Transcript Epilepsy: Prognosis and Treatment

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
devel
infection
trauma
CVD
tumor
degen
50
40
30
20
10
0
<15
15-24
25-44
45-64
Annegers 1993
>65
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
T½
Drug interactions
Therapeutic level
(μmol/L)
lamotrigine
1-3h
55%
hepatic
15-60
AEDs
10-60
gabapentin
2-3h
dose
0
renal
6-7h#
minimal
40-120
tiagabine
1-2h
96
CYP3A
5-8h
AEDs
#
vigabatrin
1-2h
0
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
0
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
0
hepatic
30-60 hr
AEDs
300-600
5-7h#
#
Calcium
channels
GABA
system
Glutamate
receptors
Clinical Efficacy
Drug
Sodium
channels
Phenytoin
++
Y
Carbamazepine
++
Oxcarbazepine
++
Lamotrigine
++
Zonisamide
LRE
PGE
SGE
N
N
Y
N
N
Y
N
N
+
Y
Y
Y
++
+
Y
Valproate
+
+
+
Y
Y
Felbamate
+
+
+
+
Y
Y
Topiramate
+
+
+
+
Y
Y
Ethosuximide
++
+
N
Gabapentin
++
+
Y
Levetiracetam
+
+
Y
Phenobarbital
+
+
Y
+
Y
Y
N
Epilepsy Therapy in 525 Patients
Kwan and Brodie 2000
Veterans Administration Cooperative
Study
Percent Continuing
100
sl
sl
l
l
s
80
s
l
l
s
l
l
s
60
s
s
l
l
s
s
l
l
s
s
ll
s
s
40
ll
s
s
ll
s
s
l
l
l
l
l
l
l
l
s
s
s
s
s
s
s
s
s s
l l
20
s s
l l
phenobarbital
phenytoin
primidone
carbamazepine
0
0
3
6
9
12
15
18
21
24
27
30
33
36
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
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
3
4
1
3
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,
No drug seemed superior
mental retardation, status,
> 6 AEDs
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
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
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
90
80
70
%
60
50
40
30
20
10
0
IdioPE
IGE
remission
SympPE
no remission
Sillanpaa et al 1999
dead
SecGE
Drug Therapy: Prognosis by
Seizure Type (n=1102)
60
50
40
VA118-12
VA118-24
VA264-12
VA264-24
30
20
10
0
GTC
Mixed
Mattson et al 1996
CPS
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.’’
– Cecil’s 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
Wiebe et al 2001
Controlled Temporal Lobectomy Trial
70
Seizure-free
60
50
40
30
20
10
0
surgical
2-10 years
medical
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-1ß
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
• 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
high
low
-25
-30
EO3 (p<.05)
EO5 (p<.001)
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
~4 cm
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;66:1490–1494
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