Pediatric Epilepsy

1. PHM142 Fall 2012 Instructor: Dr. Jeffrey Henderson Pediatric Epilepsy Ashley Masse Arif Mohamed Rosalie Nguyen Yusuf Majumder

2. What is Epilepsy? Epilepsy is a neurological disorder change in normal brain function. Epilepsy is not generally an inherited disease. Typically characterized by seizures. About 0.6% of the Canadian population has Epilepsy.

3. Types of Epilepsy/ Classifications There are two major types of epilepsy Idiopathic Epilepsy- no known cause Secondary/Somatic Epilepsy- the cause is attributed to a specific event (such as genetic conditions, hitting ones head, or stroke). Epilepsy is further classified by the type of seizure the person experiences. Types include: generalized tonic-clonic, absence, myoclonic, and partial.

4. Who Does it Affect? • It is estimated that there are 15,500 new cases of epilepsy diagnosed each year in Canada. • 44% are diagnosed before the age of 5. • 55% before the age of 10. • 75-85% before age 18.

5. Childhood Epilepsy About 50% of children “grow out” of the disorder and experience a complete disappearance of seizures. Some of those who continue to have seizures into adulthood often notice a decrease in intensity and frequency.

6. Epilepsy Syndromes By Age of Onset Neonatal period • BENIGN IDIOPATHIC NEONATAL SEIZURES (BINS) • Rare idiopathic syndrome often generalized • BENIGN FAMILIAL NEONATAL-INFANTILE SEIZURES (BFNIS) • Genetic based idiopathic syndrome • EARLY INFANTILE EPILEPTIC ENCEPHALOPATH (EIEE) • Rare, but severe encephalopathic form with symptomatic root

7. Epilepsy Syndromes By Age of Onset • Infancy • WEST SYNDROME • symptomatic, cryptogenic (nonidentifiable hidden cause) • Between 4 and 7 month • MYOCLONIC EPILEPSY IN INFANCY (MEI) • Rare, idiopathic generalized • Between the ages of 6 months and 3 years • DRAVET SYNDROME • Rare, symptomatic • Cases with mutations in the SCN1A gene

8. Epilepsy Syndromes By Age of Onset • Childhood • BENIGN CHILDHOOD EPILEPSY WITH CENTROTEMPORAL SPIKES • Most common idiopathic epilepsy syndrome, representing 24% of epilepsy cases among school age children • LENNOX-GASTAUT SYNDROME (LGS) • Onset is 2nd to 6th year of life • accompanied by developmental delay and psychological and behavioral problems • LANDAU-KLEFFNER SYNDROME (LKS) • Peak onset between the ages of 3 and 7 years • Two-thirds of affected children are male

9. Underlying Causes of Pediatric Epilepsy • 1) Abnormalities in the glial cells (Glial cells and the blood-brain barrier are still developing). • 2) Differences in the activity of ion channels as well as the release of neurotransmitters (Glutamate and GABA). • 3) Role of structural anomalies (Lesions) • 4) Genetic predisposition (Monogenic channelopathies) • 5) Exposure to epileptogenic stimuli (fever, infection or hypoxia during development)

10. Description of epilepsy in general • Primarily affects the cerebral cortex. • In all cases, epilepsy can be described as “abnormal hypersynchronous electrical activity” due to an imbalance between excitation and inhibition. • The main characteristic of epileptic neurons is their increase in excitability, which leads to excessive discharges.

11. Neurotransmitters- GABA • Can be inhibitory or excitatory depending on the neurotransmitter and the receptor that it binds. • Main inhibitory- GABA= Opening of chloride channels (GABA A receptor) or reduction in amount of neurotransmitter released and opening of potassium channels (GABA B receptor). • Reduction in GABA inhibition either by: • Decrease in GABA (neurotrasmitter) release. • GABA receptors can no longer respond to GABA. • Changes in ionic gradient due to “intracellular accumulation of chloride ions”.

12. Overview of the Mechanisms of Epilepsy-Paroxysmal Depolarizing Shift (PDS), Spreading and Termination • PDS is composed of two components: * Slow component: • Long lasting, and sustained depolarization * Rapid component: - Additional rapid and sharp depolarizations. • Spreading of seizures possible due to more activation and/or loss of inhibition leading to: -The extracellular potassium level is increased, and thus it is more difficult for potassium to leave the cell. -The net current will be inward leading to depolarization that will occur to the extent that calcium currents will “be triggered”, so more neurotransmitter released. - Activation of NMDA receptors by glutamate. • Termination - Inactivation of the inward current. - Activation of the potassium outward current. - Increase in chloride current into the cell.

13. Diagnostic Tests • Several tests can be performed to diagnose a patient following a seizure. • EEG: to verify that person had a seizure and to determine if seizures are partial or general. (Looks at changes in electrical patterns). • MRI or CT scan: these methods are used to rule out other abnormalities that may cause seizures (such as a tumor). • Blood tests may also be ordered to rule out other disorders or infections

14. Treatment of Pediatric Epilepsy Anti-epileptic medication Surgery Changes in diet

15. Treatment of Pediatric Epilepsy

16. Treatment of Pediatric Epilepsy Surgery: for refractory (intractable) epilepsy Corpus callosotomy: sectioning of the corpus callosum to prevent and block spread of epileptic discharges interhemispherically Can be partial or complete

17. Treatment of Pediatric Epilepsy Ketogenic diet: high fat, low carbohydrate diet Used to treat difficult-to-control, intractable epilespy

18. References Bromfield, E.B., Cavaazos, J.E., & Siven JI. (2006). An Introduction to Epilepsy. West Hartford: American Epilepsy Society. Czuczwar, S. J., & Patsalos, P. N. (2001). The new generation of GABA enhancers: potential in treatment of epilespy. CNS Drugs, 15(5), 339-350. Freeman, J. M., Vining, E. P. G., Pillas, D. J., Pyzik, P. L., Casey, J. C., & Kelly, M. T. (1998). The efficacy of the ketogenic diet – 1998: a prospective evaluation of intervention of 150 children. Pediatrics, 102(6), 1358-1363. Kim, D. Y., & Rho, J. M. (2008). The ketogenic diet and epilespy. Current Opinion in Clinical Nutrition and Metabolic Care, 11, 113-120. Meldrum, B. S. (1996). Update on the mechanism of action of antiepileptic drugs. Epilepsia, 37, S4-S11. Wong, T., Kwan, S., Chang, K., Hsiu-Mei, W., Yang, T., Chen, Y., & Yi-Yen, L. (2006). Corpus callosotomy in children. Child’s Nervous System, 22, 99-1011. World Health Organization. (October 2012). Fact Sheet N999. In Epilepsy. Retrieved November 25, 2012, from http://www.who.int/mediacentre/factsheets/fs999/en/index.html. Epilepsy Canada. (2012). Living with Epilepsy, Facts, Epidemiology, & Diagnosis and Treatment. In Epilepsy Canada. Retrieved November 25, 2012, from www.epilepsy.ca.

19. References Badawy, R. A. B., Harvey, A. S., & Macdonell, R. A. L. (2009). Cortical hyperexcitability and epileptogenesis: Understanding the mechanisms of epilepsy - part 1. Journal of Clinical Neuroscience, 16(3), 355-365. Retrieved from www.scopus.com Badawy, R. A. B., Harvey, A. S., & Macdonell, R. A. L. (2009). Cortical hyperexcitability and epileptogenesis: Understanding the mechanisms of epilepsy - part 2. Journal of Clinical Neuroscience, 16(4), 485-500. Retrieved from www.scopus.com Pellock, J.M. et al. (2008). Pediatric Epilepsy. New York: Demos Medical Publishing. Blume W. T. (2003). Diagnosis and management of epilepsy. CMAJ, 168: 441-448 Canadian Pharmacists Association. (2012). , Seizures and Epilepsy, Therapeutic Choices. (pp 292-301) Webcom, Toronto, ON. Deivasumathy Muthugovindan, and Adam L. Hartman. (2010). Pediatric Epilepsy Syndromes. The Neurologist, 16: 223-237. David R. Fish, Shelagh J. Smith, Luis F. Quesney, Frederick Andermann, Theodore Rasmussen ( 2005). Surgical Treatment of Children with Medically Intractable Frontal or Temporal Lobe Epilepsy: Results and Highlights of 40 Years' Experience. Epilepsia, 34: 244-247.

20. Summary There are different types of epilepsy common in different stages of childhood. Epilepsy can be described as “abnormal hypersynchronous electrical activity” due to an imbalance between excitation and inhibition.  Paroxysmal depolarising shift leads to sustained and repetitive or burst firing.  During seizures, 1) It is more difficult for potassium to move outwards 2) Calcium accumulates, so more neurotransmitter is released 3) Activation of NMDA by glutamate. Terminated with chloride entering, potassium leaving or inactivation of inward current.  GABA is a neurotransmitter that regulates inhibition, therefore a reduction in GABA leads to less control. Pediatric epilepsy can be treated with Na+ channel blockers (carbamazepine, phenytoin), GABA receptor agonist (phenobarbital), Ca++ channel blockers (ethosuximide) to prevent frequent firing of neurons. Intractable pediatric epilepsy may be treated with corpus callosotomy or with ketogenic diet.