Welcome and Introductions

Jacqueline A. French, MD (Chair) Co-Director, Penn Epilepsy Center Professor of Neurology University of Pennsylvania Hospital of the University of Pennsylvania Department of Neurology Philadelphia, Pennsylvania

Just a reminder
This symposium is jointly sponsored by the American Epilepsy Society and The BioContinuum Group. It has been made possible through an educational grant from UCB Pharma, Inc. The faculty has disclosed any commercial relationships and discussion of unlabeled or unapproved uses of drugs. Please use the online Medical Educational Evaluator to obtain CME and pharmacy education credit for attending this symposium. See your syllabus for details. We will take questions from the audience after each presentation. We will also collect question cards. Blank cards are located at the back of your syllabus. Please turn off your cell phones and beepers.
2

An Insult Occurs Epilepsy Emerges What Happens Next?

E y eps pil

Insult

Time

Agenda
7:10
PM

7:40

PM

Epileptogenesis After the Onset of Epilepsy Douglas A. Coulter, PhD Question and Answer Session Clinical Epidemiology of Refractory Epilepsy W. Allen Hauser, MD Question and Answer Session

7:40 7:45

PM PM

7:45 8:15

PM PM

8:15

PM

8:20

PM

Agenda (contd)
8:20
PM

8:50

PM

Evidence for Progressive Structural and Neuropsychological Abnormalities in Epilepsy Kimford J. Meador, MD Question and Answer Session Do Antiepileptic Drugs Alter the Course of Epilepsy? Jacqueline A. French, MD Question and Answer Session Concluding Remarks Jacqueline A. French, MD
5

8:50 8:55

PM PM

8:55 9:25

PM PM

9:25

PM

9:30 9:30

PM PM

Clinical Epidemiology of Refractory Epilepsy

W. Allen Hauser, MD Professor of Neurology and Epidemiology College of Physicians and Surgeons Columbia University Sergievsky Center New York, New York
6

Characteristics of Optimal Data Sets to Evaluate Prognosis

Incidence cohort Population-based Full evaluation of all cases with timely categories Comprehensive follow-up Well-defined end points

End Points
Good outcomes Remission Successful drug withdrawal Social adaptation School or employment Bad outcomes Intractability but how defined? Death Lack of social adaptation, problems in school or employment
8

Points in Course of Epilepsy That Predict Outcome

After a first unprovoked seizure At the time of first diagnosis of epilepsy After remission for some predetermined period After meeting some predetermined criteria for intractability

Predictors of Seizure Recurrence After a First Seizure

Symptomatic etiology Family history Status epilepticus in symptomatic cases Todds paralysis Epileptiform EEG

EEG=electroencephalogram.

10

Predictors of Unsuccessful Drug Withdrawal in the Seizure-Free Patient

Older age at onset Type of seizures Partial Myoclonic Generalized major motor Short duration of seizure freedom Seizures after initial treatment Generalized spike and wave EEG at withdrawal
11

Medical Research Council Antiepileptic Drug Withdrawal Study Group. Lancet. 1991;337:1175-1180.

Non-Predictors of Unsuccessful Drug Withdrawal in the Seizure-Free Patient

Status epilepticus Febrile seizures Focal EEG abnormalities

Medical Research Council Antiepileptic Drug Withdrawal Study Group. Lancet. 1991;337:1175-1180.

12

What About Intractability?

More difficult to study Need to define but has been done only recently
Number of medications Adequate dose Duration of seizures Number of seizures/unit time Type of seizures

Virtually all studies in children

13

Intractability at Initial Diagnosis

470 untreated patients with newly diagnosed epilepsy Intractability defined as failure to become seizure-free for 1 year after failure of 2 anticonvulsant regimens

Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319.

14

Intractability at Initial Diagnosis (contd)

47% of patients were seizure-free as a result of first therapy An additional 13% seizure-free as a result of second therapy 4% seizure-free with third treatment regimen In patients with first treatment failure due to adverse reaction, 50% seizure-free on second drug; in patients with failure at maximal doses, 15% seizure-free on second drug
Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319. 15

Predictors of Intractability
Failure of first drug Symptomatic etiology High number of seizures before initial treatment Family history of epilepsy Psychiatric comorbidity

Kwan P, Brodie MJ. CNS Spectr. 2004;9:110-119.

16

Dutch Cohort
Referrals to 2 university hospitals Well-defined diagnostic criteria
Type of seizures Syndrome Etiology

Consensus diagnosis Diagnostic workup defined, therapy outlined

Arts WF et al. Epilepsia. 1999;40:726-734. Stroink H et al. J Neurol Neurosurg Psychiatry. 1998;64:595-600. 17

Dutch Cohort (contd)

Follow-up at clinic or by phone for those patients who were seizure-free Poor outcome: failure to reach at least 6-month terminal remission Good outcome: remission of 1 year or more

Arts WF et al. Epilepsia. 1999;40:726-734. Stroink H et al. J Neurol Neurosurg Psychiatry. 1998;64:595-600.

18

Dutch Cohort: 2-Year Outcome

466 patients 31% had poor outcome 56% had good outcome Predictor of poor outcome at intake Type of seizures Seizure frequency At 6 months No remission for 3 months Seizure frequency in the 6-month period
Arts WF et al. Epilepsia. 1999;40:726-734. Stroink H et al. J Neurol Neurosurg Psychiatry. 1998;64:595-600. 19

Dutch Cohort: 2-Year Outcome (contd)

Many children not treated 60% of patients seizure-free on first drug 11% never achieved 6-month remission on further follow-up, but feeling is that 7% are truly intractable by these definitions

Arts WF et al. Epilepsia. 1999;40:726-734. Stroink H et al. J Neurol Neurosurg Psychiatry. 1998;64:595-600.

20

Nova Scotia
Population-based series identified from EEG laboratory Exclusions for prognostic studies included progressive disease and only akinetic, myoclonic, absence, or infantile spasms Intractable is defined as trial with patients taking more than 3 drugs and having 1 seizure a month for the last year of follow-up
Camfield C et al. J Pediatr. 1993;122:861-868. 21

Nova Scotia (contd)

Of those patients successfully treated in the first year, 4% intractable If unsuccessful in first year, 29% intractable More likely to have complex partial seizures

Camfield C et al. J Pediatr. 1993;122:861-868.

22

Nova Scotia (contd)

Predictors of remission
<12 years of age Normal intelligence No neonatal seizures <20 seizures before first treatment

Remission: at 1 year after diagnosis, above criteria plus seizure-free from 6 months

Camfield C et al. J Pediatr. 1993;122:861-868.

23

Copparo Series
Incidence cohort
All cases identified over a 20-year period Incidence in children: 86/100,000

Follow-up with medical records and personal follow-up Classification by seizure type and broad syndrome

Casetta I et al. Neuroepidemiology. 1997;16:22-28.

24

Copparo Series (contd)

Intractability defined as monthly seizures for 2 years and failure of 3 antiseizure regimens Interesting exclusions: 3 cases with progressive disease and 45 cases with absence Compared 31 intractable cases with remaining 95 cases in remission

Casetta I et al. Neuroepidemiology. 1997;16:22-28.

25

Copparo Series (contd)

Intractability predicted by
Symptomatic etiology Age of onset: <1 year old High density of seizures before treatment

Significant in univariate
Status at onset Partial seizures

Casetta I et al. Neuroepidemiology. 1997;16:22-28.

26

Copparo Series (contd)

Also evaluated remission in idiopathic and cryptogenic cases Found no predictors among numerous variables

Casetta I et al. Neuroepidemiology. 1997;16:22-28.

27

Connecticut Series
Referrals to pediatric neurologists in the state and selected pediatricians and adult neurologists Well-defined diagnostic criteria Classification by seizure type and syndrome Consensus review

Berg AT et al. Neurology. 2001;56:1445-1452.

28

Connecticut Series (contd)

Review of medical records and telephone followup every 3 months Definition of intractable epilepsy
Monthly seizures for 18 months Failure of 2 antiseizure medications

Good outcome: seizure-free for 1 year

Berg AT et al. Neurology. 2001;56:1445-1452. Berg AT et al. Epilepsia. 2001;42:1553-1562.

29

Connecticut Series (contd)

613 patients 10% meet criteria for intractable epilepsy 74% attain remission (1 year seizure-free), although 24% subsequently relapse

Berg AT et al. Neurology. 2001;56:1445-1452. Berg AT et al. Epilepsia. 2001;42:1553-1562.

30

Frequency of Intractability

Risk (%)

Nonidiopathic (n=415) Overall (n=599)

Idiopathic (n=184)

Berg AT et al. Early development of intractable epilepsy in children: a prospective study. Neurology. 2001;56(11):1445-1452. Reprinted with permission of Lippincott Williams & Wilkins.

Time (mo)

31

Connecticut Series: All Patients (n=613)

Risk Factor Cryptogenic/symptomatic generalized syndrome Log of seizure frequency Focal EEG slowing Other status Idiopathic syndrome Age of onset: 59 years old
Berg AT et al. Neurology. 2001;56:1445-1452.

Rate Ratio 3 1.4 2.3 6 0.2 0.4

32

Relapse After Remission

24% of patients relapsed Of those followed for a mean of 3 years,
60% were again in remission 4% met criteria for intractability

Berg AT et al. Epilepsia. 2001;42:1553-1562.

33

Connecticut Series: Predictors of Relapse After Remission

Risk Factor Idiopathic partial epilepsy Seizure frequency Age of onset <1 y old Never on medication JME EEG focality Rate Ratio 0.3 0.9 0.3 0.2 2.7 2.1

JME=juvenile myoclonic epilepsy.

34

Indeterminate Group at 2 Years

55% of patients in remission at 4 years 8% intractable at 4 years Only 1 child in remission at 2 years was intractable at 4 years

Berg AT et al. Epilepsy Res. 2001;43:75-84.

35

Finnish Studies
Incidence and prevalence series: all patients were <15 years old with recurrent seizures in region over a 3-year period Population-based Personally assessed Excellent follow-up Exclude progressive neurological illness Epilepsy: 3 or more seizures
Sillanp M. Epilepsia. 1993;34:930-936. 36

Finnish Studies (contd)

Intractability defined as at least 1 seizure a year for at least 9 of the preceding 10 years Original sample: 245 patients 178 were followed 40 intractable by above definition compared with remainder of patients

Sillanp M. Epilepsia. 1993;34:930-936.

37

Finnish Studies (contd)

Predictors of intractability
High initial seizure frequency Status epilepticus Symptomatic etiology Poor initial response to medication

Remission in 98% if patients had none of the above; no remission in patients with all 4 of the above
Sillanp M. Epilepsia. 1993;34:930-936. 38

Finnish Studies (contd)

Overall, 74% of patients seizure-free at last follow-up Despite seizure freedom in these patients, social adaptation and job status are less than those of comparison population 36 (15%) of original cohort dead; about half were epilepsy-related

Jalava M et al. Epilepsia. 1997;38:708-715. Sillanp M et al. N Engl J Med. 1998;338:1715-1722.

39

British Birth Cohort Studies

All births for 1 week 1946 1958 1970 For 1958, extensive case findings at 23 years of age Classification of seizures Prognosis Death
40

Kurtz Z et al. BMJ. 1998;316:339-342.

British Birth Cohort Studies: 1958 Cohort

124 patients Incidence: 42/100,000 Prevalence at 23 years of age: 6.3/1000 35% in remission 9 dead; 5 associated with seizures

Kurtz Z et al. BMJ. 1998;316:339-342.

41

What Happens to Intractable Cases?

42

Remission in Intractable Cases

Huttenlocher study: 145 intractable children followed for 5 to 20 years from diagnosis
1.5% per year in those with mental retardation 4% per year in remainder of cohort

Huttenlocher PR, Hapke RJ. Ann Neurol. 1990;28:699-705.

43

Outcome in Intractable Cases

12% of intractable cases entered remission 17% dead

Berg AT et al. Neurology. 2001;56:1445-1452.

44

Summary
Most newly identified cases do well Despite varying definitions of intractability, factors associated with drug resistance or intractability are somewhat consistent and include Syndrome Etiology High density of seizures before treatment (but not high number of seizures) Early response to therapy

45

Summary (contd)
Even those patients who do well in terms of seizure control have problems in other areas
Social adjustment Employment

Those patients who progress to intractable epilepsy have a high mortality rate

46

Summary (contd)
Remission in intractable cases is 3% to 4% per year in adults and children Not necessarily explained by innovative therapies

47

Question and Answer Session

48

Evidence for Progressive Structural and Neuropsychological Abnormalities in Epilepsy

Kimford J. Meador, MD Melvin Greer Professor of Neurology University of Florida McKnight Brain Institute Gainesville, Florida

49

Early Observations
Before the advent of effective anticonvulsants in the mid-19th century, epilepsy was viewed by some as a degenerative brain disease Lennox and Lennox (1960) noted negative impact of lifetime number of seizures on cognition
1471 patients 9% impaired if <10 convulsions 54% impaired if >1000 convulsions
Lennox WG, Lennox MA. Epilepsy and Related Disorders. Boston, Mass: Little, Brown; 1960. 50

Factors Potentially Affecting Progressive Structural or Functional Decline in Epilepsy

Etiology of epilepsy Epilepsy syndrome Seizure type, frequency, and severity Duration of epilepsy Treatments
51

Hippocampal Atrophy and Sclerosis

Hallmark of temporal lobe epilepsy Associated with epilepsy duration, not age of onset1-4

1. Kalviainen R et al. Neurology. 1998;50:1377-1382. 2. Tasch E et al. Ann Neurol. 1999;45:568-576. 3. Theodore WH et al. Neurology. 1999;52:132-136. 4. Jokeit H et al. J Neurol. 1999;246:926-933.

52

Longitudinal Report of Progressive Hippocampal Sclerosis and Atrophy in Epilepsy

32 month-old child with status epilepticus involving left side of body MRI 24 hours post status epilepticus: increased T2 right hippocampus Subsequent CPSs and 3 additional episodes of status epilepticus MRIs at 33 and 37 months of age showed progressive hippocampal atrophy
CPSs=complex partial seizures; MRI=magnetic resonance imaging. Nohria V et al. Epilepsia. 1994;35:1332-1336. 53

Longitudinal Report of Progressive Hippocampal Atrophy1

24 hours post status epilepticus

4 months post status epilepticus

1. Nohria V et al. Magnetic resonance imaging evidence of hippocampal sclerosis in progression: a case report. Epilepsia. 1994;35:1332-1336. Reprinted with permission from Blackwell Publishing Ltd.

54

of Hippocampal Volumes (mm2) in a Patient with Epilepsy

Year 1991* 1992 1996
*

Left Hippocampal Right Hippocampal Volume Volume 2243 1890 1409 2273 1863 1406

First MRI volumes were 2 months after onset of status epilepticus in a 30 year-old woman who developed refractory epilepsy.
55

Wieshmann UC et al. Epilepsia. 1997;38:1238-1241.

Longitudinal Study of Hippocampal Atrophy

12 patients with unilateral temporal lobe epilepsy Repeat MRI at average of 3.4 years (range 2.5 to 5.2 years) Progressive hippocampal atrophy occurred only in patients with temporal lobe epilepsy and continuing seizures
Fuerst D et al. Ann Neurol. 2003;53:413-416. 56

Longitudinal Study of Hippocampal Atrophy

At 41 years of age At 44 years of age Patient had 75 partial seizures and 5 GTCS in 3 years. Onset of seizures was at 2 years of age. GTCS=generalized tonic-clonic seizures.
Fuerst D et al. Hippocampal sclerosis is a progressive disorder: a longitudinal volumetric MRI study. Ann Neurol. 2003;53:413-416. Copyright 2003 American Neurological Association. Reproduced with permission of John Wiley & Sons, Inc. http://www3.interscience.wiley.com/cgi-bin/jabout/76507645/ProductInformation.html

57

Longitudinal Study of Hippocampal Volumes (mm2)

Time 1
Ipsilateral Hippocampal Volumes Seizure-free Continued seizures Contralateral Hippocampal Volumes Seizure-free Continued seizures
Significant change in volume across time. Fuerst D et al. Ann Neurol. 2003;53:413-416.
*

Time 2 Difference

2721 2662

2733 2391

+12 -271*

3697 3717

3678 3661

-19 -56
58

Histological Studies of Temporal Lobe Epilepsy

Dendritic spine density remote from focus reduced with increased epilepsy duration1 Hippocampal neuron density declines further with chronic habitual seizures2-5

1. Multani P et al. Epilepsia. 1994;35:728-736. 2. Mathern GW et al. Brain. 1995;118:105-118. 3. Mathern GW et al. Epilepsy Res. 1995;21:133-147. 4. Mathern GW et al. J Neurosurg. 1995;82:220-227. 5. Mathern GW et al. Epilepsy Res. 1996;26:151-161.

59

PET Hypometabolism in a Patient with Left Temporal Lobe Epilepsy

PET=positron emission tomography. Jokeit H et al. Bilateral reductions of hippocampal volume, glucose metabolism, and wada hemispheric memory performance are related to the duration of mesial temporal lobe epilepsy. J Neurol. 1999;246:926-933. Reprinted with permission of Springer.

60

PET: Temporal Hypometabolism

Predicts seizure outcome from anterior temporal lobectomy1,2 Results from neuronal loss and functional factors Can occur without atrophy Extends beyond seizure focus Associated with epilepsy duration3-5 Uncoupling of blood flow and metabolism increases with epilepsy duration6
1. Theodore WH et al. Ann Neurol. 1992;32:789-794; 2. Radtke RA et al. Neurology. 1993;43:1088-1092; 3. Jokeit H et al. J Neurol. 1999;246:926-933; 4. Spanaki MV et al. Epilepsia. 2000;41:1227-1229; 5. Theodore WH et al. Epilepsia. 2004;45:276-279; 6. Breier JI et al. Neurology. 1997;48:1047-1053. 61

Extratemporal Volume Loss and Hypometabolism in Temporal Lobe Epilepsy

Whole brain volumes are reduced1 Temporal lobe epilepsy thalamic volumes and metabolism are reduced2 Greater thalamic reduction ipsilateral to focus3 Contralateral thalamic hypometabolism predicts poor anterior temporal lobectomy outcome3 Reduced cerebellar metabolism related to epilepsy duration4
1. Lee JW et al. Epilepsia. 1998;39:727-736; 2. Deasy NP et al. Neuroradiology. 2000;42:346-351; 3. Henry TR et al. Arch Neurol. 1993;50:582-589; 4. Sandok EK et al. Epilepsia. 2000;41:1315-1320. 62

Normalization of PET Abnormalities After Successful Temporal Lobe Epilepsy Surgery

Metabolism normalizes in contralateral mesial temporal lobe and in ipsilateral frontal cortex and thalamus1-3

1. Hajek M et al. Neurology. 1994;44:2125-2132. 2. Spanaki MV et al. Arch Neurol. 2000;57:1447-1452. 3. Spanaki MV et al. Epilepsia. 2000;41:1227-1229.

63

Magnetic Resonance Spectroscopy in Temporal Lobe Epilepsy

Magnetic resonance spectroscopy from right and left temporal lobes in patient with right temporal lobe epilepsy. Note lower NAA/Cr on right.

NAA=N-acetylaspartate; Cr=creatine. Kantarci K et al. Comparative diagnostic utility of 1H MRS and DWI in evaluation of temporal lobe epilepsy. Neurology. 2002;58(12):1745-1753. Reprinted with permission of Lippincott Williams & Wilkins.

64

Spectroscopic Abnormalities in Temporal Lobe Epilepsy1-4

Reduced NAA/Cr in temporal lobe epilepsy Ipsilateral > contralateral to focus

1. Hugg JW et al. Ann Neurol. 1993;34:788-794. 2. Cendes F et al. Ann Neurol. 1994;35:211-216. 3. Ende GR et al. Radiology. 1997;202:809-817. 4. Vermathen P et al. Radiology. 2003;226:195-202.

65

Spectroscopy NAA/Cr Correlations in Temporal

Lobe Epilepsy
Interictal temporal lobe epilepsy discharge rates1 Surgical outcome2,3 Memory4-6 Correlation with memory is better than with hippocampal volumes7
1. Park SA et al. Epilepsia. 2002;43:1385-1389; 2. Suhy J et al. Neurology. 2002;58:821-823; 3. Kantarci K et al. Neurology. 2002;58:1745-1753; 4. Martin RC et al. Neurology. 1999;53:2052-2058; 5. Kikuchi S et al. Seizure. 2001;10:188-193; 6. Ferrier CH et al. Neurology. 2000;55:1874-1883; 7. Sawrie SM et al. Epilepsia. 2001;42:1403-1407. 66

Spectroscopy and Hippocampal Volumes in Temporal Lobe Epilepsy

82 patients with refractory temporal lobe epilepsy Duration related to reduced ipsilateral and contralateral NAA/Cr and still significant (r=-.302 ipsilateral and -.316 contralateral) after controlling for age of onset Duration related to reduced ipsilateral hippocampal volume (r=-.399) and still significant (r=-.360 ipsilateral) after controlling for age of onset Early fixed injury with overlaying progressive injury
Tasch E et al. Ann Neurol. 1999;45:568-576. 67

Normalization of Magnetic Resonance Spectroscopic Abnormalities After Temporal Lobe Epilepsy Surgery
NAA/Cr increased to normal range on side of surgery in all seizure-free patients1 NAA/Cr (ipsilateral and contralateral) increased 50% by 6 months and 95% by 25 months in seizure-free patients2 Contralateral hippocampus NAA improved3,4
1. Cendes F et al. Neurology. 1997;49:1525-1533. 2. Serles W et al. Epilepsia. 2001;42:190-197. 3. Hugg JW et al. Ann Neurol. 1996;40:236-239. 4. Vermathen P et al. Neurology. 2002;59:633-666. 68

Identical Twins: One with Epilepsy

Each had a viral infection at 11 months of age Twin 1 had seizures until 2 y/o, then was seizure-free until 12 y/o when taken off primidone Refractory CPS with secondary GTCS Twin 1s FSIQ=79 at 16 y/o Twin 1s FSIQ=66 at 31 y/o
Bilateral Mesial Temporal Sclerosis on MRI

Twin 2 is a college graduate and has an MBA

FSIQ=full scale intelligence quotient; MBA=master of business administration. Meador K, unpublished data, 2004. 69

Identical Twins: Both with Epilepsy

Onset of GTCS
Twin 1 at 5 y/o Twin 2 at 6 y/o

Both with EEGs showing generalized spike-wave discharges Lifetime number of GTCS by 19 y/o
Twin 1: 37 Twin 2: 7

FSIQ at 19 y/o
Twin 1: 64 Twin 2: 86
70 EEG=electroencephalogram. Dodrill CB et al. Arch Neurol. 1976;33:604-607.

Severe Verbal Amnesia Secondary to Seizure Recurrence After Right Anterior Temporal Lobectomy in 2 Patients
Delayed Recall
Patient 1 Patient 2

Recognition
Patient 1 Patient 2

Pre-op 3 months postop Post status epilepticus/ flurry

(9 and 4 months after seizure, respectively)

5 3 0

5 8 1

10 3 -4

13 14 -2

Dietl T et al. Epilepsy Behav. 2004;5:394-400.

71

Cross-Sectional Neuropsychological Studies in Epilepsy Patients

Relationship of Epilepsy Duration and Mental Deterioration Strong Moderate Lennox and Lennox (1960) Dodrill and Troupin (1976) Dodrill (1986) Hermann et al (2002) Oyegbile (2004) Mild Trimble (1988) Jokeit (1999) Dikman and Matthews (1977) Jokeit and Ebner (1999) Jokeit et al (2000)

None for duration but present for age of onset Strauss (1995) Helmstaedter and Elger (1999)
72

Cross-Sectional Neuropsychological Study in Unilateral Temporal Lobe Epilepsy

209 patients FSIQ of WAIS-R Multiple regression Duration of epilepsy: =-.195, P<.01 Education: =.543, P<.01 IQ for patients with >30 years duration was worse than for patients with 15 to 30 years and with <15 years duration IQ for patients with 15 to 30 years duration and with <15 years duration did not differ
73

WAIS-R=Wechsler Adult Intelligence Scale-Revised (1981). Jokeit H et al. J Neurol Neurosurg Psychiatry. 1999;67:44-50.

Cross-Sectional Neuropsychological Study in Temporal Lobe Epilepsy

Early Onset Late Onset Healthy Controls

n FSIQ

37 90*

16 100

62 107

FSIQ and duration (r=-.40, P<.01) MRI volumes: early < late onset patients for temporal, frontal, parietal, and occipital lobes, especially for white matter
FSIQ for early onset patients < late onset patients or healthy controls. Hermann B et al. Epilepsia. 2002;43:1062-1071.
*

74

Cross-Sectional Neuropsychological Study in Temporal Lobe Epilepsy

96 patients with temporal lobe epilepsy 82 healthy controls After adjustment for age, gender, and education, patients with temporal lobe epilepsy worse for IQ, memory, language, executive function, and motor speed Duration of epilepsy correlated with number of abnormal test scores: r=.42, P<.001 Especially evident in those with less education

Oyegbile TO et al. Neurology. 2004;62:1736-1742.

75

Neuropsychological Studies in Nonsurgical Temporal

Lobe Epilepsy
Year 19941 19982 20003 20014 20015 20036 n 28 25 47 20 17 102 Interval 18 yrs 210 yrs 5 yrs 6 yrs 210 yrs sl + -Verbal and VS IQ sl + Memory Unchanged Unchanged -VS sl +

10 yrs sl + PIQ

Sl + =slightly improved; PIQ=performance intelligence quotient; VS=visual-spatial. 1. Selwa LM et al. Epilepsia. 1994;35:743-749; 2. Holmes MD et al. Epilepsia. 1998;39:1189-1193; 3. Helmstaedter C et al Nervenarzt. 2000;71:629-642; 4. Aikia M et al. Epilepsy Behav. 2001;2:20-27; 5. Bjornaes H et al. Seizure. 2001;10:250-259; 76 6. Helmstaedter C et al. Ann Neurol. 2003;54:425-432.

Longitudinal Study of Cognition in Chronic Temporal Lobe Epilepsy

102 patients with nonsurgical temporal

lobe epilepsy

Follow-up for 2 to 10 years % of Patients With Loss or Gain* Loss Memory function 50% Gain 12%

Executive function 28% 22% * Losses were primarily in patients who were not seizure-free. Losses were associated with seizure frequency and severity. 77
Helmstaedter C et al. Ann Neurol. 2003;54:425-432.

Repeated Brief Seizures in Rats

Olfactory bulb kindled rats and controls 0 to 136 generalized seizures (Class V) Spatial memory deficit after 30 generalized seizures or 40 afterdischarges Progressive decline in memory with increasing number of seizures Neuronal loss in hippocampus
Kotloski R et al. Prog Brain Res. 2002;135:95-110. 78

Conclusions
Chronic uncontrolled epilepsy appears to produce progressive structural and cognitive impairments Need for additional long-term studies Need to understand mechanisms
eg, genetic susceptibility

Ultimate goal is seizure freedom and prevention of additional brain damage

79

Question and Answer Session

80

Do Antiepileptic Drugs Alter the Course of Epilepsy?

Jacqueline A. French, MD Co-Director, Penn Epilepsy Center Professor of Neurology University of Pennsylvania Hospital of the University of Pennsylvania Department of Neurology Philadelphia, Pennsylvania

81

Patient Example
25-year-old male presents after having 2 GTCS History reveals several probable CPS over last year MRI shows left MTS Will selection of AED have any impact on Long-term course of disease Likelihood of complete remission Likelihood of seizure worsening Long-term neuropsychological function
GTCS=generalized tonic-clonic seizure(s); CPS=complex partial seizure(s); MRI=magnetic resonance imaging; MTS=mesial temporal sclerosis; AED=antiepileptic drug. 82

How AEDs Could Negatively Alter Course of Disease

Might treat seizure, but not epilepsy Might alter future AED response
Resistance
Multiple drug resistance gene-1

Cross-tolerance

Might be neurotoxic
Memory

83

How AEDs Could Positively Alter Course of Disease

Might be neuroprotective
Antiepileptogenesis Protect against CNS deterioration
Neuropsychological testing MRI

CNS=central nervous system.

84

Can We Answer the Question?

Animal models Clinical trials

85

AED Resistance: P-glycoprotein

P-glycoprotein pump
Can export planar, hydrophobic molecules from neuroectodermal cells1

AEDs may be exported back to endothelial cells, then to vascular space, decreasing CNS concentrations
Phenytoin, carbamazepine, phenobarbital substrates Substrates often upregulate proteins

1. Tishler DM et al. Epilepsia. 1995;36:1-6.

86

AED Resistance: P-glycoprotein (contd)

PB: piriform cortex

PB=phenobarbital.

No PB

PB

Intensity Score Endothelium parenchyma

Labeled Area

Reprinted from Eur J Pharmacol, Vol 451, Seegers U et al, Lack of effects of prolonged treatment with phenobarbital or phenytoin on the expression of P-glycoprotein in various rat brain regions, 149-155, Copyright 2002, with permission from Elsevier.

No PB

PB

No PB

PB
87

Modulation of Future AED Effect (Cross-Tolerance)

LTG administered to kindled rats
Robust suppression of kindled seizures; increased seizure threshold

High-dose LTG administered before each kindling stimulation

LTG no longer suppressed kindled seizures1 CBZ no longer suppressed kindled seizures!2

LTG=lamotrigine; CBZ=carbamazepine. 1. Postma T et al. Epilepsia. 2000;41:1514-1521. 2. Krupp E et al. Exp Neurol. 2000;162:278-289.

88

Control of Seizures, Not Epilepsy

Limbic status induced by sustained electrical stimulation in rats
Effect on Status
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 PB MK- 000 PHT Control

Effect on Development of Epilepsy

00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

% Rats w/EEG Suppression

PHT=phenytoin; EEG=electroencephalogram.
Adapted from Prasad A et al. Phenobarbital and MK-801, but not phenytoin, improve the long-term outcome of status epilepticus. Ann Neurol. 2002;51:175-181. Copyright 2002 American Neurological Association. Reproduced with permission of John Wiley & Sons, Inc. http://www3.interscience.wiley.com/cgi-bin/jabout/76507645/ProductInformation.html

PB

M K000 PHT 0hour 0hour 0hour

Control

89

How Will We Know If AEDs Have an Impact?

Can we conduct studies to determine long-term effect of AEDs?
Animal Human

90

Seizure Frequency Over Time

0 00 .

00 .

% Change From Baseline (x100) % Change From Baseline (x000 )

00 .

00 .

0 .0 0 .0 0 .0 0 .0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Time (mo)

St ar td

Patient 1 Patient 2 Patient 3 Patient 4

ru g

91

Causes of Worsening or Improvement

Noncompliance Addition or removal of medications Spontaneous exacerbation or remission How can we sort out long-term AED effect? Randomization Stability
92

Active Controlled Comparison in the Newly Diagnosed Patient

Treatment B

Treatment A Titration Treatment (4252 weeks)

93

Active Controlled Trials in the Newly Diagnosed Patient

Advantage: randomization between 2 active treatments and treatment is stable for up to 1 year If new AEDs alter course of disease, how would that be reflected in outcome?
Shape of Kaplan-Meier curve: look for differences Statistical assessment of exits during different time periods (first 3 months versus last 3 months)

94

Analysis for Tolerance in Active Controlled Trials

% of Patients Seizure-Free

LTG CBZ LTG vs CBZ*

Days From Start of Study

Active control equivalence trial in newly diagnosed patients Reprinted with permission from Elsevier (The Lancet, 1995, Vol 345, 476-479).
*

95

Randomized Controlled Trials in Refractory Patients

Advantage Randomized, very stable Can look at the effect of addition of drug versus customary care Disadvantage Too short! Can assess only early effects Best methodology Seizure-free days
96

Seizure-Free Days: Levetiracetam (LEV)

Seizure-Free Days per Year Adjusted to Baseline 3-Day Period, Pooled Data
70 60 50 70

Placebo
Seizure-Free Days

60 50 40 30 20 10 0

LEV

Seizure-Free Days

40 30 20 10 0 -10 -20 -30 -40 -50 -50-40-30-20-10 0 10 20 30 40 50 60 70 80 90100

-10 -20 -30 -40 -50 -50-40-30-20-10 0 10 20 30 40 50 60 70 80 90100

No. of Days to/From First Uptitration Day

French J et al. Neurology. 2000;54(suppl 3):A83. Abstract. Reprinted with permission of Lippincott Williams & Wilkins.

No. of Days to/From First Uptitration Day97

Long-Term Follow-Up Studies

Disadvantages No control group Addition or subtraction of AEDs other than study drug permitted Patients with poor response leave the study; responders remain Advantages Very long-term (up to 15 years) follow-up on single AED Seizure calendars maintained AED changes tracked
98

GBP Long-Term Analysis: Patients Remaining in Study for at Least Six 12-Week Periods

GBP=gabapentin.
Reprinted from Epilepsy Res, Vol 18, The US Gabapentin Study Group, The long-term safety and efficacy of gabapentin (Neurontin) as add-on therapy in drug-resistant partial epilepsy, 67-73, Copyright 1994, with permission from Elsevier.

99

GBP Long-Term Analysis: All Evaluable Patients

Reprinted from Epilepsy Res, Vol 18, The US Gabapentin Study Group, The long-term safety and efficacy of gabapentin (Neurontin) as add-on therapy in drug-resistant partial epilepsy, 67-73, Copyright 1994, with permission from Elsevier.

100

LEV Exposure
Still treated: 562/1422 Retention rate: 40% Duration of exposure (d)
Mean: 622 Median: 399 Range: 12984

Patient-years: 2421
Ben-Menachem E et al. Epilepsy Res. 2003;53:57-64. 101

LEV: Long-Term Outcome

-00 Median % Change From Baseline
Median % Change From Baseline

-00 -00 -00 -00 -00 -00

0 0 0 44 0 0 0

44

0 0 0 000000004 4 4 000000000000 0 0 0 0 0 0 0 0 0 0 0 0 0

Summary Visits (wk)

0mo (n=0 0 ) 00 0 mo (n=0 0 0 0) 0 mo (n=0 0 0 0) 0 mo (n=0 0 0 0) 0 mo (n=0 0 0 0) 0 mo (n=0 0 0 0) 0 mo (n=0 0 0 0) 0 mo (n=0 0 0 0) 0 mo (n=0 0 0 0)

Reprinted from Epilepsy Res, Vol 53, Ben-Menachem E et al. Evidence for sustained efficacy of levetiracetam as add-on epilepsy therapy, 57-64, Copyright 2003, with permission from Elsevier.

102

ZNS: Long-Term Outcome

Median % Change From Baseline

Summary Visits (wk)

6 mo (n=226) 24 mo (n=164) 42 mo (n=121) 12 mo (n=192) 30 mo (n=152) 48 mo (n=113) 18 mo (n=179) 36 mo (n=131) 54 mo (n=104)

French JA. Epilepsia. 2002;43(suppl 7):241. Abstract. Reprinted with permission from Blackwell Publishing Ltd.

103

Alternate Analysis
Calculate seizure frequency for all patients for first 3 months at initial target dose Compare with seizure frequency during last 3 months on drug Include all patients, irrespective of reason for discontinuation (loss of efficacy, alternative treatment, or study termination)

104

ZNS: Preliminary Long-Term Data

Seizure outcomes were assessed for the following time points
Baseline seizure rate (BSR)
Seizure rate during baseline

ZNS initial seizure rate (ZISR)

Seizure rate for 3 months after ZNS target dose achieved

ZNS terminal seizure rate (ZTSR)

Seizure rate during last observed 3 months on ZNS treatment

ZNS=zonisamide. French JA et al. Epilepsia. 2002;43(suppl 7):241. Abstract.

105

Seizure Outcome
ZTSR demonstrated a median partial seizure reduction of 69.9% from BSR and a median reduction of 22.2% from ZISR ZTSR was higher than BSR in only 13.6% of patients 25 of 79 patients (31.7%) completing the long-term extension protocol successfully were seizure-free for the last 3 months on ZNS

French JA et al. Epilepsia. 2002;43(suppl 7):241. Abstract.

106

Long-Term Improvement
Does this mean disease modification? Do patients with refractory epilepsy improve over time? Natural history of disease is unknown!

107

What About MRI/Neuropsychological Testing?

Many confounders in humans!
Initial insult Seizure frequency Drug changes
Different drugs Different doses

Makes analysis almost impossible

108

Can We Address the Effect of Disease Progression in Animals?

Advantages
Always compliant Fewer confounders Could randomize treatments

109

Can We Address the Effect of Disease Progression in Animals? (contd)

Disadvantages
Are animal models sufficiently similar to human condition? Very difficult to monitor long-term for chronic seizures

2 sz 3 sz
110

Conclusion
Newly diagnosed patients: need to define methodology for analyzing active controlled trials Refractory epilepsy: no ideal methodology

Must analyze all trials with similar methodology

Must determine natural history of refractory epilepsy
111

Question and Answer Session

112

Concluding Remarks
Jacqueline A. French, MD (Chair) Co-Director, Penn Epilepsy Center Professor of Neurology University of Pennsylvania Hospital of the University of Pennsylvania Department of Neurology Philadelphia, Pennsylvania
113