Management of Patients With Epilepsy

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 • 8th 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. Partial Seizures Simple Partial Complex Partial Secondarily GTC Generalized Seizures GTC Absence Myoclonic Clonic Tonic Atonic Seizure Classification • 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 TypeRochester, MN 1935-1984

9. Proportion of Cases By EtiologyRochester, 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

16. Major Side Effects

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

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

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