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Outlines Definitions Anti epileptic Drugs Epilepsy Surgery Vagal Nerve Stimulation

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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Outlines Definitions Anti epileptic Drugs Epilepsy Surgery Vagal Nerve Stimulation

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

  2. Outlines • Definitions • Anti epileptic Drugs • Epilepsy Surgery • Vagal Nerve Stimulation • Ketogenic Diet

  3. 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)

  4. 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

  5. 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.

  6. SEIZURE CLASSIFICATION Seizure types • Partial (focal, localization-related) • Generalized Seizure etiology : • idiopathic • symptomatic

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

  8. 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)

  9. EFFICACY OF ANTIEPILEPTIC DRUGS FOR COMMON SEIZURE TYPES DRUG PARTIAL TONIC-CLONIC ABSENCE MYOCLONICATONIC/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

  10. 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

  11. 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

  12. 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.

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  21. 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)

  22. 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.

  23. VNS Therapy

  24. 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

  25. 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

  26. 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

  27. 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.

  28. 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.

  29. 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.

  30. 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

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

  32. 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

  33. 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”.

  34. 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

  35. 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

  36. Ketogenic Diet –Side effects • Renal stones • Hyperuricemia • Acidosis • Hypocalcemia • Eating problems • Secondary carnitine deficiency

  37. 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.

  38. Agatha Christie Thomas Edison Joan of Arc Alexander the Great Leonardo Da Vinci Feodor Dostoevski Jullius Caesar Charles Dickens Napoleon Bonaparte

  39. Thank you

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