Transcript Epilepsy Update for the Internal Medicine Residents

Management of Patients With
Epilepsy
Definition
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Seizure
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Single provoked/unprovoked episode
Epilepsy
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Two or more unprovoked seizures
Numbers….Numbers
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Unprovoked seizure:
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Risk in US ~ 1/100
Epilepsy/Recurrent unprovoked seizures
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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
 International League Against Epilepsy (ILAE) in 1981
 Based on Semiology/Ictal behavior and EEG
 Partial Seizures
 Generalized Seizures
 Simple Partial
 GTC
 Complex Partial
 Absence
 Secondarily GTC
 Myoclonic
 Clonic
 Tonic
 Atonic
 Epilepsy Syndrome based classification
Complex Partial Seizure
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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
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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 Type
Rochester, MN 1935-1984
Proportion of Cases By Etiology
Rochester, MN 1935-1984
Consequences of Epilepsy
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Morbidity
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Mortality
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Accidents, Injuries
Sudden unexpected death in epilepsy
Status epilepticus, Suicide, Accidents, Cancer, Infections etc.
Socioeconomic Outcome
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School performance
 56% finish high school and 15% finish college
Intellectual functioning (seizures vs. drugs)
Social adjustment
Employment
Driving
Management
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Important to establish diagnosis and etiology
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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)
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SPECT, PET
Everything that shakes is not a
seizure!!!
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Non-epileptic spells can be extremely hard to
differentiate from seizures
30% of all patients
Risk factors:
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Epilepsy
Family member with epilepsy
Psychiatric problems
Most have conversion disorder
Need video EEG monitoring to confirm diagnosis
Medical Management
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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 Effects
Phenobarbital
Sedation, Hyperactivity, Rash, Osteomalacia
Phenytoin
Gingival hyperplasia, Hirsutism, Peripheral Neuropathy, Bone
marrow suppression, Osteomalacia
Primidone
Sedation, Hyperactivity, Rash, Osteomalacia
Ethosuximide
Carbamazepine
GI Upset, Mood changes, Lethargy, Hiccups, Headache
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
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dose-dependent side effects are
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drug-specific side effects are
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common:
dizziness, somnolence, ataxia,
diplopia
common
hyponatremia, tremor, cardiac
effects, encephalopathy,
cognitive suppression
AE’s occur at lower serum
concentrations
AE’s more likely to result in noncompliance
Weight Gain/Loss
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Most medications are weight neutral
Valproic Acid and Gabapentin typically
associated with weight gain
Felbamate, Topiramate and Zonisamide
associated with weight loss
Zonisamide
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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
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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
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Can occur with TPM, ZNS, Ketogenic Diet
~4% incidence of all clinically possible or confirmed
kidney stones
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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
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Richards et al., Neurology 2005
Choice of Therapy
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Partial Seizure
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Oxcarbazepine
Lamotrigine
Zonisamide
Levetiracetam, Pregabalin, Phenytoin
Generalized Seizures
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Topiramate
Lamotrigine
Valproic Acid
Zonisamide
New AED’s: FDA Approved Indications
Felbamate
Gabapentin
Lamotrigine
Seizure Type and Age Range
Initial
Monotherapy
Partial with and without
generalization in adults
LSG: Pediatric and Adult
Yes
Partial with and without
generalization above age 12
Partial from 3-12
No
Partial: Adults
No (Approved for
Conversion to
Monotherapy)
No
LGS: Pediatric and Adult
No
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)
Partial: Adults
No
Zonisamide
Issues To Discuss
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Driving
Interaction with contraceptives
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Pregnancy issues
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>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
Decreased serum drug concentrations
Birth defects
Eventual outcome of treatment
Driving in Texas
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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
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Definite/Possible
interaction
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Carbamazepine
Oxcarbazepine
Phenobarbital
Phenytoin
Tiagabine
*Topiramate
**Lamotrigine (OCD’s
reduce LTG levels)
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No interaction
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Felbamate
Gabapentin
Levetiracetam
Zonisamide
Pregnancy and Delivery
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Higher fetal death rate (~ 1.3-14%)
Malformations of 2 main types:
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“Minor” malformations: Cleft lip, Cleft palate, digit
and crease abnormalities
 Fetal hydantoin syndrome
 Fetal anticonvulsant syndrome
“Major” malformations: Neural tube defects
Malformations
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Risk factors:
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Polytherapy
Uncontrolled seizures
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Both GTC and CPS
Higher plasma levels of medications
Neural tube defects: VPA
Mechanism
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? Association with folate metabolism
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Enzyme-inducing AEDs accelerate folate metabolism
VPA interferes with folate absorption
Pregnancy: Recommendations
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Pre-Pregnancy
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Pregnancy
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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
Level 2 ultrasound at 16-18 weeks
Amniocentesis if indicated
Delivery
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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
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VPA and PB seem to have highest
risk for neural tube defects
Monitor AED levels closely
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LTG levels will decrease by 50% by end
of second trimester
No AED is completely safe
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Association of LTG with cleft lip/palate
Outcome of Medical Management
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Kwan and Brodie, NEJM 2000
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Prospective study
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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
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Unacceptable control despite multiple drugs
Acceptable control with unacceptable side
effects
Reasons for unsatisfactory control
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Correct AED, but not working
Incorrect AED
Incorrect diagnosis
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~ 10-20% of patients have “non-epileptic events”
Options For
Medically Intractable Patients
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Epilepsy Surgery
Other:
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Brain Stimulation
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Vagal Nerve Stimulation
Cerebellar, Caudate, Thalamus, Hippocampus
Results of Surgical Treatment, Worldwide
(1986-1990; Retrospective Data)
Engel J. NEJM 1996
Outcomes, %
Surgical Procedure
Patients
Seizurefree
Worthwhile
improvemen
t
No Worthwhile
improvement
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
Temporal lobe resections
- Anterior temporal
lobectomy
Risks of Epilepsy Surgery
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Wiebe S et al, NEJM 2001
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10% complications in surgery group, 1 death (2.5%) in medical
management group
Rydenhag and Silander, Neurosurgery 2000, 449 procedures
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Risk is higher with
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Major complications 3.1%, Minor 8.9%
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
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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
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Definition:
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Incidence:
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2 or more seizures without full recovery or
more or less continuous seizure activity
lasting >30 minutes
50,000-150,000 cases annually in the U.S.
Most common in children and the
elderly
Etiology
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Prior history of seizures:
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Most common: Medication changes or non-compliance
Breakthrough seizures because of stress, lack of sleep, menstrual
cycles.
Unknown
New Onset:
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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
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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
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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……
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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
Lorazepam
(0.1 mg/kg)
70
60
50
Phenobarbital
(15 mg/kg)
40
30
20
10
0
Cessation %
Phenytoin (18
mg/kg) +
Diazepam
(0.15 mg/kg)
Phenytoin (18
mg/kg)
Lorazepam is reasonable as the initial drug of choice in
the treatment of GCSE.
Other Medications
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Rectal Diazepam Gel (Diastat@)
Midazolam
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Propofol
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0.1-0.3 mg/kg slow IVP followed by 0.05-0.4 mg/kg/hr
infusion
2-2.5 mg/kg IV (40mg q10min) followed by 0.1-0.2
mg/kg/min IV
IV Valproate (Depacon@)
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15-20 mg/kg IV followed by 250-500 mg q6 hrs
Status Epilepticus: Goal
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Stop seizures as quickly and as
aggressively as possible
Duration of status correlates inversely
with outcome
Additional Information…..
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Epilepsy Foundation of America
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www.efa.org
National Institute of Neurological
Disorders and Stroke (NINDS)
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www.ninds.nih.gov