AN EPILEPTIC SEIZURE Incidence of Epilepsy Focal Seizure

AN EPILEPTIC SEIZURE

excessive neuronal discharges Pediatrics Symptomatic Epileptic Syndromes 29 July 2009 TES meeting

Clinical seizures ก

PROPOSED DIAGNOSTIC SCHEME FOR PEOPLE WITH Incidence of epilepsy EPILEPTIC SEIZURES AND WITH EPILEPSY r Engel et al. Epilepsia 2001;42(6):796-803 a 200

y / Axis 1 Ictal phenomenology

0 - detailed description of symtoms during the seizure

150 0 Axis 2 Seizure type or types

/ - according to ictal phenomenology and EEG

c 100

n Axis 3 Syndrome

i - list of syndromes, syndromic diagnosing is not always possible

n 50

I Axis 4 Etiology - genetic defects, or specific pathological substrates for symptomatic focal epilepsies 0 0 5 10 20 40 60 80 Axis 5 Impairment Age (years) - disability caused by epilepsy

Epilepsy Classification: ILAE1981 Focal seizure

1.Partial(Focal,Local) Seizures A. Simple partial seizures B. Complex partial seizures w/ cons. impairment at onset SPS=>CPS C. Partial seizures (A,B) evolving into GTC. 2.Generalized Seizures Convulsive vs Non-convulsive 3.Unclassified Epileptic Seizures

NBased 1st on EEG then semiology PROPOSED DIAGNOSTIC SCHEME FOR PEOPLE WITH Generalized seizure EPILEPTIC SEIZURES AND WITH EPILEPSY Engel et al. Epilepsia 2001;42(6):796-803

Axis 1 Ictal phenomenology - detailed description of symtoms during the seizure

Axis 2 Seizure type or types - according to ictal phenomenology and EEG

Axis 3 Syndrome - list of syndromes, syndromic diagnosing is not always possible

Axis 4 Etiology - genetic defects, or specific pathological substrates for symptomatic focal epilepsies

Axis 5 Impairment - disability caused by epilepsy

% Etiology of epilepsy Epileptic Syndromes #A collection of :

70 • most important clinical features – seizure type, frequency and sequence 60 Unknown – age at onset, evolution and prognosis 50 Birth injury – mode of inheritance, family history 40 Infections – physical and mental signs and symptoms 30 Head trauma – response to treatment 20 Stroke • most important laboratory tests 10 Brain tumor – EEG, videoEEG 0 Other <1 v. 1-9yrs 10- 20-29 30- >50yrs – imaging: structural and functional 19yrs yrs 39yrs – hematological and biochemical investigations Age at onset – molecular genetics

ILAE Classification of Epilepsy Localization-Related (named by Generalized (named by Syndrome Type Def: location) disease) Idiopathic Benign Rolandic epilepsy (Benign childhood epilepsy with Benign Neonatal Convulsions (+/- centro-temporal spikes) familial) • Idiopathic epilepsy syndrome: A syndrome that is Benign occipital epilepsy of childhood Benign myoclonic epilepsy in infancy only epilepsy, with no underlying structural brain Autosomal dominant nocturnal frontal lobe epilepsy Childhood absence epilepsy Primary Reading Epilepsy Juvenile absence epilepsy lesion or other neurological signs or symptoms. Juvenile myoclonic epilepsy Epilepsy with GTCs on awakening Etiology presumed to be genetic. Usually age- Some reflex epilepsies dependent Symptoma Temporal lobe Early myoclonic encephalopathy tic Frontal lobe Early infantile epileptic encephalopathy Parietal lobe with suppression- burst (Ohtahara’s • Symptomatic epilepsy syndrome: Epileptic seizures syndrome) Occipital lobe are result of an identifiable structural lesion Cortical abnormalities -malformations (Rasmussen’s encephalitis) • Probably symptomatic epilepsy syndrome: Epileptic -dysplasias (Most Reflex epilepsies) Metabolic abnormalities seizures are believed to be symptomatic, but no - amino acidurias - organic acidurias aetiology has been identified - mitochondrial diseases - progressive encephalopathies of • Benign epilepsysyndrome: Epileptic seizures are childhood West’s Syndrome easily treated or need no treatment and remit Lennox-Gastaut Syndrome without sequelae Cryptogeni (Any occurrence of partial seizures without obvious Epilepsy with myoclonic-astatic seizures c pathology.) Epilepsy with myoclonic absence Idiopathic vs Symptomatic Early infantile epileptic encephalopathy with suppression-bursts (EIEE, Generalized Epilepsies Ohtahara´s syndrome) Insidence: no data Idiopathic Symptomatic Age of onset: within first 3 months 1. Etiology Genetic Acquired/Genetic Etiology: cerebral dysgenesis, anoxia, cryptogenic 2. Seizure Absence Atypical absences Seizures: tonic spasm, focal motor, hemiconvulsions, types Myoclonic Myoclonic generalized seizures Tonic-clonic Tonic, atonic Tonic-clonic Background EEG: suppression-burst 3. Exam Normal Intellectual disability Ictal EEG: diffuse synchronization, cluster of fast activity Therapy: ACTH, B6-vit., VPA, other AEDs, surgery 4. EEG Normal background, Background Spike-wave 3 Hz Slowing, Prognosis: static impairment to severe mental retardation, Spike-wave 2,5Hz quadraplegia and bed-ridden, evolution to West 5. Imaging Normal Often focal or diffuse and Lennox Gastaut syndrome, high incidence (cortical abnormality) lesions of death 6. Prognosis Good Poor

Early (neonatal) myoclonic encephalopathy (EME) Non Ketotic Hyperglyinemia

Insidence: no data Age of onset: neonatal Etiology: inborn errors of metabolism, familial, cryptogenic Seizures: erratic or fragmentary myoclonus, massive myoclonus, simple partial seizures, infantile spasms, tonic EEG: suppression-burst Therapy: ACTH ineffectíve, pyridoxine may be tried Prognosis: progressive impairment to vegetative state, infantile spasms, high mortality in infancy Dx : CSF / Srum Glycine Ratio

Imaging

Nonketotic Hyperglycinemia (NKH) What is affected? • aka glycine encephalopathy • Glycine Cleavage System – Autosomal recessive hereditary metabolic – mutation in the GCS disorder • inadequate supply of the enzymes necessary to • affects the breakdown of the amino acid glycine the break down of glycine causing a build up of in infants glycine in the body. – Characterized by abnormally high levels of – The AMT and GLDC genes the amino acid glycine in the blood, urine, Fig. infant brain with NKH and the cerebrospinal fluid. • cause extensive neuronal damage in neonatal brain • via N-methyl-D-aspartate glutamate receptor-mediated Symptoms and Effects Symptoms and Effects CONT. Four forms of this disorder: • Mild-episodic form • Neonatal form – appears during childhood episodes of – seen in the first few days after birth delirium; involuntary, jerky movements • low muscle tone (hypotonia), and drowsiness (chorea); inability to look upward (vertical • seizures and mental retardation gaze palsy) • Infantile form • fever and mild mental retardation – six months of seemingly normal development • Late-onset form • with the exception of occasional feeding difficulties & – during childhood with progressive stiffness seizures in both legs and degeneration of the optic • varying degrees of mental retardation become evident. nerve, leading to loss of sight. • Neither seizures nor mental retardation are associated

How common is NKH? Can it be treated? How?

• Rare metabolic disorder that • At this time there are no existing usually affects infants soon after birth. treatments. – Estimated 1 in 60,000 – Rarely children grow out of NKH and go • Males & females appear to be on to live normal lives. affected in equal proportions. • Both parents are carriers • For some individuals glycine levels – 25% chance child will be born with the disease have decreased but mental – 50% chance child will be a carrier retardation and seizures may still for the gene defect. persist.

West syndrome (infantile spasms, psychomotor deterioration, hypsarrhytmia)

Insidence: 3-5/10 000 live births Age of onset: 50-77% between 3-7 mnths, 93% up to 2 yrs Etiology: Malformations, TS, 10-20% cryptogenic Seizures: Tonic spasms in clusters, partial seizures preceding or associated with spasms EEG: Ictal generalized fast activity, interictal hypsarrhytmia Therapy: VGB, ACTH Prognosis: mortality 5-31%, mental retardation 80%, epilepsy 60-80%, Lennox-Gastaut 40-60% Lennox Gastaut syndrome Lennox Gastaut syndrome

Prevalence: 2-3 % of childhood epilepsies Age of onset: 1-8 years (peak 3-5 yrs) • Onset : Early childhood 3-5 Y(1-8 Y range) Etiology: malformations, neurocutaneous disorders, • Clinical : MR, Multiple seizure types, Tonic infections, 20-30% cryptogenic Seizures: tonic-axial, atonic and atypical absence seizures seizures EEG: abnormal background activity, generalized slow • EEG : Slow SWC on abnormal background spike-waves <3 Hz and, often multifocal abnormalities. During sleep, bursts of fast • DOC : ? rhythms (∼ 10 Hz) appear Therapy: VPA, LTG,TPM,LEV,benzodiazepines • Precautions: benzodiazepine can induce Prognosis: mental retardation 78-96%, resistant epilepsy tonic seizures

Lennox Gastaut syndrome

• ก 10 4 ก กก กก 5 ก ก ก 2-3 carbamazepine ก ก กกก ก diazepam กก valproic acid กก Interictal EEG generalized 1-2 Hz waves maximum bifrontal Acquired epileptic aphasia (Landau-Kleffner) Insidence: rare, exact numbers not available Age of onset: 2-8 years (peak 5-7 years) Etiology: epileptogenic functional lesion in the speech cortex Seizures: sz’s present in 70-80%: atypical absences, myoclonic sz, focal sz’s w/ 2° generalization, variable prognosis Clinical : verbal auditory agnosia →→→ aquired aphasia →→→ behavioural and psychiatric problems EEG: bilateral symmetrical/asymmetrical multifocal spikes and SW in temporal and parieto-occipital regions, sleep enhances spiking up to CSWS (85% of slow wave sleep) Therapy: VPA, BZDs, ESM, TPM,(steroids, surgery, immunoglobulin) Prognosis: aphasia usually improves wtih EEG normalization before adulthood, 10-20 % may achieve complete normalization, others are left with permanent sequalae

Epilepsy & malformations of the cerebral cortex Hemimegalencephaly

• abnormal proliferation of neurons and glia – hemimegalencephaly • A five month old girl who started having – focal cortical dysplasia clonic jerking of the right arm at age four – schizencephaly month • abnormal neuronal migration – gray matter heterotopia • NSVD, Uneventful prenatal history – bilateral periventricular nodular heterotopia • G+D Regrad face 2 m, Follow 3 m, Sit – classical lissencephaly and subcortical band heterotopia with support 5 m • abnormal cortical organization • syndromes resulting from regional polymicrogyria

• Med : • Video-EEG monitoring : • Phenobarbital 20 mg/kg/day, Bl level > • Interictal : > 90% Lateralized left 130 uG/ml hemisphere 10 % Rt C4 P4 • PHT, CBZ, Vigabatrin, Topiramate • Ictal EEG : > 90 % Lateralized Lt • B6 100 mg trial Hemisphere Diagnosis

Severe cortical dysplasia and hemimegalencephaly.

STURGE-WEBER SYNDROME: STURGE-WEBER SYNDROME: • Encephalotrigeminal angiomatosis – 1) leptomeningeal angiomatosis – 2) skin of face – typically the V1 and V2 portions of the Facial Nerve • LA may be unilateral or bilateral • Functional Neuroimaging: – may demonstrate a greater area of functional than anatomic abnormality Neurologic Manifestations Classification • Complete SWS: both brain and eye • 1) Seizures • Incomplete: when only one area is affected • 2) Focal deficits, such as hemiparesis • Roach Scale: and hemianopia – I: Both facial and leptomeningeal angiomas • 3) Stroke-like episodes • may have glaucoma • 4) Headaches – II: Facial angioma alone • 5) Developmental delay • may have glaucoma – more common with bilateral hemangiomas – III: Isolated LA; • usually not with glaucoma

Age of Presentation Seizures in SWS • Incidence: 75 - 90% • Typically presents at birth with facial angiomas • May have dual pathology: microgyria • However, not all children with PWS have SWS • Survey SWF: seizures in 136/171 • “Incomplete forms” occur without cutaneous features (Type III) • Median age onset 6 months, range birth to 23 years – May have no suspicion until seizure or other • Age of Sz onset: neurolgic problem occurs – 75% onset during first year – 86% before two years • Klippel-Trenauney-Weber: hemangiomas, hemihypertrophy – 95% before 5 years • Sz in 71% with unilateral and 87% with bilateral lesions

Seizures in SWS Predictors Poor Outcome • Majority focal • SWF survey: 50% complete control, 39% had • Early Sz onset • Focal Sz with II Genl only partial control • Extensive LA • Increasing Sz frequency, • Later seizure onset: lower incidence dev • Refractory Sz duration or post-ictal deficits delay, fewer special needs • Relapsing/permanent motor deficits • Focal or diffuse atrophy • Roach: onset < 2 years: greater chance • HA, trauma with transient • Progressive atrophy and refractory epilepsy and MR deficits calcification • Earlier onset with bilateral disease • Progressive neurologic • Hemiparesis disorder • Intellectual regression SWI T1 WEIGHTED

Sturge-Weber Syndrome: MRI

STURGE-WEBER SYNDROME: Sturge-Weber Syndrome: Neuroimaging Rapid Progression of Severe Hypometabolism is Associated with Good Cognitive Outcome

5 months 38 months 5 years

STURGE-WEBER SYNDROME: Tuberous Sclerosis

MRI FDG PET A 3 year old girl, presented with giggling!

Large Area of Mild Glucose Hypome tabolism is Associat ed with Poor Cognitiv e Outcom e Angioma Tuberous Sclerosis Tuberous Sclerosis • Epiloia or Bourneville’s disease. • CNS pathology : Multiple cortical tubers • 1:5000-1:10000 / SEGA-> Hydrocephalus • Damage of one of two genes which • CCF : regulate growth. – Not all the tubers are epileptogenic, • Hamartomas in variety of organ. – Interictal EEG/Video EEG monitoring and Ictal SPECT can elucidate the tuber which • Most common - brain, kidneys, skin. is “epileptogenic” • Can present at any age. – Good Surgical outcome-> significantly • Variation in severity improved seizure control

Adenoma Sebaceum

Tuberous Sclerosis : Genetics Ash-leaf Spots

• AD transmission, variability in symptoms. • Mutation on either TSC1 (Tuberous sclerosis) gene (chromosome 9) or TSC2 gene (chromosome 16). – Gross deletion/insertions and micromutations. • 60-70% are sporadic (new mutations).

• Cutaneous Manifestations • Neurologic Manifestations – Others – Cortical tubers • Cafe-au-lait spots (7-16%) • Focal, gray-white matter interface • Fibromas: flattened and can appear on • Microscopically - loss of normal the trunk, gingivae, periungual region, cytoarchitecture, abnormal neurons and and along the hairline or eyebrows. glial cells. • Koenen's Tumors (20%): Subungual or • MRI > CT periungual fibromas, usually first appear • Number and size correlate with seizures in adolescence, toes>fingers. and mental retardation. • Neurologic Manifestations • Neurologic Manifestations – Subependymal nodules – Seizures (60-90%) • Usually line the third ventricle. Large, irregular cells that • Most common symptom of TS. are more densely aggregated and more uniform in appearance compared with the cortical tubers. • Risk of sudden epileptic death. • Some will grow > than 3 cm in diameter => called • Initially may present as infantile spasms: subependymal giant cell astrocytomas (5%). – 25-50% of patients with infantile spasms • Histologic features similar to cortical nodules. later develop signs of TS. • Subependymal giant cell astrocytomas can cause severe clinical manifestations: elevated intracranial pressure, – Can appear as early as 1 week of age. diminished vision, hemiparesis. – Later develop other types of generalized • Later in life, subependymal nodules often calcify. seizures.

• Mental health - • Development and learning disorders – Very common, very difficult. – More in children with epilepsy. – Developmental delay (40-60%). – May be associated with tubers in temporal area. – Learning difficulties (40-60%). – Autism (25%) and autism spectrum – More in children who present with infantile spasm and epilepsy. disorders (50%). – The earlier the onset of seizures the – Sleep disturbances. greater the likelihood of mental – ADDH +/- hyperactivity. retardation (if seizures begin <1 year of – Anxiety and depression. age a 92% chance of MR).

Rasmussen’s Encephalitis Figure 3 Epilepsy surgery in Rasmussen's encephalitis

• A 9 year old girl with a 2-3 years Hx of Rt arm jerking. • Initially controlled with CBZ for 1-2 months • Progressively worsen to the face / leg with right hemiparesis Kuzniecky R and Devinsky O (2007) Surgery Insight: surgical management of epilepsy Nat Clin Pract Neurol 3: 673–681 10.1038/ncpneuro0663 PrayForJessie.org Progression of a Rasmussen’s Case Home Welcome! Imagine being told that your child has a very cruel Hemi Foundation and extremely rare brain disease, and the only hope for survival was the removal of half their brain. Cris and Kristi didn’t know what to do, nor whom to Jessie’s Angels speak with. Having access to a referral list of fellow parents going through this same nightmare, would have meant the world to them. Donate There was no foundation or charity in place to seek for organized support or the distribution of Media Appearances educational materials. More > Age 8 Age 9 Age 15 Age 18 pre-operative 2 months post-op 6 years post-op 9 years post-op Pray for Jessie Latest News

On April 20, 2008, I met a spunky Tuesday June 17 - HORRRAYYY !!! Jessie little girl named Jessie Hall. I had is out of Intensive Care!! no idea that on this day, my life would never again be the same. I fell in love with the most darling little girl. Let me tell you a bit about Jessie and her impact on me. More >