1. Management of Patients With Epilepsy

2. Definition Seizure Single provoked/unprovoked episode Epilepsy Two or more unprovoked seizures

3. Numbers….Numbers Unprovoked seizure: Risk in US ~ 1/100 Epilepsy/Recurrent unprovoked seizures 8 th leading cause of morbidity 50 million people worldwide, 2 million in US Age-adjusted prevalence 2.7-40/1000 Incidence and prevalence is much higher in under developed nations >50% of seizures are untreated Annual cost is $12.5 billion

4. Age Adjusted Incidence

5. Seizure Classification Partial Seizures Simple Partial Complex Partial Secondarily GTC Generalized Seizures GTC Absence Myoclonic Clonic Tonic Atonic  International League Against Epilepsy (ILAE) in 1981  Based on Semiology/Ictal behavior and EEG  Epilepsy Syndrome based classification

6. Complex Partial Seizure Impaired consciousness Clinical manifestations vary with site of origin and degree of spread Presence and nature of aura Automatisms Other motor activity Duration (15 sec.—3 min.)

7. Generalized Tonic Clonic Seizure Variable symmetry, intensity, and duration of tonic (stiffening) and clonic (jerking) phases Usual duration 30-120 sec. Postictal confusion, somnolence, with or without transient focal deficit May be primary or secondarily generalized

8. Proportion of Cases By Seizure Type Rochester, MN 1935-1984

9. Proportion of Cases By Etiology Rochester, MN 1935-1984

10. Consequences of Epilepsy Morbidity Accidents, Injuries Mortality Sudden unexpected death in epilepsy Status epilepticus, Suicide, Accidents, Cancer, Infections etc. Socioeconomic Outcome School performance 56% finish high school and 15% finish college Intellectual functioning (seizures vs. drugs) Social adjustment Employment Driving

11. Management Important to establish diagnosis and etiology Classify seizure type and syndrome Good history (from patient and spouse/friend) Labs EEG (sleep deprived vs. routine) Imaging (MRI is far superior to CT) SPECT, PET

12. Everything that shakes is not a seizure!!! Non-epileptic spells can be extremely hard to differentiate from seizures 30% of all patients Risk factors: Epilepsy Family member with epilepsy Psychiatric problems Most have conversion disorder Need video EEG monitoring to confirm diagnosis

13. Medical Management Mid 1800’s: Bromides 1912: Phenobarbital 1938: Merritt and Putnam - Phenytoin

14. Year Introduced Phenobarbital1912 Phenytoin1938 Primidone1954 Ethosuximide1960 Carbamazepine1974 Valproate1978 Felbamate1993 Gabapentin1993 Lamotrigine1994 Topiramate1996 Tiagibine1997 Levetiracetam2000 Oxcarbazepine2000 Zonisamide2000 Other Available AEDsDiazepam, Lorazepam, Diastat, Depacon, ACTH……

16. Major Side Effects PhenobarbitalSedation, Hyperactivity, Rash, Osteomalacia PhenytoinGingival hyperplasia, Hirsutism, Peripheral Neuropathy, Bone marrow suppression, Osteomalacia PrimidoneSedation, Hyperactivity, Rash, Osteomalacia EthosuximideGI Upset, Mood changes, Lethargy, Hiccups, Headache CarbamazepineHyponatremia, Leucopoenia, Hepatitis, Rash ValproateThrombocytopenia, Tremor, Hair loss, Weight gain, Hepatitis, Pancreatitis FelbamateHepatic Failure, Aplastic Anemia GabapentinSleepiness, Weight gain LamotrigineRash (increased risk with VPA) TopiramateCognitive slowing, Renal stones, Acute Glaucoma, Weight Loss TiagibineDizziness, Somnolence, Spike Wave Stupor LevetiracetamSleepiness OxcarbazepineHyponatremia, Rash (No Leucopoenia) ZonisamideRash, Renal stones

17. Epilepsy in the Elderly Adverse Effects (AE) of Medications dose-dependent side effects are common: dizziness, somnolence, ataxia, diplopia drug-specific side effects are common hyponatremia, tremor, cardiac effects, encephalopathy, cognitive suppression AE’s occur at lower serum concentrations AE’s more likely to result in non- compliance

20. Weight Gain/Loss Most medications are weight neutral Valproic Acid and Gabapentin typically associated with weight gain Felbamate, Topiramate and Zonisamide associated with weight loss Zonisamide Weight loss: 28.9% of patients on ZNS compared to 8.4% on placebo lost more than 5 lbs. Weight loss occurred in the first 3 months

21. Hyponatremia Seen with carbamazepine and oxcarbazepine Clinically significant hyponatremia (sodium <125 mEq/L) has been observed in 2.5% of OXC-treated patients in controlled clinical trials Measurement of serum sodium levels should be considered for patients at risk for hyponatremia Most (79%) of these patients were receiving concomitant sodium-depleting medications including carbamazepine, antidepressants, diuretics, and cathartics The observed hyponatremia was usually asymptomatic and occurred within the first 90 days of treatment

22. Renal Stones Can occur with TPM, ZNS, Ketogenic Diet ~4% incidence of all clinically possible or confirmed kidney stones Less than 50% of calculi are symptomatic Analyzed stones are mostly composed of calcium or urate salts No increased risk of stone in patients on Ketogenic diet and ZNS or TPM History of calculi may not be absolute contraindication for use of the AED’s Richards et al., Neurology 2005

23. Choice of Therapy Partial Seizure Oxcarbazepine Lamotrigine Zonisamide Levetiracetam, Pregabalin, Phenytoin Generalized Seizures Topiramate Lamotrigine Valproic Acid Zonisamide

24. Seizure Type and Age RangeInitial Monotherapy Felbamate Partial with and without generalization in adults LSG: Pediatric and Adult Yes No Gabapentin Partial with and without generalization above age 12 Partial from 3-12 No Lamotrigine Partial: Adults LGS: Pediatric and Adult No (Approved for Conversion to Monotherapy) No Topiramate Partial: Pediatric (>2) and adults Primary GTC LGS Yes (Adults and Children>10) Tiagibine Partial: Adults and Children (>12)No Levetiracetam Partial: AdultsNo Oxcarbazepine Partial: Adults and Children (>2)Yes (Children and Adults >4) Zonisamide Partial: AdultsNo New AED’s: FDA Approved Indications

25. Issues To Discuss Driving Interaction with contraceptives >50μg ethinyl estradiol/mestranol if taking enzyme-inducing AED (phenobarbital, primidone, phenytoin, carbamazepine) OC’s do not alter seizure control, but they may accelerate metabolism of enzyme-inducing AED Pregnancy issues Decreased serum drug concentrations Birth defects Eventual outcome of treatment

26. Driving in Texas Doctors not required to report patients Seizure-Free Period: 6 months, with doctor's recommendation Annual periodic medical updates required Doctors not liable for their opinions and recommendations Allowed to drive if: Only nocturnal seizures Breakthrough seizure due to a physician directed change in medication Intrastate License: The U.S. Department of Transportation (DOT) bars anyone with any history of epilepsy

27. Interaction with Hormonal Contraception Definite/Possible interaction Carbamazepine Oxcarbazepine Phenobarbital Phenytoin Tiagabine *Topiramate **Lamotrigine (OCD’s reduce LTG levels) No interaction Felbamate Gabapentin Levetiracetam Zonisamide

28. Pregnancy and Delivery Higher fetal death rate (~ 1.3-14%) Malformations of 2 main types: “Minor” malformations: Cleft lip, Cleft palate, digit and crease abnormalities Fetal hydantoin syndrome Fetal anticonvulsant syndrome “Major” malformations: Neural tube defects

29. Malformations Risk factors: Polytherapy Uncontrolled seizures Both GTC and CPS Higher plasma levels of medications Neural tube defects: VPA Mechanism ? Association with folate metabolism Enzyme-inducing AEDs accelerate folate metabolism VPA interferes with folate absorption

30. Pregnancy: Recommendations Pre-Pregnancy Limit risk factors Genetic counseling High risk Obstetrician Folic acid supplementation 400 micrograms/day (70% reduction in neural tube defect incidence) ENROLL IN PREGNANCY REGISTRY Pregnancy Level 2 ultrasound at 16-18 weeks Amniocentesis if indicated Delivery Vitamin K 10 mg/day, during last week to prevent Hemorrhagic Disease due to reduced activity of Vit K-dependent clotting factors (II, VII, IX, X) and protein S/C with enzyme-inducing AEDs

31. Pregnancy: Recommendations VPA and PB seem to have highest risk for neural tube defects Monitor AED levels closely LTG levels will decrease by 50% by end of second trimester No AED is completely safe Association of LTG with cleft lip/palate

32. Outcome of Medical Management Kwan and Brodie, NEJM 2000 Prospective study 525 patients 9-93 yrs of age Patients diagnosed, treated and followed at a single center for 13 years ~60% respond to the first to medications Significant number of patients have side effects

33. Medical Intractability Unacceptable control despite multiple drugs Acceptable control with unacceptable side effects Reasons for unsatisfactory control Correct AED, but not working Incorrect AED Incorrect diagnosis ~ 10-20% of patients have “non-epileptic events”

34. Options For Medically Intractable Patients Epilepsy Surgery Other: Brain Stimulation Vagal Nerve Stimulation Cerebellar, Caudate, Thalamus, Hippocampus

35. Results of Surgical Treatment, Worldwide (1986-1990; Retrospective Data) Engel J. NEJM 1996 Outcomes, % Surgical ProcedurePatientsSeizure- free Worthwhile improvemen t No Worthwhile improvement Temporal lobe resections - Anterior temporal lobectomy 357967.924.08.1 Amygdalohippocampectomy41368.822.39.0 Neocortical resection60545.135.219.8 Lesionectomy29366.621.511.9 Hemispherectomy19067.421.111.6 Multilobar resection16645.235.519.3 Callosotomy5637.660.931.4

36. Risks of Epilepsy Surgery Wiebe S et al, NEJM 2001 10% complications in surgery group, 1 death (2.5%) in medical management group Rydenhag and Silander, Neurosurgery 2000, 449 procedures Major complications 3.1%, Minor 8.9% Risk is higher with Intracranial electrode placement Extra-temporal surgery especially in/around eloquent cortex Pre-operative w/u (Neuropsychological testing, Amobartbital test) provides assessment of post-operative memory problems Superior quadrantanopsia ~ 30% patients (assymptomatic) Post-operative depression/psychosis

37. Outpatient Management: Conclusions Epilepsy is an extremely common condition ~60% of patients are well controlled on a single first appropriate medication Early identification of medically refractory patients Epilepsy surgery is an effective and safe treatment Goal is Seizure Freedom

38. Status Epilepticus Definition: 2 or more seizures without full recovery or more or less continuous seizure activity lasting >30 minutes Incidence: 50,000-150,000 cases annually in the U.S. Most common in children and the elderly

39. Etiology Prior history of seizures: Most common: Medication changes or non-compliance Breakthrough seizures because of stress, lack of sleep, menstrual cycles. Unknown New Onset: Metabolic problems e.g., electrolyte disturbances, renal failure, sepsis and hypoxia, especially in the hospitalized patient Head trauma, central nervous system infection and cerebral hemorrhage or infarction. Intracranial tumors, substance abuse or other drug toxicity/withdrawal and HIV.

40. Generalized Convulsive SE Most common type of SE ~70% of all cases of SE ~65,000-150,000 new cases every year Responsible for considerable morbidity and mortality (~3-53%) Prevalence of nonconvulsive status epilepticus in comatose patients: 8% (236 patients with no overt seizure activity) Towne et al., Neurology 2000

41. Standard Treatment Algorithm: Initial Treatment Assess and control airway (100% oxygen, intubation if needed) Monitor vital signs (including temperature)-- hyperthermia occurs in 29-78%, passive cooling or cooling blanket if needed (hyperpyrexia is an important cause of poor outcome) Conduct pulse oximetry and monitor cardiac function Perform finger-stick blood glucose Call EEG technician and begin EEG stat.

42. While you are treating…… Begin focused history and examine patient Known seizure disorder or other illnesses? Trauma? Focal neurological signs? Signs of medical illnesses (e.g. infection, hepatic or renal disease, substance abuse?) Throughout protocol: Manage other medical problems Determine and treat underlying etiology of status

44. VA cooperative trial of 384 patients with a diagnosis of overt generalized status epilepticus Treiman et al: NEJM 1998 Lorazepam is reasonable as the initial drug of choice in the treatment of GCSE.

45. Other Medications Rectal Diazepam Gel (Diastat @ ) Midazolam 0.1-0.3 mg/kg slow IVP followed by 0.05-0.4 mg/kg/hr infusion Propofol 2-2.5 mg/kg IV (40mg q10min) followed by 0.1-0.2 mg/kg/min IV IV Valproate (Depacon @ ) 15-20 mg/kg IV followed by 250-500 mg q6 hrs

46. Status Epilepticus: Goal Stop seizures as quickly and as aggressively as possible Duration of status correlates inversely with outcome

47. Additional Information….. Epilepsy Foundation of America www.efa.org National Institute of Neurological Disorders and Stroke (NINDS) www.ninds.nih.gov