www.elsevier.com/locate/yebeh

Epilepsy & Behavior 8 (2006) 451–461

Review

Nonepileptic seizures treatment workshop summary q

W. Curt LaFrance Jr. *, Kenneth Alper, Debra Babcock, John J. Barry, Selim Benbadis,Rochelle Caplan, John Gates, Margaret Jacobs, Andres Kanner, Roy Martin,

Lynn Rundhaugen, Randy Stewart, Christina Vert (for the NES TreatmentWorkshop participants1)

Brown Medical School, Departments of Neurology and Psychiatry, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA

Received 28 January 2006; accepted 3 February 2006Available online 15 March 2006

Abstract

In May 2005, an international, interdisciplinary group of researchers gathered in Bethesda, MD, USA, for a workshop to discuss thedevelopment of treatments for patients with nonepileptic seizures (NES). Specific subgroup topics that were covered included: pediatricNES; presenting the diagnosis of NES, outcome measures for NES trials; classification of NES subtypes; and pharmacological treatmentapproaches and psychotherapies. The intent was to develop specific research strategies that can be expanded to involve a large segment ofthe epilepsy and psychiatric treatment communities. Various projects have resulted from the workshop, including the initial developmentof a prospective randomized clinical trial for NES.� 2006 Elsevier Inc. All rights reserved.

Keywords: Nonepileptic seizures; Somatoform disorders; Conversion disorder; Treatment; Clinical trials; Pharmacotherapy; Psychotherapy

1. Introduction

Psychological nonepileptic seizures (NES) are neuropsy-chiatric disorders that present with a combination of neu-rological signs and underlying psychological conflicts andwithout associated epileptogenic pathology. For more thana century, the medical community has accumulated a sub-stantial amount of data on and insights into the phenom-enology, epidemiology, risks, comorbidities, and prognosisof NES. The use of intensive video/electroencephalogra-phy (video/EEG) monitoring has also increased our

1525-5050/$ - see front matter � 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.yebeh.2006.02.004

q This paper is dedicated to the memory of Dr. John Gates, who wasinstrumental in the first two NES workshops, and who has contributedgreatly to our understanding of NES in the past two decades.

* Corresponding author. Fax: +1 401 444 3298.E-mail address: William_LaFrance_Jr@Brown.edu (W.C. LaFrance

Jr.).1 Committee members and participants are listed at the end of this

article under Acknowledgments.

knowledge of NES. For example, we know that NES areoften unresponsive to conventional treatments and canhave devastating health and social consequences. The caus-es of NES are thought to be multifactorial, and result froma combination of developmental and environmentalinsults, though no specific pathophysiological (e.g., ani-mal) model exists. Currently, progress is being madetoward understanding the comorbid psychiatric diagnosesand neuropsychological characteristics of patients withNES. However, the lack of biological models, clear diag-nostic classifications, and rigorously validated interven-tions continues to have a negative impact on treatmentdevelopment. Thus, there is a great need for interdisciplin-ary collaboration to address the issue of approach totreatment.

Conceptually, as the disciplines of neurology and psy-chiatry are being reunified, a joint perspective of mind/brain interactions is regaining prominence. The ‘‘Decadeof the Brain’’ brought great therapeutic advances for manyneuropsychiatric disorders. However, NES still occupy the

452 W.C. LaFrance Jr. et al. / Epilepsy & Behavior 8 (2006) 451–461

gap between neurology and psychiatry, and treatmentremains poorly studied. Despite our knowledge, we havenot progressed much beyond anecdotal reports of treat-ments for NES, and no blinded, randomized, controlledtrials of treatment for the disorder have been completed.The purpose of the NES Treatment Workshop was to stim-ulate future research in this understudied area.

The workshop, which took place in Bethesda on May 1–3,2005, was sponsored by the National Institute ofNeurological Disorders and Stroke (NINDS), the NationalInstitute of Mental Health (NIMH), and the American Epi-lepsy Society (AES). Participants included a multidisciplin-ary group of neurologists, psychiatrists, neuropsychiatrists,psychologists, neuropsychologists, statisticians, nurses,and other health researchers familiar with NES, whose focuswas to propose a research agenda for NES treatment trials.This effort built on the two NES conferences organized byDr. John Gates and the NINDS in the 1990s, held in FortLauderdale and Bethesda. Results of these workshops yield-ed information on diagnosis, neurological and psychiatriccomorbidities, and psychological functioning in patientswith NES, which was subsequently published in a booknow in its second edition [1]. The goal of the current work-shop was to lay the groundwork for optimizing NES treat-ment strategies and clinical trial designs.

Goals of the workshop included:

characterization of diagnostic and treatment models of

NES;assessment of the potential efficacy of therapies in indi-vidual patients by examining past treatment reports andpilot trials for NES;establishment of a collaborative network that enablesinvestigators to design and implement controlled treat-ment trials for NES.

As a means of focusing discussion, the meeting beganwith a brief presentation by the organizers as to workshopobjectives:

A history of ‘‘psychogenic’’ diagnoses

A brief overview of diagnostic classification in NESA review of treatment studies in NES: progress andobstaclesAn overview of pharmacology and psychotherapy inNES in adults and children: strategies for treatmentdevelopmentA review of clinical trials in behavioral disorders rele-vant to NES

These introductory lectures provided a framework forthe discussion groups that followed. Each group was askedto use three questions to guide their discussions: (1) Whatdo we know about existing treatments for NES? (2) Whatdo we need to know about NES to develop better treat-ments? (3) How do we achieve the goal of effective, scientif-ically validated treatments for NES?

2. NES treatment workshop group task

The goal of the workshop as a whole was to reviewissues and generate testable research hypotheses. Prior tothe meeting, participants were organized into fivesubgroups:

Pediatric SubgroupPresenting the Diagnosis of NES Subgroup

Classification SubgroupOutcome Measurement SubgroupNES Treatment Trial Subgroup

Each subgroup was charged with identifying the majorproblems and questions most relevant to NES treatmentin its topic area, and recommending strategies for address-ing the areas. The major issues and recommendations fromeach subgroup are now summarized.

3. Pediatric NES subgroup summary

3.1. Background

A pediatric subgroup was included because of develop-mental changes in NES characteristics, and because evenless information is available about the disorder in children.

From the developmental perspective, there are differenc-es in the incidence, etiology, clinical presentation, treat-ment, and outcome of NES in younger compared witholder patients [1]. Thus, children who experience nonepi-leptic events have a wide range of seizurelike manifesta-tions [1–4] that vary by age [1]. In children younger than5, these include physiological nonepileptic events, includingstereotyped movements, hypnic jerks, parasomnias, andSandifer syndrome [1–4], as opposed to psychologicalNES, which are noted to occur after age 6. In children aged5–12, NES might be an expression of a psychogenic conver-sion disorder, inattention or daydreaming, stereotypedmovements, hypnic jerks, and paroxysmal movement disor-ders. However, in adolescents, conversion disorder is themain diagnosis underlying NES [1]. In addition, comorbidepilepsy is more commonly reported in younger childrenwith NES than in older children or adults with NES. For-ty-eight percent of children with NES under the age of 5 havecomorbid epilepsy, whereas only 25% of those aged 5–12years and 19% of adolescents do so [1]. It was noted that inchildren of all ages, the manifestations of syncope also canbe confused with both epilepsy and NES [5].

Unlike adult NES, there is a dearth of informationregarding the incidence, etiology, clinical presentation,cognitive, linguistic, and social skills, treatment, and out-come of NES in children and adolescents. For example,the gender distribution of NES appears to change duringdevelopment, being similar in young boys and girls, buthigher in female teens than male teens [1]. These findingsare based on a small sample size and need to be replicated.Similarly, other than a number of small studies of seizure

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outcomes in children and adolescents with NES [6–9],there have been no controlled studies of comorbid epilepsyor of the behavioral and functional outcomes of youthswith NES.

3.2. What needs to be assessed?

To address this question, the subgroup began by dis-cussing the available data:

Eleven to fifteen percent of children in telemetry unitshave NES [1,4]. There are no differences by age in the

presentation of motor versus nonmotor ‘‘unresponsive’’NES [1].Forty-four percent of 16 cases had a past history of headtrauma in the single study that examined premorbidneurological risk factors [4]. Nine- to eighteen-year-oldswith psychogenic NES (N = 34) had the followingcomorbid psychiatric diagnoses: mood disorders (majordepression, bipolar disorder, dysthymic disorder) in 11(32%); separation anxiety in 8 (24%); posttraumaticstress disorder (PTSD) in 3 (10%); other anxiety orbehavioral disorders in 3 (10%); and brief reactive psy-chosis in 2 (6%) [9].With respect to prior traumatic events, 11 (32%) had a his-tory of sexual abuse (particularly those with mood disor-ders); 2 (6%) had a history of physical abuse; and 15 (44%)had severe family stressors (such as recent parentaldivorce, parental discord, or death of a close family mem-ber) [9].A greater than 70% improvement 1.5 to 4 years after theinitial diagnosis was reported in children and adoles-cents [7–9]. Seizure-free percentages were approximately75% or better for children compared with 25–40% foradults at 1, 2, and 3 years of follow-up [10].Predictors of good outcome included multiple seizuretypes, younger age at presentation, and female gender.Comorbid epilepsy predicted a worse outcome [7].

Other relevant data included the following:

Children with other types of somatic disorders (e.g.,

conversion disorder, chronic pain, body dysmorphic dis-order) had high rates of academic and social difficulties,as well as difficulties identifying and/or expressing emo-tions (alexithymia) (see review in [11]).Correlates of functional symptoms identified predomi-nately in pediatric pain patients include: female gender(after puberty); substance use; comorbid anxiety disor-ders; prior medical illness, physical injury, and hospi-talization; childhood trauma; school problems; andparent factors (i.e., a distressed parent, a parent withphysical or psychiatric symptoms, parent discourage-ment of children’s positive coping efforts, or excessiveparental attention to symptoms) [9,12–20]. Similarstudies have not been conducted in children withNES.

These findings illustrate the differences in psychiatriccomorbidities between children and adults with NES,with lower rates of PTSD and depression in children,and the better prognosis for NES resolution inchildren.

3.3. Recommendations

The Pediatric Subgroup concluded that more informationwas needed on NES in terms of: demographics, seizure semi-ology, seizure control, type of antiepileptic drugs (AEDs),neurological risk factors, family functioning, comorbid psy-chiatric diagnoses, and psychosocial risk factors (i.e., trau-ma, loss, conflict, and impaired academic and socialfunctioning).

Because of the morbidity, marked cost of health careservices, and poor psychological outcome in children withlate or no intervention, the Pediatric Subgroup discussedthe importance of early identification and intervention,particularly for those with conversion and other comorbidpsychiatric disorders, using an integrated biological, psy-chological, familial, and social approach.

Finally, in addition to identifying children and adoles-cents at risk for development of NES, the subgroupthought that is was important to develop treatment stud-ies for these patients. However, a decision was made tofocus first on obtaining basic descriptive data beforeembarking on treatment studies. Knowledge about therates of conversion disorder, mood disorders, anxiety dis-orders, psychosis, as well as attention deficit hyperactivitydisorder (ADHD) and other disruptive disorders wouldhelp determine if cognitive behavioral therapy, psychotro-pic drugs, or a combination of both approaches isindicated.

To summarize, the information currently available onNES in children and adolescents is based on a few descrip-tive studies, some of which have been small, retrospective,and have focused on NES rather than on behavioral andfunctional outcome. The pediatric NES subgroup conclud-ed, therefore, that the gaps in our knowledge of the biopsy-chosocial features of children with NES need to beaddressed first, through well-designed and hypothesis-driv-en prospective studies that include established and stan-dardized measures. The findings of such studies willprovide the basis for pediatric intervention studies.

4. Presenting the NES Diagnosis Subgroup summary

A major obstacle to treatment of NES is patients’ refusalto accept the diagnosis. The reasons for refusal vary andinclude the concern that they will be thought of as being ‘‘cra-zy’’ or that they are ‘‘faking their spells.’’ The way in whichthe diagnosis of NES is presented to patients and their fam-ilies following video/EEG monitoring is therefore consid-ered pivotal in acceptance of the diagnosis and of therecommendation to pursue further psychological or psychi-atric treatment.

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To minimize rejection of the diagnosis of NES, variousauthors have suggested protocols on how to informpatients of this diagnosis [21]. The complexity of the prob-lem became apparent in the extensive subgroup discussionsthat followed the initial brief review. In short, there was alack of consensus on the terminology to use when referringto NES, whether a psychogenic causality could be impliedwhen no axis I or II diagnosis is present in the small subsetof NES patients, and if a psychiatrist/psychologist shouldbe present during discussion of the diagnosis. To resolvethis disagreement, the subgroup recommended two obser-vational multicenter studies.

The first should identify which approach is most effec-tive: (1) calling the event functional versus psychogenic ver-sus another term; (2) identifying it as a nonepileptic seizure(NES) versus a nonepileptic event (NEE); (3) using thepatient’s videotaped event versus a standardized verbalexplanation; or (4) providing the patient with written edu-cational material versus a clinician’s verbal explanation.The primary outcome variables would be acceptance ofthe diagnosis of NES and acceptance of recommendationsfor further psychiatric/psychological treatment.

Additional variables could include level of education,IQ, age, gender, ethnicity, mood at the time of diagnosticvideo/EEG monitoring, and history of prior video/EEGdiagnostic evaluation, information on NES, or psychiatrictreatment.

The second study should identify interrater reliability onthe diagnosis of NES. This was envisioned to be a multi-center study in which investigators who were blind to thediagnosis would rate video clips of NES, epileptic seizuresmimicking NES, and physiologic NEE (including examplesof sleep disorders, movement disorders, syncope, and panicattacks). Interrater agreement would then be measuredwith a j statistic.

5. Classification Subgroup Summary

The focus of the Classification Subgroup was to reviewissues relevant to NES classification. The goal of classifica-tion is to identify independent variables that are predictiveof treatment efficacy.

5.1. General issues regarding classification and subtyping

5.1.1. Limitations of present standard definitions ofpsychiatric disorders in neurological populations

The Diagnostic and Statistical Manual of Mental Disor-

ders, Fourth Edition, Revised (DSM-IV-TR) [22] is not pop-ular among many neurologists, who find that it fails tocapture distinctive features of psychiatric presentations inepilepsy and other neuropsychiatric conditions. The absenceof classifying personality alterations in epilepsy is probablythe diagnostic issue most commonly invoked as illustratingDSM-IV-TR’s deficiency in this regard. There currently isno consensus on an alternative classification system. Evenif one existed it would be difficult for it to gain widespread

use because the psychiatric community and health careinsurers universally use DSM-IV-TR. It would be amonumental effort to create a widely adopted alternativeto DSM-IV-TR, and for practical purposes, it appears nec-essary to work within the DSM-IV-TR diagnosticframework.

Some of the problems with DSM-IV-TR would be com-mon to alternative classifications. This is largely becausethe biological bases of most psychiatric disorders are notunderstood, which limits the use of pathophysiology as avalidating principle (not excluding our growing knowledgeof dopamine hypersensitivity in schizophrenia, serotonindeficiency in depression, autonomic hyperarousal in anxi-ety disorders, etc.). Another problem is the ‘‘lumper versussplitter’’ dilemma. ‘‘Lumpers’’ tend toward broadly inclu-sive categories that might obscure important differenceswithin a population. ‘‘Splitters’’ tend toward classificationon the basis of fine differences that might create anunwieldy excess of trivial diagnostic categories.

5.1.2. Dissociative versus somatoform disorder

This is an old and fundamental debate regarding thenosological position of conversion, the most commonNES presentation, within psychiatric disorders. DSM-IV-TR subsumes Conversion Disorder under SomatoformDisorders, whereas the International Statistical Classifica-tion of Diseases and Health Related Problems (ICD-10)[23] regards conversion as a Dissociative Disorder. InDSM-IV-TR, the reason for classification of ConversionDisorder within Somatoform Disorders is ‘‘to emphasizethe importance of considering neurological or other generalmedical conditions in the differential diagnosis’’ [22].

Both systems agree that dissociation is a very impor-tant mechanism in the production of conversion symp-toms, and the DSM-IV-TR acknowledges that theDissociative and Conversion categories share commonfeatures: ‘‘Both disorders involve symptoms that suggestneurological dysfunction and may also have shared ante-cedents.’’ DSM-IV-TR specifies that ‘‘when both conver-sion and dissociative symptoms occur in the sameindividual both diagnoses should be made.’’ However,DSM-IV-TR confines the Dissociative Disorder classifica-tion to relatively extreme presentations such as Dissocia-tive Identity Disorder and Dissociative Fugue. Thisavoids the situation that Conversion Disorder would near-ly always be classified as both a Somatoform Disorder anda Dissociative Disorder.

5.2. Specific research questions regarding classification and

subtyping

Should ‘‘reinforced behavior’’ be designated as a distinct

subtype of NES? The term is intended to designateNES, usually in the context of developmental disordersor mental retardation, for which a behavior modifica-tion approach (and not a cognitive or psychodynamicapproach) may be indicated [24]. Given that most

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NES, including those in developmentally normal indi-viduals, are ‘‘reinforced’’ in some sense, how do wedefine the diagnostic boundaries of such behavior?

With respect to the DSM-IV-TR criteria for conversion

disorder, is the ‘‘B’’ criterion useful and valid (p. 457:

‘‘Psychological factors are judged to be associated with

the symptom. . .’’)? Criticisms of this criterion include itsquality of post hoc reasoning and lack of specificity inthat physiological epileptic seizures are frequently associ-ated with, if not exacerbated by, psychological stress.

How is the DSM-IV-TR ‘‘C’’ criterion assessed (‘‘The

symptom or deficit is not intentionally produced or

feigned. . .’’)? Regardless of whether one believes that adynamic explanation exists for the intent, its unconsciousnature appears essential to the diagnostic concept of con-version.However, there is substantial uncertainty regard-ing the accuracy of our attribution of conscious versusunconscious intent or, indeed, whether ‘‘conscious’’ and‘‘unconscious’’ are nonoverlapping states. Likewise, theissue of how to clinically distinguish intentionality inpatients is relevant for cases of malingering. Can thisuncertainty be avoided when diagnosing conversion?

What is ‘‘dissociation’’? In DSM-IV-TR, dissociation isdefined as a ‘‘failure in the usually integrative functionsof identity, memory, or consciousness’’ [22]. Should it beregarded as a unitary concept? If not, what are its under-lying constituent dimensions?

5.3. Variables and issues relevant to treatment decisions

Putative subtypes of dissociation (detachment vs com-partmentalization) [25]

Presence versus absence of abuse or trauma historyPresence of genetic markers associated with antidepres-sant response, regardless of phenotypic expression ofclinical depression [26]Conversion versus nonconversion NES [27,28]Utility of functional neuroimaging in subtyping NES(e.g., dissociation versus conversion versus reinforced)[29].Presence or absence of neurological impairment (e.g.,EEG abnormality, history of traumatic brain injury,‘‘soft signs,’’ or nonverbal learning disability)A specific role for right hemisphere dysfunction [30]Presence or absence of comorbid psychopathologyStatus of family or relational systems that may reinforceillness behavior

6. Outcome Measurement Subgroup summary

The Outcome Measurement Subgroup addressedquestions that would help inform development of NEStreatment studies. One major purpose of outcome measure-ment in NES is to operationalize the dependent variablesfor hypotheses regarding treatment outcome.

6.1. General issues regarding outcome measurement in NES

6.1.1. Should choice of outcome measures be linked to an

underlying theoretical model?

Several conference participants emphasized that out-come measures should be linked to an explicitly stated the-oretical model of underlying etiology or the mechanism ofthe intervention. It was pointed out that if the interventionimproved seizure control without changing the hypothe-sized etiology, the validity of the treatment could be calledinto question. On the other hand, it was suggested thatmore pragmatic endpoints such as driving, work, socialrestrictions, and patients’ perception of distress would bevalid outcome variables, and may be more useful for prac-tical-based outcome studies. The question of whetherpatients would care about changes in ‘‘illness perception’’if their seizures were not controlled was raised. This issuesuggests that patient-oriented outcome measure develop-ment may be warranted, for use with the standardized toolsalready available. The use of similar adjunctive measure-ment tools has been advocated for epilepsy treatment out-come studies previously [31].

The attendees agreed that there is no single etiology forNES (see Classification Subgroup Summary), although sev-eral leading causal contenders were nominated. Endogenousanxiety, avoidance behavior, dissociation, nondissociativeposttraumatic stress, abuse, interpersonal dynamics, per-sonality structure, and societal factors may all play a predis-posing, precipitating, or perpetuating role and may interactwith each other. Several theoretical models were describedto account for NES development, including psychodynamic,cognitive–behavioral, and learning theory [32–34]. Forexample, in a recent study, Goldstein et al. [34] explicitlytested a ‘‘fear avoidance’’ model of NES using cognitive–be-havioral therapeutic techniques. This prospective, nonran-domized trial used specific instruments tapping theproposed theoretical constructs under investigation.

6.1.2. Statistical power and breadth of focus in outcome

measures

Selecting a single primary outcome variable or a few keyvariables helps minimize the statistical burden placed onthe study design in terms of reducing the proliferation offalse-positive errors. The more outcome measuresemployed, the more demand is placed on establishing sta-tistical power of the intended clinical trial (i.e., increasedsample size, increased effect size of measure). A batteryassessment with focus and breadth may help strike a bal-ance between too narrow or too broad an outcome focus.A narrow outcome focus may miss important changes thatan intervention may produce. A broader outcomeapproach may be sufficiently comprehensive to test keyareas of a theoretical model that underpins the interventiontrial. From a statistical point of view, allowing for a greaterbreadth of measurement may reveal significant treatmenteffects that would not be revealed with narrowly focusedoutcome measures.

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In view of the etiological complexity of different NESdisorders, outcome measures focusing on one particularfactor (like fear avoidance) may not apply in a substan-tial proportion of cases. If an outcome measure thatreflects a relatively narrow etiological model is chosen,it may show no effect across a treated group, althoughit may well have been relevant for some of the peopletreated. The use of measurements that have goodspecificity for their targets will help in maintaining theclarity of research conclusions regarding etiology andintervention.

6.1.3. What variables or domains should be regarded as

reflecting ‘‘outcome’’?Subgroup members and other conference attendees

offered a diversity of potential measures. As previouslymentioned, several workshop attendees emphasized thateach measure be linked in some fashion to the underly-ing etiological model proposed to account for NESbehavior. It was pointed out that the selection ofoutcome measures would necessarily depend on the inter-vention model designed. Overall, several areas of NES-relevant outcome measures were identified as potentiallyuseful markers of intervention endpoints. Identified areasincluded psychosocial outcomes (e.g., employment status,return to prior functional status, family functioning),clinical outcome (e.g., seizure outcome, seizure pattern),psychiatric status and symptom presentation (e.g.,depression, avoidance behavior, other dissociativesymptoms), health-related quality of life, medicalresource utilization (e.g., emergency department visits,hospitalization, medication usage), and psychophysiolog-ical markers (e.g., arousal).

The subgroup concluded that a standard efficacyapproach (seizure freedom or reduction) that was supple-mented by carefully selected generic patient-oriented quali-ty-of-life and health-care utilization measures wouldprobably be most easily interpreted by the medical commu-nity. However, several conference participants noted thathaving a range of outcome measures would be valuable inany intervention trial design. For example, the Goldsteinet al. trial employed measures assessing clinical outcome(seizure frequency diary), psychosocial outcome (workand social adjustment), psychopathology outcome (fear,depression), as well as several secondary outcome measuresof health perceptions and locus of control [34]. Reuber et al.[35] examined long-term NES outcomes from the stand-point of seizure outcome and government disability statusand found that several clinical and psychological factorswere associated with better prognosis. However, they point-ed out that some variables are not conducive to interven-tion, such as history of better education and less violentseizures. Similarly, changing maladaptive personality char-acteristics may also prove difficult. Targeting personalitycharacteristic change may also prove difficult, but they sug-gested that it may be possible to ‘‘concentrate on the identi-fication and management of stressors or triggers in the

(social) environment that interact with personality vulnera-bility’’ [35].

6.2. Specific issues regarding outcome measurement in NES

6.2.1. How can socioeconomic/medical utilization outcomesbe measured?

Some participants advocated socioeconomic/medicalutilization outcomes, at least as secondary outcomes. Itwas felt that an intervention with positive impact on thesemore society-level outcomes would have the additionaladvantage of support from current cost-effectiveness mod-els. If an intervention resulted in a reduction of medicalresource utilization or return to employment, then a stron-ger case could be made for acceptance of that interventionas a standard of care [36,37]. The Martin et al. [37] studydemonstrated that utilization rates (emergency departmentvisits, medication usage, diagnostic procedures) could bemeasured and that changes do occur in the pattern anduse of medical services after definitive diagnosis. Demon-strating that health care expenditures are reduced byNES diagnosis and intervention would be important andcompelling data for insurance carriers. The psychiatricintervention literature examining cost-effectiveness of vari-ous pharmacotherapies and psychotherapies has shownthis to be a successful strategy for encouraging widespreadacceptance of a given intervention (e.g., Schoenbaum et al.[38]).

6.2.2. How do the qualitative and quantitative features ofnonepileptic events reflect outcome?

There was some debate regarding the relevance ofincluding change in seizure characteristics (frequency, pre-sentation, etc.) as outcome variables. Some participantsfelt that assessing change in seizure frequency during anintervention might reflect change in the underlying etio-logical process. It was pointed out that the patient’s focusmight change during the intervention, as the initial preoc-cupation with symptoms and seizure frequency (i.e.,‘‘harm to self’’) shifts to an awareness of deeper psycho-logical issues, and that this might be reflected in a changein seizure frequency. As is the case with epilepsy,improvement or positive change in quality of life forpatients with NES is often negligible unless seizures total-ly abate [39]. Others felt that seizure frequency should beconsidered a secondary measure, with change in otherpertinent psychological variables identified as the primarytargets. Certainly, support was expressed for the inclusionof seizure frequency with the other outcome variables.This raised further discussion as to the reliability of sei-zure frequency measurement. This topic has been thor-oughly discussed in the epilepsy treatment literature(e.g., Baker et al. [40]), but not in terms of NES. It wasagreed that a spectrum of seizure measurement shouldbe included that would capture aspects of the seizurebehavior. This could include seizure frequency, seizureseverity, seizure triggers, and seizure semiology.

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6.2.3. Potential dependent variables/outcome domains

Seizure frequencyIndividual concerns (e.g., Epilepsy Foundation ofAmerica Concerns Index)Employment (return to work), disability statusPsychiatric symptoms (DSM-IV-TR axes I and II, BeckDepression Inventory, Hamilton, Symptoms CheckList-90, etc.)Personality characteristicsHealth-related quality of lifePsychophysiological variables (e.g., arousal)Family/psychosocial factors (e.g., Family AssessmentDevice)Medical resource utilization (e.g., emergency depart-ment visits, hospitalizations)Illness cognition/perceptions (e.g., label, cause, treat-ability, time line, consequences)

It should be noted that the assessments/tools in the pre-ceding list include measures of how people feel in generaland about their seizures, but not what they think aboutthem. There is evidence from health psychology studies inother areas that illness cognitions or perceptions are relatedto outcome.

6.3. What are the preferred characteristics of a given

outcome measure for NES clinical intervention trials?

As mentioned before, the outcome measures shouldinclude items linked to the theoretical constructsof underlying psychopathology that are beinginvestigated.

The measures chosen should be instruments/techniquesthat have demonstrated the most robust psychometricproperties (i.e., reliable, valid) and the most data support-ing their use. Excellent reviews of this topic have been pre-sented and have described ideal measurement features suchas the responsiveness of the instrument to change from theintervention [41,42].

The literature should be searched for available mea-sures already in existence that could be applied to theintervention study. However, new instruments to assessNES treatment outcome could be constructed. Instru-ment development under the umbrella of a NES treat-ment trial task force could elicit expertise from multiplesources.

Instruments should be of a length that patients can read-ily complete in a timely manner. Patient burden may beconsiderable with a lengthy, repetitive questionnaire pack-et. In such cases, participants are less likely to completetheir responses, increasing the probability of missing orinaccurate data.

In addition to the number of instruments used, the levelof complexity of the instruments should be taken into con-sideration. That is, will patients understand what they arecompleting? Evidence suggests that neurocognitive impair-

ments can be observed in the NES population [43] and thismay hinder accurate comprehension of the intended ques-tionnaires that are used for outcome assessment.

Measurement tools should be sensitive to change atmultiple time points while the intervention is in progress.For example, using change in medical disability as anoutcome may not be a sensitive endpoint after 6 months.However, assessing change in mood status or seizure fre-quency at the same 6-month endpoint may be morelikely to reveal an effect. Outcome measures that maybe more sensitive to postintervention short-term change(i.e., weeks/months) may include (but are not limitedto) seizure frequency, mood status, medical resource uti-lization, anxiety symptoms, self-report of somatic com-plaints, and reduced avoidance behaviors. Otheroutcome measures that may not be sensitive to changeuntil a longer postintervention interval has elapsedinclude change in vocational status, medical disabilitystatus, or dynamic relationships between patient andtherapist [44].

Issues pertaining to the importance of querying mul-tiple sources of information were discussed by the NESworkshop participants. Reliance on self-report datamay limit an outcome measure’s validity. Interventiontrials should use instruments that gain clinical datafrom a range of sources, including the patient, his orher family members, or the treating physician. Clinicianrating forms are commonly employed in clinical trialdesign to assess a variety of outcomes including mentalstatus and mood. Family reporting of participantmood, behavior, or other clinical variables (i.e., sei-zures, medical resource utilization) may also be helpfulin gathering a reliable estimate of the outcome variableof interest.

6.3.1. Proposed characteristics for NES clinical trial

outcome measures

The outcomes should:

Be linked to theoretical constructs of underlying

psychopathologyEmploy standardized measures with solid psychometricpropertiesUse existing measures available in the scientific litera-ture from other areasEmploy measures that are sensitive to the intendedtreatment changes: short-term change (weeks/months),long-term change (years)Use measures that the subjects can complete andcomprehendLimit the burden of the outcome battery (time andpsychological)Use a multi-informant approach to outcomemeasurement (self-report, clinician rating scales,observational, neuropsychological, generic quality-of-life measures allowing for across conditioncomparison)

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Given that there is not only cross-sectional but also lon-gitudinal heterogeneity in patients with NES, the subgroupnoted that for a treatment study in this area, interventionscan either be quite basic and widely applicable to a lessselected or restricted NES patient population or can bemore specific in its criteria (for newly developed NES, forNES in the context of trauma or somatization disorder,for those with mixed NES/epilepsy or those with loneNES, etc.).

6.3.2. Suggested inclusion/exclusion criteria for a treatment

study on NES

6.3.2.1. Inclusion criteria.

Video/EEG confirmation of NES, capturing a typical

eventDiagnosis by DSM-IV-TR criteria of Conversion Disor-der presenting as NES, or Undifferentiated SomatoformDisorder or Somatization Disorder in which NESoccurs as a conversion symptom

6.3.2.2. Exclusion criteria.

MalingeringPending litigation

Major psychotic disorder; i.e., schizophrenia, schizoaf-fective disorderAcute need for psychiatric hospitalizationPregnancyNonconversion NES [27]IQ < 70Neurological disorder associated with progression; i.e.,multiple sclerosis, malignant neoplasm (The presenceof epilepsy should be duly noted, but epilepsy is notexclusionary.)

7. NES Treatment Trial Subgroup summary

The NES Treatment Subgroup attempted to reviewthe present status of intervention strategies. A vastarray of interventions have been suggested to be ofsome use in treating patients with NES, but we foundno double-blinded, randomized, placebo-controlled trialsin two extensive literature reviews [45,46]. In developinga multicenter study, the subgroup realized the potentialstatistical complexity of evaluating too many interven-tions and recognized the advantage of ‘‘keeping it sim-ple.’’ Dr. Goldstein and Dr. Mellers (who areevaluating a cognitive–behavioral intervention at theMaudsley Hospital in the United Kingdom) and Dr.LaFrance (who is investigating a pharmacological inter-vention in the United States) will have data on theirrespective pilot randomized, controlled studies by early2007, which will inform the multicenter trial protocol.The subgroup advocated ‘‘lumping instead of splitting’’with respect to NES diagnostic inclusion (as noted inthe Classification Subgroup and Outcome Subgroup

summaries) and discussed the following treatment proto-col proposal.

The recommended NES treatment study would havethree arms: a neurological follow-up control group, a cog-nitive–behavioral therapy (CBT) intervention group, and apsychopharmacological treatment group. Patients wouldbe randomized into one of these groups. Exclusion criteriawould include current suicidality, current alcohol and illicitsubstance abuse, current psychosis, as well as the presenceof pending litigation and the other exclusions presentedearlier. Only patients with current NES without concurrentepilepsy would be included in this initial study, but a histo-ry of epilepsy would not be exclusionary. In disagreementwith the Outcome Subgroup, the NES Treatment TrialSubgroup recommended that patients with current, con-comitant epilepsy be excluded, at this stage. Bipolar disor-der would not be a reason for exclusion, but there wasdebate on this issue with the differences over the antiepilep-tic drug issue (discussed later).

A neurological and psychiatric evaluation would becompleted in all patients. The primary outcome would beNES prospectively collected seizure logs. The pros andcons of using seizure count as the primary outcome werediscussed. In addition to the dependent variables outlinedin the previous section, other scales considered for second-ary analysis might include: Beck Depression Inventory,Dissociative Experiences Scale, SCID and SID-P, Symp-toms Check List—90, Quality of Life in Epilepsy—31, atrauma questionnaire, a coping scale, a family functioningscale, and a general function scale. In addition, theHypnotic Induction Profile and the Barrett ImpulsivityScale could also have some utility, but administrationand training may be an issue with the Hypnotic InductionProfile.

Addition or deletion of medications induced a lively dis-cussion. Based on the methodological idea of simplicity ininterventions, one proposal was that all medications wouldbe fixed on the dosages at the time of trial evaluation. Theonly intervention would be the addition of an SSRI, oraddition of CBT to the current regimen, or neurologicalfollow-up in the treatment-as-usual control group. Reasonswere given for not withdrawing AEDs: First, AEDs areused in patients with NES for their effects on mood andimpulsivity and for headache or pain prophylaxis. Second,withdrawing a drug is an intervention in itself. Finally,after diagnosis with video/EEG or long-term monitoring,patients are often returned to a previous drug regimenbefore discharge. Many patients with NES would havebeen treated with AEDs for a number of years prior toenrolling in the trial, and withdrawing a medication wouldbe a significant intervention. After the trial was concluded,the effect of withdrawal of AEDs could be evaluated in asecondary analysis.

Conversely, the argument against continuing a patienton AEDs was as follows: First, if the diagnosis of currentepilepsy is excluded in all patients, there is no indicationfor continuing AEDs for NES treatment. Patients have

W.C. LaFrance Jr. et al. / Epilepsy & Behavior 8 (2006) 451–461 459

demonstrated safe withdrawal of AEDs when the diagnosisof NES has been documented by video/EEG monitoring[47]. Most importantly, to continue AEDs incurs the risksof toxicity, teratogenicity, and expense. Second, althoughwithdrawal of AEDs is a treatment in itself, this wouldbe carried out equally in all three treatment groups andso would not bias outcome. Finally, from a CBT perspec-tive, continuing AED therapy in lone NES would reinforcethe patient’s belief that he or she still has epileptic seizuresand would mitigate against the acceptance of psychologicalfactors in the production of seizure activity. In addition,anxiety about stopping the AED could be dealt withduring the treatment sessions, and similar reassuranceabout AED discontinuation could be given to the controlgroup. This antianxiety intervention could be evaluatedin economic terms and would also be an importantoutcome measure.

The argument against continuing AEDs in patients withNES who have unipolar depression was discussed. Whilemany patients have a mood disorder, other treatments(SSRI, psychological therapies) would be first-line inter-ventions, not the mood stabilizers. Also, mood-stabilizingefficacy has not been established for many commonly usedAEDs (e.g., phenytoin, levetiracetam, topiramate). Whereit is better established (carbamazepine, valproate, and lam-otrigine), the evidence is in patients with bipolar affectivedisorder, not mild depression or dysthymia, as is morecommon in patients with NES. In addition, AEDs mayhave negative psychotropic properties and discontinuationwould have a positive effect. To fix AED dosage on enroll-ment, we would have to make clear to patients that theywould be asked to remain on AEDs for the duration ofthe study, even though this medication was no longer indi-cated in their case and could be associated with a range ofadverse effects. If AEDs were tapered, an allowance couldbe made for those patients who meet criteria for bipolaraffective disorder, as measured by the SCID, where AEDswith confirmed psychotropic effects in the disorder, i.e.,valproate, carbamazepine, and lamotrigine, would be con-tinued. In conclusion, there are pros and cons to contin-uing or to discontinuing AEDs in the proposed trial, andthis is an ongoing discussion.

A baseline observation period would establish if NESpersisted with enrollment. During a 1-month waiting peri-od, we would investigate the concept that patients mayimprove just from having been given a definite diagnosisand being reassured that they do not have epilepsy.

After 1 month, if NES persisted, patients would be ran-domized to one of three groups. The first group would beseen by their neurologist on a twice-a-month schedule,and AEDs would remain stable (or would be withdrawn,as discussed earlier). The evaluating neurologist would alsosee the other members of the study with the same frequen-cy. The second group would receive CBT intervention forapproximately 12 sessions over a 4-month period, and thiswould be based on the Maudsley protocol. The pharmaco-logical intervention would follow that of Dr. LaFrance’s

trial, i.e., sertraline treatment under the same inclusion cri-teria implemented in his current pilot randomized controltrial. Finally, we discussed the possibility of patients cross-ing over into the CBT or pharmacological arm after the 4-month intervention was completed. Another possibility istailored intervention, perhaps based on specific diagnosticcomorbidities in NES (see Rusch [44]).

The statistical feasibility of this three-armed, random-ized controlled trial was discussed, including the lack ofeffect sizes established in NES treatment trials, the ran-domization procedure with or without stratification ofrisk factors, and potential site intervention differences.The proposed intervention study would ideally be aninterdisciplinary, multisite, international, NIH-supportedtrial.

8. Conclusion

Although great strides have been made in understandingictal semiology, patient characteristics, and diagnosis withvideo/EEG monitoring, validated treatments and con-trolled trials are lacking. Neurologists, psychiatrists, psy-chologists, and emergency departments are aware of thedifficulty in treating patients with NES. Estimates are that10 to 50% of patients with ‘‘intractable epilepsy’’ haveeither lone NES or a combination of epileptic and nonepi-leptic seizures. Many patients experience significant medi-cal, family, vocational, and societal consequences of theirdisorder. This underscores the need for effective, testedtreatments for NES.

The participants at this multidisciplinary, internationalNES Treatment Workshop assessed the state of the scienceand laid the groundwork to fill the treatment void. Thegoals were addressed through discussion topics, whichfocused on: NES in children; presenting the diagnosis ofNES; classification of NES subtypes; outcome measuresfor NES trials; and lastly, pharmacological treatmentapproaches and psychotherapies, such as cognitive–behav-ioral therapy, hypnosis, and group and family therapies.The intent was to develop specific research strategies thatcan be expanded to involve a large segment of the epilepsyand psychiatric treatment communities. The workshopgenerated recommendations for studying existing interven-tions and developing novel therapeutic interventions.

Several potential studies emerged from the breakout ses-sions. These included: (1) a retrospective review of historiesof children diagnosed with NES, combined with a prospec-tive collection of information on behavior, cognitive test-ing, school performance, and psychosocial environment;(2) a multisite interrater reliability study to evaluate thereliability of diagnosis using video/EEG monitoring; (3) amulticenter observational study to identify which approachto presenting the NES diagnosis is most likely to result intreatment compliance; (4) a survey of comprehensive epi-lepsy centers to determine if there is a therapeutic standardof care; and (5) a three-armed, randomized, clinical trial totest the efficacy of current treatments.

460 W.C. LaFrance Jr. et al. / Epilepsy & Behavior 8 (2006) 451–461

The workshop illustrated the need for collaborativeresearch efforts among those treating patients with NES.Dissemination of workshop results may increase the knowl-edge of NES and foster further treatment protocols. Alongwith the publication of this summary, the results of these pre-liminary discussions were presented at the NES SpecialInterest Group at the AES meeting in December 2005, andare being presented at meetings of psychiatric and nursingsocieties as well. Those attending and sponsoring the work-shop considered this an important first step in a concertedeffort to find effective treatments for patients with NES.

Acknowledgments

The workshop was funded by the National Institute ofNeurological Disorders and Stroke, the National Instituteof Mental Health, and the American Epilepsy Society.

NES Treatment Workshop committee: W. Curt La-France, Jr (chair), Kenneth Alper, Debra Babcock, JohnJ. Barry, Selim Benbadis, Rochelle Caplan, John Gates,Margaret Jacobs, Andres Kanner, Roy Martin, LynnRundhaugen, Randy Stewart, Christina Vert.

NES Treatment Workshop participants: Donna Joy An-drews, Joan Austin, Richard Brown, Brenda Burch, JohnCampo, Paul Desan, Michael First, Peter Gilbert, LauraGoldstein, Jonathan Halford, Mark Hallett, CynthiaHarden, Gabor Keitner, Helena Kraemer, Roberto Lew-is-Fernandez, Gregory Mahr, Claudia Moy, Greer Mur-phy, Sigita Plioplys, Mark Rusch, Chris Sackellares,Steve Schachter, Patricia Shafer, Daphne Simeon, DavidSpiegel, Linda Street, Michael Trimble, Valerie Voon,Elaine Wyllie, and Charles Zaroff.2

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