Relationship between Diffusion Tensor Fractional Anisotropy and Long-term Motor Outcome in Patients with Hemiparesis after Middle Cerebral Artery Infarction Tetsuo Koyama, MD, PhD,*† Kohei Marumoto, MD, PhD,† Hiroji Miyake, MD, PhD,‡ and Kazuhisa Domen, MD, PhD†

Background: Magnetic resonance diffusion tensor fractional anisotropy (DTI-FA) is often used to characterize neural damage after stroke. Here we assessed the relationship between DTI-FA and long-term motor outcome in patients after middle cerebral artery (MCA) infarction. Methods: Fractional anisotropy (FA) maps were generated from diffusion tensor brain images obtained from 16 patients 14-18 days postinfarction, and tract-based spatial statistics (TBSS) analysis was applied. Regions of interest were set within the right and left corticospinal tracts, and mean FA values were extracted from individual TBSS data. Hemiparesis motor outcome was evaluated according to Brunnstrom stage (BRS: 1-6, severe-normal) for separate shoulder/ elbow/forearm, hand, and lower extremity functions, as well as the motor component score of the Functional Independence Measure (FIM-motor: 13-91, null-full) 5-7 months after onset. Ratios between FA values in the affected and unaffected hemispheres (rFA) were assessed by BRS and FIM-motor scores. Results: rFA values were .636-.984 (median, .883) and BRS scores were 1-6 (median, 3) for shoulder/ elbow/forearm, 2-6 (median, 3) for hand, and 3-6 (median, 5) for the lower extremities. FIM-motor scores were 51-90 (median, 75). Analysis revealed significant relationships between rFA and BRS data (correlation coefficient: .687 for shoulder/elbow/forearm, .579 for hand, and .623 for lower extremities) but no significance relationship between rFA and FIM-motor scores. Conclusions: The results suggest that DTI-FA is applicable for predicting the long-term outcome of extremity functions after MCA infarction. Key Words: Infarct—paresis—prognosis— recovery—stroke. Ó 2014 by National Stroke Association

From the *Department of Rehabilitation Medicine, Nishinomiya Kyoritsu Neurosurgical Hospital; †Department of Physical Medicine and Rehabilitation, Hyogo College of Medicine; and ‡Department of Neurosurgery, Nishinomiya Kyoritsu Neurosurgical Hospital, Nishinomiya, Hyogo, Japan. Received February 11, 2014; revision received April 21, 2014; accepted May 19, 2014. This research was partly supported by a Grand-in-Aid for Scientific Research (B), the Japan Society for the Promotion of Science (KAKENHI [25282168]), and by the Medical Research Fund of Hyogo Medical Association (MRF-H-08-12). Address correspondence to Tetsuo Koyama, MD, PhD, Department of Rehabilitation Medicine, Nishinomiya Kyoritsu Neurosurgical Hospital, 11-1 Imazu-Yamanaka-cho, Nishinomiya, Hyogo 663-8211, Japan. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2014 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.05.017

Introduction Cerebral infarction is a leading cause of disability in the elderly population,1 and its associated social welfare costs are a serious concern in most advanced countries.2,3 Clinical manifestations after cerebral infarction are numerous and varied; some patients exhibit visual acuity deficits (eg, after posterior cerebral artery infarction), whereas others suffer from executive dysfunction (eg, after anterior cerebral artery infarction). The most prevalent symptom is hemiparesis, which often accompanies middle cerebral artery (MCA) infarction.4 Because hemiparesis often results in disabilities in locomotion and hand manipulation, it is frequently associated with poor functional outcome.5 To minimize disability, rehabilitation is typically prescribed.

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The evaluation of brain images to determine clinical severity is critically important in facilitating the most effective rehabilitative treatment. A newly developed magnetic resonance (MR) technique, diffusion tensor imaging (DTI), has recently been applied for such evaluation.6 DTI detects the diffusion gradient path of water molecules with high sensitivity to reveal the orientation of neural fibers, which consequently enables clinically useful characterization of Wallerian degeneration after cerebral infarction.7 Of the parameters obtained from DTI, fractional anisotropy (FA) is a proven index of white matter axonal degeneration.8 Recent studies on FA brain images have applied tract-based spatial statistics (TBSS) analysis for various kinds of neural diseases such as idiopathic normal pressure hydrocephalus and Parkinson disease.9,10 Using computer-automated technology, TBSS transforms each FA brain image into the standard brain space, a procedure that enables intersubject statistical analysis, such as direct comparisons between groups or quantitative evaluation of regional FA changes in relation to clinical manifestations.11 However, few studies have used TBSS to assess whole brain FA changes in patients after MCA infarction and in relation to its clinical symptoms.12-14 The aim of this study was to characterize the FA changes caused by MCA infarction in relation to long-term motor outcome using TBSS methodology.

Methods Patients The study sampled patients admitted to Nishinomiya Kyoritsu Neurosurgical Hospital for MCA infarction between June 2010 and March 2013. Patients were typically transferred to our hospital soon after stroke onset. They were then examined by diffusion-weighted magnetic resonance imaging (MRI), and cerebral infarction was diagnosed. Brain diffusion-weighted imaging (DWI) images were inspected by our acute stroke care team consisting of board-certificated neurologists, neurosurgeons, and physiatrists. Patients who exhibited high-intensity areas within the MCA territory were diagnosed as having MCA infarction. Patients underwent conservative treatments such as medication (eg, anticoagulant or antiplatelet agents). During hospitalization, patients also received physical therapy, occupational therapy, and speech therapy for a combined daily total of up to 180 minutes. The protocols for these rehabilitative treatments followed the conventional methods stated in the Japanese Guidelines for the Management of Stroke.15 Patients (or relatives when necessary) provided written consent for inclusion in the study, and the study protocol was approved by the hospital’s institutional review board. To minimize the variability arising from differences in prestroke status and lesion sites, the sample population

was limited to first-ever stroke patients able to walk unaided who had been functionally independent in activities of daily living (ADL) in the local community before stroke. For MRI safety, patients with metal implants were excluded. Patients who subsequently required acute medical services (for recurrence of stroke, angina pectoris, or other coincidental conditions) were also excluded. To minimize the variability arising from differences in the rehabilitative therapeutic regimen, we collected data from the patients transferred to our affiliated long-term rehabilitation facility (Nishinomiya Kyoritsu Rehabilitation Hospital) to receive inpatient rehabilitative care for at least 3 months.

DWI Acquisition On arrival at our hospital, patients with hemiparesis or related symptoms were suspected of stroke and underwent head MRI with a 3-T (Trio; Siemens AG, Erlangen, Germany) or 1.5-T (Signa; General Electric Medical Systems, Milwaukee, WI) scanner depending on availability. For the 3-T scanner, which used a single-shot echo-planar imaging sequence, the DWI scheme acquired an image with diffusion gradients (b 5 1200 seconds/mm2) and non-DWI (b 5 0 seconds/mm2). In total, 22 axial slices were obtained from each patient. The field of view was 220.0 mm 3 220.0 mm, the acquisition matrix was 128 3 128, and slice thickness was 5 mm with a 1.5 mm gap. Echo time was 81 ms and repetition time was 5000 ms.16 Settings for acquisition parameters were the same for the 1.5-T scanner, except for the diffusion gradient (b 5 1000 seconds/mm2) and echo time (100 ms).16

DTI Acquisition DTI was performed 14-18 days after admission using a 3-T MR scanner (Trio; Siemens AG) with a 32-channel head coil. Previous reports have indicated a requirement of 2 weeks before signal changes can be reliably detected after ischemic stroke.7,17,18 By means of a single-shot echo-planar imaging sequence, the DTI scheme acquired 12 images with noncollinear diffusion gradients (b 5 1000 seconds/mm2) and 1 non–diffusion-weighted image (b 5 0 seconds/mm2), and a total of 64 axial slices were obtained from each patient. The field of view was 230.4 mm 3 230.4 mm, the acquisition matrix was 128 3 128, and slice thickness was 3 mm with no gaps, which resulted in voxel dimensions of 1.8 mm 3 1.8 mm 3 3.0 mm. Echo time was 83 ms and repetition time was 7000 ms.16 We also obtained T1- and T2-weighted MR images for other diagnostic purposes. The total time for MRI acquisition including these scans was approximately 20 minutes per patient. Patients who were unable to remain still long enough to complete MRI acquisition were excluded from the final analytical database.

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Outcome Measurements The Brunnstrom stage (BRS),19 commonly used by Japanese rehabilitation therapists,15 was used to assess postinfarction motor function impairment of the upper and lower extremities on the affected side. The recovery process of the affected extremities was evaluated in terms of the associated reactions and the flexion and extension synergy patterns of the extremities (6-point scale, severe to normal). Conventionally, BRS is used for separate functional evaluation of proximal (shoulder/elbow/forearm) and distal (hand) portions of the upper and entire lower extremities, and its reliability and validity have been well established.20,21 Assessments were made by occupational or physical therapists blinded to the purpose of the study. In addition to extremity function, scores for the motor component of the Functional Independence Measure (FIM-motor), a commonly used method for evaluating stroke rehabilitation, was obtained.22,23 This method uses a 7-point scale (total assistance to complete independence) for the following 13 items: eating, grooming, bathing, dressing upper body, dressing lower body, toileting, bladder and bowel management, transfer to bed/chair/ wheelchair, transfers to toilet, transfer to tub/shower, walking or wheelchair propulsion, stair climbing, and total summations. These items are often used to index independence in ADL (scale range, 13-91).22,23 BRS and FIM-motor scores were assessed on a monthly basis, and data were collected from our long-term rehabilitation facility at discharge.

Image Processing The brain image analysis package FSL,24 comprising various tools, including the Brain Extraction Tool (BET), FMRIB’s Diffusion Toolbox (FDT), FMRIB’s Nonlinear Image Registration Tool (FNIRT), and FSLUTILS, was used for image processing.25,26 FDT was used to correct for motion and eddy current distortions by aligning all images with the first image (b 5 0 seconds/mm2), whereas BET was used to exclude extracerebral matter from the images. Then, to evaluate tensor diffusion and calculate brain FA values, DTI data were analyzed using FDT (FA brain map). Next, FSL’s TBSS module was used to outline the brain regions showing neural fiber degeneration associated with MCA infarction. This procedure enables the assessment of cerebral white matter by using the intrinsic anisotropic properties of white matter to project the FA of local tract structures onto a virtual skeleton, thereby providing an alignment-invariant tract representation of the median part of the tract.27 For simplicity, we used the default settings recommended in the TBSS manual. In brief, FA maps for each subject were registered into a standard brain template (FMRIB58_FA, part of the FSL suite) using FNIRT. An FA image of mean values was then compiled

Figure 1. Mean fractional anisotropy (FA) image mapped in the standard brain (gray), FA skeleton representing tract centers (green), and regions of interest set within the corticospinal tracts (red). Slices are coordinated in the standard space (Y and Z axes; mm). Abbreviations: L, left; R, right.

by averaging aligned FA maps from each subject (Fig 1). Next, to generate a mean FA skeleton representing the centers of all tracts common to the group, the voxel threshold was set to show FA values $.2. The aligned FA data for each participant were projected onto the standard skeletonized FA image (FMRIB58_FA-skeleton, packaged in FSL) by searching the area around the skeleton in a direction perpendicular to each tract, locating the highest local FA value, and assigning it to the skeleton (Fig 2).27 To evaluate the FA decrease in the skeleton due to MCA infarction, a voxel-wise spatial comparison was performed between the MCA infarction group and a control group. The details of the control group are reported elsewhere.11 In brief, this group consisted of 21 outpatients whose chief complaint was headache, dizziness, or both, whose medical examination results, such as computed tomography and blood analysis, were inconclusive, and

Figure 2. Representative brain images of 3 cases (Table 1), showing diffusion-weighted images in the native space (upper panels) and the FA and skeletonized FA maps in the standard space (middle and lower panels). Abbreviations: L, left; R, right.

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whose symptoms were alleviated within a 2-week followup period. Comparative analysis of the 2 groups was carried out using the ‘‘randomize’’ program in FSL, which performs permutation testing.28 Thresholding was carried out using threshold-free cluster enhancement, a new method for finding significant clusters in MRI data without the need to define them as binary units.29 Clusters were assessed for significance at P , .01 and fully corrected for multiple comparisons across space. To quantitatively assess neural degeneration within the brain, the skeletonized FA images of each patient (Fig 2) were sampled using FSLUTILS.30 In this assessment, the right and left corticospinal tracts were set for regions of interest with reference to the standard brain for white matter (Johns Hopkins University DTI White-Matter Atlas; Fig 1).31 To index the degree of neural degeneration, the ratio between the FA values in the affected and unaffected sides (rFA) of the corticospinal tracts was calculated. All procedures were performed using FSLUTILS.

Analysis of the Relationships between rFA and Outcome Measurements Spearman rank correlation test was used to determine the relationship between rFA values and outcome measurements (BRS and FIM-motor scores), and P , .05 was considered significant. All statistical analysis was performed using the JMP software package (SAS Institute, Cary, NC).

Results During the study period, 92 patients with MCA infarction underwent DTI acquisition. Of them, 23 were discharged directly from our hospital, 35 were transferred to our long-term rehabilitation hospital, and the remaining 34 were transferred to other long-term rehabilitation hospitals or nursing homes (total facilities, 13), typically close to their homes. Of the 35 patients transferred to our long-term rehabilitation hospital, 19 were discharged early, leaving 16 patients for entry into the final analytical database. Table 1 presents the profiles of these 16 patients (median age, 70 years; age range, 47-80 years), 10 with right hemisphere lesions and 6 with left hemisphere lesions. rFA values ranged from .636 to .984 (median, .883). BRS ranged from 1 to 6 (median, 3) for shoulder/ elbow/forearm, from 2 to 6 (median, 3) for hand, and from 3 to 6 (median, 5) for lower extremities. FIM-motor scores ranged from 51 to 90 (median, 75). The normative FA values obtained from the control subjects were .648 6 .025 for the right hemisphere and .638 6 .020 for the left hemisphere (mean 6 standard deviation). Figure 2 shows the brain images from 3 patients (patients 1, 8, and 16 in Table 1). Despite the variations in

lesion size, FA brain images transformed into the standard space were comparable across patients, as were skeletonized FA images, indicating that intersubject analyses on these images were adequately performed. Figure 3 shows the results obtained from the direct comparison of the brain images between the MCA infarction and control groups. Voxels showing significantly smaller FA extended along the entire length of the corticospinal tracts, including the cerebral peduncle, the posterior limb of the internal capsule, and the corona radiata. Direct comparison showed no significant voxel clusters, with higher FA values for the MCA infarction group than the control group (data not shown). Figure 4 shows the relationships between rFA and motor outcome measurements. Analysis revealed significant relationships between rFA and extremity functions. rFA values showed moderate correlations between shoulder/elbow/forearm (correlation coefficient, .687; P 5 .003), hand (correlation coefficient, .579; P 5 .019), and lower extremity (correlation coefficient, .623; P 5 .010) functions. In contrast, analysis of rFA and FIM-motor scores did not reach statistical significance (correlation coefficient, .282; P 5 .291). Close inspection revealed that 2 patients (8 and 9 in Table 1) were almost independent (FIM-motor scores $78; mean score of 6: modified independence across 13 FIM-motor items) in ADL, even with relatively severe impairment (BRS, 2-3) in upper extremity function.

Discussion Previous DTI studies on patients after MCA infarction have reported that lower FA in the corticospinal tracts is associated with severe hemiparesis.12-14 The present study extends the utility of DTI-FA by applying TBSS, which enables assessment of FA representation of the median parts of the tracts. The results obtained from direct image comparisons (Fig 3) confirmed that neural degeneration occurred along the corticospinal tracts, the region of interest in this study (Fig 1). In addition, quantitative analysis showed that the FA values within the corticospinal tracts correlated moderately with the long-term outcome of extremity functions (Fig 4), suggesting that DTI data obtained approximately 2 weeks after onset can be used for long-term outcome prediction in patients after MCA infarction. Using similar methodology, we previously investigated relationships between DTI-FA and long-term outcome in patients after thalamic/putaminal hemorrhage.16 The results indicated that DTI-FA values assessed in the cerebral peduncle, a part of the corticospinal tract, were more tightly associated with upper extremity functions (correlation coefficient: .863 for the shoulder/elbow/forearm and .834 for the hand) than those observed in the present study. The time course of neural damage is a plausible contributing factor to the differences between MCA

FA Patient number

Age (y), M/F

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

67, M 80, F 71, M 69, M 76, M 75, M 75, F 68, M 55, F 47, M 77, F 62, M 49, M 71, M 64, M 80, F

Lesion type L R R L R L R R L R R L L R R R

AT CE AT AT CE CE AT BAD BAD BAD AT CE AT AT AT CE

Brunnstrom stage

Lesion area

Lesion volume (mL)

R

L

rFA

S/E/F

Hand

L/E

FIM-motor

LOS

Cx Cx 1 CR CR Cx 1 CR Cx 1 CR Cx 1 CR Cx CR CR CR PLIC Cx 1 CR Cx 1 CR Cx 1 CR Cx 1 CR Cx 1 CR

22.4 79.5 7.5 20.6 152.3 159.7 17.4 12.5 14.2 11.5 7.8 109.6 124.6 68.4 79.0 110.7

.600 .649 .576 .629 .584 .666 .580 .583 .672 .532 .531 .650 .638 .466 .463 .402

.591 .666 .611 .592 .633 .613 .647 .656 .590 .625 .624 .551 .498 .610 .618 .632

.984 .974 .944 .942 .923 .921 .897 .889 .878 .852 .851 .849 .781 .762 .750 .636

6 6 3 5 3 4 3 3 2 4 3 5 3 2 1 2

6 6 2 5 2 4 3 2 2 3 3 4 3 2 2 2

6 6 5 5 5 5 6 4 4 5 3 6 3 3 4 4

86 73 60 76 54 84 83 78 84 90 69 85 74 70 51 67

139 187 174 166 149 193 194 161 169 150 185 130 185 173 186 151

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Table 1. Patient profiles

Abbreviations: AT, atherothrombotic; BAD, branch atheromatous disease; CE, cardioembolic; CR, corona radiate; Cx, cortex; F, female; FA, fractional anisotropy; FIM-motor, motor component of the Functional Independence Measure; L, left; L/E, lower extremity; LOS, length of hospital stay; M, male; PLIC, posterior limb of the internal capsule; R, right; rFA, ratio between FA values within the region of interest in the affected and unaffected hemispheres; S/E/F, shoulder/elbow/forearm. Patients are presented according to rFA value (highest to lowest). Three patients (2, 12, and 13) underwent intravenous administration of tissue plasminogen activator.

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Figure 3. Comparison between middle cerebral artery (MCA) infarction and control groups. Voxels with significantly smaller FA values in the MCA infarction group are shown in blue. To aid visualization, regions showing significantly lower FA values (P , .01) were thickened using the ‘‘tbss_fill’’ command implemented in FSL. Results are overlaid on the mean FA map (gray) and FA skeleton (green). Abbreviations: L, left; R, right.

infarction and thalamic/putaminal hemorrhage groups.7 It is common for patients after some subtypes of ischemic stroke to exhibit progressive deterioration of neural deficits several days, or even a week, after onset (eg, branch atheromatous disease).32,33 Such variability in the time course of neural deficits may affect the extent of the FA decrease in cases of ischemic stroke.7,13 However, for simplicity, we did not take time course data into

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account in our analytical model. Further studies are thus needed to clarify this simple but important issue. In line with previous studies,12-14 the present results support the notion that neural damage within the corticospinal tract is a major factor for determining motor outcome after MCA infarction. In contrast, recent studies using DTI reported that reconstruction of neural fibers in other areas outside the corticospinal tracts, such as the red nucleus and dorsal pons, plays a potential role in functional recovery in some stroke patients.34,35 Accordingly, more sophisticated models integrating the corticospinal tracts and other motor pathways (eg, corticorubrospinal pathway) might better explain the variance in motor outcomes.36 The result of correlation analysis between rFA and FIMmotor scores did not reveal significant findings (P 5 .291). Inspection of the data of patients 8 and 9 (Table 1) revealed that these patients were almost independent in ADL, with minimum involvement of the affected upper extremity and reliance on their unaffected upper extremities.37 Consequently, DTI-FA may not be an effective predictor of long-term outcome in terms of independence in ADL. In this study, of the 92 total samples, we entered only 16 (17%) into the final analytical database. Given such a small population, confounds arising from sampling bias may be a critical concern. The aim of this study was to

Figure 4. Correlation analysis of rFA and motor outcome. Thin red lines indicate density ellipses (.90) for statistically significant relationships (P , .05). Abbreviations: BRS, Brunnstrom stage; FIM-motor, motor component of the Functional Independence Measure; R, correlation coefficient; rFA, ratios of fractional anisotropy values for the affected and unaffected hemispheres.

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determine the relationship between FA decrease within the corticospinal tracts and the severity of clinical outcome in hemiparesis. It is very common for patients who exhibit mild hemiparesis to return home directly from acute care service. Our previous report in the same line as the present study indicated that patients with mild hemiparesis often showed less evident decreases in FA values within the corticospinal tracts.38 Accordingly, in this study, we focused on patients who were transferred to long-term rehabilitative facilities. Of the 69 patients who were transferred to a total of 14 longterm rehabilitative facilities, we obtained data from 16 patients who transferred to our affiliated facility, where we can systemically monitor long-term outcomes. The assignment of long-term rehabilitative facilities was typically based on the patients’ areas of residence. Although we sampled only 17% (16 of 92) of the total study population, the possibility of sampling bias was minimal. In the present study, we collected outcome data at discharge from our affiliated long-term rehabilitative facility on days 130-194 (quartile, 150-186) after stroke. Although we initially planned to obtain outcome measurements at a fixed time point (eg, 6 months after onset), it proved logistically difficult to collect patient data after discharge in such a fashion. However, previous studies have indicated that functional recovery often reaches a ceiling around 6 months after stroke,39,40 and similar effects were observed in the present study. Accordingly, the differences in sampling time points across subjects likely had minimal effect on the present findings. The present study has a number of limitations. First, during the 34-month-long study period, we were only able to collect data for 16 cases. Yet, as shown in Figure 4, our analysis did yield significant results. However, future studies are required to confirm our correlation results using a larger number of samples from multi-institutional databases. Second, we collected our samples in a long-term hospitalization setting. This may have caused an underestimation of the predictive utility of DTI-FA in more generalized populations, including those with mild hemiparesis after MCA infarction. Third, we limited our inclusion criteria to patients who were functionally independent before stroke. Due in part to this limitation, our samples showed relatively good recovery in terms of independence in ADL. Nevertheless, careful consideration should be taken when applying our findings to geriatric patients requiring assistance in ADL before stroke. Fourth, we focused on clinical severity using BRS and FIM-motor assessment only. Impairment of higher brain functions such as aphasia and hemineglect may be overlooked with the use of such scoring systems. Despite these limitations, our results suggest that DTI-FA is an effective predictor of long-term outcome in terms of extremity functions in patients after MCA infarction. In conclusion, computer-automated TBSS methodology in combination with regionally segmented FA assessment

based on the standard brain template showed that FA values in the corticospinal tracts correlate moderately with long-term motor outcomes of the affected extremity. Our findings suggest the clinical utility of DTI-FA for predicting the long-term outcome of hemiparesis in patients after MCA infarction.

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Relationship between diffusion tensor fractional anisotropy and long-term motor outcome in patients with hemiparesis after middle cerebral artery infarction.

Magnetic resonance diffusion tensor fractional anisotropy (DTI-FA) is often used to characterize neural damage after stroke. Here we assessed the rela...
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