Dr. Rahi kiran.BSenior residentDept. of NeurologyGMC Kota

A group of heterogeneous brain disorders occurring at a critical period of brain development, where frequent abnormal ictal and/or interictal EEG epileptiformactivity is mainly responsible for behavioral, cognitive and motor regression.

(1) electrographic EEG paroxysmal activity that is often aggressive, (2) seizures that are usually multi-form and intractable, (3) cognitive, behavioral, and neurological deficits that may be relentless, (4) sometimes early death.

Not fully understood, not same for all

Aggressive ictal(seizure) and electrical(EEG) epileptogenic activity in developing brain leading to excessive excitability

which varies acc to age and stage of brain maturity

In neonates – burst-suppression

Infancy – hypsarrythmia

Child – GSWD

As age advances, these also change

Epileptic Encephalopathy Syndromes in neonates

Onset < age 3 m

Male = female

Etiology - Inborn errors of metabolism - mc-nonketotic hyperglycinemia, methylmalonic acidemia.

Triad of intractable seizures – Erratic myoclonus f/b simple focal seizures f/b Tonic seizures

Erratic myoclonus - shift typically from one part of the body to another in a random, asynchronous fashion.

simple focal seizures –

Tonic seizures - a diffuse tonic contraction, usually extending to the extremities.

Psychomotor devt – abnormal from onset

Interictal EEG - suppression–burst activity, evolves into atypical hypsarrhythmia after 3 to 5 months of life,

accentuated during sleep

Myoclonus – no EEG expression, follows burst

CT and MR - related to etiology,grossly normal or have asymmetrical enlargement of one hemisphere,

dilatation of the corresponding lateral ventricle, or cortical atrophy

the serum levels of amino acids should be determined, especially glycine and glycerol

The inter-ictal EEG of early myoclonic encephalopathy is a repetitive suppression–burst pattern without physiological rhythms

The prognosis is poor - >50% die within weeks or months.

no effective therapy – pyridoxine trial can be tried

ILAE Definition Very early onset, within the first few months of life, frequent tonic spasms and a

suppression–burst EEG pattern in both the waking and sleeping states.

Onset - 10 days to 3 months of age (occ. Intrauterine).

Etiology – mc – malformations, no familial cases

(hemimegaloencephaly, porencephaly, Aicardi syn, focal cortical dysplasia)

Tonic spasms - forward tonic flexion lasting 1–10 s that is singular or in long clusters 10–300 times every 24 h.

Alternating hemiconvulsions or GTCS are exceptional.

Myoclonic seizures are rare.

Burst suppression with pseudorhythmic periodicity,

disappears in 6 months - Most survivors evolve to West syndrome with hypsarrhythmia, or later to LGS.

prognosis is poor with severe psychomotor retardation

Psychomotor development may be slightly better if the infants do not develop West or Lennox-Gastaut syndrome.

Half of the children are likely to die in infancy or childhood

No effective treatment

vigabatrin and zonisamide – some benefit

ACTH – not useful

invasive surgery, such as a partial resection or complete hemispherectomy.

Epileptic Encephalopathy Syndromes in Infancy

frequent partial seizures of multifocal onset, with autonomic or motor involvement

The interictal EEG reveals multifocal epileptiform activity and slowing, diffuse slowing of the background activity. asymmetry between different recordings

The ictal EEG confirms multifocal onsets,

No burst-suppression

difficult to control with standard AEDs.

Bromides, stiripentol, and clonazepam may be helpful

Triad of infantile spasms, arrest of psychomotor development, and hypsarrhythmia.

Onset - age of 3 and 12 months.

Male(60%) > female

Etiology – symptomatic(80%), idiopathic cerebral malformations, infection, hemorrhage, hypoxicischemic injury, metabolic

disorders, and genetic conditions,such as Down syndrome, TS

Epileptic spasms - Clusters of sudden, brief (0.2–2 s), bilateral tonic contractions of the axial and limb muscles involving extension and/or flexion

Occurs in clusters – 1-30 / day, each with 20 – 150 attacks

Precipitating factors- twilight state,sudden loud noises or tactile stimulation,feeding.

Spasms – flexor – extensor – mc Flexor – salaam spasmsExtensor – like moro reflex

Psychomotor delay – from the onset

interictal -Gibbs and Gibbs –hypsarrhythmic EEG.(2/3 rds) Disorganized pattern with asynchronous, very high amplitude slowing and frequent

multifocal spike and sharp wave discharges

Sleep – REM – normal NREM – more synchronous

By 2-4yrs - LGS

Ictal EEG – mc – high voltage, gen. slow wave

episodic,low amplitude slow wave

diffuse attenuation(electrodecremental ictal EEG pattern).

Brief flexor spasm associated with high voltage slow wave discharge

Good if treated early

Mortality - 5%.

60% - develop other seizure types – LGS

50%-permanent motor disabilities

2/3rd -severe cognitive and psychological impairment.

5–12% - normal mental and motor development.

First line ACTH and vigabatrin (TS)

No role of pyridoxine

valproate, levetiracetam, topiramate, zonisamide, lamotrigine, and benzodiazepines

ketogenic diet is helpful in most cases

Hemispherectomy - medically intractable

No specific AED has been shown to affect long-term developmental outcome

Onset – day 1 to 5yrs

Female : male – 2: 1

Etiology – 50 % - a/w angelman syn, 20% - birth asphyxia

c/b – fixed, non-progressive encephalopathylong-lasting recurrent episodic erratic myoclonic status epilepticus with atypical absence seizures.

interictal EEG-multifocal epileptiform discharges and background slowing

Ictal EEG - continuous generalized slow spike and wave, or an absence pattern

Myoclonic status – improves but with residual disability

Treatment myoclonic status – BZDs Others - valproate with ethosuximide or clobazam

Onset - always <1yr of life, with a peak age of 5 m.

Male : female – 2:1

Etiology – 50% genetic, SCN1A mutation – mostly sporadic

Tetrad of seizuresEarly onset infantile febrile clonic convulsionsMyoclonic jerksAtypical absencesComplex focal seizures.

In second year - more frequent and persistent, partial & myoclonic jerks start, not a/w fever, ppted by – hot and light, gradual regression of milestones

Precipitating Factors - Febrile illnesses , warm environment (hot baths), Photic and pattern stimulation.

Inter-Ictal EEG

Normal till 18mnths age

Initial -20% show normal BG with photoparoxysmal discharges of spikes/ polyspikes-slow waves.

Within 1 year, EEG - abnormal slow background with frequent asymmetricalparoxysms of polyspikes (GPSWD)

Ictal EEG

Varies according to seizuretype.

Brain scans are usually normal. SCN1A” mutation - 70 per cent of children

Treatment very resistant – initial - Phenobarbital, sodium valproate Other - stiripentol, topiramate ,clonazepam ,clobazam, LEV combination of sodium valproate with either topiramate or stiripentol may be the

most helpful. c/I – PHT,CBZ,LMT short course of a steroid (called prednisolone) and the ketogenic diet may also be

helpful.

Epileptic Encephalopathy Syndromes in Childhood

1–4% of childhood epilepsies.

Onset - Starts between 1 and 7 yrs with a peak at 3–5 years.

Male > female

Triad-

Polymorphic intractable seizure that are mainly tonic (80%), atonic (50%)and

atypical absence seizures (70%), Myoclonic Jerks(11–28%) – sleep & awake

Cognitive and behavioural abnormalities.

EEG with paroxysms of fast activity and slow (less than 2.5 Hz) generalised spike-

wave discharges (GSWD).

symptomatic - 70–78% of patients with LGS –

encephalitis and/or meningitis,

tuberous sclerosis,

brain malformations

(e.g., cortical dysplasias),

Idiopathic –

▪ normal psychomotor development occurred prior to the onset of symptoms,

▪ no underlying disorders or definite presumptive causes are present,

▪ no neurologic or neuroradiologic abnormalities are found.

birth injury

hypoxia-ischemia injury,

frontal lobe lesions

trauma.

ILAE inclusion criteria –

Atleast 2 seizure types – tonic, atonic, atypical absence(mandatory)

EEG – GSWD with episodic fast activity

Impaired intellectual functioning

Not imp. – onset age, imaging, etiology

Tonic seizures – 80 – 100% mc & most characteristic,

Symmetrical, brief, awake & NREM, not in REM

Atonic – 50%

Atypical absence – 2/3rd

Myoclonic jerks – 11-28%

Drop attacks -

Inter-ictal EEG – abnormal BG – fragmented alpha, excess slow waves

Ictal EEG –

a) tonic – paroxysmal fast activity

b) Atonic – gen. polyspikes, slow GSWD

c) Atypical absence - <2.5Hz GSWD

d) Myoclonic – gen. polyspikes with/without slow waves

Tonic seizure started clinically with a scream and episodic nystagmusThe ictal EEG consisted of an high-amplitude generalised sharp and

slow waves at approximately 1 Hz.

The EEG returned to its pre- ictal state after approximately 1 min

from the onset of theseizure.

10–30% of cases develop from West syndrome or other epileptic encephalopathies.

Bad prognosis

5% - die

90%- seizures in adult life also

Almost all – cognitive impairment- more in symptomatic cases

AEDs – First line – all types - VPA, clobazam, zonisamide, rufinamide, topiramate & felbamate (serious adverse effects)

Lamotrigine – all but myoclonic, LEV – all but tonic

PHT – tonic clonazepam – myoclonic

Drop attacks – most difficult to treat- topiramate, felbamate,Lamotrigine, rufinamide

Atonic ,Atypical absence, Myoclonic – better

ACTH & steroids – in SE

ketogenic diet-refractory to AED

Surgical-

corpus callosotomy – resistant drop attacks

vagus nerve stimulation – tonic & atonic

focal cortical resection

LGS EM-AS of Doose

type Focal Generalised

Main types Tonic, atonic, atypical absence Myoclonic, atonic

tonic common never

atypical absence common uncommon

Devt. Before onset abnormal normal

West syndrome common uncommon

Background EEG abnormal normal

“Partly reversible, epileptic encephalopathy of childhood manifesting with acquired verbal auditory agnosia and fluctuating course of the linguistic disturbances that occur together with other cognitive and neuropsychological behaviouralabnormalities.”

Age at onset : 2–8 yrs with a peak at 5–7 yrs.

male-to female ratio, 2 : 1

Etiology - unknown

Linguistic abnormalities- normal developmental milestones before aphasia symptoms

All pts will have language abnormalities, 3/4th seizures

First symptom – verbal auditory agnosia, later all types of aphasia

Imp. Feature - fluctuating course

Cognitive & Behavioural problems- 3/4th – ADHD

Seizures – 3/4th , nocturnal,

Types not well defined - (a/e tonic)

Posterior temporal lobe foci of sharp-slow waves, multifocal and bi-synchronous

CSWS also occur(not needed for diagnosis) – also persist in REM sleep

Length of CSWS has strict correlation with language recovery

Seizures,EEG abnormalities and language disturbance usually remit by 15yrs of age.

50% of patients relatively normal life with 10–20% achieving complete normalisation.

50% left with permanent sequelae that may be very severe.

AEDs 1st line – VPA + clobazam

Phenobarbital, carbamazepine, and phenytoin – worsen EEG Discharges

Valproic acid, ethosuximide, and benzodiazepine alone or in combination – effective

clobazam and levetiracetam to be the most efficacious in the treatment of ESES.

corticosteroids & ACTH – if AED fail

IVIG & ketogenic diet – no proven benefit

surgical intervention with multiple subpial transections (MSTs) – mainly in cases with secondary b/l synchrony

Continuous spike-andwave during sleep. All discharges vanished after receiving ACTH

Partly reversible, age-related childhood epileptic encephalopathy c/b “subclinical” spikes and waves occurring almost continuously during slow sleep and appearing every night for a variable length of time in children

triad of: EEG CSWS Seizures(except tonic seizures). Neuropsychological and motor impairment.

Onset of seizures - 2 m to12 yrs, with a peak at 4–5 yrs.

Male : female – 2/3rd

seizure types- u/l or b/l clonic seizures, GTCS, absence, partial motor seizures.

Tonic seizures, however, never occur.

About 60% of patients also exhibit several types of Seizures

The majority of affected children never return to normal levels, particularly in the verbal area and attention

MRI brain – abnormal in many

Inter-ictal – fronto or centro-temporal slow spikes

The typical EEG changes appear 1 year to 2 years after the first seizure and are associated with behavioral deterioration.

characteristic feature-continuous B/L spike-wave discharges on the EEG during NREM sleep(cause Unknown)

SWI – spike wave index - > 50 % NREM

> 85 % - poor prognosis

< 85% - better performance

I stage is before the discovery of CSWS The EEG shows multi-focal spikes and bisynchronous generalised sharp or spike-wavedischarges. First seizure is usually nocturnal

II stage is when CSWS is found Increase in seizures and the appearance or deterioration of neuropsychological symptoms (frontal & temporal)that prompt a sleep EEG. Tonic seizures never occur Continuous bilateral and diffuse slowspikes-waves of 1.5–2 Hz during NREM

sleep is the defining EEG patternof ECSWS.

III stage is after clinical and EEG remission starts –2-7yrs from onset, seizures remit in all pts, EEG normalises, left with residual deficits

Seizures remit in all by 10 – 15yrs age – irrespective of etiologyGood prognosis

Cognition & behaviour – incomplete recovery

Early treatment - better

may or may not respond - benzodiazepines, valproate, ethosuximide, carbamazepine, phenytoin.

Only benzodiazepines and adrenocorticotrophic hormone have been reported to suppress the electrical Status

TOC - benzodiazepines + valproate

long-lasting improvement of the language function - multiple subpial transectionsof the region of focal epileptic discharges

LKS CSWS

Seizures 3/4th All

Language Verbal auditory agnosia Expressive

Bahavioral Common All

CSWS onEEG 80% 100%

Spike localisation Temporal Frontal

Normal life 50% 25%

Other Severe Epileptic Encephalopathies

Both sexes are equally affected

Etiology- chronic viral infection, immune response to infection,immune-mediated causes.

typically shows –

1. Focal motor seizures or epilepsia partialis continua (EPC)

2. Generalized seizures contralateral to the ictal and interictal epileptiform activity

3. Unilateral hemispheric cortical brain atrophy on MRI (abnormal signal T2/FLAIR and atrophy or hyperintense signal of the ipsilateral caudate head)

MRI - to exclude other causes of focal seizures

EEG -

response to treatment is very poor

“A previously normal child, aged 2–15 years, within a few days of developing a FOU, develops an acute prolonged perisylvian refractory convulsive status epilepticus, persisting for more than 1 month”

Later develops chronic pharmacoresistant epilepsy and cognitive dysfunction

Cause unknown, may be immune-mediated.

Interictal EEG - diffuse slowing

Ictal EEG - fast activity intermixed with spikes

MRI brain - normal or may show b/l hippocampal abnormality

seizures are resistant to AEDs

Steroids/ immunotherapy may be tried

prognosis is poor

Early Myoclonic Encephalopathy- Suspected if –

Early Continuous shifting Segmental and erratic myoclonus f/b focal seizures, rarely tonic seizures

burst short, suppression long on EEG

Ohtahara Syndrome

Early Tonic seizures, focal seizures

Burst suppression EEG with Pseudo-rhythmic appearance

burst long, suppression short on EEG

Dravet Syndrome

Intractable myoclonic jerks and MR within 1-2 yrs from onset along with

febrile seizures –

prolonged > 15min

unilateral

mainly clonic

frequent

ppted by low fever

early onset (<1yr)

West syndrome Infantile spasms, clustering on arousal

Lennox–Gastaut Syndrome Multiple seizure types with preexisting or newly developing cognitive and

behavioural problems

Epileptic Encephalopathies

Neonates(Burst suppression on EEG)

Infants(Hypsarrythmia on EEG) Children

(GSWD on EEG)

EME Ohtahara syn West synDravet syn LGS LKS CSWS

LKS CSWS

Seizures 3/4th All

Language Verbal auditory agnosia

Expressive

Bahavioral Common All

CSWS onEEG

80% 100%

Spike localisation

Temporal Frontal

Normal life 50% 25%

Infantile spasmsHypsarrythmia30 % LGSDOC–ACTH + vigabatrin

Multiple seizures-tonic,

atonic, atypical absence

EEG-GSWD with paroxysmal fast activity

SCN1A mut –70%Atypical febrile seizuresStiripentol-recently approved

MC cause-Inborn errors of metabolismImp – erratic myoclonus, no tonic spasams

MC-structural abnormalitiesImp-tonic seizures, rarely myoclonus

The spectrum from neonatal to early childhood is c/b variable clinical and EEG features – reflecting developmental age rather than underlying etiology.

Early treatment & prevention of seizure activity gives better cognitive outcomes and quality of life

As these are drug resistant, further studies are needed

Khan S, Baradie RA. Epileptic Encephalopathies: An Overview Hindawi Publishing Corporation,Epilepsy Research and Treatment. Volume 2012, 8 pages doi:10.1155/2012/403592

Bradley’s textbook of Neurology, 7th edition

Covanis A. Epileptic encephalopathies (including severe epilepsy syndromes).Epilepsia, 53(Suppl. 4):114–126, 2012 doi: 10.1111/j.1528-1167.2012.03621.x

eMedicine@medscape:Epileptic and Epileptiform Encephalopathies