Efficacy of Magnetic Resonance Diffusion Tensor Imaging and ThreeDimensional Fiber Tractography in the Detection of Clinical Manifestations of Central Nervous System Lupus Shiou-Ping Lee, Chien-Sheng Wu, Li-Chun Hsieh, Wing-Keung Cheung, Ming-Chung Chou PII: DOI: Reference:

S0730-725X(14)00048-4 doi: 10.1016/j.mri.2014.02.005 MRI 8143

To appear in:

Magnetic Resonance Imaging

Received date: Revised date: Accepted date:

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Please cite this article as: Lee Shiou-Ping, Wu Chien-Sheng, Hsieh Li-Chun, Cheung Wing-Keung, Chou Ming-Chung, Efficacy of Magnetic Resonance Diffusion Tensor Imaging and Three-Dimensional Fiber Tractography in the Detection of Clinical Manifestations of Central Nervous System Lupus, Magnetic Resonance Imaging (2014), doi: 10.1016/j.mri.2014.02.005

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ACCEPTED MANUSCRIPT Efficacy of Magnetic Resonance Diffusion Tensor Imaging and Three-Dimensional Fiber Tractography in the Detection of Clinical Manifestations of Central Nervous

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System Lupus

Shiou-Ping Lee1, Chien-Sheng Wu2, Li-Chun Hsieh1, Wing-Keung Cheung1,

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and Ming-Chung, Chou3

Department of Medical Imaging, Far Eastern Memorial Hospital, Taipei, Taiwan

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Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan

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Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung,

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Correspondence to:

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Ming-Chung Chou, PhD

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Taiwan

Assistant Professor of Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan

Address: 100, Shih-Chuan First Road, Kaohsiung City, 80708, Taiwan E-mail: [email protected] TEL: 886-7-312-1101 ext 2357-23 FAX: 886-7-311-3449 Word count: 3,323 (including references)

Submitted to Magnetic Resonance Imaging as a case report

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ACCEPTED MANUSCRIPT Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease frequently associated with

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neuropsychiatric manifestations. No follow-up case report has characterized white matter alterations in patients with neuropsychiatric lupus erythematosus (NPSLE) before and after treatment.

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In this study, a 16-year-old NPSLE patient with severe neuropsychological symptoms was treated with steroid pulse therapy, and was scanned with conventional magnetic resonance (MR) and diffusion

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tensor imaging (DTI) at onset and 17 months after treatment. Conventional MR images showed

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diffuse brain atrophy and focal vasogenic edema in the putamen, but they did not reveal abnormalities in the corpus callosum. Region-of-interest analysis of DTI images showed that

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fractional anisotropy and fiber tracts increased significantly, while axial diffusivity, radial, and mean diffusivity decreased significantly in the corpus callosum after treatment. The results indicated that

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the vasogenic edema was present in the corpus callosum at onset and was significantly reduced after

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treatment. These changes were generally compatible with the patient’s clinical manifestations. Hence, we concluded that MR-DTI and fiber tractography are helpful to reveal the relationship between white matter alterations and neurological dysfunctions in NPSLE patients.

Keywords: NPSLE, DTI, Fiber Tractography, Corpus Callosum

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ACCEPTED MANUSCRIPT 1. Introduction

Systemic lupus erythematosus (SLE) is an inflammatory disease affecting many organ systems.

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Neuropsychiatric lupus may present in 10–20% of patients with SLE [1, 2] and has a significant impact on the clinical outcome [3]. The involvement of the central nervous system (CNS) is one of the most

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frequent causes of morbidity and mortality in neuropsychiatric lupus erythematosus (NPSLE). NPSLE is known to be associated with white mater alterations; however, the correlation between clinical

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manifestation and white matter changes has not been well understood. Previous reports have

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indicated that clinical signs and symptoms of NPSLE are associated with signal abnormalities in conventional T1-weighted, T2-weighted, fluid-attenuated inversion recovery (FLAIR), and diffusion-

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weighted images (DWI) after an episode with symptoms[4, 5], and are also related to abnormal diffusivity in the brain [6]. However, some NPSLE patients with active disease show negative

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conventional magnetic resonance imaging (MRI) results [7]. Diffusion tensor imaging (DTI), which is

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known to successfully detect three-dimensional distribution of water molecules in vivo, was therefore widely utilized to detect subtle changes of diffusion anisotropy in NPSLE patients [8-12]. In addition, previous studies have shown that brain abnormalities are frequently observed in the corpus callosum [4, 5, 8-10] and that the fiber tracts are generally decreased in NPSLE patients [8]. However, little is known about the serial changes in the white matter integrity of the corpus callosum in NPSLE patients after steroid pulse therapy [13]. Here we report an NPSLE patient who underwent follow-up DTI examinations before and after steroid pulse therapy. DTI indices and the number of fiber tracts in the corpus callosum of the patient were compared statistically before and after treatments to reveal changes in white matter integrity.

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ACCEPTED MANUSCRIPT 2. Case report

A 16-year-old girl with SLE was admitted because of apathy as well as slowed speech and eating for

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two weeks. She was diagnosed with SLE with an initial presentation of a positive antinuclear antibody (ANA) test, positive anti-dsDNA test, pleural effusion, anemia, and one episode of seizure at

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the age of 14. No other CNS manifestations were noted until this episode. She underwent MR examinations after providing well-informed consent. A mini-mental state exam (MMSE) was also

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performed at the same time to evaluate her cognitive impairments, and she scored 16 points. Her

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erythrocyte sedimentation rate (ESR) was 106 mm/hr, and her SLE Disease Activity Index (SLEDAI) [14] score was 23. According to the American Association of Rheumatology classification of

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neuropsychiatric manifestation of SLE, the patient was diagnosed with NPSLE.

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Methylprednisolone pulse therapy (1000 mg) was administered for three days. The patient was

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discharged with 20 mg prednisolone every other day and 100 mg azathioprine daily. One month later, her mood changed from apprehension to delight, and she showed less apathy and improved eyesight. Her motor function was completely restored and she exhibited normal movements. She underwent a second MMSE and achieved a full score. In addition, her SLEDAI improved from 23 to 18 and her ESR decreased from 106 mm/hr to 25 mm/hr. The clinical manifestations and clinical data indicated that the patient’s symptoms were well controlled by the treatment. A follow-up DTI was performed 17 months later.

2.1 Magnetic resonance imaging

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ACCEPTED MANUSCRIPT In MR examinations, the patient was scanned on a 1.5-T MR system (Sonata; Siemens, Erlangen, Germany). The conventional axial T1-weighted (TR/TE = 467/13 ms, ETL = 1, NEX = 1, FOV = 230 x 173 mm2, matrix size = 256 x 154, slice thickness = 5 mm), T2-weighted (TR/TE = 4260/101 ms, ETL = 17,

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NEX = 1, FOV = 230 x 173 mm2, matrix size = 512 x 230, slice thickness = 5 mm), and FLAIR-weighted

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(TR/TE/TI = 7500/117/2200 ms, ETL = 29, NEX = 1, FOV = 230 x 176 mm2, matrix size = 256 x 147, slice

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thickness = 5 mm) images were acquired by using turbo spin-echo pulse sequence with slice orientation parallel to anterior-posterior commissure line. Afterwards, a single-shot echo-planar

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diffusion-weighted pulse sequence was used to acquire whole brain DTI images with the following parameters: TR/TE = 8900/95 ms, diffusion weighting factor (b-value) = 1000 s/mm2 applied in 13

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non-collinear directions plus one b = 0 image, field of view = 280 x 280 mm2, matrix size = 128 x 128,

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and slice thickness = 2.2 mm (isotropic resolution), number of excitations = 2, and number of slices = 50. The scan time for DTI acquisition was approximately 13 min. A follow-up DTI scan was also

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performed 17 months later with identical imaging parameters.

2.2 Image processing

All DTI data were transferred to a stand-alone workstation and post-processed on a MATLAB (MathWorks; Natick, Massachusetts, USA) platform. First, all the diffusion-weighted volumes were co-registered with the native b = 0 image using affine image registration with a cost function of normalized mutual information to minimize eddy current distortions. Subsequently, a diffusion tensor was fitted on a voxel-by-voxel basis using a least square method to obtain three eigen values and three corresponding eigen vectors, which were harnessed to calculate DTI indices, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) [15]. In addition, diffusion tensor maps were further utilized to trace neuronal fibers using tensor

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ACCEPTED MANUSCRIPT deflection tractography with an adaptive step size [16] and the following criteria: FA > 0.15, turning angle < 30 degrees, and tract length > 60 mm.

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2.3 Data analysis

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For regional comparison, regions of interest (ROIs) were placed on the mid-sagittal FA maps to encompass the entire body, genu, rostrum, and splenium of the corpus callosum before and after

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treatment, as shown in Fig. 1. The means and standard deviations of FA, MD, AD, and RD in those

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regions were then calculated. For fiber tractoraphy, the seed points were placed globally and the ROIs in Fig. 1 were used as the targeting regions to trace the neuronal fibers of the entire body, genu,

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rostrum, and splenium of the corpus callosum. Subsequently, the tract distribution map was generated by counting the number of fibers in each voxel, and the number of fibers in each ROI

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region was counted for comparison. Finally, the Wilcoxon signed-rank test was used to determine

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whether there was a significant difference in DTI indices and the number of fiber tracts between the two scans. The difference was considered significant if P < 0.05. Besides, since the manual drawing of ROIs may influence the statistical results, this study performed the test-retest reproducibility of DTI indices and number of fiber tract by drawing ROIs ten times in ten days (one time per day). The coefficients of variation (CVs) of ten measurements were calculated to assess the intra-observer reproducibility, and CV of less than 10% was considered as good reproducibility.

2.4 Results

Conventional MR images showed diffuse brain atrophy and focal hypersignal intensity in the putamen at onset, as shown in Fig. 2. However, abnormal signals in the corpus callosum of the patient were not observed. After 17 months treatment, the focal hypersignal intensity persisted in 6

ACCEPTED MANUSCRIPT the putamen. Region-of-interest analysis of DTI images showed that the FA values in the entire body, genu, rostrum, and splenium were 0.33 ± 0.19, 0.28 ± 0.14, 0.25 ± 0.10, and 0.37 ± 0.23 respectively at onset, and these values increased to 0.38 ± 0.19, 0.37 ± 0.17, 0.29 ± 0.08, and 0.41 ± 0.20 after

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treatment. Only the entire body and genu of the corpus callosum had significant increases in FA value, as shown in Fig. 3a. In contrast, the MD values in the entire body, genu, and rostrum of the

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corpus callosum were 1.29 ± 0.48, 1.39 ± 0.53, and 1.46 ± 0.49 × 10−3 mm2/s respectively at onset, and these values significantly decreased to 1.15 ± 0.44, 1.06 ± 0.53, and 1.16 ± 0.38 ×10−3 mm2/s after

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treatment. For the splenium of the corpus callosum, the initial MD value was 1.12 ± 0.42 × 10−3

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mm2/s, but it slightly increased to 1.14 ± 0.40 × 10−3 mm2/s after treatment, as shown in Fig. 3b. Similar to MD values, the AD values in the entire body, genu, and rostrum of the corpus callosum were 1.72 ± 0.42, 1.77 ± 0.51, and 1.82 ± 0.46 × 10-3 mm2/s respectively at onset, and these values

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significantly decreased to 1.63 ± 0.45, 1.47 ± 0.60, and 1.54 ± 0.47 × 10−3 mm2/s after treatment.

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However, the initial AD value in the splenium of the corpus callosum was 1.57 ± 0.40 × 10−3 mm2/s,

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while it was significantly increased to 1.66 ± 0.36 × 10−3 mm2/s after treatment, as shown in Fig. 3c. The RD values in the entire body, genu, and rostrum of the corpus callosum were 1.08 ± 0.53, 1.20 ± 0.55, and 1.28 ± 0.51 × 10−3 mm2/s respectively at onset, and these values significantly decreased to 0.91 ± 0.47, 0.85 ± 0.52, and 0.98 ± 0.35 × 10−3 mm2/s after treatment, as shown in Fig. 3d. Although the RD values in the splenium of the corpus callosum decreased from 0.90 ± 0.47 to 0.88 ± 0.46 × 10−3 mm2/s after treatment, no significant difference was noted between these values.

Moreover, using fiber tractography, the numbers of fiber tracts in the entire body, genu, rostrum, and splenium of the corpus callosum were 1591, 76, 32, and 1108 respectively at onset, and these values slightly increased to 1794, 245, 55, and 1166 after treatment, as shown in Fig. 3e. However, no significant difference in number of fiber tracts was noted between the two scans. The mid-sagittal tract distribution maps and top-view of tractograms showed that the number of fiber tracts increased 7

ACCEPTED MANUSCRIPT in the genu of corpus callosum after treatment, as shown in Fig. 4. The test-retest analysis showed that the intra-observer reproducibility was good in ROI analysis for most regions. However, the CVs of tract number in the rostrum were larger than other regions before and after treatment due likely

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to its fewer tracts. The CVs of DTI indices and number of fiber tracts before and after treatment were

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listed in Table 1.

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3. Discussion

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Our study showed that DTI can provide more information than conventional MRI and can reveal serial changes in white matter tissues over the clinical course of NPSLE. The conventional MR images

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showed hyper T2 and FLAIR signals and hypo T1 and DWI signals in the putamen, suggestive of vasogenic edema in the tissue. The putamen is known to be the main structure of the basal ganglia

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that serves as an intermediate relay in the basal ganglia-thalamocortical circuit [17]. Previous studies

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have shown that the motor dysfunctions of ecstasy users were associated with impairments in the basal ganglia-thalamocortical circuit [18, 19]. The frontal-subcortical and prefrontal-basal ganglia circuit dysfunctions were also associated with apathy and impaired executive functions [20-22]. In our patient, the executive and motor functions as well as the apathy noted in our patient were likely associated with tissue alterations in the putamen.

In our patient, conventional MRIs did not show any abnormality in the corpus callosum. DTI analysis further showed that the corpus callosum, particularly the anterior part, exhibited lower FA and higher AD, RD, and MD values before treatment, suggestive of vasogenic edema in the tissue. A previous study on multiple sclerosis patients showed that verbal fluency is strongly affected by anterior corpus callosum lesions [23]; therefore, the lower FA and higher diffusivity in the anterior corpus callosum were likely responsible for the patient’s manifestation of slowness in speech. In 8

ACCEPTED MANUSCRIPT addition, the significant increase in FA together with reduced AD, RD, and MD values in the genu of corpus callosum suggested that vasogenic edema resolved after steroid pulse therapy. In contrast, the splenium of corpus callosum exhibited higher FA and AD, but almost constant RD and MD values

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after treatment, suggestive of slight improvement of tissue integrity. However, when compared with age-matched normal subjects as reported in previous DTI studies [24, 25], the FA and diffusivity

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values in the corpus callosum of our patient differed from normal values, which indicated that

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vasogenic edema still existed.

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Fiber tractography revealed more callosal fibers in the patient after treatment, probably due to the resolution of vasogenic edema, suggesting that steroid pulse therapy improved the integrity of inter-

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hemispheric connectivity. It is known that white matter fibers in the genu and rostrum of the corpus callosum play crucial roles in linking the frontal and prefrontal lobes of the cerebral hemispheres, and

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fibers in the splenium of the corpus callosum link the parietal lobules and occipital cortex of the brain

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[26]. Previous studies have also demonstrated that abnormalities in the corpus callosum are correlated with neuropsychological [12, 27] and motor dysfunctions [28]. Hence, the increased number of callosal fibers observed in our patient was likely to be responsible for the improvements in her cognitive and motor functions.

Because NPSLE is known to be associated with abnormalities in the corpus callosum [4, 5, 8-10], this study analyzed only the diffusion characteristics and fiber tracts of the corpus callosum. However, the clinical symptoms of our patient may also relate to abnormalities in other brain regions [20, 22, 29] that were not analyzed in this study. Thus, the improvement in cognitive and motor functions observed after treatment may not be fully attributable to the reduced edema and increased fiber tracts in the corpus callosum. Another limitation of this study is the use of MMSE for measuring cognitive functions. MMSE is a mental test that evaluates the general cognitive functions of a patient 9

ACCEPTED MANUSCRIPT and cannot discriminate specific psychological disorders [30]. Hence, if the discrimination of a cognitive disorder is important for the patient, it would be necessary to perform more specific cognitive tests such as the Wisconsin Card Sorting Test [31], phonemic association tests [32], and

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other similar tests that await further investigations. Finally, although the test-retest analysis showed good intra-observer reproducibility, there may be operating errors in manual ROI analysis even with

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careful attention; therefore, the results of this study may have been affected by such errors.

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4. Conclusion

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White matter lesions in NPSLE are usually overlooked due to a lack of appropriate study tools. MRDTI is a well-established method for characterizing white matter alterations, and fiber tractography

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aids the identification of pathway-specific clinical symptoms. This study described an NPSLE patient

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who suffered from severe neurological symptoms but had corpus callosum white matter that was normal in appearance based on conventional MRI. With the DTI technique, subtle white matter alterations in the corpus callosum were detected by analyzing DTI indices and fiber tractography, and these alterations were generally compatible with the patient’s clinical manifestations before and after treatments. Therefore, we conclude that MR-DTI is helpful for detecting white matter alterations in NPSLE patients and has the potential to be a surrogate marker for evaluating disease activity and treatment response in patients with CNS lupus.

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ACCEPTED MANUSCRIPT Acknowledgements

This study was supported in part by grant NSC-101-2134-B-037-047-MY2 from National Science

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Council of Taiwan

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ACCEPTED MANUSCRIPT Figure legends

Figure 1. The mid-sagittal FA maps obtained from the SLE patient before (a) and after (b) treatment

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respectively. The dotted regions show the ROIs for the measurements of DTI indices and fiber tracts

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in genu (yellow), rostrum (red), splenium (blue), and the entire body of corpus callosum.

Figure 2. Conventional T1 (a), T2 (b), FLAIR (c), and DWI (d) of the 16-year-old SLE patient with

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neuropsychiatric syndromes show diffuse brain atrophy of the brain at onset. Slight atrophy is

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observed in the patient and abnormal hypersignal intensities are noted in the putamen, as indicated

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by white arrows. However, no abnormal signal is observed in the corpus callosum.

Figure 3. Comparisons of FA (a), MD (b), AD (c), RD (d), and number of fiber tracts (e) between the

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entire body, genu, rostrum, and splenium of corpus callosum in the NPSLE patient before and after

asterisks (*).

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treatment. Those with significant difference (P < 0.05) between the two scans are indicated by

Figure 4. The mid-sagittal tract distribution maps and top-view of fiber tractograms obtained from the SLE patient before (a, c) and after (b, d) treatment respectively. Color bar indicates the number of fiber tracts. A mild increase of fiber tracts is noted in the genu of corpus callosum, as indicated by yellow arrows in (a) and (b). In tractogram, fibers that pass through the genu of corpus callosum are apparently increased after treatment in the frontal regions, as indicated by yellow arrows in (c) and (d).

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ACCEPTED MANUSCRIPT Table 1 The CVs (%) of ten-repeated measurements of DTI indices and number of fiber tract in the corpus

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callosum before and after treatment

Body CC

2.22

1.19

1.04

0.73

2.90

3.35

1.56

16.23

2.00

1.00

Rostrum

SCC

Body CC

3.82

2.20

2.09

3.56

1.24

1.60

2.65

0.77

0.95

10.27

4.23

1.86

2.20

6.03

48.04

2.82

1.61

Rostrum

CV(FA)

1.82

3.05

CV(MD)

2.05

2.36

CV(AD)

1.76

1.62

CV(RD)

2.31

CV(tract number)

4.82

After Treatment

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CV(FA)

4.74

CV(MD)

8.52

CV(AD)

6.56

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CV(RD)

CV(tract number)

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3.56

1.59

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GCC

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Before Treatment

CC = corpus callosum; GCC = genu of corpus callosum; SCC = splenium of corpus callosum

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Efficacy of magnetic resonance diffusion tensor imaging and three-dimensional fiber tractography in the detection of clinical manifestations of central nervous system lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease frequently associated with neuropsychiatric manifestations. No follow-up case report has c...
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