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 Type of Financial Relationship NINDS, AES, EF, Siravo Foundation Grant support Cambridge University Press Editor s royalties for Nonepileptic Seizures, 2010 American Epilepsy Society Annual Meeting
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
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)
Interdisciplinary NES Research (LaFrance, et al. E&B. 2006;8:451-461)
Physiologic Nonepileptic Events (different than psychogenic NES) (Gates J, in: Psychiatric Comorbidity in Epilepsy, Eds: McConnell & Snyder. 1998, p.192)
NES, Tremor and Gait Disorder (Schachter & LaFrance, Eds. Nonepileptic Seizures, 3 rd Ed, 2010)
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 42 48 Supported by family 22 6 Seizure frequency (% with >12 seizures/year) 77 77 (Krawetz, et al. J Nerv Ment Disord. 2001; 189:38-43)
NES: Ictal Characteristics Description (n=33) Generalized trembling, jerking, uncoordinated movements; nonresponsive 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 9 (Rusch, M, et al. E&B 2001;2:277-83)
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)
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. (Syed, et al,. Annals of Neurology. 2011)
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
Biomarkers: BDNF in NES and Epilepsy vs. HCs LaFrance, et al. Neurology. 2010. (Siravo Foundation)
Biomarkers: Stress, Hippocampus and Depression (Duman. Biol Psy. 2006;59:1116-27)
NES Outcome Studies: Overview Study Study Group Outcome N = 16 Number Of Subjects Mean Follow-up (months) NES E included % PNESfree % 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 (Reuber, 2003)
Quality of Life and Epilepsy: AED Side Effects, Depression and Seizures (Gilliam. Neurology. 2002:58(8Supp8):S9-20)
Quality of Life and Nonepileptic Seizures: Symptoms, Depression and Seizures (LaFrance and Syc. Neurology. 2009:73(5):366-371)
(Richer, 1881)
Evidence Based Outcomes: Classifications Study Characteristic Class of Study I II III IV Control Group Representative Population Assessment Independent of R x Blinded Outcome Assessment Prospective Design Randomized * * Also meets standards of: Yes No Primary outcomes defined; Exclusion/inclusion criteria defined; Dropout rate low and accounted for; Baseline characteristics detailed and substantially equivalent.
Historical and Future Approaches to NES: Treatments Review (LaFrance & Devinsky. Epilepsia. 2004;45(sup2):15-21)
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)
What causes functional weakness? Biological Psychological Social Predisposing Genetic Childhood adversity Modelling Precipitating Injury Disease Emotional disorder Life events (Home / Work) Functional Weakness (or NES) Perpetuating Deconditioning CNS Plasticity? Emotional disorder Illness beliefs (LaFrance & Bjørnæs, NES. 2010, adapted Jon Stone, PMD conference, 2003) Reinforcement of illness (family, money, doctors)
Standard Medical Care for NES (LaFrance et al. E&B 2008;12:388-94.)
Treatment of NES Trials 8 week, open label pharmacologic trial 14 week, double blind, pilot randomized placebocontrolled 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)
Pilot Pharm RCT for NES: Seizure frequency LaFrance et al. Neurology. 2010; 75(13):1166-73 (NINDS K23)
Treatments: CBT for NES (LaFrance et al. E&B 2009;14(4):591-596.)
Seizure Frequency (per week) Figure 1. Seizure frequency per week at baseline, month 1, and final visit 20 18 17.2 16 14 12 10 8 10.9 7 11.8 7.1 Mean Seizure Frequency Median Seizure Frequency 6 4 4 4 2 0 Pre-enrollment at week 1 at Month 1 Timeat Final week 0 (LaFrance et al. E&B 2009;14(4):591-596.)
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.)
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)
Systems approach to management of seizures (LaFrance & Devinsky. Epilepsy and Beh. 2002;3(5) S19-23)
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
(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
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