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, NY: Demos; 1991:1.

Etiology of Symptomatic Epilepsy USA

80 70 60 50 40 30 20 10 0 <15 15-24 25-44 45-64 >65 devel infection trauma CVD tumor degen

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):S10.

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
gabapentin

1-3h
2-3h dose 1-2h 1-2h

55%
0

hepatic
renal

15-60
6-7h#

AEDs
minimal

10-60
40-120

tiagabine vigabatrin

96 0

CYP3A

5-8h 5-7h#

AEDs

# #

Topiramate Oxcarbazepine (MHD metabolite)

2-4h 1-2h

15 40

mixed Non-CYP mediated

18-23h 10-12 hr (MHD metabolite) 15-23hr 80-130

Lithium, OCs, some AEDs AEDs oral contraceptives

10-60 50-140 (MHD)

Felbamate Phenobarbital Phenytoin

2-6h 1-4 h 2-6 hr

22-25 40-55 90

hepatic hepatic Hepatic***

AEDs extensive extensive

200-400 50-130 40-80

Carbamazepine

Slow, variable

70-75

hepatic

18-55 hr* 12 hr** 6-10 hr 50-60 hr 10-15 hr

extensive

15-45

Levetiracetam Zonisamide Valproic acid

1-2 h 3-4 h 1-2 h

0 40-60 90&

Renal CYP3A Hepatic

minimal extensive AEDs

# 35-200 300-600

Ethosuximide

3-5 h

hepatic

30-60 hr

AEDs

300-600

Drug

Sodium channels
++ ++

Calcium channels

GABA system

Glutamate receptors

Clinical Efficacy
LRE Y Y PGE N SGE N

Phenytoin Carbamazepine

Oxcarbazepine
Lamotrigine Zonisamide Valproate

++
++ ++ + + + + +

Y
Y Y Y

N
Y

N
Y

Felbamate Topiramate Ethosuximide

+ +

+ + ++

+ + +

+ +

Y Y N Y

Y Y N

Gabapentin Levetiracetam Phenobarbital

++ + +

+ + + +

Y Y Y

Epilepsy Therapy in 525 Patients

Kwan and Brodie 2000

Veterans Administration Cooperative Study

100
s s l l l l s s

Percent Continuing

80

l l s s

l l s

l l s s

l l
s s

l l s s

l l s s

60

l l s s

l l s s

l l s s

l l s s s s

l l s s

40 20

l l

s s l l

phenobarbital phenytoin primidone carbamazepine

36

0 0 3 6 9 12 15 18 21 24 27 30 33

Months
Reproduced with permission from Mattson RH, et al. N Engl J Med. 1985;313:145-151.

SANAD Study

Time to 12 month remission

% remaining on drug

Marsan et al 2007

Reasons for AED Failure VA Cooperative Study

CBZ
N=101

PHT
N=101

PB
N=110

PRM
N=109

All
N=421

Toxicity Toxicity+ seizures Seizures Total

12 30 3 45

19 33 4 56

18 29 1 48

36 25 3 74

85 127 11 233

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, No drug seemed superior mental retardation, status, > 6 AEDs Callhagan et al 2008

Some Emerging AEDs

AED Brivaracetam Carisbamate
Eslicarbazepine

CPS (> placebo) 22% 18-20%

PGE 78% photosensitity

SGE

toxicity
GI

CNS

~ 20%
20-25% 20-25% 20% total 40% atonic

CNS, GI
CNS, GI CNS CNS, GI

Lacosamide Retigabine Rufinamide

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

 Natural history of untreated epilepsy unknown

Bromides since 1857 PB available since 1912

Alfred Hauptman

Charles Locock

Natural History of Epilepsy

Natural History of Epilepsy

Natural history of untreated epilepsy unknown.
Course may fluctuate.

No difference in seizure-free 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 Seizure-free* Side Effects No Yes Outcome 1A 1B

undetermined
Treatment failure No Yes undetermined

1C
2A 2B 2C

Undetermined

No
Yes undetermined

3A
3B 3C

*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

90 80 70 60 50 40 30 20 10 0 IdioPE IGE remission SympPE no remission dead SecGE

Sillanpaa et al 1999

Drug Therapy: Prognosis by Seizure Type (n=1102)

60 50 40 30 20 10 0

VA118-12 VA118-24 VA264-12 VA264-24

GTC

Mixed

CPS

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
25 20 15 10 5

depression ~ seizure 0 control % depressed 6.1% new depression preop in non-seizure free Devinsky et al Neurology 2005; patients Baker Neurology 2006

% anxious NSF SF

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
70 60

Wiebe et al 2001 Controlled Temporal Lobectomy Trial

Seizure-free

50 40 30 20 10 0 surgical medical

2-10 years

One year

The Ketogenic Diet

20% Protein 10% Protein
5% Carbs

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
0

Requires surgery, but extracranial

-5 -10 % reduction versus -15 baseline -20 -25 -30 EO3 (p<.05) EO5 (p<.001) high low

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

~4 cm

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

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
CPS GTCS Total Disabling

% with 50%
32 63 26

Overall %
27 59 29

% with 50%
40 55 41

Overall %
34 66 35

Barkley et al AES 2006

 TMS

Risks of Brain Stimulation

Epilepsy therapy trials are at 1 hz

Rare seizures at high (>10hz) frequency

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