; for the NES Treatment Trial (NEST-T) Consortium IMPORTANCE There is a paucity of controlled treatment trials for the treatment of conversion disorder, seizures type, also known as psychogenic nonepileptic seizures (PNES). Psychogenic nonepileptic seizures, the most common conversion disorder, are as disabling as epilepsy and are not adequately addressed or treated by mental health clinicians. OBJECTIVE To evaluate different PNES treatments compared with standard medical care (treatment as usual). DESIGN, SETTING, AND PARTICIPANTS Pilot randomized clinical trial at 3 academic medical centers with mental health clinicians trained to administer psychotherapy or psychopharmacology to outpatients with PNES. Thirty-eight participants were randomized in a blocked schedule among 3 sites to 1 of 4 treatment arms and were followed up for 16 weeks between September 2008 and February 2012; 34 were included in the analysis. INTERVENTIONS Medication (flexible-dose sertraline hydrochloride) only, cognitive behavioral therapy informed psychotherapy (CBT-ip) only, CBT-ip with medication (sertraline), or treatment as usual. MAIN OUTCOMES AND MEASURES Seizure frequency was the primary outcome; psychosocial and functioning measures, including psychiatric symptoms, social interactions, quality of life, and global functioning, were secondary outcomes. Data were collected prospectively, weekly, and with baseline, week 2, midpoint (week 8), and exit (week 16) batteries. Within-group analyses for each arm were performed on primary (seizure frequency) and secondary outcomes from treatment-blinded raters using an intention-to-treat analysis. RESULTS The psychotherapy (CBT-ip) arm showed a 51.4% seizure reduction (P = .01) and significant improvement from baseline in secondary measures including depression, anxiety, quality of life, and global functioning (P < .001). The combined arm (CBT-ip with sertraline) showed 59.3% seizure reduction (P = .008) and significant improvements in some secondary measures, including global functioning (P = .007). The sertraline-only arm did not show a reduction in seizures (P = .08). The treatment as usual group showed no significant seizure reduction or improvement in secondary outcome measures (P = .19). CONCLUSIONS AND RELEVANCE This pilot randomized clinical trial for PNES revealed significant seizure reduction and improved comorbid symptoms and global functioning with CBT-ip for PNES without and with sertraline. There were no improvements in the sertraline-only or treatment-as-usual arms. This study supports the use of manualized psychotherapy for PNES and successful training of mental health clinicians in the treatment. Future studies could assess larger-scale intervention dissemination. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00835627

Objective: The diagnosis of psychogenic nonepileptic seizures (PNES) can be challenging. In the absence of a gold standard to verify the reliability of the diagnosis by EEG-video, we sought to assess the interrater reliability of the diagnosis using EEG-video recordings.Methods: Patient samples consisted of 22 unselected consecutive patients who underwent EEGvideo monitoring and had at least an episode recorded. Other test results and histories were not provided because the goal was to assess the reliability of the EEG-video. Data were sent to 22 reviewers, who were board-certified neurologists and practicing epileptologists at epilepsy centers. Choices were 1) PNES, 2) epilepsy, and 3) nonepileptic but not psychogenic ("physiologic") events. Interrater agreement was measured using a coefficient for each diagnostic category. We used generalized coefficients, which measure the overall level of between-method agreement beyond that which can be ascribed to chance. We also report category-specific values. Results: Conclusions:Interrater reliability for the diagnosis of psychogenic nonepileptic seizures by EEGvideo monitoring was only moderate. Although this may be related to limitations of the study (diagnosis based on EEG-video alone, artificial nature of the forced choice paradigm, single episode), it highlights the difficulties and subjective components inherent to this diagnosis.

Objective: There have been few treatment trials for psychogenic nonepileptic seizures (PNES).Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES. Methods:We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG-confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables.Results: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p ϭ 0.03) vs an 8% increase in placebo (p ϭ 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline.Conclusions: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study. Level of evidence:This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25-1.05, p ϭ 0.29), adjusting for differences at baseline. Neurology ® 2010;75:1166-1173 GLOSSARY AED ϭ antiepileptic drug; CI ϭ confidence interval; DSM-IV ϭ Diagnostic and Statistical Manual of Mental Disorders, 4th edition; ES ϭ epileptic seizures; ITT ϭ intent to treat; PNES ϭ psychogenic nonepileptic seizures; PTSD ϭ posttraumatic stress disorder; QOL ϭ quality of life; RCT ϭ randomized controlled trial; RIH ϭ Rhode Island Hospital; RR ϭ risk ratio; SSRI ϭ serotonin selective reuptake inhibitor; vEEG ϭ video-EEG.

Objective: To further evaluate the relationship between the clinical profiles and limbic and motor brain regions and their connecting pathways in psychogenic nonepileptic seizures (PNES). Neurite Orientation Dispersion and Density Indices (NODDI) multicompartment modeling was used to test the relationships between tissue alterations in patients with traumatic brain injury (TBI) and multiple psychiatric symptoms. Methods: The sample included participants with prior TBI (TBI; N = 37) but no PNES, and with TBI and PNES (TBI + PNES; N = 34). Participants completed 3T Siemens Prisma MRI high angular resolution imaging diffusion protocol. Statistical maps, including fractional anisotropy (FA), mean diffusivity (MD), neurite dispersion [orientation dispersion index (ODI)] and density [intracellular volume fraction (ICVF), and free water (i.e., isotropic) volume fraction (V-ISO)] signal intensity, were generated for each participant. Linear mixed-effects models identified clusters of between-group differences in indices of white matter changes. Pearson's r correlation tests assessed any relationship between signal intensity and psychiatric symptoms. Results: Compared to TBI, TBI + PNES revealed decreases in FA, ICVF, and V-ISO and increases in MD for clusters within cingulum bundle, uncinate fasciculus, fornix/stria terminalis, and corticospinal tract pathways (cluster threshold a = 0.05). Indices of white matter changes for these clusters correlated with depressive, anxiety, PTSD, psychoticism, and somatization symptom severity (FDR threshold a = 0.05). A follow-up within-group analysis revealed that these correlations failed to reach the criteria for significance in the TBI + PNES group alone. Interpretation: The results expand support for the hypothesis that alterations in pathways comprising the specific PNES network correspond to patient profiles. These findings implicate myelin-specific changes as possible contributors to PNES, thus introducing novel potential treatment targets.

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

Background: Links between dissociation and functional neurological disorder (FND)/conversion disorder are well-established, yet the pathophysiology of dissociation remains poorly understood. This MRI study investigated structural alterations associated with somatoform and psychological dissociation in FND. We hypothesized that multimodal, paralimbic cingulo-insular regions would relate to the severity of somatoform dissociation in patients with FND. Methods: FreeSurfer cortical thickness and subcortical volumetric analyses were performed in 26 patients with motor FND and 27 matched healthy controls. Patients with high dissociation as measured by the Somatoform Dissociation Questionnaire-20 (SDQ) or Dissociative Experiences Scale (DES) were compared to controls in stratified analyses. Within-group analyses were also performed with SDQ and DES scores in patients with FND. All cortical thickness analyses were whole-brain corrected at the cluster-wise level. somatoform dissociation (SDQ > 35) showed reduced left caudal anterior cingulate cortex (ACC) cortical thickness compared to controls. In within-group analyses, SDQ scores inversely correlated with left caudal ACC cortical thickness in patients with FND. Depersonalization/derealization scores positively correlated with right lateral occipital cortical thickness. Both within-group findings remained statistically significant controlling for trait anxiety/depression, borderline personality disorder and posttraumatic stress disorder, adverse life events, and motor FND subtypes in post-hoc analyses. Conclusion: Using complementary between-group and within-group analyses, an inverse association between somatoform dissociation and left caudal ACC cortical thickness was observed in patients with FND. A positive relationship was also appreciated between depersonalization/derealization severity and cortical thickness in visual association areas. These findings advance our neuropathobiological understanding of dissociation in FND. Hum Brain Mapp 39:428-439, 2018.V C 2017 Wiley Periodicals, Inc.

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The assessment of functional neurological disorders (FND) requires an interdisciplinary approach. The authors retrospectively reviewed charts for 100 outpatients with FND and used univariate and regression analyses to investigate neuropsychiatric associations with gender, illness duration, and work disability; secondary analyses evaluated for differences across motor FND subtypes. Men reported higher rates of cognitive complaints and functional weakness, whereas women endorsed increased past physical/sexual trauma. Number of self-reported medication allergies/sensitivities positively correlated with illness duration. Individuals with functional weakness compared with other motor FND subtypes exhibited lower rates of past psychiatric hospitalization and head trauma. This study supports the feasibility of integrating FND research.