ADVANCES IN THE MANAGEMENT OF PEDIATRIC EPILEPSY
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ADVANCES IN THE MANAGEMENT OF PEDIATRIC EPILEPSY Hadassa Goldberg-Stern MD Director, Epilepsy Service Schneider Children ’ s Medical Center of Israel, Petah Tikva, Israel. Outlines Definitions Anti epileptic Drugs Epilepsy Surgery Vagal Nerve Stimulation Ketogenic Diet.

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Advances in the management of pediatric epilepsy hadassa goldberg stern md director epilepsy service schneider childr

ADVANCES IN THE MANAGEMENT OF PEDIATRIC EPILEPSYHadassa Goldberg-Stern MDDirector, Epilepsy ServiceSchneider Children’s Medical Center of Israel, Petah Tikva, Israel


Advances in the management of pediatric epilepsy hadassa goldberg stern md director epilepsy service schneider childr

  • Outlines

  • Definitions

  • Anti epileptic Drugs

  • Epilepsy Surgery

  • Vagal Nerve Stimulation

  • Ketogenic Diet


Definitions

DEFINITIONS

  • Epilepsy -a disorder of the brain characterized by a predisposition to generate epileptic seizures.

    (At least 2 episodes)

  • Epileptic Seizures – an abnormal excessive synchronous neural activity in the brain

  • Epileptic syndrome – based on seizure type, EEG findings, prognosis. (JME, BECTS)


Epilepsy in children incidence and prevalence

EPILEPSY IN CHILDREN – INCIDENCE AND PREVALENCE

  • 0.5% of the world population

  • 300,000 people have an initial seizure each year

  • 181,000 new cases of epilepsy each year

  • 120,000 are under the age of 18 years

  • Incidence highest under age 2 years and over 65 years


When to start antiepileptic therapy

WHEN TO START ANTIEPILEPTIC THERAPY?

  • Recurrence risk following first unprovoked seizure ranges from 27% to 76% (33%) (only 3% of recurrence occurred after 5 years).

  • However, epilepsy secondary to some conditions, (cortical dysplasia) have a high seizure recurrence risk.


Seizure classification

SEIZURE CLASSIFICATION

Seizure types

  • Partial (focal, localization-related)

  • Generalized

    Seizure etiology :

  • idiopathic

  • symptomatic


Antiepileptic drugs

ANTIEPILEPTIC DRUGS

  • Narrow spectrum=effective for one type of seizure only (Ethosuximide)

  • Broad spectrum= effective for several types of seizures (Depalept, Topiramate)


Epilepsy algorithm for therapy

EPILEPSY – ALGORITHM FOR THERAPY

  • Antiepileptic drugs

    Old:Carbamazepine (Tegretol)

    Valproic Acid (Depalept)

    Phenobarbitone (Luminal)

    Epanutin (Dantoin)

    Sulthiame (Ospolot)

    New: Lamotrigine (Lamictal)

    Oxcarbamazepine (Trileptin)

    Topiramate (Topamax)

    Gabapentin (Neurontin)

    Levetiracetam (Keppra)

    Zonisamide (Zonogram)


Efficacy of antiepileptic drugs for common seizure types

EFFICACY OF ANTIEPILEPTIC DRUGS FOR COMMON SEIZURE TYPES

DRUG PARTIAL TONIC-CLONIC ABSENCE MYOCLONICATONIC/TONIC

Phenobarbital+ + 0 ?+ ?

Phenytoin + + - - 0

Carbamazepine + + - - 0

Sodium valproate+ + + + +

Ethosuximide0 0 + 0 0

Benzodiazepines + + ? + +

Gabapentin+ + - - 0

Lamotrigine + + + + +

Oxcarbazepine+ + 0 0 0

Topiramate+ + ? + +

Tiagabine+ + - - 0

Zonisamide + + ?+ + ?+

Levetiracetam+ + + + ?

Felbamate+ + ?+ ?+ +

Vigabatrin+ + - - ?

_______________________________________________________________________________

+ = efficacy; ?+ = probable efficacy; 0 =ineffective; - + worsens seizures; ? = unknown


General aspects of prognosis

GENERAL ASPECTS OF PROGNOSIS

FOUR GROUPS

  • Benign epilepsies– (20-30%) in which remission occurs after a few years and treatment can often be avoided

    (e.g. BECTS, Benign Occipital)

  • Pharmacosensitive– seizure control is easy and spontaneous remission occurs after a few years

    (e.g. childhood absence)

  • Pharmacodependent– drug treatment will control seizures but no spontaneous remission occurs

    (e.g. JME)

    4.Pharmacoresistant (refractory) – poor prognosis


Anti epileptic drugs therapy

ANTI EPILEPTIC DRUGS - THERAPY

  • Among 470 epileptic patients about 47% responded to their first AED

  • 13% responded to a second AED

  • 4% responded to a third monotherapy

  • Only 35 were controlled with 2 AED’s

  • About 30% are “pharmacoresistant”

    = refractory epilepsy

    Brodie, Neurology 2002


Pharmacoresistant epilepsy

Pharmacoresistant Epilepsy

Previously Untreated Epilepsy Patients (n=470)

Seizure-free with 1st drug

Seizure-free with 2nd drug

Seizure-free with 3rd ormultiple drugs

Pharmacoresistant epilepsy

36%

47%

4%

13%

Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.


Epilepsy management

EPILEPSY MANAGEMENT

  • 60% of newly diagnosed epilepsy patients will becontrolled on monotherapy, usually with the first or second AED chosen

  • 30-40% will be “refractory”

  • Localization-related epilepsies are less likely to be controlled than idiopathic generalized syndromes

  • Patients with difficult-to-control epilepsy commonly have underlying cerebral pathology and highernumbers (>20) of seizures prior to treatment


Staged approach to epilepsy management

STAGED APPROACH TO EPILEPSY MANAGEMENT

  • Tolerability and long-term safety are the most important factors in choosing the first drug

  • If the first AED is poorly tolerated at low dosage an alternative should be chosen

  • If the first AED does not completely abolish seizures – combination therapy may be tried

  • Work-up for epilepsy surgery should be considered after failure of two well-tolerated AED’s

  • If needed, subsequent combinations of two or at most three AED’s may be effective


Epilepsy surgery

Epilepsy Surgery

  • ~10% of epilepsy patients become medically intractable to consider surgical therapy

  • Types of surgical treatment:

    - lesionectomy

    - lobectomy (Mesial Temporal Sclerosis)

    - corticectomy, hemispherectomy

    - corpus callosotomy

    - multiple subpial transection


Contraindications to epilepsy surgery

Contraindications to Epilepsy Surgery

  • Underlying degenerative or metabolic disorders

  • Benign epilepsy syndromes (BRE, BOE)

  • Idiopathic generalized epilepsy (genetic)

  • Multifocal EEG

  • Interictal psychosis

    relative

    Medication noncompliance


Surgically remediable syndromes

Surgically Remediable Syndromes

Chronic epilepsy associated with:

  • Sturge - Weber Syndrome

  • Tuberous Sclerosis

  • Focal cortical dysplasia

  • Hemimegalencephaly

  • Rasmussen’s syndrome

  • Low-grade cortical tumors

  • Hippocampal sclerosis


Mesial temporal lobe epilepsy mtle

Mesial Temporal Lobe Epilepsy (MTLE)

  • 70-80% of patients with MTLE will become seizure free following anterior temporal lobectomy

  • Early insult (prolonged febrile convulsions)

  • Latent period habitual seizures


Mtle cont

MTLE (cont)

  • History:complex febrile seizures

  • Clinically:Onset: First decade, complex partial seizures with an aura of epigastric rise, alimentary automatisms, amnesia for the event.

  • EEG: Unilateral or bilateral anterior temporal spikes


Vagal nerve stimulation vns historical review

Vagal Nerve Stimulation (VNS) – Historical Review

  • Articles from 1930’s present evidence of a vagal

    effect on the EEG in animals

  • VNS was first tried in man in November l988 by

    Dr. Kiffin Penry


Vagus n stimulation in refractory epilepsy

Vagus N. Stimulation in Refractory Epilepsy

  • Stimulation of left vagus nerve with the neuro-

    cybernetic prosthesis (cyberonics)

  • It involves surgical implantation of the generator and subcutaneous lead and connection of the lead to the cervical vagus nerve

  • Device stimulation begun –2 weeks after implantation

  • The patient is given a magnet that turns off stimulation when continually held over the generator and activates stimulation when held over the generator (may abort seizures if applied at seizure onset)


Vagus nerve cranial nerve x

Vagus Nerve: Cranial Nerve X

Left cervical vagus nerve

  • 80% afferent fibers, mostly myelinated

  • 20% efferent fibers, mostly unmyelinated parasympathetic fibers to viscera, with myelinated fibers to vocal muscles

Henry TR. Neurology. 2002;59(suppl 4):S3-S14.


Advances in the management of pediatric epilepsy hadassa goldberg stern md director epilepsy service schneider childr

VNS Therapy


Vagus n stimulation clinical use

Vagus N. Stimulation – Clinical Use

  • Refractory epilepsy to 3 AED’s used as monotherapy and 1 combination

  • Partial or symptomatic generalized seizures (e.g. LGS)

  • Unsuitability of patient for resective epilepsy surgery or when previous surgery was not successful


Vagus n stimulation vns possible mechanisms

VAGUS N. stimulation (VNS) possible mechanisms

  • Blocking ion currents across neuronal membranes (Na, K, Ca)

  • GABA – increasing brain inhibition

  • Attenuation of glutaminergic neurotransmission

  • Modifying monoaminergic regulation of seizure controlHowever, the mechanism by which VNS modulates seizure control has not been fully elucidated


Vns efficacy

VNS - Efficacy

  • Reduces seizure frequency by 50% in 40% of patients

  • 20% achieved 75% or greater reduction in seizure frequency after 1 year

  • Attenuates seizure severity

  • Positive changes in alertnessand mood

  • Abort seizure


Improvement in seizure control over time patient outcome registry and clinical trial data

E05, 3 months; n=941

Registry, 3 months; n=22292

Registry, 12 months, n=22292

Improvement in Seizure Control Over Time Patient Outcome Registry and Clinical Trial Data

60

Median Seizure Reduction

56%

50

43%

40

30

Reduction (%)

23%

20

10

0

12 months

E05

3 months

1Handforth A, et al. Neurology. 1998;51:48-55.

2Data on file. Cyberonics, Inc. Houston, TX; April 25, 2003.


Vns therapy long term seizure control in pediatric patients eo1 eo5

VNS Therapy Long-term Seizure Control in Pediatric Patients (EO1-EO5)

50

44%

37%

40

31%

30

Median Decrease in

Seizure Frequency (%)

23%

20

10

0

3 months

6 months

12 months

18 months

Last Visit Carried Forward (n=60)

Murphy JV.J Pediatr.1999,134 (5):563-566.


Vns therapy quality of life in patients 18 years patient outcome registry constant cohort

VNS Therapy Quality of Life in Patients <18 Years Patient Outcome Registry (Constant Cohort)

Patients/Parents Report Better or Much Better

Alertness

Post-ictal

Clusters

Verbal Skills

Mood

Achievements

3 Months (n=743)

12 Months (n=743)

Memory

0

10

20

30

40

50

60

70

80

Patients (%)

Fewer than 8% of patients/parents reported worse or much worse outcome by any single measure

Data on file. Cyberonics, Inc. Houston, TX; April 25, 2003.


Vns side effects

VNS – side effects

  • Voice changes may occur

    Dyspnea on exertion with stimulation

  • Surgical complications:

    infection (1.5%)

    vocal cord paresis (1%)

    unilateral facial weakness (1%)

  • No effect on heart rate


Ketogenic diet

Ketogenic Diet

  • An alternative for intractable epilepsy not amenable to surgery since 1920’s

  • Fasting for seizure control has been suggested since biblical times


Ketogenic diet possible mechanisms

Ketogenic Diet – Possible Mechanisms

  • Acidosis

  • Water balance and dehydration

  • Direct action of acetoacetate or hydroxybutyrate

  • Changing energy sources of the brain from glucose to ketones


Ketogenic diet clinical use

Ketogenic diet-clinical use

  • Absence

  • Symptomatic myoclonic

  • Lennox-Gaustaut Sy

    At Johns Hopkins: “The Ketogenic diet is considered for all children who have intractable seizures of any type and from any cause who have not responded to a variety of regimens”.


Ketogenic diet1

Ketogenic Diet

  • Classic: Ratio of Ketogenic to antiketogenic

    is 4 : 1

    fat (protein + carbohydrates)

  • The diet allows 1 gr of protein/kg body weight daily

  • Restriction of fluids

  • Vitamins supplement


Ketogenic diet efficacy

Ketogenic Diet - efficacy

  • 1/3 – complete seizure control

  • 1/3 – greater than 50% seizure improvement

  • 1/3 – no improvement

  • 2/3 – one drug reduced

  • 10% - all drugs discontinued


Ketogenic diet side effects

Ketogenic Diet –Side effects

  • Renal stones

  • Hyperuricemia

  • Acidosis

  • Hypocalcemia

  • Eating problems

  • Secondary carnitine deficiency


Epilepsy treatments

Epilepsy Treatments

Age

ChildrenAdults

Primarily children

Children

Adults

Children

Adults

Indication

Specific AEDs for specific seizure types

All seizure types

Pharmacoresistant or localisation-related epilepsy

Pharmacoresistant epilepsy, localisation-related seizures

Efficacy

64% sz freedom1

54% pts >50% sz reduction at 3 months2

70% in select patients sz freedom3

43% of pts >50% sz reduction at 3 years4

Side Effects

Vary by AED, typically CNS- and endocrine-related

Lipid disorders, ketoacidosis

Cognitive effects, surgery-related risks

Voice alteration, cough, pharyngitis, dyspnea

Treatment

AEDs

Ketogenic Diet

Epilepsy Surgery

VNS Therapy

1Brodie MJ, Kwan P. Neurology. 2002;58(suppl 5):S2-S8.

2Vining EP, et al. Arch Neurol. 1998;55:1433-1437.

3Van Ness PC. Arch Neurol. 2002;59:732-735.

4Morris GL III, Mueller WM. Neurology. 1999;53:1731-1735.


Advances in the management of pediatric epilepsy hadassa goldberg stern md director epilepsy service schneider childr

Agatha Christie

Thomas Edison

Joan of Arc

Alexander the Great

Leonardo Da Vinci

Feodor Dostoevski

Jullius Caesar

Charles Dickens

Napoleon Bonaparte


Advances in the management of pediatric epilepsy hadassa goldberg stern md director epilepsy service schneider childr

Thank

you


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