566881 research-article2015

EEGXXX10.1177/1550059414566881Clinical EEG and NeuroscienceWillment et al

Article

Cognitive Impairment and Evaluation in Psychogenic Nonepileptic Seizures: An Integrated Cognitive-Emotional Approach

Clinical EEG and Neuroscience 2015, Vol. 46(1) 42­–53 © EEG and Clinical Neuroscience Society (ECNS) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1550059414566881 eeg.sagepub.com

Kim Willment1,2,3, Melanie Hill1, Gaston Baslet2,3, and David W. Loring4

Abstract Neuropsychological studies comparing patients with psychogenic nonepileptic seizures (PNES) to those with epilepsy have been largely equivocal. The variability in the neuropsychological literature highlights the heterogeneity of the PNES population across a number of psychiatric and neurologic factors. Phenotypic presentations in PNES arise from complex interactions between vulnerable cognitive and emotional systems. We propose that variability in neuropsychological findings in PNES emerge in the context of diverse psychiatric, neurologic, and clinical factors. Traditional assessments that fail to integrate cognitive and emotional/behavioral profiles sufficiently would fall short in characterizing the complexity of brainbehavior relationships in this population. To advance the neuropsychology of PNES, we propose a systematic approach to measure a number of factors that influence cognitive impairment in this population. We begin by reviewing the current neuropsychological literature in PNES and discussing a number of factors that influence cognitive deficits. We then present a comprehensive neuropsychological battery designed to capture elements (cognitive dysfunction, psychopathology, emotion processing deficits) underlying the proposed vulnerable cognitive-emotional system in PNES. It is our hope that the proposed battery will facilitate the aggregation of data across neuropsychological investigations, to allow more advanced statistical analyses, and ultimately enhance our understanding of PNES and the development of effective management and treatment options. Keywords neuropsychology, PNES, psychogenic seizures, cognition

Introduction Individuals with PNES often present with cognitive complaints that significantly contribute to functional impairment. To address these concerns, patients frequently undergo a neuropsychological evaluation to characterize cognitive functions across multiple domains (eg, attention, memory, language, executive functioning). The neuropsychological literature comparing patients with PNES to those with epilepsy has been largely equivocal, with reports of worse cognitive performance in PNES,1,2 better performance in PNES,3 and no difference between the two populations.4-9 The variability in these findings has been attributed to several factors, particularly the psychiatric and neurologic heterogeneity of the PNES population.10 Conceptual models of PNES11-13 propose that complex interactions between vulnerable cognitive control and emotional systems underlie the varied phenotypic presentations of this disorder. The “vulnerable cognitive-emotional system” model proposes that an emotionally valenced stimulus (internal or external) can “destabilize” or desynchronize the components of the cognitive-emotional system, and interfere with the coordination of attentional resources, resulting in aberrant behavioral, cognitive, and/or sensorimotor responses.11 This and other

conceptual models not only predict the presence of cognitive deficits in PNES, but also suggest that the careful characterization of emotional and psychopathological functioning is necessary to fully understand these deficits. Recent resting-state functional magnetic resonance imaging (fMRI) studies in PNES support the vulnerable cognitive-emotional model, by demonstrating alterations in connectivity between emotional, executive control, and sensorimotor networks.14,15 Variability in the neuropsychological literature in PNES emerges in the context of diverse psychiatric, neurologic, and clinical factors. As such, it may be that traditional assessment 1

Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA 2 Department of Psychiatry, Brigham and Women’s Hospital, Boston, MA, USA 3 Harvard Medical School, Boston, MA, USA 4 Departments of Neurology and Pediatrics, Emory University, Atlanta, GA, USA Corresponding Author: Kim Willment, Department of Psychiatry, Brigham and Women’s Hospital, 221 Longwood Avenue M80, Boston, MA 02115, USA. Email: [email protected]

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Willment et al fails to integrate cognitive and emotional/behavioral profiles, and thus fall short in characterizing brain-behavior relationships in this population. Therefore, a systematic approach to measure factors that influence cognitive impairment is needed to advance the neuropsychology of PNES. A number of research questions remain concerning how best to characterize the heterogeneity of PNES (etiology, cognition, psychopathology, emotion processing style). The framework described may support the development of a more unified approach to understanding cognitive-emotional vulnerabilities in PNES. We begin by reviewing the current neuropsychological literature and discussing diverse factors proposed to influence cognitive deficits. We then present a battery designed to capture cognitive, psychopathological, personality, and emotional factors proposed to influence cognitive impairments in PNES. This battery aims to capture elements implicated in the cognitiveemotional system model.

Current Neuropsychology of PNES Despite variability in the neuropsychological literature comparing epilepsy with PNES, individuals with PNES often perform outside normal limits on objective cognitive measures.1,3,16-18 In the next section we review the neuropsychological literature in PNES by individual cognitive domain. The purpose is to highlight evidence that may clarify the variability. In cognitive domains, where no discernible patterns have been reported, we discuss research questions.

Attention and Executive Functioning Altered attention is perhaps the most consistent finding reported in individuals with PNES,8,17 and it has been argued that impaired attention plays the main role in cognitive deficits in PNES.5 These attention problems are considered “nonspecific” because it is unclear whether they are specific to PNES or a network disruption common to many psychiatric and neurologic conditions. Attention is conceptualized as a multiple component process19-21; however, neuropsychological studies in PNES have not carefully characterized which specific components of attention (selective, divided, sustained, executive) are impaired. Recharacterization of existing findings within more detailed frameworks of attention, and further investigation of attention components, may clarify the specific problems in PNES. For example, larger mismatch negativity responses (electrophysiologic responses to a novel stimulus in a sequence of repetitive stimuli) have been reported in PNES.22 This finding suggests heightened vigilance, or diminished ability to ­filter out irrelevant sensory stimuli. Executive attention, or cognitive control, involves the selection of an optimal course of action to achieve a goal, and require intent to act, focus on available response alternatives and selection.20 As the name implies, executive attention overlaps traditionally considered executive function. Response inhibition, sustained attention, visuosmotor sequencing and set-shifting all require executive attention to maintain a focused response,

while simultaneously inhibiting others. Studies of response inhibition and visuomotor set-shifting have found impaired performances in PNES.4,23 Insular and cingulate cortices demonstrate aberrant functional connectivity within the executive control network in PNES,24 suggesting a mechanism for dysfunctional attentional processes involved in response selection, salience, and inhibition.25-27 Weaknesses in working memory and cognitive flexibility have also been reported on tests of set-shifting and problem solving.23 Earlier age of onset, and greater frequency of events, have been associated with reductions in executive function in PNES, most notably on a visuomotor sequencing and setshifting task.23 Furthermore, as discussed in greater detail below (see Dual Cognitive-Emotion Task section), emotionally stressful experimental manipulations are associated with executive control deficits in these patients.28-30

Memory Verbal memory impairments in PNES have been shown to be comparable to those seen in temporal lobe epilepsy (TLE).31 Kent et al31 also found greater verbal memory impairments with increased duration of spells and earlier age of onset. The etiology of these memory deficits is unclear, but studies have shown hippocampal atrophy in chronic stress-related psychiatric disorders, including posttraumatic stress disorder, dissociative disorders, and severe depression,32 all highly comorbid with PNES. Twin studies of PTSD have also found evidence that hippocampal volume reductions may be a vulnerability factor for the development of mood and anxiety disorders, as opposed to an acquired pathology.33 Recognition memory response patterns discriminate between individuals with PNES and epilepsy, such that PNES patients have increased memory sensitivity (ability to discriminate between targets and distractors) and demonstrate a negative response bias.18 The authors suggest that these findings are less related to hippocampal-based memory functioning in PNES, but rather to higher-order attentional and executive functioning that result in differences in decision-making or response biases (negative or nay-saying bias).18 In fact, executive functioning performance has been shown to strongly relate to verbal, and even visual, memory performance, regardless of format or content (presence of semantic structure), particularly during encoding and retrieval.34 Several important questions are raised by this research, including the identification of which components of attention and executive functioning affect memory performance and whether there is a unique pattern in PNES.

Language Language performance, particularly confrontation naming, has been strongly related to general verbal skills in PNES,35 suggesting a role for factors related to lexical exposure instead of an acquired language deficit. A study of the type and frequency of errors, during confrontation naming, found no difference in frequency of semantic errors between PNES, dominant TLE, and nondominant TLE groups. However, dominant TLE

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patients produced significantly more phonemic errors than did the nondominant TLE and PNES groups.35 Patients with epilepsy, regardless of laterality, produced greater phonemic and semantic errors than did PNES patients. These findings suggest that the types of language errors common in PNES differ from language impairment often associated with TLE, particularly TLE within the language dominant hemisphere. TLE and PNES patients have comparable verbal fluency deficits on rapid word generation trials.23 Reduced verbal fluency in PNES, however, has been attributed to attention and executive functioning difficulties that can impact the efficiency of information retrieval more generally.23

Visuospatial Functioning Visuospatial skills have not been systematically studied in PNES; however, posterior parietal cortex abnormalities, involved in visuospatial and integrative bodily related processes, have been described in conversion disorder populations.36 One study reported somewhat contradictory findings with longer PNES duration associated with better perceptual/ constructional performance.23 In contrast, the authors found the expected pattern of longer disease duration and reduced visuospatial functioning in TLE patients. Executive functioning deficits can certainly impact performance on visuospatial tasks. Therefore, future research in PNES should attempt to clarify the role of attention and executive functioning in visuospatial deficits. In addition, determining whether posterior parietal cortex abnormalities are comparable in PNES and other conversion disorders, and whether these correspond with visuospatial deficits may be informative.

Personality Profiles Most personality studies, focusing on sensitivity to discriminate PNES from epilepsy, have reported good success.16,37-41 Both the Minnesota Multiphasic Personality Inventory (MMPI-2/MMPI2-RF) and the Personality Assessment Inventory (PAI) differentiate PNES from epilepsy;39-42 the PAI has greater overall differential diagnostic accuracy at 74% compared with MMPI’s 69%.43 This discrepancy may be related to differences in the psychometric properties, as the PAI has nonoverlapping, conceptually derived clinical scales, while MMPI items contribute to multiple clinical scales.44 The Conversion “V” profile is the most common finding on the MMPI/MMPI-2. This pattern describes greater elevations of hypochondriasis (scale 1) and hysteria (scale 3) than on depression (scale 2).37 On the MMPI-2-RF, PNES shows elevations on validity scales that characterize infrequent somatic responses and symptom validity, in addition to elevations on restructured clinical scales that identify somatic complaints and cynicism.39 These patterns have an overall accuracy of 71% in discriminating PNES from epilepsy.6 In the context of the Conversion “V” profile, patients with uncertain seizure etiology, are 5 times more likely to be diagnosed with PNES by video EEG.45 In terms of the PAI,40 a PNES diagnosis was reported to be approximately 15 times more likely when scores

on the Health Concerns subscale were less than scores on the Conversion subscale.

Performance Validity Neuropsychological testing typically includes formal measures designed to reflect whether patients are sufficiently engaged so that results can be considered to reflect true ability levels.46 Although these tests are often called measures of effort or motivation, they are increasingly called performance validity measures since they cannot determine an underlying reason for poor performance.46 It is important to recognize, however, that performance validity measures are also influenced by true ability levels,47 and that failure criterion, including performance thresholds to infer invalid responding, have not yet been fully established. Performance validity failure rates, in PNES, are reported to be higher (at 28% or greater), compared with 8% in individuals with epilepsy and the general medical population.48,49 Malingering or the volitional manipulation of symptoms for secondary gain, is not a major factor in the etiology of PNES50 or the main source of variability in performance validity findings. Such variability may be due to a number of internal factors not under volitional control (emotional conflict, psychiatric severity/complexity, distress). Pain and depression are not associated with poor performance validity scores,51-53 suggesting that mood symptoms and psychological distress alone do not explain poor scores. A role of the dysregulated deployment of attentional resources has been proposed, as individuals with PNES may alternate between states of hyper- and hypoarousal,11 as has been observed in individuals with trauma histories.54 This pattern of alternation between attentional states may lead to periods of fixation or compulsivity and periods of distractibility and disengagement. Thus, reduced performance validity may not invalidate neuropsychological data collected in this population; instead it may capture an important psychopathological phenomenon reflecting current, though potentially modifiable, cognitive abilities.

Dual Cognitive-Emotional Tasks Tasks, which directly measure the interaction of emotion and cognition, have demonstrated attentional biases, or heightened vigilance, to social threat in PNES.28 Reliable executive function impairments have been reported when PNES patients perform simultaneous cognitive and emotional processes.29 For example, PNES and controls performed face-categorization switching, indicating either an emotion (happy vs angry) or an age (young vs old). When switching between emotion and age the PNES group used the less effective emotion strategy of expressive suppression (hiding external signs of internal feelings, as measured by higher scores on an emotion suppression measure).29 Bakvis et al30 tested the impact of stress sensitivity on working memory, using neutral and emotional distractors on an N-back task, as well as N-back performance, after stress induction. They found more impaired working memory in individuals with PNES, relative to healthy controls, in the emotional but not the neutral condition. Stress induction improved

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Willment et al working memory for the control group but not the PNES group, and patients with higher cortisol stress-response showed greater working memory impairments.30 Emotional processing significantly influences cognitive performance in PNES. Individual variability in interpretation of stressful or threatening stimuli in PNES may explain some of the performance variability on cognitive tasks. Social cognition is a cognitive-emotional processing domain with useful standardized measures that are often included in clinical cognitive evaluations for autism spectrum disorders and frontotemporal dementia. Therefore, it may be reasonable to develop standardized dual cognitive-emotional tasks, such as the emotional distracter version of the N-back or emotional Stroop test to characterize the interaction between emotion and cognitive processing in clinical neuropsychological evaluations of PNES.

Factors Influencing Cognitive Impairments in PNES Conceptual and neuroimaging findings predict the presence of cognitive difficulties in PNES. However, the PNES population is psychiatrically and neurologically heterogeneous,10 which is reaffirmed by the neuropsychological literature. One way to approach this problem is to systematically account for factors proposed to influence cognitive impairment in PNES. In what follows, we outline a set of factors that characterize the heterogeneity of PNES. The neuropsychological literature has largely focused on comparisons of PNES to individuals with epilepsy and normal populations. By accounting for factors related to etiology, cognition, psychopathology, and emotional processing styles, it will be possible to develop a richer understanding of the vulnerabilities of cognitive and emotional functioning in this complex population.

Neurologic Implications A substantial proportion of PNES patients present with histories that implicate neurologic factors. They often undergo unnecessary antiepileptic drug (AED) treatment with cognitive side effects.55 They also have higher rates of structural and functional brain abnormalities compared with the general population, as documented by brain imaging, EEG abnormalities and increased rates of traumatic brain injury.56-58 However, it is unclear whether rates of structural and functional brain abnormalities are comparable or exceed those in comorbid conditions, such as major depression or dissociation, and whether these findings represent a vulnerability to or consequence of PNES. Given the potential neurologic factors in this population, neuropsychological studies have not appropriately taken such variables into account. In many studies it is unclear to what extent neurologic factors are based on subjective report of head injury versus those confirmed by medical records and/or imaging. In those cases where neurologic histories can be corroborated, it is unclear whether PNES cognitive profiles more closely resemble those of neuropathological lesions, psychopathological patterns, or a combination. A number of cognitive and behavioral side effects of AEDs (eg, anxiety, depression,

aggression, attentional and short-term memory difficulties, processing speed deficits) overlap with psychiatric symptoms common in PNES and make it difficult to determine the extent to which neuropsychological profiles can be attributed to any specific underlying etiology.

Psychopathological Mechanisms A number of psychopathological mechanisms, such as conversion/dissociation, somatization, and PTSD, co-occur in PNES (for a review, see Baslet11) and require examination in the context of a comprehensive neuropsychological evaluation. While these psychiatric disorders exist on a continuum, and their expression often overlaps, there is evidence of unique regional brain involvement for each mechanism, which may differentially affect cognitive functioning. Dissociation has been proposed as a common underlying factor in the etiology of PNES, and dissociative disorders have been reported in 22% to 91% of PNES patients (for a review, see Reuber59). Dissociation is generally viewed as a disruption of the usually integrated functions of consciousness, memory, identity, and perception.60 However, dissociation is a broad concept which can manifest in a variety of ways. For instance, dissociation is generally defined as the disruption of integrated psychological and cognitive functions; however, somatoform functions and reactions may also be susceptible to dissociation61 and a “bipartite model” of dissociation has been proposed.62 Psychological dissociation has been termed psychoform dissociation62 or detachment.63 Meanwhile, dissociation of somatoform functions is called somatoform dissociation61 and compartmentalization is a closely related concept.63 Somatoform dissociation aligns with the DSM-5 definition of conversion disorder (functional neurological symptom disorder) as they both describe dissociative disorders of movement and sensation.64,65 Studies using self-report measures of these separate forms of dissociation (psychoform and somatoform) tend to show elevations in both forms of dissociation in PNES62,66-68; however, these studies did not account for heterogeneity in their PNES samples, either in semiology or in psychopathology. Comparisons of somatoform dissociation/ compartmentalization between PNES and epilepsy patients have yielded variable results after controlling for levels of general psychopathology. Nonetheless, there is a general trend for significantly elevated somatoform dissociation in PNES.62,68 Likewise, findings of differences in psychoform dissociation/ detachment between PNES and epilepsy have been variable.62,66-70 Therefore, the extent that the PNES population may diverge according to this “bipartite model” of dissociation is currently unclear.62 However, studies of semiologic subtypes in PNES71 support this “bipartite model”. Several studies have described events with little motor involvement (long periods of immobility and unresponsiveness) and events with more prominent motor symptoms, as well as events with prominent subjective symptoms (sensory or emotional experiences, with retained consciousness and behavior).71,72 Patients presenting with nonmotor events (termed catatonic, according to Selwa’s classification73) endorsed lower levels of psychopathology and

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lower conversion symptom ratings on a personality inventory than did motor groups.74 The motor groups also had greater elevations on subscales describing brooding (worry, psychological distress) and lack of impulse control/dissociation of affect. These studies suggest a link between phenotypic presentation and underlying psychopathological mechanisms. Future neuroimaging studies that characterize both event type and psychopathology are necessary to determine the possible involvement of distinct brain systems. Neuroimaging studies of psychoform and somatoform dissociation14,24 have revealed an association between dissociation and altered working memory networks. Alterations in resting state networks may contribute to the variability of dissociative processes in PNES, as well as phenotypic presentation.24 Changes in the fronto -parietal network, involved in perception, visceral-somatic processing, and pain,74 appear to be related to perception that self-generated movements are involuntary. Furthermore, insular alterations may prevent PNES patients from recognizing and correcting maladaptive behavior. Finally, alterations in the cingulate gyrus may impact sensorimotor function through impaired response or action selection.24 While these findings are preliminary, they suggest that involvement of distinct brain regions contribute to unique cognitive profiles, which may explain some of the heterogeneity in the current neuropsychological literature in PNES. PNES events have also been conceptualized as expressions of posttraumatic stress disorder (PTSD).75 A meta-analysis examining the frequency of trauma and PTSD in PNES found that 44-80% of patients reported trauma, including physical and sexual abuse.76 PTSD is composed of both dissociative and intrusive symptoms,77 and PNES may represent the recurrence of such symptoms following trauma. In fact, common comorbidities with PNES include PTSD, panic disorder, anxiety disorders, and depression.66,78-80 Dissociation is a common avoidance symptom of PTSD, and may be a response to hyperarousal, serving to protect the individual from acute anxiety or unpleasant thoughts and feelings.67,81 The most robust cognitive deficits associated with PTSD appear in memory, particularly verbal declarative memory.82 In a study to determine the specific influences of PNES and PTSD on cognition, patients with combined PNES and PTSD performed significantly worse than PNES patients without PTSD on narrative memory.83 Therefore, active PTSD symptoms are associated with verbal memory impairments beyond the level expected in PNES alone. This study demonstrates an effective research design to determine whether PTSD contributes to distinct cognitive deficits beyond those expected from the psychopathological mechanisms of PNES.

Emotional Processing, Coping Styles, and PNES Subtypes A number of studies have investigated subgroups within PNES.3,37,84-91 These studies examine topics closely related to psychopathology, but focus on mechanisms that may be particularly informative to understand the development of PNES.

They suggest that PNES patients have difficulty regulating emotion, and at least two types of maladaptive emotional regulation styles have emerged: “undermodulators” and “overmodulators.”84 The “undermodulator” group was characterized by emotional reactivity, poor arousal tolerance, and difficulties controlling affect; they likely align with PNES groups that employ emotion-focused coping strategies. The “overmodulator” group was characterized by relatively normal personality profiles, minimal psychiatric comorbidity, emotional avoidance, excessively controlled behavior, and a tendency toward somatization. They appear to utilize more task-oriented and avoidant coping strategies.92 These subtypes largely correspond to earlier cluster analytic studies.37,89,91 Individuals with PNES, compared with epilepsy, report higher measures of emotion dysregulation and alexithymia, or the inability to identify and describe internal emotional experience.84 When classified by emotion modulation style, only the “undermodulators” reported difficulty with most aspects of alexithymia and emotional regulation.84 Instead, “overmodulators” endorsed higher levels of depression than epilepsy patients, suggesting emotion recognition and a stronger role for depression-like emotion regulation strategies, such as suppression or avoidance in this subtype.93 While PNES subtypes have been delineated according to psychopathological mechanisms and emotion processing style, little is known about the relationship between these. For instance, do “overmodulators” more often present with somatoform dissociation and “undermodulators” with psychoform dissociation? Neuropsychological studies have yet to compare cognitive profiles of individuals with PNES based on emotion processing styles. One could hypothesize that the emotional dysregulation in “undermodulators” may result in attention variability, reduced task engagement, and lower frustration tolerance, which could result in reductions in cognitive performance more globally. In contrast, “overmodulators,” may present with stronger attention, normal task engagement, and relatively intact cognitive profiles.

Baseline Cognitive Functioning Full Scale Intelligence Quotients (FSIQs), ranging from extremely low (intellectual disability range) to superior, have been reported in PNES.2,4,8,9,94 However, many studies have found mean FSIQ in PNES groups to be significantly below the normative mean of 100.17 Some authors argue that attention and working memory weaknesses may be influencing these findings4; however, detailed investigations of individual IQ constructs have not been reported in PNES. Individuals with low IQ, intellectual disability, or learning disabilities may represent a unique subtype of PNES. Events in this group are thought to result from reinforced behavior as opposed to psychopathological mechanisms.94,95 That is, in individuals with low IQ, events may be unconsciously learned behaviors that allow patients to control the environment and are reinforced by caregivers.94 Immediate circumstantial triggers are also more common in PNES patients with learning disabilities,94 suggesting that events

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Willment et al are manifestations of reinforced behaviors. However, cognitive and learning disabilities were poorly defined in these studies, and no explicit cognitive data were presented. Therefore, more research is needed to support the concept of PNES events as reinforced behavior in patients with low IQ and/or learning disorders. IQ also correlates with the availability of psychological resources (eg, frustration tolerance, self-esteem) and ability to cope effectively with stress.96 The link between IQ and personality traits/ PNES risk factors (limited coping resources, suggestibility) models an integrative cognitive-emotional systems approach to clarifying the nature of neuropsychological function in PNES.

Subjective Cognitive Concerns Many individuals with PNES present with significant cognitive complaints. While multiple studies demonstrate PNES patients overestimate cognitive impairment,9,97 others found no such differences between PNES and epilepsy.98,99 Specific patterns in PNES patients include a bias toward underestimating memory functioning and overestimating language functioning, but accurately assessing attention and concentration.9 These findings suggest a certain degree of misinterpretation of abilities, similar to somatization as a misinterpretation of bodily symptoms. In addition, in PNES, higher levels of mood disturbance correlated with underestimation of cognitive abilities.9 Given the high frequency of somatization in PNES, research should investigate whether subjective cognitive concerns are related to somatic complaints, and may therefore be a “cognitive” manifestation of somatization. Alternatively, patients with PNES may report their most extreme cognitive symptoms that take place surrounding PNES events or at the height of emotional distress, rather than their typical experience. Without manipulating emotional or stress-related factors, current standardized neuropsychological measures cannot capture cognitive dysfunction resulting from heightened emotional states, creating a mismatch between what is being reported and what is being measured.

Neuropsychology of PNES Moving Forward: Integrated CognitiveEmotional Model The prevailing neuropsychological approach in PNES, for both clinical and research purposes, separately characterizes cognitive, basic psychopathology, personality, and performance validity. This disjointed approach has yielded few consistent findings, and generally emphasizes the variability and heterogeneity of this complex population. From a clinical standpoint, the cognitive profiles are generally characterized as “nonspecific” for underlying etiology, and personality/psychopathology profiles are only minimally helpful for directing effective treatment. In this section, we propose components of a neuropsychological battery designed to explore PNES through an integrated cognitive-emotional lens. We view this proposed battery as a first step toward understanding the vulnerable cognitive-emotional system in PNES, and expect the elements of the battery to be refined and modified over time.

Given that PNES is the top differential diagnosis for epilepsy, we draw on standardized measures included in the National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements (CDE) project for epilepsy. The CDE was created to develop data standards to increase efficiency and effectiveness of clinical research studies. A major limitation of most PNES research is small sample size; therefore, an integrated approach among researchers to aggregate a unified data set is necessary. A distinct set of CDE measures has not been recommended for PNES, and we hope this proposed battery will energize the field to move toward a similar unified approach for this population. The battery proposed in Table 1 is organized by domain, and subdomain (where relevant), to provide a structure for implementing open research questions highlighted in this article. Recommendations for measuring neurologic and illness factors (eg, age of onset, duration of events) are not included: the NINDS CDE project for epilepsy gives examples of how to define and collect these data. PNES semiology may also be an important factor in understanding the vulnerable cognitive-emotion system. Several studies have adapted the classification proposed by Griffith et al72 that includes four major subgroups: catatonic events (characterized by long periods of immobility and unresponsiveness), major motor events, minor motor events (motion of only one limb or hemibody resembling focal motor seizures), and subjective events (“aura-like”). While it remains to be seen whether this system is most effective in characterizing PNES semiologies, this schema represents a starting point to direct future research on semiology and underlying mechanisms.

Research Agenda This article highlights a number of open research questions. Without identifying factors that influence cognitive function, the characterization and contextualization of cognitive deficits in this population will remain elusive. To account for the complexities, nonlinear statistical analyses that require large data sets are needed.136 To facilitate this, aggregation of data is needed among researchers, according to a systematic set of measures, similar to that proposed by the CDE for epilepsy. The presented battery accounts for the majority of factors proposed to contribute to the heterogeneity of PNES. Our battery will provide a useful starting point, and is not intended to be definitive. Cognitive-emotional tasks are not included in the battery because standardized measures are not available; however, exploration of these tasks may provide information that is critical to understanding the interaction of cognitive and emotional processing in PNES.

Clinical Impact While neuropsychological evaluation adds valuable information to aid diagnosis of PNES, capturing an event on videoEEG remains the gold-standard. Therefore, one of the primary roles of the neuropsychological evaluation is to facilitate development of treatment protocols. Characterization of the vulnerable cognitive-emotional system, and the heterogeneity of this

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Table 1.  Proposed Neuropsychological Battery. Intellectual functioning

 

  General IQ estimate: Estimates of IQ are used to approximate what can be expected of an individual’s cognitive skills

American National Adult Reading Test (AmNart)a,100

  Formal IQ testing

Wechsler Adult Intelligence Scale–Fourth Edition (WAIS-IV),a Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), Processing Speed Index (PSI), General Ability Index (GAI)101

Attention: Attention refers to a number of processes that allow an individual to selectively direct or orient cognitive resources to a target while decreasing the allocation of cognitive resources to unwanted or irrelevant inputs23   Basic attention span/registration

Wechsler Adult Intelligence Scale–Fourth Edition (WAIS-IV)101 Digit Span Subtesta

  Sustained attention

Conners’s Continuous Performance Test (CPT-II)102

Selective/focused attention

Conners’ Continuous Performance Test (CPT-II)102 Brief Test of Attention103

Executive functioning: Executive functioning skills encompass a wide range of higher-level cognitive and behavioral capacities that allow an individual to pursue goal-directed behavior. Examples of executive functioning skills include working memory, response inhibition, problem solving, and reasoning   Working memory          

Processing speed Flexibility–Set shifting Flexibility–Response inhibition Flexible problem solving Abstract reasoning

Wechsler Adult Intelligence Scale–Fourth Edition (WAIS-IV) Working Memory Index (WMI; Digit Span,a Arithmetic101 WAIS-IV Processing Speed Indexa (PSI; Coding, Symbol Search)101 Trail-Making Test Ba,104 Stroop Color-Word Interference Test105 Wisconsin Card Sorting Testa,106 WAIS-IV Subtests Similarities, Matrix Reasoninga,101

Memory: Refers to the process of encoding, storing, and retrieving information   Verbal memory

Rey Auditory Verbal Learninga,107 Wechsler Memory Scale–Fourth Edition (WMS-IV)108 Subtest–Logical Memorya

  Nonverbal memory

Brief Visuospatial Memory Test–Revised (BVMT-R)a,109

Language: The neuropsychological evaluation of language skills typically involves, at the very least, a screen of basic linguistic functioning (eg, comprehension, repetition, reading, writing) and an account of higher order language abilities (eg, confrontation naming, verbal fluency) Confrontation naming

Boston Naming Testa,110

Verbal fluency

Controlled Oral Word Association–Phonemic and Semantic Fluencya,107

Visuospatial functioning: The measurement of visual-perceptual skills, visuospatial processing (eg, mental rotation, line judgment), and visual constructional skills Construction skills

WAIS-IV Subtest Block Designa,101 Rey Osterrieth Complex Figure Copy104

Motor functioning: In PNES, reductions in motor speed may be related to number of factors, including antiepileptic medications, psychomotor retardation, or factors specific to PNES that have not been fully characterized   Speed of fine-motor dexterity

Lafayette Grooved Pegboard111

Psychopathology   Psychiatric comorbidities

  Somatoform dissociation   Psychoform dissociation  Personality

Beck Depression Inventory–Second Edition (BDI-II)a,112 Beck Anxiety Inventory (BAI)a,113 Generalized Anxiety Disorder (GAD-7)a,114 Psychiatric Diagnostic Screening Questionnaire (PDSQ)a,115 Somatoform Dissociation Questionnaire (SDQ-20)61 Dissociative Experiences Scale (DES)116 Personality Assessment Inventory (PAI)117 (continued) Downloaded from eeg.sagepub.com at University of Birmingham on March 21, 2015

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Willment et al Table 1.  (continued) Intellectual functioning

 

Emotional processing and coping styles   Subjective cognitive concerns

 Alexithymia   Emotional regulation

  Emotional intelligence   Experiential avoidance   Coping strategies   Perceived level of stress   Perceived capacity to tolerate distress

Everyday Problems Checklist (EPCL)118 Memory Complaints Inventory119 QOLIE-31a,120 Toronto Alexithymia Scale–20 (TAS-20)121 Berkeley Expressivity Questionnaire (BEQ)122 Affective Style Questionnaire123 Difficulties in Emotion Regulation Scale (DERS)124 Emotion Regulation Questionnaire (ERQ)125 Trait Meta-Mood Scale (TMMS)126 Multidimensional Experiential Avoidance Questionnaire (MEAQ)127 Acceptance and Action Questionnaire–II128 Brief COPE129 Perceived Stress Scale130 Depression Anxiety and Stress Scale131 Distress Tolerance Scale132

Validity, effort, motivation: It is generally recommended that formal, stand-alone measures of performance validity and performance measures embedded in traditional tests be interwoven throughout neuropsychological assessments133   Formal measure

Test of Memory Malingering (TOMM)134

  Embedded measures

Reliable Digit Span135 using the WAIS-IV Digit Span subtest Personality Assessment Inventory (PAI) Negative Impression and Positive Impression Management subscales117

a

NINDS Common Data Element for Epilepsy.

population, will enable development of more effective management and treatment. Ultimately, a primary goal of the clinical neuropsychological evaluation will be to direct patients to the most appropriate treatments. Neuropsychologists may be well positioned to implement interventions in this population. Neuropsychology feedback sessions can correct misperceptions about subjective cognitive concerns. As another example, the presence of significant attentional variability may indicate different interventions, such as attention retraining or mindfulness. The inclusion of all the recommended instruments in a clinical neuropsychological evaluation would likely be impractical in most settings. That should not discourage clinical neuropsychologists from taking an integrated cognitive-emotional approach to assessing PNES. This entails more detailed measurement and integration of cognition, emotional processing, and psychopathology, to draw comprehensive, individualized conclusions that will provide patients with more nuanced treatment recommendations. For example, the field is starting to recognize performance validity findings as one of the many manifestations of mechanisms underlying various symptoms in PNES. In this framework, symptoms such as dissociation, somatization, and cognitive deficits are not unexpected. Rather, they are closely tied to emotional processing styles and psychopathologic mechanisms similar to other functional neurological

disorders, mood disorders, and anxiety disorders (including PTSD).

Summary The literature identifies diverse factors thought to contribute to the variability of neuropsychological findings in PNES, and draws attention to its complexity. It was our goal to review the literature, examine what is known about the heterogeneity of PNES, and provide a neuropsychological battery to investigate an integrated cognitive-emotional model. Detailed and nuanced neuropsychological investigations have the potential to expand the current understanding of this complex condition, leading to more effective management and treatment. Acknowledgments We thank Drs Barbara Dworetzky and David Perez for providing guidance and editorial comments.

Author Contributions Drs. Willment and Baslet and Ms. Melanie Hill contributed to the conception, interpretation, and drafting (including critical revisions) of this review article. Dr. Loring contributed to the interpretation and critical revisions. All authors have given their final approval of this review article.

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Declaration of Conflicting Interests Drs Willment and Baslet and Ms Melanie Hill do not have any commercial or financial interests that could be construed as a potential conflict of interest. Dr Loring receives consulting fees from NeuroPace and Supernus and current grant support from PCORI and NIH. He receives royalties from Oxford University Press, serves on the Professional Advisory Board for the Epilepsy Foundation, and sits on the editorial boards for Epilepsia, Epilepsy Research, and Neuropsychology Review. He also receives funds related to neuropsychological assessment, including Wada testing, of patients with epilepsy.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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