1. Pediatric Epilepsy Update James J. Riviello, Jr., MD

2. The IOM Report, Epilepsy IOM Committee on the Public Health Dimensions of the Epilepsies

4. IOM Report: Types of Patient Education Epilepsy-specific knowledge & skills Seizures Treatment Safety Comorbid conditions Chronic care knowledge & skills Healthy lifestyle Partnership with health care team Independent living

5. Care of the Child with Epilepsy: Understanding the Mechanisms Treatment Anti-epileptic Drugs Metabolism-based Treatment (KGD) Neuromodulation Epilepsy Surgery Quality of Life Co-Morbidities

6. AEDs Ketogenic Diet Neurostimulation or Nonresective Surgery Resective Surgery Therapeutic Selection for Patients With Refractory Epilepsy

7. When To Refer for Epilepsy Surgery Medically Refractory Epilepsy Children – Uncontrolled by medical therapy Failure two or three AEDs – Disabling seizures, side effects – MRI reveals surgical lesion (epileptogenic lesion) – Criteria and Referral for evaluation of pediatric epilepsy surgery; ILAE Epilepsia 2006;47:952-959.

8. Epilepsy Quality Measures Approved AAN, January 2012 the frequency of each seizure type should be reported at each visit -the etiology (or epilepsy syndrome) should be reported at each visit - counseling for women of child bearing potential with epilepsy should be provided annually

9. Co-Morbidities

10. Co-Morbidity – Definitions and Concepts  Co-morbidity refers to the co-occurrence of two supposedly separate conditions that occur together more than chance.  Depression occurs more frequently in patients with epilepsy than in the normal population, thus epilepsy and depression are co- morbidities.

11. Co-Morbidity - Definitions and Concepts Co-morbidities may be related to the epilepsy or treatment, e.g.: Frequent absence seizures may result in attention deficit Headaches can occur following seizures Cognitive impairment may be related to epileptiform discharges/seizures AED-induced agitation, ADHD, suicidality

12. Co-Morbidity - Definitions and Concepts Co-morbidities are not necessarily causal. Both conditions may have a common biological substrate An independent variable triggers one of the co- morbidities Phenobarbital triggers depression Gabapentin triggers agitation Co-morbidities often precede onset of the epilepsy

13. Co-Morbidity Paradigm Brain Disorder Epilepsy Co-Morbidities

14. Behavior Problems in Children with Epilepsy: Austin 2002 Major risk factors for behavior problems in pediatric epilepsy: neurological dysfunction seizure variables family environment side effects of AEDs Children with new-onset seizures (rank order of total behavior problems): recurrent seizures > single seizure > sibling Raises possibilities that both are caused by an underlying neurological disorder.

15. Behavioral Problems in New-Onset Epilepsy: Austin 2002 Evaluated 224 children with new-onset seizures (aged 4-14 years) and 159 siblings (4-18 years). During the 2-year evaluation period, 163 (73%) children had at least one additional seizure, and 61 (27%) had none. Children had more behavioral problems when experiencing recurrent seizures than when not experiencing recurrent seizures. Siblings had significantly lower behavioral problems than both children experiencing and not experiencing recurrent seizures. Recurrent seizures significantly predicted behavior problems very early in the course of a seizure condition.

16. Practice Tools for Cognitive and Behavioral Effects of Epilepsy (AES) Cognitive (neuropsychological) well being: Children with epilepsy are at an increased risk for cognitive and behavioral impairment. Consider referral for neuropsychological evaluation for children/adolescents with epilepsy who are experiencing difficulty at home or in school. In particular, children are at risk of neuropsychological deficits who present with two or more of the following: – epileptiform activity on EEG; – regression in academic abilities or motor function – abnormality on MRI (or symptomatic epilepsy syndrome**); – absence seizures; – use of antiepileptic medications; – undercontrolled (pharmacoresistent) seizures Cognition generally improved for individuals who are seizure free.

17. Practice Tools for Cognitive and Behavioral Effects of Epilepsy (AES) Anti-epileptic drugs: Discuss / review potential impact of anti- epileptic drugs (AEDs) on child’s cognitive functioning and behavior. Cognitive and behavioral functions generally improve for individuals who are seizure free. Academic Success: Verify with parent that school has assessed child for attention deficits, intellectual delays, and learning disability to determine if an individualized educational plan is warranted. Assess for regression in academic abilities. Behavioral/psychological/psychiatric problems: Screen for symptoms of depression and anxiety and other behavioral problems and treat or refer accordingly.

18. Practice Tools for Cognitive and Behavioral Effects of Epilepsy (AES) Attention: Screen for attention problems/ Attention Deficit Hyperactivity Disorder (ADHD) and treat or refer accordingly Sleep: Assess sleep behaviors/environment and provide children, adolescents and parents with lifestyle changes to improve sleep for optimizing seizure control and cognitive and behavioral functioning. Consider evaluation of seizure patterns to assess if having negative impact on sleep. If sleep problems persist after implementing lifestyle changes, consider formal sleep consultation. Quality of Life/Psychosocial adjustment: Ask patient how epilepsy affects them the most in everyday activities and explore resources to address those concerns/needs. More information/resources available at www.epilepsy.com. Note: Neuropsychological evaluation is not a substitute for Psychiatric evaluation. Both are likely to benefit patient and family.

19. Epilepsy and Common Comorbidities: Improving the Outpatient Encounter  Screen for adverse AED effects  Assess physical fitness, activity  Review sleep hygiene  Screen for mood disorders (depression, anxiety)  Screen for educational functioning  Screen for behavior problems  Assess other family, patient concerns

20. Relationship Between Seizures & Cognitive Dysfunction Brain Injury Seizures and EEG anormalities Cognitive Impairment Secondary Injury?

21. AEDs: Old and New

22. Understanding the Mechanism of Action: Sodium (Na) Channels Phenytoin Carbamazepine/Oxcarbazepine Lamotrigine Zonisamide Lacosamide Rufinamide

23. Understanding the Mechanism of Action: Calcium Channels Ethosuximide (blocks the T-type calcium channel)

24. Understanding the Mechanism of Action: GABA Receptor Phenobarbital/Primidone Tiagabine Vigabatrin Benzodiazepines Valproate

25. Understanding the Mechanism of Action: Glutamate Receptor Perampanel (AMPA receptor)

26. Understanding the Mechanism of Action: Multiple Mechanisms of Action Valproate Felbamate Topiramate

27. Understanding the Mechanism of Action Gabapentin: binds to calcium channel alpha-2- delta protein Pregabalin: binds to calcium channel alpha-2- delta protein Levetiracetam: exact MOA unknown; binds to synaptic vesicle glycoprotein SV2A, inhibits pre-synaptic calcium channels Ezogabine: activates the potassium channel (unique MOA)

28. New AEDs

29. Sulthiame, Sultiame (Opsolot) MOA: carbonic anhydrase inhibitor Used for focal (partial) seizures Tablet Size: 50, 200 mg It is a good spike suppressor; used for the benign focal epilepsies and as a spike suppressor for the epileptic encephalopathies

30. Pregabalin (Lyrica) MOA: binds to the alpha 2 delta subunit of the calcium channel; decreases release of glutamate, norepinephrine, substance P, and calcitonin Tablet Size: 25, 50, 75, 100, 150, 200, 225, 300 mg Solution: 20 mg/mL Used more for neuropathic pain

31. Lacosamide (Vimpat) MOA: stabilizes the Na channel (enhances slow inactivation; the slow inactive state) Tablet Size: 50,100,150, 200 mg Solution: 10 mg/mL

32. Rufinamide (Banzel) MOA: unknown; presumably stabilizes the inactive state of the sodium channel (keeping it closed) Approved for Lennox-Gastaut Syndrome, ages > 4 years Efficacy for focal seizures Tablet Size: 200,400 mg Suspension: 40 mg/mL

33. Ezogabine (Potiga) Retigabine (international name) MOA: activates the Potassium Channel, NCNQ/Kv7 Relatively free drug interactions Tablet Size: 50,200,300,400 mg Urinary Retention Mood, Behavior Changes

34. Perampanel (Fycompa) MOA: non-competitive AMPA receptor antagonist Tablet Size: 2,4,6,8,10,12 mg AEs: dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, dysarthria; weight gain (2.5 pounds)

35. Why is Epilepsy Refractory?

36. Multiple Drug Resistance Genes ABCB1 (ATP-binding cassette subfamily B member) transporter MDR1 and P-glycoprotein 170 Functions as an active drug-efflux pump, may be involved in maintaining the BBB Calcium channel blockers (verapamil) inhibit the expression of p-glycoprotein

37. Pre-VerapamilVerapamil Treatment

38. Status Epilepticus

40. Mechanistic Definition: Failure of the mechanisms that normally stop seizures BZPs are GABAergic Kapur (1994) loss GABA- a Receptors Kapur, McDonald (1997): functional change in GABA receptors Goodkin (2005): internalization of GABA receptors

41. “Home Remedies” or No IV access No IV access – Midazolam, nasal, buccal, IM – Diazepam, rectal Home Remedies – Diazepam, rectal – Midazolam, nasal, buccal

42. Diazepam: Comparison of IV, IM, Oral, and Rectal Moolenaar et al. Int. J. Pharm 1980;5:127-137

43. Buccal Midazolam

44. Buccal Midazolam versus Rectal Diazepam: McIntyre J (Lancet 2005) Diazepam Midazolam AGEDOSE 3 -11 months2.5 mg 1- 4 years5 mg 5 – 9 years7.5 mg 10 -12 years10 mg Therapeutic Success: 61/109 (56%) for MDZ versus 30/110 for DZP No difference respiratory depression: 9/109 for MDZ; 13/110 for DZP

45. Nasal AEDs Midazolam: At first, the solution was used Now, pharmacies have made an aerosol – 5mg/ml (0.1 ml = 0.5 mg) – Start at 3 sprays/nostril – May repeat after 5 minutes

46. MDZ plasma concentrations by various routes; Wermeling DP

47. Importance of Research Mechanism-Specific Drugs Disease-Specific Treatments

48. Epileptic Encephalopathy Genes

50. Tuberous Sclerosis: Disease Modifying Treatments

57. mTOR Pathway in Epilepsy Tx

58. Epileptic Encephalopathies: Recognition and Treatment

59. Epileptic Encephalopathy An epileptic encephalopathy is a disorder in which the spike and sharp wave (epileptiform) activity on the EEG impairs brain function. This typically occurs when the epileptiform activity occur during sleep. This activity may respond to anti-seizure medications. Certain seizures and epilepsy syndromes commonly cause an epileptic encephalopathy.

60. The Center for Epileptic Encephalopathies (CEE) at NYU:

61. EEG Findings in Epileptic Encephalopathies An epileptic encephalopathy may exist without an actual clinical seizure. The EEG is critical to evaluate a child for an epileptic encephalopathy: to identify the epileptiform activity and quantify its abundance, especially during sleep. The hallmark EEG finding is electrical status epilepticus of sleep (ESES). The more sleep- activated the EEG, the more likely an associated cognitive or behavioral problem. The severity is determined by scoring the spike-wave index, done only by very specialized epilepsy centers.

62. The Center for Epileptic Encephalopathies (CEE) at NYU: Successful treatment requires the teamwork of various specialists, including an epileptologist, psychopharmacologist, neuropsychiatrist, neuropsychologist, nurse practitioner, and dietician. Is this different than a neuropsychiatrist?

63. EEG: Electrical Status Epilepticus of Sleep and the Ideal Treatment Situation: An “all or none” EEG response. EEG “normalizes” with a spike suppressor.

64. NKH: before and after dextromethorphan

65. Inflammation and Epilepsy

66. Inflammatory Cascade In Epilepsy

67. IVIG in Intractable Childhood Epilepsy

68. Dosing: – IVIG 2 grams/kg given in 4 divided doses over four days – IVIG 1 gram/kg over 2 days over 6 months; then discontinued Response: Defined as a > 50 % decrease in seizure frequency during the 6 th month If relapse, IVIG restarted at 1 gram/kg every month for 1 year

69. Results: Males responded better than females

70. Metabolism-Based Treatments (Ketogenic Diet): Four Versions Four Versions 1) Classic ketogenic diet 2) MCT ketogenic diet – can’t do 3/1 ratio, usually g-tube fed 3) Low glycemic index treatment 4) Modified Atkins/ modified ketogenic diet Certain Syndromes Myoclonic-Atonic Epilepsy (Doose Syndrome) Severe Myoclonic Epilepsy of Infancy (Dravet Syndrome) Infantile Spasms Tuberous Sclerosis Rett Syndrome Pyruvate dehydrogenase Deficiency Glucose Transporter Defect

71. Ketogenic Diet: Efficacy Benefits: – Seizure control without AED side effects Results: – Original Hopkins cohort of 150 children at 3 years (2001), 13% (20) were seizure free and 14% (21) had a greater than 90% seizure reduction 1 – Systematic review (2000): 11 studies; 16% were seizure free; 32% had a greater than 90% reduction 2 – Italian multicenter cohort (2002): 12.5% seizure free (7/56) 3 1.Hemmingway C, et al. Pediatrics. 2001;108:898-905. 2.Lefevre F, Aronson N. Pediatrics. 2000;105:E46 3.Coppola G, et al. Epilepsy Rev. 2002;48:221-227

72. Ketogenic Diet: Contraindications Carnitene Deficiency – Primary, CPT I or II, translocase deficiency B-Oxidation defects Pyruvate Carboxylase Deficiency Porphyria Relative Contraindications: – Inability to maintain adequate nutrition – Surgical Focus – Parent or Caregiver Noncompliance

73. Neuromodulation Vagus Nerve Stimulation Deep Brain Stimulation (anterior thalamic nucleus) Responsive Neurostimulation Transcranial Magnetic Stimulation

74. The END