Management of Patients With Epilepsy

Definition Seizure

Single provoked/unprovoked episode

Epilepsy Two or more unprovoked seizures

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

Age Adjusted Incidence

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

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.)

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

Proportion of Cases By Seizure TypeRochester, MN 1935-1984

Proportion of Cases By EtiologyRochester, MN 1935-1984

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

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

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

Medical Management

Mid 1800’s: Bromides 1912: Phenobarbital 1938: Merritt and Putnam -

Phenytoin

Year Introduced

Phenobarbital 1912

Phenytoin 1938

Primidone 1954

Ethosuximide 1960

Carbamazepine 1974

Valproate 1978

Felbamate 1993

Gabapentin 1993

Lamotrigine 1994

Topiramate 1996

Tiagibine 1997

Levetiracetam 2000

Oxcarbazepine 2000

Zonisamide 2000

Other Available AEDs Diazepam, Lorazepam, Diastat, Depacon, ACTH……

Major Side EffectsPhenobarbital Sedation, Hyperactivity, Rash, Osteomalacia

Phenytoin Gingival hyperplasia, Hirsutism, Peripheral Neuropathy, Bone marrow suppression, Osteomalacia

Primidone Sedation, Hyperactivity, Rash, Osteomalacia

Ethosuximide GI Upset, Mood changes, Lethargy, Hiccups, Headache

Carbamazepine

Hyponatremia, Leucopoenia, Hepatitis, Rash

Valproate Thrombocytopenia, Tremor, Hair loss, Weight gain, Hepatitis, Pancreatitis

Felbamate Hepatic Failure, Aplastic Anemia

Gabapentin Sleepiness, Weight gain

Lamotrigine Rash (increased risk with VPA)

Topiramate Cognitive slowing, Renal stones, Acute Glaucoma, Weight Loss

Tiagibine Dizziness, Somnolence, Spike Wave Stupor

Levetiracetam Sleepiness

Oxcarbazepine Hyponatremia, Rash (No Leucopoenia)

Zonisamide Rash, Renal stones

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

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

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

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

Choice of Therapy Partial Seizure

Oxcarbazepine Lamotrigine Zonisamide Levetiracetam, Pregabalin, Phenytoin

Generalized Seizures Topiramate Lamotrigine Valproic Acid Zonisamide

Seizure Type and Age Range Initial 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

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: Adults No

Oxcarbazepine Partial: Adults and Children (>2) Yes (Children and Adults >4)

Zonisamide Partial: Adults No

New AED’s: FDA Approved Indications

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

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

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

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

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

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

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

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

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”

Options For Medically Intractable Patients

Epilepsy Surgery Other:

Brain Stimulation Vagal Nerve Stimulation Cerebellar, Caudate, Thalamus,

Hippocampus

Results of Surgical Treatment, Worldwide (1986-1990; Retrospective Data) Engel J. NEJM 1996

Outcomes, %

Surgical Procedure Patients

Seizure-free

Worthwhile

improvement

No Worthwhile

improvement

Temporal lobe resections

- Anterior temporal lobectomy

3579 67.9 24.0 8.1

Amygdalohippocampectomy

413 68.8 22.3 9.0

Neocortical resection 605 45.1 35.2 19.8

Lesionectomy 293 66.6 21.5 11.9

Hemispherectomy 190 67.4 21.1 11.6

Multilobar resection 166 45.2 35.5 19.3

Callosotomy 563 7.6 60.9 31.4

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

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

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

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.

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

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.

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

VA cooperative trial of 384 patients with a diagnosis of overt generalized status epilepticus Treiman et al: NEJM 1998

0

10

20

30

40

50

60

70

Cessation %

Lorazepam(0.1 mg/ kg)

Phenobarbital(15 mg/ kg)

Phenytoin (18mg/ kg) +Diazepam(0.15 mg/ kg)Phenytoin (18mg/ kg)

Lorazepam is reasonable as the initial drug of choice in the treatment of GCSE.

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

Status Epilepticus: Goal Stop seizures as quickly and as

aggressively as possible

Duration of status correlates inversely with outcome

Additional Information….. Epilepsy Foundation of America

www.efa.org

National Institute of Neurological Disorders and Stroke (NINDS) www.ninds.nih.gov