2. Epilepsy Gregory B. Sharp, M.D. Chief of Pediatric Neurology University of Arkansas For Medical Sciences Medical Director, Neuroscience Center of Excellence

3. Objectives – To Review: Basic mechanisms of epilepsy Basic mechanisms of epilepsy Classification of seizures Classification of seizures Seizure types Seizure types Epilepsy syndromes Epilepsy syndromes Non-epileptic seizures Non-epileptic seizures

4. Synaptic Transmission Neuron to neuron communication is mediated by neurotransmitters (NTs) and resultant EPSPs and IPSPs Neuron to neuron communication is mediated by neurotransmitters (NTs) and resultant EPSPs and IPSPs Excitatory NTs Excitatory NTs Glutamate Glutamate Aspartate Aspartate Inhibitory Inhibitory GABA GABA Glycine Glycine

5. Burst Firing Some neurons have the ability to fire very rapidly in bursts Some neurons have the ability to fire very rapidly in bursts Prolonged after-depolarization produced decreased inactivation of Na + and Ca 2+ conductance occurs within the dendritic tree Prolonged after-depolarization produced decreased inactivation of Na + and Ca 2+ conductance occurs within the dendritic tree Allows repetitive activation of action potentials producing burst firing Allows repetitive activation of action potentials producing burst firing This especially occurs in the hippocampus This especially occurs in the hippocampus

6. Glutamate Receptors At least 3 primary classes with multiple subtypes At least 3 primary classes with multiple subtypes NMDA NMDA AMPA AMPA Kainate Kainate Activation of NMDA receptors plays an important role in the spread of epileptic activity Activation of NMDA receptors plays an important role in the spread of epileptic activity

7. Recurrent Excitatory Pathways Recurrent excitatory pathways occur in the hippocampus and neocortex via pyramidal collateralls Recurrent excitatory pathways occur in the hippocampus and neocortex via pyramidal collateralls This provides activation that is normally governed by widespread inhibitory circuits This provides activation that is normally governed by widespread inhibitory circuits Promotes spread of the seizure discharge Promotes spread of the seizure discharge

8. Hippocampal Sclerosis Hippocampal anatomy promotes epileptogenesis Hippocampal anatomy promotes epileptogenesis Hippocampal sclerosis is common in temporal lobe epilepsy Hippocampal sclerosis is common in temporal lobe epilepsy Significant synaptic reorganization and increased axonal collateralization provide increased excitatory input between neurons Significant synaptic reorganization and increased axonal collateralization provide increased excitatory input between neurons Promotes synchronous epileptic firing and seizure propagation Promotes synchronous epileptic firing and seizure propagation

9. Frequency Related Synaptic Enhancement High frequency repetitive firing results in increase accumulation of Ca near the presynaptic terminal produces High frequency repetitive firing results in increase accumulation of Ca near the presynaptic terminal produces Facillitation – increased glutamate release Facillitation – increased glutamate release Potentiation – enhanced synaptic activity Potentiation – enhanced synaptic activity

10. Synaptic Inhibition: GABA GABA A receptors: mediate brief opening of Cl - channels GABA A receptors: mediate brief opening of Cl - channels GABA B receptors: prolong activation of K + channels GABA B receptors: prolong activation of K + channels Repetitive firing depresses inhibitory synaptic activity Repetitive firing depresses inhibitory synaptic activity

11. Electrical Coupling of Neurons In areas with densely packed neurons (hippocampus), neurons may be connected directly via gap junctions or communicate via ephatic transmission due to close apposition of membranes allowing direct propagation of the seizure discharge In areas with densely packed neurons (hippocampus), neurons may be connected directly via gap junctions or communicate via ephatic transmission due to close apposition of membranes allowing direct propagation of the seizure discharge

12. Cellular Mechanisms of Epilepsy Burst firing Burst firing Recurrent excitatory connections Recurrent excitatory connections Synaptic enhancement and potentiation produced by rapid firing Synaptic enhancement and potentiation produced by rapid firing Depression of inhibitory synapses by high frequency firing Depression of inhibitory synapses by high frequency firing Nonsynaptic spread of electrical activity Nonsynaptic spread of electrical activity

13. Epilepsy Recurrent seizures produced by abnormal repetitive neuronal firing in the brain Recurrent seizures produced by abnormal repetitive neuronal firing in the brain Occurs in 1-2% of the population Occurs in 1-2% of the population

14. “Epsilepsee” in Arkansaw Big Seizure Little Seizure “ Grandma Seizure” vs. “Petit Mal Seizure” “Mini-Mall”

15. Seizure Classification Partial (Focal)Primary Generalized SimpleComplex May secondarily generalize AbsenceMyoclonicAtonicConvulsive Tonic Clonic Tonic-clonic Clonic-tonic-clonic

16. Partial Onset Seizure – Left Temporal Generalized Onset Seizure

17. General Guidelines for Therapy: Epilepsy Pearls Correct classification of seizures leads to correct AED selection Correct classification of seizures leads to correct AED selection Treat when the benefit of therapy outweighs the risk Treat when the benefit of therapy outweighs the risk

18. Natalie 3-week-old infant with no apparent perinatal complications 3-week-old infant with no apparent perinatal complications Hypotonia Hypotonia Slow feeder, poor suck Slow feeder, poor suck Several spells per day of staring with slight jerking movements Several spells per day of staring with slight jerking movements

19. Neonatal Seizure

20. Causes of Neonatal Seizures Cerebrovascular Cerebrovascular IVH IVH Hypoxic ischemic injury Hypoxic ischemic injury Cerebral infarction Cerebral infarction Genetic/Metabolic Genetic/Metabolic Chromosomal abnormalities Chromosomal abnormalities Inherited Inherited Benign familial Benign familial Amino acid disorder Amino acid disorder Organic acidemia Organic acidemia Urea cycle defect Urea cycle defect Non-ketotic hyperglycinemia Non-ketotic hyperglycinemia Mitochondrial disorder Mitochondrial disorder Neurocutaneous disorder Neurocutaneous disorder Others Others Acute Metabolic Problems Hypoglycemia Hypocalcemia Hypo/hypernatremia Infectious Bacterial meningitis TORCH Viral encephalitis Cerebral Anomalies Hydrocephalus Migrational abnormalites Agenesis of corpus calosum Holoprosencephaly Lissencephaly Others

21. 7-month-old infant with cerebral injury from “shaken baby” syndrome 7-month-old infant with cerebral injury from “shaken baby” syndrome Now with episodes described as “startle reflexes” commonly occurring in clusters Now with episodes described as “startle reflexes” commonly occurring in clusters Not responsive to maintenance phenobarbital Not responsive to maintenance phenobarbital SamuelSamuel

22. Infantile Spasms

23. Flexion or extension spasms Flexion or extension spasms Tend to occur in clusters Tend to occur in clusters Cryptogenic vs. symptomatic Cryptogenic vs. symptomatic Many potential causes Many potential causes Onset: Birth to 2 years Onset: Birth to 2 years Peak onset: 5-6 months Peak onset: 5-6 months 80% develop mental retardation 80% develop mental retardation 60-70% have lifelong epilepsy 60-70% have lifelong epilepsy Hypsarrhythmia pattern on EEG Hypsarrhythmia pattern on EEG

24. 9-year-old boy with long-standing history of intractable epilepsy with tonic-clonic, tonic, myoclonic, atypical absence and atonic seizures 9-year-old boy with long-standing history of intractable epilepsy with tonic-clonic, tonic, myoclonic, atypical absence and atonic seizures Moderate mental retardation Moderate mental retardation Frequent injuries from falls Frequent injuries from falls CharlieCharlie

25. Head Drops: Lennox Gastaut

26. Lennox-Gastaut Syndrome Onset in early childhood Onset in early childhood Many underlying etiologies, often cryptogenic Many underlying etiologies, often cryptogenic Multiple seizure types including Multiple seizure types including Atypical absence, generalized convulsive, atonic, myoclonic, partial Atypical absence, generalized convulsive, atonic, myoclonic, partial Negative neurodevelopmental impact Negative neurodevelopmental impact Mental retardation Mental retardation Slow spike and wave (2 hertz) Slow spike and wave (2 hertz)

27. Atonic No warning, abrupt onset No warning, abrupt onset Injuries common Injuries common Very difficult to treat Very difficult to treat May respond well to VNS May respond well to VNS Corpus callosotomy may prevent falls Corpus callosotomy may prevent falls

28. Atonic

29. Terry 2-year-old boy with 3-week history of recurrent episodes of sudden fear or panic 2-year-old boy with 3-week history of recurrent episodes of sudden fear or panic Initial frequency of 2-3 per day, now increased to 1 per hour or more Initial frequency of 2-3 per day, now increased to 1 per hour or more Maintenance of consciousness Maintenance of consciousness LMD felt these were not seizures LMD felt these were not seizures

30. Simple Partial Seizure

31. Gabrielle 12 y/o Hispanic girl with 1-year history of frequent spells with several daily 12 y/o Hispanic girl with 1-year history of frequent spells with several daily Diagnosed with “pseudoseizures” Diagnosed with “pseudoseizures” Maintenance of consciousness Maintenance of consciousness Events are stereotypical with extension of the right arm and turning to the left, followed by agitated movements and vocalization with an abrupt recovery Events are stereotypical with extension of the right arm and turning to the left, followed by agitated movements and vocalization with an abrupt recovery

32. Frontal Lobe Seizure

33. Simple Partial Focal onset Focal onset Aura is common Aura is common No alteration of consciousness No alteration of consciousness May secondarily generalize May secondarily generalize

34. William 12-year-old boy with intractable seizures with episodes of confusion and disorientation 12-year-old boy with intractable seizures with episodes of confusion and disorientation Ash leaf spots noted on Wood’s lamp exam Ash leaf spots noted on Wood’s lamp exam Intractable seizures despite numerous AED’s Intractable seizures despite numerous AED’s

35. MRI: Tuberous Sclerosis Subependymal nodulesHamartoma

36. Complex Partial Seizure

37. Complex Partial Aura is common Aura is common Represents the ictal onset Represents the ictal onset Stereotypical, but may be difficult to describe Stereotypical, but may be difficult to describe Alteration of consciousness Alteration of consciousness Automatisms Automatisms Postictal confusion Postictal confusion May secondarily generalize May secondarily generalize

38. 9-year-old girl with 2 seizures during the last 4 months 9-year-old girl with 2 seizures during the last 4 months First episode occurred during sleep consisting of a brief generalized convulsion First episode occurred during sleep consisting of a brief generalized convulsion Second seizure occurred during wakefulness and involved the right face and arm with subsequent secondary generalization Second seizure occurred during wakefulness and involved the right face and arm with subsequent secondary generalization ChelseaChelsea

39. Benign Focal Epilepsy of Childhood Rolandic (centrotemporal) or occipital spikes Rolandic (centrotemporal) or occipital spikes Benign Rolandic Epilepsy of Childhood Benign Rolandic Epilepsy of Childhood Benign Occipital Epilepsy of Childhood Benign Occipital Epilepsy of Childhood Nocturnal seizures are common Nocturnal seizures are common Seizures are usually infrequent Seizures are usually infrequent Remits by 15-16 years of age or earlier Remits by 15-16 years of age or earlier

40. 13 y/o girl with frequent staring episodes described as a blank stare with unresponsiveness, noted daily at school 13 y/o girl with frequent staring episodes described as a blank stare with unresponsiveness, noted daily at school Decreasing school performance Decreasing school performance *Key question: Is there an acute arrest of activity? *Key question: Is there an acute arrest of activity? TinaTina

41. Absence

42. Absence Brief stare with unresponsiveness Brief stare with unresponsiveness May have associated eye flutter or simple automatisms May have associated eye flutter or simple automatisms Sudden onset with arrest of activity Sudden onset with arrest of activity No aura or postictal confusion No aura or postictal confusion Generalized 3 per second spike and wave Generalized 3 per second spike and wave 80% will experience resolution with age 80% will experience resolution with age 20% will have convulsive seizures. 20% will have convulsive seizures.

43. Absence Followed by Clonic-Tonic-Clonic

44. Primary Generalized Convulsive No warning; abrupt onset No warning; abrupt onset Tonic, clonic, tonic-clonic or clonic-tonic- clonic activity Tonic, clonic, tonic-clonic or clonic-tonic- clonic activity Bowel and bladder incontinence common Bowel and bladder incontinence common Postictal unresponsiveness or confusion Postictal unresponsiveness or confusion Generalized spike and wave Generalized spike and wave

45. 13-year-old boy who had a single generalized convulsion 3 weeks ago 13-year-old boy who had a single generalized convulsion 3 weeks ago No previous history of seizures No previous history of seizures *Key question: Do you ever have small jerks of your arms, especially early in the morning? *Key question: Do you ever have small jerks of your arms, especially early in the morning? Answer: “Oh yeah, I’ve been doing that for a couple of years” Answer: “Oh yeah, I’ve been doing that for a couple of years” BubbaBubba

46. Myoclonic Seizure

47. Myoclonic Sudden single jerks of the arms and head Sudden single jerks of the arms and head Single or in clusters Single or in clusters No alteration in consciousness No alteration in consciousness May progress to clonic-tonic-clonic seizure May progress to clonic-tonic-clonic seizure Generalized multispike wave Generalized multispike wave

48. Juvenile Myoclonic Epilepsy (JME) Myoclonic seizures with onset in late childhood or adolescence Myoclonic seizures with onset in late childhood or adolescence May develop generalized convulsive or absence seizures May develop generalized convulsive or absence seizures Autosomal dominant inheritance Autosomal dominant inheritance Chromosome 6 Chromosome 6

49. 14 year old girl with 1 week history of new onset convulsive seizures 14 year old girl with 1 week history of new onset convulsive seizures Hospitalized and loaded with phenytoin with worsening seizures Hospitalized and loaded with phenytoin with worsening seizures Normal EEG Normal EEG MonicaMonica

50. Is it Real or is it Memorex? Pseudoseizure

51. NES - 65 children (video EEG) NES - 65 children (video EEG) 7-17 years (mean 13) 7-17 years (mean 13) 42 girls, 23 boys 42 girls, 23 boys 1/4 Coexisting history of epilepsy 1/4 Coexisting history of epilepsy 3/4 had an identifiable psychosocial stressor 3/4 had an identifiable psychosocial stressor Non-Epileptic Seizures in Children (ACH study)

52. * #1 Sexual or physical abuse * #1 Sexual or physical abuse Others: Others: Death of a family member Death of a family member Forced separation from family members Forced separation from family members Physical disability or illness of a parent Physical disability or illness of a parent Significant family conflict Significant family conflict Major illness Major illness Financial stressors Financial stressors Moving Moving Relational difficulties Relational difficulties NES in Children: Psychosocial Stressors

53. Alternative Therapy for Epilepsy Ketogenic diet Ketogenic diet Vagus nerve stimulator Vagus nerve stimulator Epilepsy surgery Epilepsy surgery

54. First described by Wilder, Mayo Clinic Bulletin, 1921 First described by Wilder, Mayo Clinic Bulletin, 1921 Mark 9:29 “This kind can come forth by nothing, but by prayer and fasting.” Mark 9:29 “This kind can come forth by nothing, but by prayer and fasting.” Typically reserved for children with severe, debilitating and intractable seizures Typically reserved for children with severe, debilitating and intractable seizures 4:1 (Fat: Protein + Carbohydrates) 4:1 (Fat: Protein + Carbohydrates) 75-90% of caloric intake as fat 75-90% of caloric intake as fat Urinary ketosis 80- 160 millimolar Urinary ketosis 80- 160 millimolar Ketogenic Diet

55. Ketogenic Diet: Efficacy 150 children prospectively evaluated 150 children prospectively evaluated Age range: 4 months - 16 years Age range: 4 months - 16 years Average of 410 seizures per month Average of 410 seizures per month Results after 1 year: Results after 1 year: 55% remained on the diet 55% remained on the diet 1/2 had > 50% reduction in seizures 1/2 had > 50% reduction in seizures 1/4 had > 90% decrease in seizures 1/4 had > 90% decrease in seizures Freeman, Vining, et.al. Pediatrics, December, 1998

56. Vagus Nerve Stimulator: Rule of Thirds 1/3 have prominent improvement 1/3 have prominent improvement 1/3 have moderate improvement 1/3 have moderate improvement 1/3 have little or no improvement 1/3 have little or no improvement Benefits Benefits fewer seizures, less severe seizures, shorter recovery period, decreased medications and side effects, less fear and anxiety, more control fewer seizures, less severe seizures, shorter recovery period, decreased medications and side effects, less fear and anxiety, more control

57. Epilepsy Surgery: Criteria for Consideration Seizures must be medically intractable Seizures must be medically intractable Seizures must be debilitating Seizures must be debilitating There should be no chance for spontaneous resolution There should be no chance for spontaneous resolution

58. Epilepsy Surgery Temporal lobectomy Temporal lobectomy 75-90% seizure free 75-90% seizure free Extratemporal lesional resection Extratemporal lesional resection 50-75% seizure free 50-75% seizure free Extratemporal non-lesional resection Extratemporal non-lesional resection < 50% seizure free < 50% seizure free Functional hemispherectomy Functional hemispherectomy considered in extreme circumstances considered in extreme circumstances Corpus callosotomy Corpus callosotomy good for atonic and brief tonic seizures good for atonic and brief tonic seizures

59. go THE END