Psychogenic nonepileptic seizures

Epilepsy & Behavior 22 (2011) 85–93

Contents lists available at ScienceDirect

Epilepsy & Behavior j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / ye b e h

Review

Psychogenic nonepileptic seizures☆ Richard J. Brown a, Tanvir U. Syed b, Selim Benbadis c, W. Curt LaFrance Jr.

d,e

, Markus Reuber f,⁎

a

Division of Clinical Psychology, University of Manchester, Manchester, UK Department of Neurology, University Hospitals, Case Medical Center Faculty, Case Western Reserve University School of Medicine, Cleveland, OH, USA c Department of Neurology, University of South Florida and Tampa General Hospital, Tampa, FL, USA d Division of Neuropsychiatry and Behavioral Neurology, Rhode Island Hospital, Providence, RI, USA e Departments of Psychiatry and Neurology, Brown Medical School, Providence, RI, USA f Academic Neurology Unit, University of Sheffield, Sheffield, UK b

a r t i c l e

i n f o

Article history: Received 8 February 2011 Accepted 10 February 2011 Available online 29 March 2011 Keywords: Psychogenic nonepileptic seizures Dissociative disorder Conversion disorder Pseudoseizures

a b s t r a c t This review by three established clinicians/researchers and two 'rising stars' in the field of psychogenic nonepileptic seizures (PNES) describes recent progress in this area and highlights priorities for future research. Empirically testable models of PNES are emerging but many questions about the aetiology of PNES remain unanswered at present. Video-EEG has made it possible for doctors to make secured diagnoses of PNES in more cases. However, unacceptable diagnostic delays and misdiagnoses are still common. Non-specific EEG changes are often misinterpreted as evidence of epilepsy. A better understanding of the symptomatology of PNES may allow earlier and more accurate diagnoses using self-report questionnaires. The communication of the diagnosis and the engagement of patient in psychological treatment can be difficult. A recent pilot RCT has demonstrated the effectiveness of a psychological treatment in reducing seizures in the short term, but longer-term effectiveness is yet to be demonstrated. © 2011 Elsevier Inc. All rights reserved.

1. Introduction Psychogenic nonepileptic seizures (PNES) are episodes of altered movement, sensation, or experience resembling epileptic seizures, but not associated with ictal epileptiform discharges in the brain but which, instead, have a psychological origin. In the current diagnostic manuals most PNES are categorized as a manifestation of dissociative or somatoform (conversion) disorder [1,2]. This means that they are interpreted as an involuntary response to emotional, physical, or social distress. It is appropriate to discuss PNES in this special issue because they are one of the commonest differential diagnoses of epilepsy and are typically diagnosed by physicians specializing in the treatment of seizures. They are by far the most common nonepileptic condition diagnosed in epilepsy (video/EEG) monitoring units. The fact that research interest in PNES has grown exponentially since the introduction of video/EEG monitoring is encouraging for the future. However, the impressive number of publications on this topic in the last two decades also demonstrates there still are many questions to answer. In Sections 2–4, three experienced clinicians who have

☆ From a special issue of Epilepsy & Behavior: "The Future of Clinical Epilepsy Research" in which articles synthesize reviews from senior investigators with the contributions and research directions of promising young investigators. ⁎ Corresponding author at: Department of Neurology, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK. Fax: +44 114 2713158. E-mail address: [email protected] (M. Reuber). 1525-5050/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2011.02.016

followed the developments of PNES research closely over this period discuss some questions that future research needs to address most urgently. Selim Benbadis focuses on topics related to the diagnostic process, Curt LaFrance writes about issues related to treatment, and Markus Reuber discusses the nature and experience of PNES. In Sections 5 and 6, two “rising stars” describe how they got involved in research in this area and what their plans are for the future: Tanvir U. Syed focuses on his work aiming to reduce diagnostic delay, and Richard J. Brown, on his development of a psychological model for PNES. 2. Diagnostic process 2.1. Selim Benbadis Recent studies have shown that an accurate diagnosis of PNES is delayed by a mean of more than 7 years and that most patients are initially thought to have epilepsy [3]. As long as patients are misdiagnosed as having epilepsy, they are at iatrogenic risk. The misdiagnosis of PNES is costly to patients, the health care system, and society. Repeated workups and treatments for what is mistakenly thought to be epilepsy are estimated to incur $100 to $900 million per year in medical services [4]. Patients with PNES are prescribed antiepileptic drugs (AEDs) that do not treat, and may exacerbate, PNES [5], have multiple laboratory tests performed, and may not receive the necessary mental health care that could benefit them. Delayed diagnosis could lead to adverse effects from unneeded AEDs, iatrogenic

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complications from invasive procedures in continuous PNES (“nonepileptic psychogenic status”) [6], medical costs resulting from unnecessary hospitalization treatment and workup, delayed referral to appropriate psychiatric treatment, and employment difficulties and disability [7]. Some of the most important directions and unresolved future directions in the diagnostic aspects of PNES can be divided into four components: (1) clinical suspicion, (2) errors in EEG use and interpretation, (3) video/EEG monitoring, and (4) especially difficult situations. 2.1.1. Diagnostic challenges at the stage of clinical suspicion Psychogenic nonepileptic seizures are initially suspected in the clinic, on the basis of the history and examination. The most important differential diagnoses are epileptic seizures and syncope. Many "red flags" appear useful in clinical practice because they increase the likelihood of seizures being psychogenic, rather than epileptic. However, their specificity and sensitivity, against the eventual diagnosis by EEG/video monitoring, need to be tested in larger series. What is more, future studies should consider the diagnostic value of clusters of features from the history rather than a small number of single items. Such studies would be most useful if they described not only the sensitivity and specificity of particular items in the differential diagnosis of epilepsy and PNES, but also the distinction of syncope from the other two most common causes of blackouts. Relevant items in the history include: specific triggers for seizures, such as "stress" and "getting upset," pain, certain movements, sounds, and lights; and the circumstances in which attacks occur, including occurrence in the physician's office or the waiting room or during the examination [8]. Which features of the past medical history can be useful? The coexisting poorly defined (probably psychogenic) conditions such as "fibromyalgia" and unexplained “chronic pain” are associated with psychogenic symptoms, with a high predictive value of 70–80% [8]. Most likely other “fashionable” unsubstantiated diagnoses such as “chronic fatigue” and seronegative chronic Lyme disease have the same value, but this has not been tested. A florid review of systems suggests somatization [9]. Some are overdiagnosed conditions, but others raise the question of association. Does the coexistence of “chronic pain,” “fibromyalgia,” or “intractable headaches” with PNES in a given patient indicate that these are psychogenic as well? In contrast to the above, there are symptoms that argue in favor of epileptic seizures, but again the exact diagnostic value (sensitivity, specificity, predictive values), need to be better studied. Significant injury, including tongue biting, has been relatively well studied, but incontinence, despite being often cited, has not [10]. Recent work has shown that how patients speak about their seizures when they talk to their neurologists (rather than what symptoms they describe) may be useful in the diagnostic process [11]. However, these findings depended on careful post hoc analysis of transcripts of clinical encounters, and future research will need to show to what extent these observations can be useful “online,” as physicians speak to their patients. 2.1.2. The issue of EEG interpretation errors Overinterpretation of the EEG is an important reason why seizures are misdiagnosed as epilepsy so commonly. This is not specific to PNES, and other conditions such as syncope and benign nonspecific symptoms are often misdiagnosed as epilepsy based on a misread EEG, but because PNES are the most common condition misdiagnosed as epilepsy, this important issue should be the subject of more research. This problem is very serious and well known to referral epilepsy centers [12,13], but it has not been studied, partly because it is politically unpleasant. The reality is that most practicing neurologists who routinely read EEGs are not appropriately trained to do so [14]. Unfortunately, in discussions about who should be reading EEGs, professional associations are sometimes more concerned about protecting the livelihood of their members than the quality of care.

Because most EEGs ordered in routine U.S. practice are not for epilepsy (typically for encephalopathy), errors in interpretation have little impact on diagnosis, management, and outcome. For the diagnosis of seizures and epilepsy, however, the consequences of misreading are significant. If we are to assume that all neurologists who want to read EEGs are qualified to do so, EEG training should be more regulated. Epilepsy, seizures, and EEGs represent one of the most voluminous parts of general neurology and child neurology practice. Some of the specific questions to be answered include the following. What EEG patterns are overread? Why are they overread? How can EEG training reduce the errors in interpretation? Should EEG training be mandatory during neurology residency (currently it is not)? In countries where EEGs are interpreted by experts but are requested by clinicians lacking expertise in the use and limitations of this investigation (such as the United Kingdom), the risk of misdiagnosis is most commonly related to the overinterpretation of nonspecific findings [15]. In such health systems, the question that needs to be explored is whether access to requesting EEGs should be restricted to those clinicians who are sufficiently trained to understand what an EEG can and cannot show. 2.1.3. Diagnostic challenges at the stage of confirmation by video/EEG monitoring The value of various semiological features has been extensively studied. Behaviors or signs strongly suggestive of PNES include the following: very gradual onset or termination; pseudosleep; and discontinuous (stop-and-go), irregular, or asynchronous (out-ofphase) activity including side-to-side head movement, pelvic thrusting, opisthotonic posturing, stuttering, and weeping [16–22]. Ictal eye closure is associated with PNES [23], and although this has been questioned [24], eye closure, especially when prolonged and associated with complete unresponsiveness, is quite specific for PNES. Behaviors that are modified by an examiner, such as avoidance of noxious stimuli, and nonanatomical progression of symptoms (various limbs moving at various times) can also help. Another useful sign is preserved awareness and ability to interact with the examiner during bilateral motor activity, which is relatively specific to PNES. Postictal responses such as whispering voice and partial motor responses have a strong association with PNES [25]. It is critical to recognize that no single characteristic is pathognomonic of PNES. In the absence of a gold standard (a definitive method, such as pathology) against which to verify the diagnosis by video/EEG monitoring (VEEG), the second best method is to study interrater reliability (IRR). In the first study of the IRR of the diagnosis by VEEG, sampling a group of 22 epileptologists found substantial IRR for epilepsy and a moderate interrater agreement for PNES [26], indicating that there is a certain component of subjective “artful” judgment. When used properly, VEEG allows the diagnosis of paroxysmal seizure-like events and, in particular, the diagnosis of PNES, with a high degree of confidence. A closer look at the data revealed that for 12 of the patients, there was agreement among ≥19 reviewers, and for 17 of the patients, there was agreement among ≥17 reviewers, which suggested that the diagnosis is not difficult in most patients, but that there are a few difficult cases that account for an only moderate overall agreement. There are many different methodological ways to study IRR of VEEG (number of reviewers, types of reviewers, type of setting or study population, type and amount of data, amount and type of data given to make a diagnosis, availability of clinical history, etc.), and has been replicated, showing higher IRR. Using computer-aided methods of video and EEG or ECG analysis also may improve diagnostic accuracy. 2.1.4. Specific difficult situations Future research should also focus on the subset of PNES that gives rise to special diagnostic difficulties. These include brief sporadic myoclonus-like episodes, episodes consistent with “simple partial”

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epileptic seizures, where ictal EEG changes can be absent, and nonepileptic psychogenic status (NEPS) [6]. Special populations in whom seizures are easily assumed to be epileptic need to be studied, as the diagnostic delay here may be even more prolonged. This includes patients with traumatic brain injuries and veterans, in whom the proportion of PNES, when investigated, is comparable to the general population of patients with refractory seizures [27,28]. 3. Treatment issues 3.1. W. Curt LaFrance, Jr. Given the number of people with PNES and the lack of treatment efficacy data, the NINDS has assigned developing treatments for PNES as one of its Epilepsy Benchmarks for research [29]. Treatment for PNES has a few components: confirming the diagnosis of PNES, delivering the diagnosis of PNES, discontinuing AEDs in lone PNES, and initiating psychiatric/psychological care for PNES and its comorbidities [30]. Two key areas that are unresolved for PNES treatment include what could be grouped in phase I (presentation of the diagnosis) and phase II (longitudinal follow-up) of treatment, which are discussed below.

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have been used for PNES comprising a number of psychotherapy modalities and pharmacological agents [49,50]. Although it is likely that a “one size fits all” approach has its limitations [51], addressing the most common etiologies of PNES (trauma/abuse and developmental issues [52]) may be the highest-yield targets for developing treatments. Advancing beyond the numerous open-label and uncontrolled trials that have been published for PNES, some modalities are showing promise in pilot controlled studies, including cognitivebehavioral therapy [53]. Pharmacologically, selective serotonin reuptake inhibitors (SSRIs) have been used as an adjunctive treatment in PNES [54] and in other conversion disorders, such as psychogenic movement disorders [55], with some reduction in symptoms. A number of other modalities incorporated into uncontrolled studies [56,57] could be tested in randomized controlled trials to examine their efficacy for PNES treatment. Given that PNES have been in the medical literature for centuries, and we still do not have definitive treatments, the major need is fully-powered, randomized controlled trials to determine the efficacy of treatments [58]. 4. Questions about the nature and experience of psychogenic nonepileptic seizures 4.1. Markus Reuber

3.1.1. Presentation of the diagnosis Phase I of treatment is presentation of the diagnosis. Given that the first step in PNES treatment is proper diagnosis, and that VEEG is the gold standard for PNES diagnosis [26,31], how the diagnosis is relayed may be a crucial element in the transition to longer-term treatment. Research shows that when patients in the seizure monitoring unit (SMU) are not given information on their diagnosis, they have a higher likelihood of no improvement or worsening of PNES [32]. A model that has been proposed and used in an uncontrolled fashion with reported good reception is presenting the diagnosis in a nonpejorative, positive manner (i.e., “the good news is you have PNES and not epilepsy”) and showing the patients the episode captured on VEEG [33]. When this is done in the SMU, a team approach composed of the neurologist, psychiatrist, psychologist, and nursing can create a collaborative environment where the transition into mental health care can be facilitated [34]. Studies for presenting the diagnosis have been proposed [35], and one study has examined what happens in the acute phase postdiagnosis [36], and two have examined intermediate-term outcomes [37,38]. Long-term results, at best, however, suggest that the decrease in PNES frequency shortly after diagnosis is not maintained longitudinally when solely giving the diagnosis is the main “intervention” [39,40]. Future studies could examine the following: Who should deliver the diagnosis [41,42]? Does calling PNES by one name or another have any impact [43–46]? When should AEDs be tapered in lone PNES [47]? Should the common risk factors (such as history of abuse) and comorbidities be addressed initially in the SMU or in the initial outpatient psychiatric session? 3.1.2. Further treatment What to address in PNES treatment has been a source of discussion and could be assessed in future trials. There are two main “types” of PNES: posttraumatic and developmental [48]. Posttraumatic PNES are thought to develop in response to acute or chronic exposure to traumatic experience(s), such as physical or psychological trauma, sexual or physical abuse. Developmental PNES refers to difficulties in coping with tasks and milestones along the individual's continuum of psychosocial development. These issues can be addressed in the context of a therapeutic relationship, in which a patient is able to divulge difficult and affect-laden material. The process may take place in an outpatient setting where the patient and clinician have a therapeutic alliance. Phase II, therefore, is the longitudinal follow-up by the mental health provider(s) and neurologist. Various treatment approaches

The fact that nonspecialists (including general neurologists) continue to struggle with the differentiation of PNES from epileptic seizures and other causes of blackout provides a clear indication that we need to learn more about how PNES can be distinguished from other diagnoses in clinical practice. However, if we want to develop a better understanding of the nature of PNES, be in a position to prevent PNES from developing, or find the most effective treatment for a particular patient, we will also need a much better understanding of subgroups within this large diagnostic entity. Although recent pilot studies show that psychotherapy may be an effective treatment modality for PNES [57,59], the modest treatment effects achieved by a single psychotherapeutic approach illustrate the limitations of what can be achieved with a "one size fits all" approach [53]. Potentially relevant subgroups of patients with PNES are defined by clinical, psychological, and semiological features. 4.1.1. Distinct clinical subgroups There are a number of studies that demonstrate important differences in terms of etiological factors, clinical presentation, and outcome between men and women with PNES [60], younger and older patients [61], patients with and without a history of sexual abuse [52], and patients with and without learning disabilities [62]. Despite many similarities, there are also important differences in how PNES are perceived (and probably treated) in different cultures [63–66]. 4.1.2. Psychological features Under the current multiaxial nosological approach, more than 90% of patients with PNES have psychiatric comorbidity (although in many cases it could be argued that PNES are actually most easily understood as a manifestation of another psychiatric disorder than a "co"-morbid condition). Patients most commonly fulfill the current diagnostic criteria for other somatoform (22–84%), other dissociative (22–91%), posttraumatic stress (35–49%), depressive (57–85%), or anxiety (11– 50%) disorders [67]. Experts have suggested linking particular forms of psychopathology to particular interventions [68], but our understanding of how different psychopathologies relate to clinical presentations, optimal treatment interventions, or outcomes is limited [69]. Studies report that 25–67% of patients with PNES fulfill the DSM criteria for personality disorder [67]. Even more patients have unusual personality profiles in studies based on multiaxial self-report questionnaires. Such studies have identified at least two different clusters of personality pathology [70,71]: One group of patients is characterized by

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high levels of emotional symptoms (termed depressed neurotics or activated neurotics by one group [71]), and a second by apparently normal levels of emotionality (termed somatic defenders [71]). Patients in the second group have better outcomes in terms of seizure persistence and dependence on health-related benefits [40]; however, there are no high-quality treatment studies that have taken these potentially important personality profiles into account.

with PNES, which may allow us to be more specific with our prediction of treatment responses in the future. 5. Promising Areas of Research and Young Investigators 5.1. Tanvir U. Syed Reducing diagnostic delay

4.1.3. Semiological factors The clinical manifestations of PNES are as heterogeneous as those of epileptic seizures. Studies using cluster analysis have identified up to six subtypes of PNES semiology [72,73], but so far our knowledge of what a particular semiological type means (or how subjective seizure experiences are linked to visible seizure manifestations) is extremely limited [74–77]. Some experts have conceptualized PNES as a dissociative response to physical arousal associated with high levels of anxiety [78]. However, this interpretation does not seem to describe all forms of PNES. We (M.R.) recently completed a study analyzing the responses of 100 consecutive patients with VEEG-proven PNES to a questionnaire combining questions from the Present State Examination (to elicit ictal symptoms of anxiety) and the Dissociative Experience Scale Taxon (to find out about pathological dissociation) [79,80]. The analysis of summary scores based on the calculated summary “anxiety” and “dissociation” scores showed a positive correlation between “anxiety” and “dissociation” (r=0.514, Pb 0.001). This suggests that some patients may well experience their PNES as a dissociative response to high levels of perceived anxiety. However, there are other patients who experience neither significant anxiety nor dissociative symptoms and who still pass out in the absence of epileptic discharges or other identifiable physiological abnormalities [81]. Future research could evaluate if the “dissociation” versus “conversion” discussion is an artifact of the artificial dichotomous categorization of DSM or a continuum of behavior. Our study also showed how varied other PNES experiences are. Few patients ticked the "never" and "always" options when prompted to endorse a large range of possible physical or mental ictal symptoms. Individual patients typically reported experiencing a range of seizure severity or symptoms. However, commonalities shared by roughly 50% of responders revealed that events tend to come on out of the blue without any warning and involve a lack of awareness of what is happening or a state in which the patient is conscious but cannot react to things. Afterward, about one-half of the patients have muscle aches. To date we do not know how or whether particular types of interictal psychopathology are associated with particular forms of seizure experience or manifestations. The limited knowledge we have suggests that patients with a previous history of sexual abuse tend to have more "severe" PNES disorders (more florid motor manifestations, prolonged seizures, emergency admissions) [40]. We are also aware that patients with more "severe" PNES disorders have a greater number of other unexplained symptoms (reflected by somatization scores) [52], higher levels of psychopathology, and more frequent dissociative experiences [75]. Future studies, it is hoped, will allow us to get better at reading the clues contained in the demographic, interactional, experiential, and semiological information available when a doctor first encounters a patient with PNES. Equipping clinicians with this knowledge will enable them to explain the diagnosis of PNES better. This may help overcome some of the considerable problems with engaging patients in treatment programs [82]. Future research will not have to rely on purely observational or self-report methods. One recent study has demonstrated that the interictal psychopathology associated with PNES can also be studied with physiological methods of investigation [83]. Another recent study identified low brain-derived neurotrophic factor in patients with PNES [84]. The findings of these studies suggest that we may be able to identify biomarkers for subgroups of patients

My first encounters with delay in diagnosis of PNES were as a neurology resident in a south Florida hospital with a three-bed inpatient epilepsy monitoring unit (EMU). One to two years into training, my fellow residents and I began to place wagers on whether we could predict, prior to the start of VEEG, if an EMU admission was going to prove epileptic or nonepileptic. Our “predictions” were made at three “well-defined” points in time: on catching a glimpse of the patient on arrival to the EMU, after hearing the patient's history, and after viewing only a video clip of a seizure recorded during the EMU stay (i.e., blinded to concurrent EEG tracings). Although we did not tabulate or statistically assess our “predictions” in the form of scientific research, we certainly reached some general conclusions. In some patients, we correctly predicted PNES with high confidence (personal, not statistical) based on patients’ interictal appearance and behavior. At times our predictions were “severely” incorrect, and we attributed this to discrepancies between what patients’ family members reported to occur during seizures and what we actually observed on EMU seizure videos. Third, whether assessing appearance, history, or seizure videos, it was generally easier to rule in PNES than to exclude it. Nevertheless, it was astonishing to learn on history taking that patients we diagnosed in our EMU with PNES had been misdiagnosed with epilepsy for 10–15 years, on average; whereas a group of budding neurologists were able to discern psychogenicity based solely on appearance or history. Just as puzzling, our “predictions” were even more accurate when we viewed EMU video clips of PNES, without accompanying EEGs, which begs the question: Why do these patients’ medical records indicate prior intubation and pharmacological sedation for bouts of “status epilepticus”? Thus, what started out as mundane observations and friendly wagers among a group of trainees turned into conceptual frameworks that underlie our current research in reducing delay in diagnosis of PNES. 5.1.1. Development of a self-administered screening questionnaire Our first observation, that one could potentially identify patients with PNES on the basis of appearance and behavior, led us to investigate the use of demographics and psychosocial information for distinguishing patients with PNES from patients with epilepsy. We sought to develop and validate a self-administered PNES screening questionnaire that patients experiencing seizures could complete in an outpatient setting, even prior to seeing a specialist [85]. Analysis of completed questionnaire items could generate an immediate prediction of PNES diagnosis and cue referral for VEEG confirmation of the diagnosis. Several prior studies had reported demographic and clinical history variables that were specific to PNES. Some studies have estimated the diagnostic accuracy of psychological and neuropsychological batteries in distinguishing patients with PNES from patients with epilepsy, although results were not consistent across multiple studies of the same inventories [86]. After reviewing the literature, we conducted a pilot study on outpatient and EMU populations to identify potential PNES indicator variables that could formulate a screening questionnaire [87]. Our pilot study yielded 26 variables (corresponding to 209 questionnaire items) pertaining to demographics, clinical history, and psychosocial identifiers of PNES. In a subsequent study, we prospectively tested these 26 variables on consecutive patients admitted to an academic epilepsy center's EMU. We learned from our pilot study that predictor variables from the three domains (demographics, clinical, psychosocial) were not simply

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additive predictors, but rather they interacted with one another in a complex nonlinear manner. For example, high seizure frequency and social support may predict PNES in women, whereas the opposite may indicate PNES in men. Therefore, in place of traditional statistical prediction models (e.g., logistic regression), we implemented artificial neural networks that detect and capitalize on nonlinear, multilevel interactions of questionnaire responses to generate a diagnostic prediction. Two variable filtering procedures reduced the questionnaire to 53 items, corresponding to 10 variables. The questionnaire and computational model were prospectively validated on naïve subsets of patients at two independent epilepsy centers, and predicted PNES with an overall accuracy of 86%. Advantages of this screening questionnaire include that it is self-administered and consists of “nonoffensive” items (i.e., there are no items pertaining to abuse, psychiatric illness, or items suggesting feigning of illness). Limitations of this questionnaire include that cognitively impaired patients cannot participate, PNES prediction requires complex computational processing of item responses, and despite avoiding certain “off-putting” items, the questionnaire does not capture important predictive information that abuse and psychiatric history may offer. Furthermore, it remains unclear how accurately the questionnaire will predict PNES when completed by outpatients in a waiting room just prior to physician visit. We are currently working to refine the questionnaire further, assess its applicability and accuracy in the outpatient setting, and implement an online, computerized version. 5.1.2. Using semiological observations to reduce diagnostic delay The second observation, mentioned at the start, led us to study semiology for reducing delay in diagnosis of PNES. The literature offers a plethora of semiological signs that might distinguish PNES from epileptic seizures; however, much of the data on these signs is several steps removed from being considered clinically useful for reducing delay in diagnosis of PNES. To begin with, most putative signs of PNES are not supported by well-designed prospective VEEG studies [88,89]. Most studies are retrospective, in which investigators who work in an EMU hypothesize a sign to distinguish PNES and epileptic seizures based on their experience observing patients with PNES undergo VEEG. In addition to the known pitfalls of retrospective studies (e.g., “unclean” data collection, publication bias), it is no surprise that these studies generate high sensitivities and specificities, as the investigators are simply testing a hypothesis and quantifying a result in a population in which they already observed the hypothesis to be true (selection bias). Moreover, it is easy for investigators to “hallucinate” the presence or absence of a sign in a seizure video, especially if the investigators are convinced that the hypothesized sign can differentiate PNES and epileptic seizures (observational bias). These factors may partially explain discrepancies and variations in reported diagnostic accuracies of semiological signs [89]. An additional major element that VEEG semiology studies neglect is assessment of how accurately eyewitnesses of patients’ seizures can report the presence or absence of a given semiological sign during history taking. That is, the true value of seizure semiology for reducing delay in diagnosis of PNES lies in history taking, during the first outpatient visits, where practitioners can inquire about PNES early in the course of disease by asking eyewitnesses of patients’ seizures to confirm presence or absence of PNES-specific signs [6]. It follows that semiology can help reduce delay in diagnosis of PNES only to the extent that eyewitnesses can recall whether or not seizure-specific signs have actually occurred in patients’ seizures [90]. For example, ictal hemibody piloerection may have a high specificity for temporal lobe epilepsy [91], yet it is of little use in ruling out PNES as lay (or even physician) eyewitnesses would be unlikely to accurately report its presence (or absence). Essentially, many of the pitfalls of retrospective VEEG studies can be overcome if studies include a prospective validation phase (or follow-up study) that uses multiple, independent, EEG- and diagnosis-blinded epileptologists to assess

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seizure videos for the presence or absence of well-defined semiological signs. Blinding is crucial in VEEG studies because it is already a challenge to truly and fully blind an epileptologist to diagnosis during seizure video review, as most specialists can accurately determine the diagnosis (and what concurrent EEG tracings would look like) just by observing seizure semiology. In addition, investigators should assess how accurately eyewitnesses can assess PNES signs by comparing eyewitness testimonies of patients’ seizure semiology with seizure video findings during VEEG. 5.1.3. Limitations of witness reports of semiological signs Our research with semiology illustrates the importance of adhering to the aforementioned principles when studying PNES signs. Our first PNES semiology study looked at ictal eye closure. Several retrospective studies suggested that ictal eye closure is a specific sign of PNES [86], and one of these studies in particular reported sensitivity and specificity near 100% [23]. With great hopes of proving ictal eye closure to be the “ideal” solution for screening for PNES, we attempted to replicate these findings in a rigorous, prospective fashion [24]. First, we used multiple, independent, EEGand diagnosis-blinded epileptologist reviewers prospectively to assess whether video-documented ictal eye closure during VEEG could truly differentiate PNES from epileptic seizures. In addition, prior to VEEG, we interviewed subjects’ family members who had witnessed seizures, and we compared their seizure testimonies with EMU seizure video findings to investigate how accurately they could report whether or not subjects’ eyes were closed during seizures. Finally, we estimated how accurately family members’ reports of ictal eye closure, prior to VEEG, could predict VEEG-ascertained PNES. In summary, we determined that video-recorded ictal eye closure was relatively specific (92%), but not as sensitive (64%) for PNES as previously reported. More importantly, family members who had witnessed subjects’ seizures, prior to VEEG, were not able to accurately report presence or absence of ictal eye closure. Our ‘ictal eye closure’ results prompted a more extensive study in which we employed similar methodology to prospectively investigate 48 literature-postulated semiological signs for distinguishing between PNES and epileptic seizures in a statistically powered consecutive patient cohort [90]. Of the 48 signs, our results identified only three signs of PNES (“preserved awareness,” “eye flutter,” “seizure intensifies or subsides when others verbally or physically intervene”) and three signs of epileptic seizures (“abrupt onset,” “eye opening/ widening,” postictal “confusion/sleep”) that were statistically significant and reliable indicators of seizure type when independently documented by multiple, EEG- and diagnosis-blinded epileptologist reviewers of EMU seizure videos. To make certain that our findings were not due to chance, we prospectively validated these six signs in a second statistically powered consecutive patient cohort. On comparing family members’ testimonies with seizure video findings, similar to our ictal eye closure results, we found that family members were not able to accurately report presence or absence of the six seizurespecific signs mentioned above. In fact, semiological signs that family members did report accurately (e.g., ictal screaming, weeping, postictal vomiting) were poor identifiers of VEEG-ascertained seizure type. Nevertheless, our results offer a potential solution to reducing delay in diagnosis of PNES, by shedding light on six semiological signs that seizure patients’ family members should be educated about to help identify seizure type early in the course of disease. Specifically, during the first outpatient encounters, practitioners should instruct potential eyewitnesses of patients’ subsequent seizures to pay attention to rapidity of onset and patients’ eyes at the start of seizures. Additionally, eyewitnesses should be educated on how to assess level of awareness (e.g., “show me two fingers”) and “reactivity to surroundings”’ during seizures and immediately after seizures to assess for confusion/sleep. Our current and future projects entail the use of patient- and practitioner-oriented educational material to

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better ascertain seizure semiology with the goal of identifying PNES early in the course of disease. We believe there is indeed a role for semiology in predicting PNES, although not without education and proactive involvement of patients and their family members. On a final note pertaining to this study, the interrater reliability of VEEG diagnosis in our cohort was “excellent” (к = 0.94), in contrast to the study by Benbadis et al. [26], which found moderate agreement (к = 0.57). There are several reasons that explain why our interrater reliability estimates were higher than those of Benbadis et al., most of which were “foretold” in the Benbadis et al. study discussion. Compared with Benbadis et al., we only used 2 (vs 22) epileptologists as raters, and consistent with practice convention, we granted raters access to data from all (vs one) VEEG seizures for each subject, we granted raters access to history, physical examination, and imaging data, and we restricted raters’ documentation to only “epileptic” or “nonepileptic” seizures (vs “epileptic,” “psychogenic nonepileptic,” or “physiological nonepileptic” seizures). Our results reaffirm the “gold standard” authenticity of VEEG for PNES diagnosis, although underscoring the importance of incorporating the “entire clinical picture.” Our third observation, mentioned at the start of this piece, was a prelude to our conclusion that it will be more challenging to find PNES signs that are sensitive than specific. We agree with Dr. Benbadis that clusters and combinations of signs stand a better chance of predicting PNES than individual features, although the number of combinations is exponentially high and would need to be studied with great rigor. The difficulty in pinpointing a sensitive PNES sign (or combination of signs) more or less reflects the high degree of variation in PNES phenotypes and, perhaps, genotypes, which we are hoping Dr. LaFrance and others will be able to identify in the future. 6. Promising Areas of Research and Young Investigators 6.1. Richard J. Brown Psychological mechanisms of psychogenic nonepileptic seizures As the overview by Dr. Benbadis, Dr. LaFrance and Dr. Reuber indicates, the majority of research in this area has focused on seizure semiology, distinguishing epileptic from nonepileptic seizures psychiatric comorbidity, and the personality correlates of PNES. Although these are crucial issues, they reveal relatively little about the pathogenesis of these events. Indeed, despite being recognized as a psychiatric phenomenon since the 17th century, the exact psychological mechanisms of PNES remain poorly understood. The lack of a widely accepted framework for understanding PNES is arguably one of the main reasons why treatments for PNES remain so limited. Developing such a framework and using it to improve the psychological treatment of PNES are the overarching goals of my work in this area. 6.1.1. Previous psychological models for psychogenic nonepileptic seizures Various ways of understanding PNES have been suggested, including the conversion of anxiety into somatic complaints [92], a dissociative response to overarousal [78] or traumatic events [93], a learnt behavior [94], a maladaptive coping strategy [95], a form of communication [96], or a combination of these. Few of these concepts have been developed or studied in detail in relation to PNES, however, and each is able to account for only limited aspects of the domain in question. Rather than seeing these approaches as mutually exclusive, I have sought to develop a model that unifies many of these concepts within a common framework that describes PNES in cognitive psychological terms [97–101]. The model assumes that similar processes are involved in PNES and many other “medically unexplained” symptoms (MUS) that characterize the

somatoform and dissociative disorders, as well as comparable phenomena elicited using suggestion or hypnosis. 6.1.2. A new psychological model for psychogenic nonepileptic seizures To explain these phenomena, the model describes some of the basic processes underlying conscious experience and the control of behavior. By this view, the basic contents of consciousness are a working model of the environment generated through the interpretation and organization of sensory data by information in memory. This working model serves as triggering input to behavioral systems, with routine behavior being controlled by well-learnt cognition and action programs selected automatically via a competitive scheduling process. This provides the system with a means of controlling cognition and action that is rapid, is highly efficient, and consumes relatively few processing resources. Much complex behavior can be managed at this level, with minimal selfawareness and conscious effort. Novel actions, in contrast, involve a higher-level attentional system that operates by biasing the activation of these simpler programs. Unlike routine actions, behavior controlled at this level is perceived as deliberately “willed” and is associated with a sense of effort and self-awareness. One crucial implication of this account is that both consciousness and behavior can be distorted by disproportionately active material in memory, leaving us prone to both misperceptions and behaviors that conflict with goals in self-awareness. When the material in memory pertains specifically to physical illness or symptoms, MUS can result. In the case of PNES, symptoms arise from the automatic and unwanted activation of an action program, with seizure semiology and phenomenology being determined by the contents of this “rogue” mental representation. Possible origins of these representations include direct exposure to seizures in oneself or others, sociocultural transmission (e.g., from information about seizures in the media), and verbal suggestion from relevant individuals (e.g., health care providers). Various factors that might contribute to the activation of rogue representations are identified in the model, including anxious anticipation of further seizures, hypervigilance for physical or emotional symptoms that might signal seizure onset, worry and rumination, positive and negative reinforcement, and illness behaviors such as avoidance, reassurance seeking, and excessive health care utilization. One aspect of the model that is relatively undeveloped is the question of why some people are less able to inhibit this automatic activation process than others. Disturbances in high-level attentional (i.e., frontal) systems are likely to be an important aspect of this, with both developmental (e.g., dysfunction arising from early neglect, abuse, and/or insecure attachment) and situational (e.g., dysfunction arising from acute or chronic stress) factors playing a role [8,12,98,102]. 6.1.3. Clinical relevance of a new psychological model for psychogenic nonepileptic seizures Although the heterogeneity of patients with PNES suggests that treatment targets and techniques will vary from case to case, the model identifies processes that are common to all PNES and, therefore, interventions that have potentially universal application. According to this approach, an important aspect of psychological treatment for PNES would be to target factors that maintain the activation of relevant action programs and seek to improve high-level attentional control over these mental representations. An obvious strength of this model is that it explains how PNES can be psychological in origin while still being involuntary phenomena. It also demonstrates that PNES can develop even when the sufferer is not psychiatrically unwell or incapable of experiencing or conveying distress more directly. Dr. Reuber and I have recently completed a cluster analytic study showing that more than 40% of patients with symptomatic PNES do not have high levels of anxiety, depression, emotion dysregulation, or attachment disturbance [article in preparation]. When comparable findings have been obtained in other

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studies [70,71], it is normally concluded that the patients in question must be suppressing or otherwise defending against distressing material by producing physical symptoms. The new model provides a more parsimonious explanation of this phenomenon, one that is arguably more palatable and face valid to patients. Importantly, however, the model is also able to explain how emotional disturbance and the avoidance of distressing material can, and often do, feed into the development and maintenance of PNES. As such, the model accommodates the heterogeneity of patients with PNES with relative ease. Allowing for this heterogeneity in future empirical studies will be a challenging but essential task. 6.1.4. Two types of dissociation: Compartmentalization and detachment A second strength of the model is that it elucidates other concepts that have been applied to PNES, but not developed in detail. For example, the model goes further than previous dissociative accounts of PNES [e.g., 93,103] by explaining the precise nature of this dissociation in information processing terms. By this view, PNES are dissociative in the sense that they involve a “compartmentalization” of information within the cognitive system, leading to a loss of control over normally accessible mental functions [101,104]. According to the model, this compartmentalization arises when high-level attentional systems become unable to inhibit the automatic activation of a lowlevel action program, resulting in involuntary and undesirable behaviors. Our theoretical work [97,101,104] suggests that a similar process of compartmentalization characterizes other dissociative phenomena, including dissociative amnesia, dissociative identity disorder, and other pseudoneurological symptoms, consistent with the increased prevalence of dissociative symptoms in patients with PNES [105,106]. Importantly, however, we have distinguished between these phenomena and conditions such as depersonalization disorder, in which the predominant experience is one of “detachment” from the self or world. Although such alterations in consciousness are also widely regarded as dissociative, we have argued that they are qualitatively different from compartmentalization phenomena, with distinct mechanisms, correlates, and treatment implications [101,104]. While detachment experiences of this sort are reported by many patients with PNES, and may even be labeled as nonepileptic events in their own right, the model assumes that they are quite different from “true” PNES that involve compartmentalization. Differentiating between these phenomena is important because treatment may be quite different depending on the type of dissociation involved. Detachment is also common in epilepsy, which may explain studies that have failed to find a difference between patients with epilepsy and patients with PNES on measures of dissociation that tend to emphasize detachment rather than compartmentalization symptoms [e.g., 107,108]. We tried to address this issue by measuring detachment and compartmentalization separately in a small study comparing patients with epilepsy and those with PNES [109]. As predicted, we found that the two groups differed only on the compartmentalization measure, suggesting that this phenomenon was specific to the PNES group. When anxiety and depression were controlled for, however, the two groups were comparable on both types of dissociation. We believe that this is due to the limitations of the measures used in this study, which were based on symptoms thought to be associated with detachment and compartmentalization tendencies rather than underlying mechanisms. One problem with this approach is that symptoms are often nonspecific and could be examples of either detachment, compartmentalization, epilepsy, or a combination of these. It also assumes that experiencing one form of compartmentalization (e.g., PNES) would necessarily be associated with a tendency to experience other compartmentalization symptoms (e.g., medically unexplained paralysis), which may be inappropriate. Comparing patients with PNES more typical of detachment or compartmentalization phenomena might be a better option in future studies.

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6.1.5. Future plans I am in the process of developing a revised version of the model as it pertains to PNES that identifies factors that distinguish this phenomenon from other medically unexplained neurological symptoms and addresses the issue of patient heterogeneity in greater detail. Understanding the nature of this heterogeneity is a crucial issue, as is ensuring that sample sizes are large enough to accommodate it in studies addressing the psychological characteristics of patients with PNES. I am especially interested in the subgroup of patients who seem to have relatively normal levels of emotionality, for whom the model may be particularly relevant. In our cluster analytic study we found that these individuals had relatively high scores on the somatoform dissociation questionnaire, suggesting a more general tendency to experience body distortions in this group. This concept is more explicit in the latest version of the model and much of our recent research has focused on developing a paradigm to study the processes underlying this tendency, with promising early results [110]. Applying this paradigm to patients with PNES is a priority for future studies. There is also a need for research testing other hypotheses from the model, particularly the idea that frontal attentional dysfunction is an important factor in the development of PNES. Research into the model is still at an early stage and it will be some time before its clinical potential (or otherwise) is properly understood. In the meantime, there is a pressing need for further research into existing psychological treatments for PNES. To that end, I have been working with Dr. Reuber and the United Kingdom-based Nonepileptic Seizure Treatment (NEST) collaboration to develop a stepped-care treatment package for PNES, consisting of a protocol for communicating the diagnosis [37], a brief psychoeducational treatment to address important maintaining factors and support healthy problem solving, and a tailored intervention for persistent PNES based on Psychodynamic Interpersonal Therapy principles [111]. Developing and evaluating this package will be an important aspect of my future research in the area. I am hopeful that the theoretical ideas outlined above will inform and extend this work. References [1] Diagnostic and statistical manual of mental disorders. Washington, DC: American Psychiatric Assoc.; 1994. [2] The ICD-10 classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Geneva: WHO; 1992. [3] Reuber M, Fernandez G, Bauer J, Helmstaedter C, Elger CE. Diagnostic delay in psychogenic nonepileptic seizures. Neurology 2002;58:493–5. [4] Da Mota Gomes M, De Souza Maia Filho H, Aparecida Martins NoÇ R. Antiepileptic drug intake adherence: the value of the blood drug level measurement and the clinical approach. Arq Neuropsiquiatr 1998;56:708–13. [5] Niedermeyer E, Blumer D, Holscher E, Walker BA. Classical hysterical seizures facilitated by anticonvulsant toxicity. Psychiatr Clin (Basel) 1970;3:71–84. [6] Dworetzky BA, Bubrick EJ, Szaflarski JP. Nonepileptic psychogenic status: markedly prolonged psychogenic nonepileptic seizures. Epilepsy Behav 2010;19:65–8. [7] LaFrance Jr WC, Benbadis SR. Avoiding the costs of unrecognized psychological nonepileptic seizures. Neurology 2006;66:1620–1. [8] Benbadis SR. A spell in the epilepsy clinic and a history of "chronic pain" or "fibromyalgia" independently predict a diagnosis of psychogenic seizures. Epilepsy Behav 2005;6:264–5. [9] Benbadis SR. Hypergraphia and the diagnosis of psychogenic attacks. Neurology 2006;67:904. [10] Benbadis SR, Wolgamuth BR, Goren H, Brener S, Fouad-Tarazi F. Value of tongue biting in the diagnosis of seizures. Arch Intern Med 1995;155:2346–9. [11] Reuber M, Monzoni C, Sharrack B, Plug L. Using Conversation Analysis to distinguish between epilepsy and non-epileptic seizures: a prospective blinded multirater study. Epilepsy Behav 2009;16:139–44. [12] Benbadis SR, Tatum WO. Overinterpretation of EEGs and misdiagnosis of epilepsy. J Clin Neurophysiol 2003;20:42–4. [13] Benbadis SR, Lin K. Errors in EEG interpretation and misdiagnosis of epilepsy: which EEG patterns are overread? Eur Neurol 2008;59:267–71. [14] Benbadis SR. Misdiagnosis of epilepsy due to errors in EEG interpretation. Pract Neurol 2007;7:323–5. [15] Smith D, Defalla BA, Chadwick DW. The misdiagnosis of epilepsy and the management of refractory epilepsy in a specialist clinic. Q J Med 1999;92:15–23. [16] Benbadis SR, Lancman ME, King LM, Swanson SJ. Preictal pseudosleep: a new finding in psychogenic seizures. Neurology 1996;47:63–7.

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