Progress in Nonepileptic Seizures

(NES) Research Benchmarks 2 December 2011

W. Curt LaFrance, Jr., MD, MPH

Director, Neuropsychiatry and Behavioral Neurology

Rhode Island Hospital

Asst. Prof. Psychiatry & Neurology (Research)

Brown Medical School

American Epilepsy Society | Annual Meeting

Disclosure

Name of Commercial

Interest

NINDS, AES, EF,

Siravo Foundation

Cambridge University Press

Type of Financial

Relationship

Grant support

Editor’s royalties for Nonepileptic Seizures, 2010

American Epilepsy Society | Annual Meeting

LaFrance 2011

Benchmarks Area III: Prevent, limit, and reverse the co-morbidities

associated with epilepsy and its treatment.

E. Develop effective methods for diagnosis, treatment and prevention of NES.

Short-term goals include:

1. Determine types and frequency of NES in general population and in epilepsy.

2. Identify common susceptibility factors and etiologies for NES.

3. Validate at least one effective treatment for NES.

(Kelley et al. Epilepsia 2009;50(3):579-582.)

Learning Objectives:

Progress in NES Benchmarks

• Recognize nonepileptic seizures (NES)

• Refer patients with NES for appropriate treatment

• Restore quality of life for patients with NES

American Epilepsy Society | Annual Meeting

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Nonepileptic Seizures (NES) Prevalence & Cost

• 5-20% of the 2.5 million people treated for Epilepsy

have nonepileptic seizures (NES).

• 20-50% of SMU admissions have NES

• up to 40% of patients in general neurology clinics

• up to 20% status epilepticus pts have “NES-status”

• Lifetime cost of treating NES for individual patient

$100,000

• Annual cost of repeated labs, diagnostic work-ups,

AEDs, outpt visits, ER visits in US= $900,000,000

(Martin, 1998; Pakalnis, 2000; Benbadis, 2004)

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Interdisciplinary NES Research

(LaFrance, et al. E&B. 2006;8:451-461)

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Physiologic Nonepileptic Events

(different than psychogenic NES)

(Gates J, in: Psychiatric Comorbidity in Epilepsy, Eds: McConnell & Snyder. 1998, p.192)

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NES, Tremor and Gait Disorder

(Schachter & LaFrance, Eds. Nonepileptic Seizures, 3rd Ed, 2010)

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Demographic Data:

NES and Epileptic Groups NES

N = 31

Epileptic

N = 31

Age (yrs) 36.7 37.2

Gender (male : female) 11 : 20 10 : 22

Marital status (% married) 61 45

Employment status (% employed) 45 45

Education (% with HS or greater) 61 77 Income Source Government assisted Supported by family

42

22

48

6

Seizure frequency (% with >12 seizures/year) 77 77

(Krawetz, et al. J Nerv Ment Disord. 2001; 189:38-43)

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NES: Ictal Characteristics Description (n=33)

Generalized trembling, jerking, uncoordinated movements;

nonresponsive

9

Staring; nonresponsive 5

Generalized tremor, jerking; responsive 5

Lightheaded, dizzy, faint, weak; nonresponsive 3

Confusion, slowing, lethargy, slurred speech; responsive 3

Falling episodes; responsive 3

Generalized stiffening; nonresponsive 2

Coordinated, complex violent behavior; responsive 2

Unilateral jerking; nonresponsive 1 (Rusch, M, et al. E&B 2001;2:277-83)

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Diagnosing Seizures: Clinical &

EEG Findings Epileptic Seizures

Characteristics

Generalized

tonic-clonic

seizures

Complex partial

seizures

Nonepileptic

Psychogenic

seizures

EEG during

seizure

Abnormal and

changed from

preictal

Almost always

abnormal and

changed from

preictal

Usually normal

and unchanged

from preictal

EEG

immediately

after seizure

Almost always

abnormal and

changed from

preictal

Frequently

abnormal and

changed from

preictal

Usually normal

and unchanged

from preictal

(Desai, 1982)

(Syed, et al,. Annals of Neurology. 2011)

IRR: The kappa statistic for interrater reliability of VEEG diagnosis was 0.94

(95% CI, 0.77– 1.00) at subject-level, indicating „„excellent‟‟ agreement .

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Prediction of NES prior to vEEG

“The rule of 2‟s”

• At least 2 events per week

• Refractory to at least 2 antiepileptic drugs

• At least 2 EEGs without epileptiform

abnormalities

- yielded 85% positive predictive value

Davis BJ. European Neurology. 2004;51:153-6

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Biomarkers: BDNF in NES and Epilepsy vs. HCs

LaFrance, et al. Neurology. 2010. (Siravo Foundation)

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Biomarkers:

Stress, Hippocampus and Depression

(Duman. Biol Psy. 2006;59:1116-27)

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NES Outcome Studies: Overview

(Reuber, 2003)

Study Study Group Outcome

N = 16 Number

Of

Subjects

Mean

Follow-up

(months)

NES E

included

%

PNES-

free

% Living

independently

% PNES

on AEDs

at FU

Range 13 – 164 12 – 60 -6 & +10 25 – 58 25 – 58 18 – 44

Mean 58.6 38.6 NA 36.8 36.0 30.0

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Quality of Life and Epilepsy:

AED Side Effects, Depression and Seizures

(Gilliam. Neurology. 2002:58(8Supp8):S9-20)

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Quality of Life and Nonepileptic Seizures: Symptoms, Depression and Seizures

(LaFrance and Syc. Neurology. 2009:73(5):366-371)

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(Richer, 1881)

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Class of Study

I II III IV Study Characteristic

Control Group

Representative Population

Prospective Design

Assessment Independent of Rx

Blinded Outcome Assessment

Yes No

Randomized *

* Also meets standards of:

• Primary outcomes defined;

• Exclusion/inclusion criteria defined;

• Dropout rate low and accounted for;

• Baseline characteristics detailed and substantially equivalent.

Evidence Based Outcomes: Classifications

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Historical and Future Approaches to NES:

Treatments Review

(LaFrance & Devinsky. Epilepsia. 2004;45(sup2):15-21)

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NES Treatment Studies Review 24 publications in total

• 13 of which were case reports/case series

• 7 chart reviews or phone call follow-up

• 4 prospective, uncontrolled trials

(all but 2 were class IV reports)

• No double blind, prospective, fully-powered

randomized controlled trials (LaFrance & Devinsky. Epilepsia. 2004;45(sup2):15-21)

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Predisposing

Precipitating

Perpetuating

Functional Weakness (or NES)

Genetic

Biological

Modelling Childhood

adversity

Psychological Social

Injury

Disease

Life events

(Home / Work)

Emotional

disorder

Deconditioning

CNS Plasticity?

Reinforcement

of illness

(family,

money,

doctors)

Emotional

disorder

Illness beliefs

(LaFrance & Bjørnæs, NES. 2010, adapted Jon Stone, PMD conference, 2003)

What causes functional weakness?

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Standard Medical Care for NES

(LaFrance et al. E&B 2008;12:388-94.)

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Treatment of NES Trials • 8 week, open label pharmacologic trial

• 14 week, double blind, pilot randomized placebo-controlled trial for psychogenic NES

• Psychotherapy trial for NES – 14 week pilot trial of Cognitive Behavioral Therapy for NES

• Multi-center pilot RCT for NES

• Multi-center NES RCT U01 proposal (submitted)

(NINDS 5K23-NS, EF ,AES; PI: LaFrance)

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Pilot Pharm RCT for NES: Seizure frequency

LaFrance et al. Neurology. 2010; 75(13):1166-73 (NINDS K23)

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Treatments: CBT for NES

(LaFrance et al. E&B 2009;14(4):591-596.)

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Figure 1. Seizure frequency per week at baseline,

month 1, and final visit

11.8

4

0

7.1

17.2

10.9

7

4

0

2

4

6

8

10

12

14

16

18

20

Pre

-enr

ollmen

t

at w

eek

1

at M

onth 1

at F

inal w

eek

Time

Seiz

ure

Fre

qu

en

cy

(per

week)

Mean Seizure

Frequency

Median Seizure

Frequency

(LaFrance et al. E&B 2009;14(4):591-596.)

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NES Psychotherapy trial Assessment Ratings at Baseline and Completion (N = 21; Locf) mean (sd)

scale cutoffs Baseline Completion

• Modified Hamilton Depression Scale [<7] 14 (7) 11 (7)

• Beck Depression Inventory-II [<14] 19 (15) 10 (7)*

• Davidson Trauma Scale [<17] 58 (38) 36 (27)*

• Barrett Impulsivity Scale [<70] 63 (14) 60 (9)*

• Dissociative Experiences Scale [<5] 13 (12) 8 (6)

• Symptom Checklist 90 [<85] 94 (77) 62 (52)*

• Global Assessment of Functioning* [>80] 50 (7) 59 (12)*

• Oxford Handicap Scale [<2] 3.3 (1) 3.5 (1.2)*

• QOLIE-31* [>63] 46 (24) 62 (19)*

• Fam Assess Device: Gen Fxn Scr [<2.00] 2.03 (.57) 1.66 (.4)*

• LIFE-RIFT (QoL measure) [<9] 12.9 (4) 11 (3.7)*

• NES frequency during trial (Biweekly sum) 17 (23) 7 (14)*

• NES Frequency (median) 7 0

*p<0.05

(LaFrance et al. E&B 2009;14(4):591-596.)

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NES Pilot Treatment Trials

• NES patients are symptomatic on a number of fronts

Hamilton Depression Scale; Symptom Checklist; Dissociative Experiences Scale; Family Assessment Device

• NES randomized treatment trials are feasible

NES Cognitive Behavioral Therapy; NES Pharmacotherapy Trial

• Neuropsychiatric patient clinical research requires solutions that are complex, global, and multi-disciplinary

Neuropsychiatrist, Epileptologist, Psychologist, Biostatistician

(LaFrance et al. AES Abstract Epilepsia 2008)

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Systems approach to management of seizures

(LaFrance & Devinsky. Epilepsy and Beh. 2002;3(5) S19-23)

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Future Directions: NES Programmatic Research

• NES Diagnosis

NES SCID module

NES comorbidities

• NES Etiology

Functional Neuroimaging / Neurophysiology / Genetics

• NES Treatment(s)

Pharmacologic

Psychotherapy(ies)

Combined Treatments

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LaFrance 2011 (Kerr and ILAE NP commission. Epilepsia, 2011;52:2133-8)

Impact on Clinical Care and Practice

Summary

Video EEG is the Gold Standard for NES Diagnosis

Promising treatments exist for NES; fully powered

RCTs are needed

Assessing comorbidities and quality of life are

important components along with addressing seizures

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Acknowledgements Brown Psychiatry & Neurology

Ivan Miller PhD

Andrew Blum MD, PhD

Christine Ryan PhD

Gabor Keitner MD

Rhode Island Hospital staff

Anita Curran

Anne Frank Webb

Joan Kelley

NINDS Staff

Brandy Fureman, PhD

NES Consultants

Orrin Devinsky MD

Michael Trimble MD

NINDS Intramural Collaborators

Valerie Voon MD

Mark Hallett MD

Funding

NINDS K-23

NIMH T-32

American Epilepsy Society

Epilepsy Foundation

Rhode Island Hospital

Siravo Foundation

Other

Bio-Logic Systems Corporation

Andrews-Reiter Epilepsy Research Program

Patients and their families