Spatial Neglect and Delirium After Stroke
Condition: Stroke; Delirium; Spatial Neglect
MeSH terms: Stroke; Delirium
Study type: Observational [Patient Registry]

Summary: 
      The goal of this study is to understand what brain mechanisms become disrupted when stroke
      survivors experience delirium. Delirium is an acute reduction in attention and cognition,
      associated with poor recovery, longer hospitalization and even death. One major factor
      increasing the risk of delirium after stroke may be spatial neglect occurring after stroke on
      the right side of the brain. Spatial neglect affects awareness, orientation, and movement.
      The study will test the hypothesis that the right-dominant brain networks for arousal and
      attention are affected in both of these disorders. It is expected that the activity and
      structural integrity of these brain networks will correlate with behavioral signs and
      severity of delirium and spatial neglect. To test this hypothesis, the study will measure
      spatial neglect and delirium symptoms in 45 acute (NYC Health + Hospitals/Bellevue ) and 30
      subacute (Kessler Institute for Rehabilitation) stroke survivors and evaluate brain scans for
      these participants. This study may contribute to knowledge about brain bio-markers of
      delirium, which will greatly aid in delirium detection in stroke and other disorders.
    

Detailed description: 
      Delirium assessment and prevention has a tremendous impact on hospitalization outcomes and
      health care costs. Delirium is a multi-component syndrome characterized by an acute reduction
      in cognitive functioning, affecting awareness, thinking, attention, and memory. Stroke
      survivors, representing 17% of the US population aged 65 and over (CDC, 2012), are at major
      risk for developing delirium (up to 50% incidence in right-hemisphere stroke). Further, about
      50% of right-hemisphere stroke patients experience spatial neglect, impairing safety and
      recovery. This study investigates a potential neural mechanism explaining the high incidence
      of both delirium and spatial neglect after right-hemisphere stroke. The study hypothesis is
      that the brain networks for arousal and attention, comprised of ascending projections from
      the mesencephalic reticular formation and integrating right-dominant dorsal and ventral
      cortical and limbic components, may be affected in these disorders. The study assesses
      magnetic resonance imaging (MRI) and behavioral data in right hemisphere stroke survivors. It
      is predicted that impaired activity and structural integrity of the brain networks for
      arousal and attention will correlate with behavioral signs of delirium and spatial neglect.
      The study will be conducted at two sites recruiting an acute (n=45) and a subacute (n=30)
      patient samples. The findings of this study have the potential to impact stroke care by
      providing a critical biomarker and behavioral profile of post-stroke delirium. This may alert
      clinicians to initiating preventive care and targeted interventions in patients who are at
      high risk of hospital morbidity and loss of independence.

      Study Hypotheses Hypothesis 1: It is hypothesized that a lesion-deficit analysis will reveal
      that in patients with delirium and/or spatial neglect, right-brain areas within the
      attention, orientation, and arousal networks are affected by stroke lesions.

      Hypothesis 2: Because it is hypothesized that both disorders stem from a dysfunction of
      common brain networks, it is expected that spatial neglect severity will be a predictor of
      delirium severity, controlling for relative lesion size and stroke severity Hypothesis 3:
      Both spatial neglect and delirium severity will be correlated with functional connectivity
      among the brain areas within the attention, orientation, and arousal networks.

      Hypothesis 4: Based on evidence from prior work in post-surgical delirium patients, neglect
      and coma patients, it is hypothesized that the integrity of white matter connections among
      brain regions comprising the cortical and subcortical networks for attention, orientation,
      and arousal is inversely correlated with the severity of delirium and spatial neglect.

      Planned Analyses:

      Hypothesis 1:

      To examine the critical network components affected in post-stroke delirium, the study will
      examine participants' structural scans. The structural scans recorded in the study will
      include a T1-weighted and a T2-weighted FLAIR image for 30 subacute stroke par-ticipants. In
      addition, clinical scans will be obtained for the 45 acute stroke participants, resulting in
      75 total brain scans. Structural lesions will be mapped using a semi-automated lesion mapping
      in MRIcron package, where each brain voxel will be scored in a binary fashion as lesioned or
      non-lesioned. Three-dimensional lesion masks will be fed into VLSM 2 software implemented in
      Matlab (Voxel Lesion Symptom Mapping). For the pseudo-continuous outcomes, such as the
      Behavioral Inattention Test (BIT) and Confusion Assessment Method-Severity (CAM-S) scores, a
      t-score will be computed testing whether lesion in a given brain voxel predicts higher or
      lower severity score. For the binary outcomes, such as delirium diagnosis, for each voxel a
      Leibermeister measure will be computed testing whether a given lesioned voxel predicts
      delirium vs. no delirium across all participants. The analysis will serially travel through
      the brain voxels and conduct a test in each voxel. The voxels will be thresholded such that
      only those that co-occur in at least 5 patients will be considered. In a typical lesion study
      this will result in hundreds of voxels considered across participants. The final results are
      corrected for multiple comparisons using False Discovery Rate of p<.05.

      Hypothesis 2:

      This hypothesis seeks to establish if any association exists between the presence and
      severity of post-stroke delirium and spatial neglect. To test this hypothesis a regression
      analysis will be conducted using the BIT score as the predictor and the CAM score as an
      outcome. The analysis will control for NIH stroke scale score and lesion size, as well as
      age. In both sets of analyses raw assessment scores will be converted to percent for scale
      uniformity.

      Hypothesis 3:

      A seed-based functional connectivity analysis will be carried out, testing for a correlation
      among time-courses of selected brain regions as a function of CAM-S and BIT scores. 16
      regions of interest (ROI) will be used to conduct this analysis within the arousal and
      attention networks. A whole brain ROI-to-voxel analysis will also be carried out to capture
      any unexpected associations with delirium and neglect severity. This analysis and data
      preprocessing will be done using CONN toolbox, a Matlab-based cross-platform software for the
      computation, display, and analysis of functional connectivity in fMRI. First, realignment
      will be performed between all successive brain volumes and the 1st volume of the series.
      Slice-timing correction will be applied to account for the time difference in the interleaved
      acquisition of brain slices. Structural segmentation will be performed to create masks of
      white matter and cerebrospinal fluid (CSF). These masks will be used in estimating a nuisance
      regressor representing physiological noise. The functional scans will be normalized (aligned)
      to the structural scans and the atlas template. This is done for group comparisons and to
      allow ROI definition using an anatomical atlas. Functional images will be smoothed with a
      6mm-radius kernel. Next, the contribution of motion outliers (large movements), continuous
      motion (roll, pitch, and yaw), and physiological noise will be regressed from the data.
      Finally, ROI-to-ROI and ROI-to-voxel connectivity will performed within each brain scan to
      allow for 2nd-order comparisons (i.e., contribution of delirium and neglect severity scores
      to functional connectivity, controlling for covariates).

      Hypothesis 4:

      A probabilistic tractography analysis will be conduced using 16 ROI, defined a priori from
      the literature. The analysis will be carried out on DTI data using diffusion tensor
      tractography tools available in the FSL analysis suite (e.g.., Probtrax, FDT Toolbox). The
      analysis is expected to identify tracts that connect regions within the attention and arousal
      networks. It will estimate voxel-wise Fractional Anisotropy (FA) as a measure of fiber
      integrity. FA is a scalar value between 0 and 1, measuring the principal diffusion direction
      of water molecules. An FA of 0 indicates a perfect sphere, i.e., uniform diffusion. Places
      where adjacent voxels have the same directional coherence of diffusion are probabilistically
      assigned to tract locations. The values are then averaged to obtain a global FA for each
      tract. Delirium and neglect severity scores will be regressed on FA values in an ANCOVA
      (accounting for clinical/demographic/physiological/patient characteristics). If the ROI-based
      approach is not successful, whole brain FA maps will be considered including areas outside
      the brain networks of interest, for an association with delirium and neglect severity scores.

      Sample Size Determination.

      A pilot investigation was conducted to estimate effect size. 19 right-brain stroke patients
      (12 females, 8 Caucasian, 8 African American, 3 Asian), aged 60 years (SD=17 years),
      comprised of 1 chronic (> 6 months post-stroke) and 18 subacute (< 1 month post-stroke)
      participated in the pilot study. R-squared value of .26 was obtained for the association
      between delirium and neglect severity. This gives an effect size (Cohen's f2) of .35. With
      this effect size, there is over 99% power to observe the effect, assuming a sample size of 75
      patients and an alpha of .05 (Hypothesis 2)

      To estimate power of our lesion deficit analysis (Hypothesis 1), data was simulated using
      15%, 30%, and 50% as proportion of the participant sample in whom the same voxel will be
      lesioned. Leibermeister approach was applied to compute p-values for testing the null
      hypothesis of no association between voxel lesion status and delirium status. With 75
      participants (Acute+Subacute Sample) there is over 80% power to detect an effect, assuming
      that at least 30 percent of the sample have the same lesion, and the lesion is between 40-100
      voxels, forming a tight cluster. These are reasonable assumptions given past studies.

      In the pilot study, a general linear model that included as regressor delirium or neglect
      severity score was applied to the 16X16 ROI connectivity measure matrix for each participant.
      The resulting t-scores for the between-subjects effects were in the range of 4.61 to 7.88 for
      the BIT measure and 7.07 to 9.31 for the CAM-S. These t-scores correspond to a large effect
      size. Using a Cohen's f of .35 (large effect) to estimate power for linear multiple
      regression, with 4 predictors, an alpha level of .05, and a two-tailed test, it is estimated
      that there will be 87% power to observe this effect, given a sample of 30 participants (Acute
      sample) (Hypothesis 3).

      A previous study reported thalamus fractional anisotropy (FA) of .315 (.026) in delirious
      compared to .333 (.023) in non-delirious patients. These values correspond to a large Cohen's
      d effect size. Assuming that FA values in a similar range will be observed, there is
      excellent power to detect these effects with a linear multiple regression model.

      Based on average patient flow, is is estimated that up to 20 patients will be screened
      monthly for study eligibility at each site. Based on recruitment rates of the pilot sample,
      it is estimated that 10-20% of the screening sample will be consented. Factoring in a
      conservative dropout estimate of 25-40%, it is more than likely that the proposed study
      sample will be recruited. To account for patient attrition, the study will over-recruit the
      target sample by 5 patients.

      Estimated rates of delirium and neglect after right brain stroke are around 50% . Therefore,
      around 50 of the study sample is expected to have neglect, delirium, or both. In addition to
      using delirium/neglect status as a dichotomous variable, quasi-continuous severity scores for
      each variable will be used, which will increase the power to detect associations between
      these two disorders and brain lesion locations.
    

Intervention name(s): Confusion Assessment Method; Behavioral Inattention Test; Magnetic Resonance Imaging; Florida Mental Status Examination; Montreal Cognitive Assessment; Geriatric Depression Scale; Kessler Foundation Neglect Assessment Process
Intervention type(s): Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test; Diagnostic Test
Intervention description(s): This test is used for delirium assessment. The CAM consists of a series of questions, measuring attention (digits forward and backwards, days of the week and months of the year backwards), orientation (person, place, time), memory (immediate and delayed recall of 3 concrete nouns); and probing for any sleep, perceptual, or thinking disturbances. It was designed to incorporate DSM-III criteria for delirium.; This test is used for neglect assessment. The BIT consists of 6 tasks: figure and shape copying; line, star, and letter cancellation, and representational drawing. Such tasks were shown to be appropriate in patients within 48 hours of stroke onset. Scoring of each test will include proportion of error responses on each test or deviation from midpoint on line bisection. Figure and shape copying and representational drawing will be scored based on each item completed.; Structural, functional and diffusion weighted scans will be obtained or acquired, depending on the cohort. Subacute sample participants will undergo a research MRI scan, whereas acute sample participants will allow the release of their clinical MRI scans.; This test is used for mental status assessment, and it will be conducted in our subacute sample only. The FMSE tests memory, attention, language, visuospatial processing, and executive function. It will help to establish patients' mental status profile, including any deficits.; MoCA is a brief cognitive screening tool for individuals with mild cognitive impairment and will be used in the acute sample.; Because depression has been previously associated with delirium, patients will be evaluated for depression with the GDS. The GDS is a self-report measure consisting of 30 yes/no questions to measure depression in the elderly. It will be used as a covariate in data analysis.; This is a 10-category scale for spatial neglect based on observation of activities of daily living (e.g., eating, dressing, grooming, gaze orientation). Thee test is based on the Catherine Bergego Scale (CBS) and administered via the standardized KF-Neglect Assessment Process developed within our program.
Other intervention name(s): CAM-S; BIT; MRI; FMSE; MOCA (basic test); GDS; KF-NAP
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        This is a prospective observational study using a consecutive patient sample. The study
        will be carried out at 2 sites: NYC Health + Hospitals/Bellevue and Kessler Institute for
        Rehabilitation. 1st ever ischemic stroke patients will be approached for interest in
        participation. Patients of both sexes whose stroke event is on the right side of the brain
        and who qualify for the study based on the inclusion and exclusion criteria will be
        recruited.