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Epilepsy: Prognosis and Treatment

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Title: Epilepsy: Prognosis and Treatment


1
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

2
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 1.33.3

Hauser WA, Hesdorffer DC. Epilepsy Frequency,
Causes, and Consequences. New York, NY Demos
19911.
3
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4
Etiology of Symptomatic Epilepsy USA
5
Epidemiology by Seizure Types
Generalized TC (23)
Complex Partial (36)
Simple Partial (14)
Unclassified (3)
Myoclonic (3)
Other Generalized (8)
Absence (6)
Partial Unknown (7)
Reproduced with permission from Hauser WA.
Epilepsia. 199233(suppl 4)S10.
6
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)

7
AED Peak Plasma concentration Protein binding clearance T ½ 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 5-7h
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
8
Table 2 AED Mechanisms and Clinical Efficacy
Drug Sodium channels Calcium channels GABA system Glutamate receptors Clinical Efficacy Clinical Efficacy Clinical Efficacy
Drug Sodium channels Calcium channels GABA system Glutamate receptors LRE PGE SGE
Phenytoin Y N N
Carbamazepine Y N N
Oxcarbazepine Y N N
Lamotrigine Y Y Y
Zonisamide Y
Valproate Y Y Y
Felbamate Y Y
Topiramate Y Y
Ethosuximide N Y N
Gabapentin Y
Levetiracetam Y
Phenobarbital Y
9
Epilepsy Therapy in 525 Patients
Kwan and Brodie 2000
10
Veterans Administration Cooperative Study
s
l
100
l
l
80
l
l
l
l
l
l
l
l
l
l
60
l
Percent Continuing
40
phenobarbital
s
s
phenytoin
20
primidone
s
s
carbamazepine
l
l
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. 1985313145-151.
11
SANAD Study
Time to 12 month remission
remaining on drug
12
Reasons for AED Failure VA Cooperative Study
CBZ N101 PHT N101 PB N110 PRM N109 All N421
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
13
Prognosis of Drug-Refractory Epilepsy Re-evaluat
ion 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 gt 10 years, mental retardation, status,
    gt 6 AEDs

No drug seemed superior
14
Some Emerging AEDs
AED CPS (gt placebo) PGE SGE toxicity
Brivaracetam ? 22 78 ? photosensitity GI
Carisbamate ?18-20 CNS
Eslicarbazepine ? 20 CNS, GI
Lacosamide ? 20-25 CNS, GI
Retigabine ? 20-25 CNS
Rufinamide ? 20 total ? 40 atonic CNS, GI
15
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16
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,

17
AED Tolerance
  • Long-term BZPs ? allosteric GABA-BZP site
    interactions
  • VGB tolerance in MES model ? GAD due to GABA
    feedback inhibition

Loscher Schmidt 2006
18
Altered NA Channel Responses?
No MTS
MTS
Remy et al 2003
19
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
20
PgP Affects Brain Phenytoin Levels
21
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

22
Natural History of Epilepsy
  • Natural history of untreated epilepsy unknown
  • Bromides since 1857
  • PB available since 1912

Charles Locock
Alfred Hauptman
23
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
24
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

25
Intractable Epilepsy Comparison of Diagnostic
Criteria
Berg et al Epilepsia 2006
26
ILAE Epilepsy Outcome Categories
Seizure Control Side Effects Outcome
Seizure-free No 1A
Yes 1B
undetermined 1C
Treatment failure No 2A
Yes 2B
undetermined 2C
Undetermined No 3A
Yes 3B
undetermined 3C
at least 12 months AND three times the longest
interseizure interval in 12 months prior to new
intervention
Kwan et al Epilepsia 2009
27
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
28
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
29
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
30
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

31
New onset TLE in Children MRI and Prognosis
32
Prospective Study of Finnish Children 1964-1992
33
Drug Therapy Prognosis by Seizure Type (n1102)
Mattson et al 1996
34
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?

35
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

36
Neuropsychological and functional Prognosis in TLE
  • Surgery accelerates decline if unsuccessful
  • Stops or reverses it if successful
  • In Finnish pediatric study, adverse
    socio-economic effects even in patients who
    entered adult life in remission off AEDs

37
Depression and Epilepsy
  • Depression in Population gt 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

38
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

39
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

40
Death
  • Standardized mortality ratio is increased in
    epilepsy, even if no underlying illness
  • Marked increase in sudden unexplained death
  • SUDEP related to
  • GTCS
  • gt 2 AEDs
  • Death after TLE
  • SMR for patients with recurrent seizures 4.69
  • seizure free patients no difference vs age- and
    sex-matched population of the United States
  • Persistent seizures death in Finnish pediatric
    study
  • Death is due to uncontrolled epilepsy

41
Approaches to Intractable Epilepsy
  • Surgery
  • Focal resection
  • hemispherectomy
  • Callosotomy (palliative)
  • Ketogenic Diet
  • Experimental Drugs
  • Brain Stimulation

42

Intractable TLE Comparison of Medical and
Surgical Outcome
Helmstaedter et al 2003
Wiebe et al 2001
Controlled Temporal Lobectomy Trial
Non-randomized Clinical Series
One year
2-10 years
43
The Ketogenic Diet
20 Protein
5 Carbs
10 Protein
30 Fat
85 Fat
50 Carbs
44
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

45
Ketogenic Diet
  • Traditionally started gradually in the hospital
    after a 24-48 hour fast
  • Families educated daily
  • Ratio (fat carbs and protein)
  • 41 more strict
  • 31 for infants, adolescents
  • Calories 60-100
  • Fluids 85-100
  • Solid foods and/or formula
  • Requires dietician support
  • Strong family committment

46
Side Effects
  • Constipation
  • Slowed weight gain
  • Acidosis when ill
  • Vitamin deficiency (if unsupplemented)
  • Renal stones
  • Impaired height and weight
  • Dyslipidemia
  • Gastrointestinal upset

47
Ketogenic Diet Randomized Controlled Study
10/65 who stopped diet not included in analysis
Neal et al Lancet Neurology 2008
48
Brain Stimulation for Epilepsy
  • Vagal Nerve Stimulation
  • Transcranial Magnetic stimulation
  • Intracranial stimulation
  • Surface electrodes (responsive)
  • Deep Brain Stimulation
  • Hippocampus
  • Thalamus
  • Cerebellum

Torpedo fuscomaculata
49
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 seizure-free
  • Only consider when no chance for resective surgery

Refractory Generalized Epilepsy Nei et al
Epilepsia 2006
50
Transcranial Magnetic Stimulation
51
TMS in Epilepsy
4 cm
  • TLE
  • Case reports and open trials
  • 30-70 seizure decreases reported
  • Blinded controlled trial
  • 16 reduction gt placebo (0.05ltplt0.10)
  • Effect lasted 2-4 weeks
  • Cortical Dysplasia
  • significantly decreased the seizures in active
    compared with sham rTMS group

52
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

53
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
54
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 20066614901494
55
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
56
RNS Placement
Courtesy of Martha Morrell
57
Courtesy of Martha Morrell
58
Preliminary RNS Efficacy (n65)
Initial 84 days Initial 84 days Most recent 84 days Most recent 84 days
Seizure-type 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
59
Risks of Brain Stimulation
  • TMS
  • Rare seizures at high (gt10hz) 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

60
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