider alternatives to medical therapy– epilepsy surgery in partial seizure disorders

Epilepsy surgery

Failure of antiepileptic medication– Trials of different drugs, >2 often predicts

refractory seizures– Identify epileptic focus;

» Video EEG, MRI, PET, SPECT

– show it could be removed safelyTemporal lobectomyFocal cortical resection of frontal, parietal

or occipital lobes

Epilepsy surgery

Temporal lobectomy– Most common surgery

» 60-70% seizure freedom

Extratemporal surgery– Focal cortical resection of frontal, parietal or

occipital lobes» Seizure freedom 40-60%

Summary points

Seizures verses EpilepsyClassification of seizures; Partial vs Generalised

seizuresAetiology of epilepsyClassification of the epileptic syndromes

First Seizure; was this a seizures or not?Seizure type?, underlying CNS dysfunction

Patient;Different?Friends?

Neurologist;Syndrome?Prognosis?

Paediatrician;Epilepsy?Syndrome?Investigations?Treatment?

GP;Referral?

Parent;Seizures?Cause?Prognosis?

School;School camp?Exams?