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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

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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
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.

epidemiology by seizure types
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. 1992;33(suppl 4):S10.

prognosis after a single seizure
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)
veterans administration cooperative study
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Veterans Administration Cooperative Study

100

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80

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Percent Continuing

40

phenobarbital

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phenytoin

20

primidone

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carbamazepine

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Months

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

sanad study
SANAD Study

Time to 12 month remission

% remaining on drug

Marsan et al 2007

prognosis of drug refractory epilepsy re evaluation of 246 patients
Prognosis of ‘Drug-Refractory’ EpilepsyRe-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

why do aeds fail
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
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
Altered NA+ Channel Responses?

No MTS

MTS

Remy et al 2003

multiple drug transporters p glycoproteins
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 AEDresistance

Loscher 2007

possible therapeutic maneuvers
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 epilepsy
Natural History of Epilepsy
  • Natural history of untreated epilepsy unknown
    • Bromides since 1857
    • PB available since 1912

Charles Locock

Alfred Hauptman

natural history of epilepsy23
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
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

ilae epilepsy outcome categories
ILAE Epilepsy Outcome Categories

*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
Drug Resistant EpilepsyILAE 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
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 years29
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

Predicting Intractable Epilepsy
what is intractable epilepsy modified after dc taylor
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
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 1929Edwin G ZabriskieAssociate Professor of Neurology, Columbia UniversityPhysician to the Neurological Institute
neuropsychological and functional prognosis in tle
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

Silanpaa et al 1998; Jokeit et al 2000; Helmstaedter et al 2003

depression and epilepsy
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
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
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
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 sex-matched 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
Approaches to Intractable Epilepsy
  • Surgery
    • Focal resection
    • hemispherectomy
    • Callosotomy (palliative)
  • Ketogenic Diet
  • Experimental Drugs
  • Brain Stimulation
slide42
‘Intractable’ TLE:

Comparison of Medical and Surgical Outcome

Helmstaedter et al 2003

Wiebe et al 2001

Non-randomized Clinical Series

Controlled Temporal Lobectomy Trial

One year

2-10 years

the ketogenic diet
The Ketogenic Diet

20% Protein

5% Carbs

10% Protein

30% Fat

85% Fat

50% Carbs

potential mechanisms of action
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
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
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
Ketogenic Diet Randomized Controlled Study

10/65 who stopped diet not included in analysis

Neal et al Lancet Neurology 2008

brain stimulation for epilepsy
Brain Stimulation for Epilepsy
  • Vagal Nerve Stimulation
  • Transcranial Magnetic stimulation
  • Intracranial stimulation
    • Surface electrodes (‘responsive’)
    • Deep Brain Stimulation
      • Hippocampus
      • Thalamus
      • Cerebellum

Torpedo fuscomaculata

slide49
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

tms in epilepsy
TMS in Epilepsy

~4 cm

  • TLE:
    • Case reports and open trials:
      • 30-70% seizure decreases reported
    • Blinded controlled trial
      • 16% reduction > placebo (0.05
      • Effect lasted 2-4 weeks
  • Cortical Dysplasia
    • significantly decreased the seizures in active compared with sham rTMS group
thalamic stimulation
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 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
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
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
RNS™ Placement

Courtesy of Martha Morrell

slide57
Anterior Lead (A)

Posterior Lead (P)

Parahippocampal

Longitudinal

Strip (not connected)

Courtesy of Martha Morrell

preliminary rns efficacy n 65
Preliminary RNS Efficacy (n=65)

Barkley et al AES 2006

risks of brain stimulation
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
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