Jerzy P. Szaflarski

Multicenter Pilot Treatment Trial for Psychogenic Nonepileptic Seizures A Randomized Clinical Trial

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.

Intravenous ketamine for the treatment of refractory status epilepticus: A retrospective multicenter study

To examine patterns of use, efficacy, and safety of intravenous ketamine for the treatment of refractory status epilepticus (RSE).

New-onset refractory status epilepticus Etiology, clinical features, and outcome

Objectives: The aims of this study were to determine the etiology, clinical features, and predictors of outcome of new-onset refractory status epilepticus. Methods: Retrospective review of patients with refractory status epilepticus without etiology identified within 48 hours of admission between January 1, 2008, and December 31, 2013, in 13 academic medical centers. The primary outcome measure was poor functional outcome at discharge (defined as a score >3 on the modified Rankin Scale). Results: Of 130 cases, 67 (52%) remained cryptogenic. The most common identified etiologies were autoimmune (19%) and paraneoplastic (18%) encephalitis. Full data were available in 125 cases (62 cryptogenic). Poor outcome occurred in 77 of 125 cases (62%), and 28 (22%) died. Predictors of poor outcome included duration of status epilepticus, use of anesthetics, and medical complications. Among the 63 patients with available follow-up data (median 9 months), functional status improved in 36 (57%); 79% had good or fair outcome at last follow-up, but epilepsy developed in 37% with most survivors (92%) remaining on antiseizure medications. Immune therapies were used less frequently in cryptogenic cases, despite a comparable prevalence of inflammatory CSF changes. Conclusions: Autoimmune encephalitis is the most commonly identified cause of new-onset refractory status epilepticus, but half remain cryptogenic. Outcome at discharge is poor but improves during follow-up. Epilepsy develops in most cases. The role of anesthetics and immune therapies warrants further investigation.

Recovered vs. not-recovered from post-stroke aphasia: the contributions from the dominant and non-dominant hemispheres.

PURPOSE Several adult studies have documented the importance of the peri-stroke areas to aphasia recovery. But, studies examining the differences in patterns of cortical participation in language comprehension in patients who have (LMCA-R) or have not recovered (LMCA-NR) from left middle cerebral artery infarction have not been performed up to date. METHODS In this study, we compare cortical correlates of language comprehension using fMRI and semantic decision/tone decision task in 9 LMCA-R and 18 LMCA-NR patients matched at the time of stroke for age and handedness. We examine the cortical correlates of language performance by correlating intra- and extra-scanner measures of linguistic performance with fMRI activation and stroke volumes. RESULTS Our analyses show that LMCA-R at least 1 year after stroke show a return to typical fMRI language activation patterns and that there is a compensatory reorganization of language function in LMCA-NR patients with shifts to the right hemispheric brain regions. Further, with increasing strength of the left-hemispheric fMRI signal shift there are associated improvements in performance as tested with standardized linguistic measures. A negative correlation between the size of the stroke and performance on some of the linguistic tests is also observed. CONCLUSIONS This right-hemispheric shift as a mechanism of post-stroke recovery in adults appears to be an ineffective mode of language function recovery with increasing right-hemispheric shift associated with lower language performance. Thus, normalization of the post-stroke language activation patterns is needed for better language performance while shifts of the activation patterns to the non-dominant (right) hemisphere and/or large stroke size are associated with decreased linguistic abilities after stroke.

Cerebral Hemodynamic Changes of Mild Traumatic Brain Injury at the Acute Stage

Mild traumatic brain injury (mTBI) is a significant public health care burden in the United States. However, we lack a detailed understanding of the pathophysiology following mTBI and its relation to symptoms and recovery. With advanced magnetic resonance imaging (MRI), we can investigate brain perfusion and oxygenation in regions known to be implicated in symptoms, including cortical gray matter and subcortical structures. In this study, we assessed 14 mTBI patients and 18 controls with susceptibility weighted imaging and mapping (SWIM) for blood oxygenation quantification. In addition to SWIM, 7 patients and 12 controls had cerebral perfusion measured with arterial spin labeling (ASL). We found increases in regional cerebral blood flow (CBF) in the left striatum, and in frontal and occipital lobes in patients as compared to controls (p = 0.01, 0.03, 0.03 respectively). We also found decreases in venous susceptibility, indicating increases in venous oxygenation, in the left thalamostriate vein and right basal vein of Rosenthal (p = 0.04 in both). mTBI patients had significantly lower delayed recall scores on the standardized assessment of concussion, but neither susceptibility nor CBF measures were found to correlate with symptoms as assessed by neuropsychological testing. The increased CBF combined with increased venous oxygenation suggests an increase in cerebral blood flow that exceeds the oxygen demand of the tissue, in contrast to the regional hypoxia seen in more severe TBI. This may represent a neuroprotective response following mTBI, which warrants further investigation.

Post-traumatic epilepsy: current and emerging treatment options

Traumatic brain injury (TBI) leads to many undesired problems and complications, including immediate and long-term seizures/epilepsy, changes in mood, behavioral, and personality problems, cognitive and motor deficits, movement disorders, and sleep problems. Clinicians involved in the treatment of patients with acute TBI need to be aware of a number of issues, including the incidence and prevalence of early seizures and post-traumatic epilepsy (PTE), comorbidities associated with seizures and anticonvulsant therapies, and factors that can contribute to their emergence. While strong scientific evidence for early seizure prevention in TBI is available for phenytoin (PHT), other antiepileptic medications, eg, levetiracetam (LEV), are also being utilized in clinical settings. The use of PHT has its drawbacks, including cognitive side effects and effects on function recovery. Rates of recovery after TBI are expected to plateau after a certain period of time. Nevertheless, some patients continue to improve while others deteriorate without any clear contributing factors. Thus, one must ask, ‘Are there any actions that can be taken to decrease the chance of post-traumatic seizures and epilepsy while minimizing potential short- and long-term effects of anticonvulsants?’ While the answer is ‘probably,’ more evidence is needed to replace PHT with LEV on a permanent basis. Some have proposed studies to address this issue, while others look toward different options, including other anticonvulsants (eg, perampanel or other AMPA antagonists), or less established treatments (eg, ketamine). In this review, we focus on a comparison of the use of PHT versus LEV in the acute TBI setting and summarize the clinical aspects of seizure prevention in humans with appropriate, but general, references to the animal literature.

Practice guideline summary: Use of fMRI in the presurgical evaluation of patients with epilepsy Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Objective: To assess the diagnostic accuracy and prognostic value of functional MRI (fMRI) in determining lateralization and predicting postsurgical language and memory outcomes. Methods: An 11-member panel evaluated and rated available evidence according to the 2004 American Academy of Neurology process. At least 2 panelists reviewed the full text of 172 articles and selected 37 for data extraction. Case reports, reports with <15 cases, meta-analyses, and editorials were excluded. Results and recommendations: The use of fMRI may be considered an option for lateralizing language functions in place of intracarotid amobarbital procedure (IAP) in patients with medial temporal lobe epilepsy (MTLE; Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C). For patients with temporal neocortical epilepsy or temporal tumors, the evidence is insufficient (Level U). fMRI may be considered to predict postsurgical language deficits after anterior temporal lobe resection (Level C). The use of fMRI may be considered for lateralizing memory functions in place of IAP in patients with MTLE (Level C) but is of unclear utility in other epilepsy types (Level U). fMRI of verbal memory or language encoding should be considered for predicting verbal memory outcome (Level B). fMRI using nonverbal memory encoding may be considered for predicting visuospatial memory outcomes (Level C). Presurgical fMRI could be an adequate alternative to IAP memory testing for predicting verbal memory outcome (Level C). Clinicians should carefully advise patients of the risks and benefits of fMRI vs IAP during discussions concerning choice of specific modality in each case.

Interactions between cannabidiol and commonly used antiepileptic drugs

To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open‐label safety study. Serum levels were monitored to identify interactions between CBD and AEDs.

Uncinate fasciculus connectivity in patients with psychogenic nonepileptic seizures: A preliminary diffusion tensor tractography study

The amygdala, hippocampus, and medial prefrontal cortex are limbic brain regions connected by the uncinate fasciculus (UF) and implicated in emotion regulation. The aim of this study was to assess the connectivity characteristics of the UF in patients with psychogenic nonepileptic seizures (PNES) and matched healthy controls. We hypothesized that white matter connectivity of the UF in patients with PNES would differ from that in healthy controls. Eight patients with PNES and eight age- and sex-matched healthy controls underwent 3T MRI and 32-direction diffusion tensor imaging (DTI). Computation of DTI indices including fractional anisotropy (FA) and diffusion tensor tractography was performed. Two regions of interest were defined to manually trace the UF in each hemisphere for each subject. Fractional anisotropy and the number of reconstructed streamlines for the left and right hemispheres of the UF and the degree of asymmetry for each measure were compared between groups. Correlations between UF measures and clinical variables were also performed. Patients with PNES exhibited a significantly greater number of UF streamlines in the right hemisphere tract than in the left hemisphere (p=0.031), with such difference not observed in controls (p=0.81). This was reflected in a significant group difference in the asymmetry index (AI) for the number of streamlines, with more rightward asymmetry in patients with PNES (p=0.021). Average FA of the UF was similar between groups and between hemispheres for each group (all p>0.05). Age at illness onset was correlated with the AI for FA (r=-0.87; p=0.0045). Previously observed differences in emotion processing between controls and patients with PNES may be related to the differences in the rightward asymmetry in the number of UF streamlines in patients with PNES. Age at PNES onset appears to also have a role in the FA asymmetry of the UF. This is the first study to investigate the structural connectivity in these regions involved in emotional regulation in patients with PNES; further research is necessary to clarify the complex relationships between clinical measures and DTI characteristics.

Voxel-based Gaussian naïve Bayes classification of ischemic stroke lesions in individual T1-weighted MRI scans.

BACKGROUND Manual lesion delineation by an expert is the standard for lesion identification in MRI scans, but it is time-consuming and can introduce subjective bias. Alternative methods often require multi-modal MRI data, user interaction, scans from a control population, and/or arbitrary statistical thresholding. NEW METHOD We present an approach for automatically identifying stroke lesions in individual T1-weighted MRI scans using naïve Bayes classification. Probabilistic tissue segmentation and image algebra were used to create feature maps encoding information about missing and abnormal tissue. Leave-one-case-out training and cross-validation was used to obtain out-of-sample predictions for each of 30 cases with left hemisphere stroke lesions. RESULTS Our method correctly predicted lesion locations for 30/30 un-trained cases. Post-processing with smoothing (8mm FWHM) and cluster-extent thresholding (100 voxels) was found to improve performance. COMPARISON WITH EXISTING METHOD Quantitative evaluations of post-processed out-of-sample predictions on 30 cases revealed high spatial overlap (mean Dice similarity coefficient=0.66) and volume agreement (mean percent volume difference=28.91; Pearsons r=0.97) with manual lesion delineations. CONCLUSIONS Our automated approach agrees with manual tracing. It provides an alternative to automated methods that require multi-modal MRI data, additional control scans, or user interaction to achieve optimal performance. Our fully trained classifier has applications in neuroimaging and clinical contexts.