Epilepsy: Prognosis and

Treatment
William H Theodore MD
Chief, Clinical Epilepsy Section
National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, Maryland, USA

Prevalence and Incidence

Third most common neurologic disorder

First seizure incidence: 20-70 / 100,000
Epilepsy incidence: 30-50 / 100, 000
Prevalence: 5-10 / 1000
Reported higher in some developing countries

Cumulative adjusted lifetime risk: 1.3%3.3%

Hauser WA, Hesdorffer DC. Epilepsy: Frequency, Causes, and Consequences. New York, N
Demos; 1991:1.

Etiology of Symptomatic Epilepsy

USA

Annegers 1993

Epidemiology by Seizure
Types
Generalized TC
(23%)
Complex Partial
(36%)

Simple Partial
(14%)

Unclassified (3%)
Myoclonic (3%)
Other Generalized
Absence (6%)
(8%) Partial Unknown
(7%)

Reproduced with permission from Hauser WA. Epilepsia. 1992;33(suppl 4):S1

Prognosis After a Single Seizure

Reported 30-70% recurrence over 3 years
sampling, etiology, seizure types
Increased if underlying lesion
Decreased if avoidable acute precipitant

CBZ reduced recurrence in children (Camfield 1989)

1/3 stopped drug due to side effects

18% Rx vs 38% no RX in 2 years

PHT, CBZ, VPA, PB (First Seizure Trial Group 1989)

AED

Peak Plasma
concentration

Protein
binding

clearance

Drug interactions

Therapeutic level
(mol/L)

lamotrigine

1-3h

55%

hepatic

15-60

AEDs

10-60

gabapentin

2-3h
dose

renal

6-7h#

minimal

40-120

tiagabine

1-2h

96

CYP3A

5-8h

AEDs

vigabatrin

1-2h

Topiramate

2-4h

15

mixed

18-23h

Lithium, OCs, some AEDs

10-60

Oxcarbazepine
(MHD metabolite)

1-2h

40

Non-CYP
mediated

10-12 hr
(MHD
metabolite)

AEDs
oral contraceptives

50-140 (MHD)

Felbamate

2-6h

22-25

hepatic

15-23hr

AEDs

200-400

Phenobarbital

1-4 h

40-55

hepatic

80-130

extensive

50-130

Phenytoin

2-6 hr

90

Hepatic***

extensive

40-80

Carbamazepine

Slow, variable

70-75

hepatic

18-55 hr*
12 hr**

extensive

15-45

Levetiracetam

1-2 h

Renal

6-10 hr

minimal

Zonisamide

3-4 h

40-60

CYP3A

50-60 hr

extensive

35-200

Valproic acid

1-2 h

90&

Hepatic

10-15 hr

AEDs

300-600

Ethosuximide

3-5 h

hepatic

30-60 hr

AEDs

300-600

5-7h#

Calcium
channels

GABA
system

Glutamate
receptors

Clinical Efficacy

Drug

Sodium
channels

Phenytoin

++

Carbamazepine

++

Oxcarbazepine

++

Lamotrigine

++

Zonisamide

LRE

PGE

SGE

++

Valproate

Felbamate

Topiramate

Ethosuximide

++

Gabapentin

++

Levetiracetam

Phenobarbital

Epilepsy Therapy in 525 Patients

Kwan and Brodie 2000

Veterans Administration Cooperative

Study
Percent Continuing

100

80

60

40

20

phenobarbital
phenytoin
primidone
carbamazepine

0
0

12

15

18

21

Months

24

27

30

33

36

Reproduced with permission from Mattson RH, et al. N Engl J Med. 1985;313:

SANAD Study

Time to 12 month remission

% remaining on drug

Marsan et al 2007

Reasons for AED Failure

VA Cooperative Study
CBZ

PHT

PB

PRM

All

N=101

N=101

N=110

N=109

N=421

Toxicity

12

19

18

36

85

Toxicity+
seizures

30

33

29

25

127

Seizures

11

Total

45

56

48

74

233

Mattson et al 1985

Prognosis of Drug-Refractory Epilepsy

Re-evaluation of 246 patients
Drug failure before index
date:
maximum tolerated dose in
54%
idiosyncratic reaction in 6.5%
intolerable side effect in 19%
unknown reasons in 21%.

6-month terminal seizure

remission:
14% of AED-treated patients
(about 5% per year of study)
52% of surgery patients

persistent intractability:
Duration > 10 years, mental
retardation, status, > 6 AEDs
No drug seemed superior
Callhagan et al 2008

Some Emerging AEDs

AED

CPS
(> placebo)

PGE

Brivaracetam

22%

78%
photosensitity

Carisbamate

18-20%

CNS

Eslicarbazepine

~ 20%

CNS, GI

Lacosamide

20-25%

CNS, GI

Retigabine

20-25%

CNS

Rufinamide

SGE

toxicity
GI

20% total
40% atonic

CNS, GI

Why do AEDs Fail?

About 30% of patients do not respond at all
About 10% of patients with good initial AED
response cease to respond
Pharmacokinetic
Drug interactions
Enzyme induction

Tolerance to non-BZP AEDs ?

Receptor, channel response changes

Drug efflux transporters

PgP, MRPs,

AED Tolerance
Long-term BZPs:
allosteric GABA-BZP
site interactions
VGB tolerance in
MES model: GAD
due to GABA
feedback inhibition

Loscher & Schmidt 2006

Altered NA Channel
Responses?
+

No MTS

MTS

Remy et al 2003

Multiple Drug Transporters

(p-glycoproteins)
Pump lipophilic drugs and
other xenobiotics out of
cells
Role in cancer
chemotherapy resistance

May be overexpressed in
human epileptic tissue,
especially TLE
Unreplicated link between
MDR gene
polymorphisms and
human AED resistance

Loscher 2007

PgP Affects Brain Phenytoin

Levels

Loscher 2007

Possible Therapeutic
Maneuvers
Manage with drug holidays, dose
adjustments?
Alternate AEDs?

Lower starting doses?

Cross-tolerance ?
Choose drugs with different mechanisms?

PgP inhibition
verapamil
tariquidar

 Bromides since 1857

PB available since
1912

Charles Locock

Natural history of
untreated epilepsy
unknown

Alfred Hauptman

Natural History of
Epilepsy

Natural History of Epilepsy

Natural history of
untreated epilepsy
unknown.
Course may fluctuate.

No difference in seizurefree rate if treatment

begun after 1st or 2d
seizure
In resource poor
countries, spontaneous
remission rate ~ 30%
prognosis not related
to pretreatment GTCS
#
Hauser et al 1998

Early onset LRE may not become clearly

intractable for many years
7 centers: 333 patients evaluated for
resective surgery for localization-related
epilepsy prospectively identified at initial
evaluation
Latency from epilepsy onset to 2 AED
failure 9.1 years
26% reported at least 1 yr remission
8.5% 5 year remission
Berg et al 2003

Intractable Epilepsy:
Comparison of Diagnostic Criteria

Berg et al Epilepsia 2006

ILAE Epilepsy Outcome Categories

Seizure Control

Side Effects

Outcome

Seizure-free*

No

1A

Yes

1B

undetermined

1C

No

2A

Yes

2B

undetermined

2C

No

3A

Yes

3B

undetermined

3C

Treatment failure

Undetermined

*at least 12 months AND three times the longest interseizure interval in 12 months
prior to new intervention
Kwan et al Epilepsia 2009

Drug Resistant Epilepsy

ILAE 2009
Failure of informative trials of two tolerated
and appropriately chosen and used AED
schedules (whether as monotherapies or in
combination) to achieve sustained seizure
freedom.

Kwan et al Epilepsia 2009

Data Needed to Determine if a Therapeutic

Intervention is Informative
Mode of application (e.g., formulation, dose,
dosing interval)
Compliance
Duration of exposure
Was there was effort to optimize dose?
Reason(s) for discontinuation
Unsatisfactory seizure control
Adverse effects
Psychosocial reasons, for example, planning for
pregnancy
Administrative reasons, for example, lost to follow up
Financial issues, for example, cannot afford drug
Other reasons
Kwan et al Epilepsia 2009

Early onset LRE may not become clearly

intractable for many years
7 centers: 333 patients evaluated for
resective surgery for localization-related
epilepsy prospectively identified at initial
evaluation
Latency from epilepsy onset to 2 AED
failure 9.1 years
26% reported at least 1 yr remission
8.5% 5 year remission
Berg et al 2003

Predicting Intractable Epilepsy

Epilepsy Pattern:
Remittent
KCNQ2 or KCNQ3 benign
familial convulsions
Some absence

Non-remittent drug
responsive
JME

Non drug-responsive but

treatable
Localization-related

Poorly responsive
LGS

Clinical Features at Onset:

Early age of onset
presentation in status
epilepticus ?
abnormal neurological exam
partial seizures at diagnosis
mixed seizure types ~
developmental delay
multiple seizures prior to
treatment
seizure clustering, density
Structural lesion

New onset TLE in Children: MRI and Prognosis

Spooner et al 2006

Prospective Study of Finnish

Children
1964-1992

Sillanpaa et al 1999

Drug Therapy: Prognosis by

Seizure Type (n=1102)

Mattson et al 1996

What is Intractable Epilepsy?

(modified after DC Taylor)
The Lesion or Disease:
mesial temporal sclerosis, malformation

The Illness:
intermittent seizures

The Predicament:
social
psychological
economic

AEDs treat the illness, not the disease

Is that important?

Progression of Epilepsy
The interparoxysmal
mental state of epileptics
often presents grave
deterioration.
Each fit apparently leaves
a change in the nerve
centers, facilitating the
occurrence of other fits.
Gowers 1890

Mental deterioration
follows relentlessly.
Cecils Textbook of Medicine 1929
Edwin G Zabriskie
Associate Professor of Neurology, Columbia
University
Physician to the Neurological Institute

Neuropsychological and functional

Prognosis in TLE
Surgery accelerates
decline if unsuccessful
Stops or reverses it if
successful
In Finnish pediatric
study, adverse socioeconomic effects even
in patients who entered
adult life in remission
off AEDs
Silanpaa et al 1998; Jokeit et al
2000; Helmstaedter et al 2003

Depression and Epilepsy

Depression in Population > 18 survey data
36.5% epilepsy
27.8% asthma
11.8% control
Adults ever told of epilepsy: RR 2.5
Adults with active epilepsy: RR 3.0

Reduced quality of life

Increased medical resource use
Cramer et al 2003, Ettinger et al
2004, 2005, Kobau et al 2006

Quality of Life
Seizure control usually considered most
important measure
Complete seizure-freedom usually has a much
greater effect on HRQOL measures than simply
reduced frequency
Depression has greater adverse impact than
seizure frequency itself in some studies
Drug side effects and unemployment
Issue of when to withdraw drugs after successful
surgery

Seizure Control, Depression, and

Anxiety
Several studies suggest
seizure frequency
predicts anxiety and
depression symptoms
Multicenter surgery
study
depression ~ seizure
control
6.1% new depression in
non-seizure free patients
Devinsky et al Neurology 2005;
Baker Neurology 2006

Death
Standardized mortality ratio is increased in epilepsy,
even if no underlying illness
Marked increase in sudden unexplained death
SUDEP related to:
GTCS
> 2 AEDs

Death after TLE

SMR for patients with recurrent seizures 4.69
seizure free patients: no difference vs age- and sexmatched population of the United States

Persistent seizures ~ death in Finnish pediatric study

Death is due to uncontrolled epilepsy

Silanpaa et al 1998; Sperling et al

1999

Approaches to Intractable
Epilepsy
Surgery
Focal resection
hemispherectomy
Callosotomy (palliative)

Ketogenic Diet
Experimental Drugs
Brain Stimulation

Intractable TLE:
Comparison of Medical and Surgical Outcome
Helmstaedter et al 2003
Non-randomized Clinical Series

2-10 years

Wiebe et al 2001
Controlled Temporal Lobectomy Trial

One year

The Ketogenic Diet

10% Protein

5% Carbs

20% Protein

30% Fat

85% Fat
50% Carbs

Potential Mechanisms of Action

Ketosis
Acetone
Aspartate, GABA
Polyunsaturated
fatty acids
Mitochondrial
uncoupling
Glucose modulation
Enhanced
glutamate transport
Opening KATP
channels
Acidosis
Caloric restriction
Decreased IL-1
Neurosteroids

Ketogenic Diet
Traditionally started gradually in
the hospital after a 24-48 hour
fast
Families educated daily

Ratio (fat: carbs and protein)

4:1 more strict
3:1 for infants, adolescents
Calories 60-100%
Fluids 85-100%
Solid foods and/or formula
Requires dietician support
Strong family committment

Side Effects

Constipation
Slowed weight gain
Acidosis when ill
Vitamin deficiency (if unsupplemented)
Renal stones
Impaired height and weight
Dyslipidemia
Gastrointestinal upset

Ketogenic Diet Randomized Controlled Study

10/65 who stopped diet not included in analysis

Neal et al Lancet Neurology 2008

Brain Stimulation for Epilepsy

Vagal Nerve Stimulation
Transcranial Magnetic
stimulation
Intracranial stimulation
Surface electrodes
(responsive)
Deep Brain Stimulation
Hippocampus
Thalamus
Cerebellum
Torpedo fuscomaculata

VNS
Requires surgery, but
extracranial
Effects broadly comparable
to new AED trials
30-40% 50% seizure
frequency reduction
In open label extension
effect sustained 12 months
Very rare patients seizurefree
Only consider when no
chance for resective surgery

Refractory Generalized Epilepsy

Nei et al Epilepsia 2006

Transcranial Magnetic Stimulation

TMS in Epilepsy
TLE:
Case reports and open
trials:
30-70% seizure decreases
reported

Blinded controlled trial

16% reduction > placebo
(0.05<p<0.10)
Effect lasted 2-4 weeks

Cortical Dysplasia
significantly decreased
the seizures in active
compared with sham
rTMS group

~4cm

Thalamic Stimulation
Centromedian
Uncontrolled studies reported improvement
Small controlled study: no effect

Anterior
Recent controlled study showed seizure
14.5% in the control group
40.4% in the stimulated group

Subthalamic
Improvement in uncontrolled studies

Long-term follow-up of patients with thalamic

deep brain stimulation for epilepsy
Long-term follow-up (mean, 5 years)
6 patients with anterior (AN)
2 centromedian thalamic deep brain stimulation

Five patients (all AN) had 50% seizure reduction

benefit was delayed in two until years 5 to 6
after changes in antiepileptic drugs.

Seizure reduction 1 to 3 months before active

stimulation
Possibility of a beneficial microthalamotomy effect.
Andrade et al Neurology 2006

Hippocampal Stimulation
Reduced CPS frequency reported in several uncontrolled
studies
One small controlled study:
Four patients with refractory MTLE
Risk to memory contraindicated temporal lobe resection

Double-blind stimulation randomly turned ON 1 month and

OFF 1 month for 6 months
Median reduction in seizures of 15%
Effects seemed to carry over into the OFF period

Possible implantation effect.

No adverse effects.
One patient treated for 4 years has substantial long-term
improvement.
Tellez-Zenteno et al NEUROLOGY 2006;66:14901494

Seizure Prediction
Energy level (red)
decision threshold (blue)
prediction output (green)
seizure onset (black)
Positive outputs
(high level in green
curve)
observed ~ 2 h
before seizures.

Esteller et al Clin Neurophysiol 2005

RNS Placement

Courtesy of Martha Morrell

Anterior Lead (A)

Posterior Lead (P)

Parahippocampal
Longitudinal
Strip (not connected)

Courtesy of Martha Morrell

Preliminary RNS Efficacy (n=65)

Initial 84 days

Most recent 84 days

Seizuretype

% with
50%

Overall %

% with
50%

Overall %

CPS

32

27

40

34

GTCS

63

59

55

66

Total
Disabling

26

29

41

35

Barkley et al AES 2006

Risks of Brain Stimulation

TMS
Rare seizures at high (>10hz) frequency
Epilepsy therapy trials are at 1 hz

Mild headache, scalp discomfort

VNS
Cough, Hoarseness when stimulator on
dyspnea, pain, paresthesia, and headaches
respond to alteration of stimulation settings

Very rare vocal cord paralysis, bradycardia during implant

DBS

Bleeding
infarction
intracranial infection
All less likely with surface RNS