ADVANCES IN THE MANAGEMENT OF PEDIATRIC EPILEPSY Hadassa Goldberg-Stern MD Director, Epilepsy Service Schneider Children

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ADVANCES IN THE MANAGEMENT OF PEDIATRIC
EPILEPSYHadassa Goldberg-Stern MDDirector,
Epilepsy ServiceSchneider Childrens Medical
Center of Israel, Petah Tikva, Israel
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• Outlines
• Definitions
• Anti epileptic Drugs
• Epilepsy Surgery
• Vagal Nerve Stimulation
• Ketogenic Diet

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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)

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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

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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.

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SEIZURE CLASSIFICATION

• Seizure types
• Partial (focal, localization-related)
• Generalized
• Seizure etiology
• idiopathic
• symptomatic

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ANTIEPILEPTIC DRUGS

• Narrow spectrum effective for one type of
  seizure only (Ethosuximide)
• Broad spectrum effective for several types of
  seizures (Depalept, Topiramate)

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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)

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EFFICACY OF ANTIEPILEPTIC DRUGS FOR COMMON
SEIZURE TYPES

• DRUG PARTIAL
  TONIC-CLONIC ABSENCE MYOCLONIC
  ATONIC/TONIC
• Phenobarbital 0
  ? ?
• Phenytoin
  -
  - 0
• Carbamazepine
  - -
  0
• Sodium valproate
  
• Ethosuximide 0 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

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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

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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 AEDs
• About 30 are pharmacoresistant
• refractory epilepsy
• 
  Brodie, Neurology 2002

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Pharmacoresistant Epilepsy
Previously Untreated Epilepsy Patients (n470)
Seizure-free with 1st drug Seizure-free with 2nd
drug Seizure-free with 3rd ormultiple
drugs Pharmacoresistant epilepsy
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47
4
13
Kwan P, Brodie MJ. N Engl J Med. 2000342314-319.
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EPILEPSY MANAGEMENT

• 60 of newly diagnosed epilepsy patients will be
  controlled 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
  higher numbers (gt20) of seizures prior to
  treatment

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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 AEDs
• If needed, subsequent combinations of two or at
  most three AEDs may be effective

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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

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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

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Surgically Remediable Syndromes

• Chronic epilepsy associated with
• Sturge - Weber Syndrome
• Tuberous Sclerosis
• Focal cortical dysplasia
• Hemimegalencephaly
• Rasmussens syndrome
• Low-grade cortical tumors
• Hippocampal sclerosis

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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

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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

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Vagal Nerve Stimulation (VNS) Historical Review

• Articles from 1930s present evidence of a vagal
• effect on the EEG in animals
• VNS was first tried in man in November l988 by
• Dr. Kiffin Penry

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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)

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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. 200259(suppl 4)S3-S14.
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VNS Therapy
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Vagus N. Stimulation Clinical Use

• Refractory epilepsy to 3 AEDs 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

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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
  control However, the mechanism by which VNS
  modulates seizure control has not been fully
  elucidated

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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 alertness and mood
• Abort seizure

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Improvement in Seizure Control Over Time Patient
Outcome Registry and Clinical Trial Data
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Median Seizure Reduction
56
50
43
40
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Reduction ()
23
20
10
0
12 months
E05
3 months
1Handforth A, et al. Neurology. 19985148-55.
2Data on file. Cyberonics, Inc. Houston, TX
April 25, 2003.
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VNS Therapy Long-term Seizure Control in
Pediatric Patients (EO1-EO5)
50
44
37
40
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Median Decrease in Seizure Frequency ()
23
20
10
0
3 months
6 months
12 months
18 months
Last Visit Carried Forward (n60)
Murphy JV.J Pediatr.1999,134 (5)563-566.
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VNS Therapy Quality of Life in Patients lt18 Years
Patient Outcome Registry (Constant Cohort)
Patients/Parents Report Better or Much Better
Alertness
Post-ictal
Clusters
Verbal Skills
Mood
Achievements
3 Months (n743)
12 Months (n743)
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.
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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

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Ketogenic Diet

• An alternative for intractable epilepsy not
  amenable to surgery since 1920s
• Fasting for seizure control has been suggested
  since biblical times

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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

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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.

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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

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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

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Ketogenic Diet Side effects

• Renal stones
• Hyperuricemia
• Acidosis
• Hypocalcemia
• Eating problems
• Secondary carnitine deficiency

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Epilepsy Treatments
Treatment AEDs Ketogenic Diet Epilepsy
Surgery VNS Therapy
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 gt50 sz
reduction at 3 months2 ?70 in select
patients sz freedom3 43 of pts gt50 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
1Brodie MJ, Kwan P. Neurology. 200258(suppl
5)S2-S8. 2Vining EP, et al. Arch Neurol.
1998551433-1437. 3Van Ness PC. Arch Neurol.
200259732-735. 4Morris GL III, Mueller WM.
Neurology. 1999531731-1735.
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