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Diffusion tensor MR imaging in spinal cord injury
G Model JINJ 7094 No. of Pages 5
Injury, Int. J. Care Injured xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Original article
Diffusion tensor MR imaging in spinal cord injury Maria M. D’souza* ,a , Ajay Choudharyb , Mahesh Pooniaa , Pawan Kumara , Subash Khushua a b
INMAS, Brig SK Majumdar Marg, Delhi, 110054, India Dept. of Neurosurgery, RML Hospital, New Delhi, India
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 20 February 2017
Background: The ability of diffusion tensor imaging (DTI) to complement conventional MR imaging by diagnosing subtle injuries to the spinal cord is a subject of intense research. We attempted to study change in the DTI indices, namely fractional anisotropy (FA) and mean diffusivity (MD) after traumatic cervical spinal cord injury and compared these with corresponding data from a control group of individuals with no injury. The correlation of these quantitative indices to the neurological profile of the patients was assessed. Material and methods: 20 cases of acute cervical trauma and 30 age and sex matched healthy controls were enrolled. Scoring of extent of clinical severity was done based on the Frankel grading system. MRI was performed on a 3T system. Following the qualitative tractographic evaluation of white matter tracts, quantitative datametrics were calculated. Results: In patients, the Mean FA value at the level of injury (0.43+/ 0.08) was less than in controls (0.62+/ 0.06), which was statistically significant (p value <0.001). Further, the Mean MD value at the level of injury (1.30+/ 0.24) in cases was higher than in controls (1.07+/ 0.12, p value <0.001). Statistically significant positive correlation was found between clinical grading (Frankel grade) and FA values at the level of injury (r value = 0.86). Negative correlation was found between clinical grade and Mean MD at the level of injury (r value = 0.38) which was however statistically not significant. Conclusion: Quantitative DTI indices are a useful parameter for detection of spinal cord injury. FA value was significantly decreased while MD value was significantly increased at the level of injury in cases as compared to controls. Further, FA showed significant correlation with clinical grade. DTI could thus serve as a reliable objective imaging tool for assessment of white matter integrity and prognostication of functional outcome. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Diffusion tensor imaging Spinal cord injury Neurological outcome
Introduction Spinal trauma can result in devastating medical, social, emotional and financial consequences, especially when associated with neurological damage. Diagnostic imaging plays a crucial role in evaluating and detecting spinal trauma. The imaging assessment of these patients has undergone dramatic changes over the past several years. Today, conventional MR imaging is performed routinely to demonstrate soft tissue and spinal cord injuries in spinal trauma [1–3]. Many advantages of MRI such as higher contrast resolution, absence of bony artifacts, multiplanar capability, and choice of various pulse sequences make it possible to diagnose spinal trauma more accurately. Conventional MRI relies heavily on changes in signal intensity for depiction of pathology.
* Corresponding author. E-mail address: [email protected] (M.M. D’souza).
However, the literature is ambivalent about the relationship between MRI findings and extent of neurological damage. According to certain reports, edema and hemorrhage in the spinal cord following trauma are well demonstrated by MR imaging and may help to predict neurologic outcome [4–6]. However, some studies suggest that although spinal cord edema, hemorrhage and interstitial fibrosis will appear as changes in signal intensity on conventional MRI, they may not always be successful in the prediction of functional deficit [7]. Diffusion tensor imaging (DTI) is a novel MR imaging technique which assesses the microstructural integrity of nerve fiber tracts. It is based on the simple principle of diffusion of water molecules in tissue. In neuronal tissue, this mobility is restricted to one particular direction by the presence of biological barriers such as cell membranes and myelin sheath, hence the diffusion is termed anisotropic. Interruption or alteration of this linear molecular diffusion at any point along the neuron can be the first sign of a
http://dx.doi.org/10.1016/j.injury.2017.02.016 0020-1383/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: M.M. D’souza, et al., Diffusion tensor MR imaging in spinal cord injury, Injury (2017), http://dx.doi.org/ 10.1016/j.injury.2017.02.016
G Model JINJ 7094 No. of Pages 5
2
M.M. D’souza et al. / Injury, Int. J. Care Injured xxx (2016) xxx–xxx
physiological disturbance, which makes DTI more sensitive to early change even before gross structural changes are evident [8]. DTI is currently the only means for non-invasive in vivo assessment of white matter tract integrity [9]. The two most widely used quantitative DTI indices are fractional anisotropy (FA) and mean diffusivity (MD). The ability of DTI to complement conventional MR imaging by diagnosing subtle injuries to the spinal cord in humans, or predict the need for early therapeutic intervention for optimal clinical outcome is a subject of intense research [10]. We hypothesized that there would be changes in DTI indices in spinal cord injury, which could correlate with the ultimate neurological deficit. Our purpose was to study changes in the DTI indices, namely FA and MD in patients with traumatic spinal cord injury and assess the correlation of these quantitative data metrics to the neurological profile of the patients. Material and methods 20 cases of cervical trauma, with/without neurologic deficit diagnosed clinically or/and by radiological imaging were recruited for the study from the neurosurgery department of a reputed hospital, within 7 days of sustaining trauma. 30 age and sex matched healthy controls were also included. Written, informed consent was obtained from all subjects. Subjects with concomitant spinal pathology (eg. old Pott’s spine) were excluded. Subjects with non MR compatible metallic implants and those with claustrophobia were excluded from the study. The institutional review board approved of the study. Following a detailed history and clinical examination, radiographs and CT scan were taken where indicated. MRI of cervical spine was performed on a three tesla (3T) MR system (Siemen’s Skyra). The MR protocol was as follows: (a) Sagittal T1: repetition time in milliseconds (msec) [TR]/echotime in msec [TE] – 450/9.5, (b) Sagittal T2:TR/TE – 3630/104, (c) Axial T1: TR/TE – 450/9.6 and (d) Axial T2: TR/TE 500/15. For DTI, we used a single shot echo planar imaging (EPI) sequence (b-value = 0,700 s/mm2) using 20 diffusion encoding directions with scan time of approximately 6 min. The image was acquired in axial plane with image matrix of 128 128, slice thickness of 5 mm with no inter-slice gap, and a field of view (FOV) of 280 280 mm. To enhance the signal-tonoise ratio and reduce the phase fluctuations, magnitudeconstructed images were repeated (averages = 4) and temporally averaged. Following image acquisition, the data was analyzed quantitatively and qualitatively. For qualitative analysis, a region of interest (ROI) was drawn in the region of the spinal cord. This became a seed-point for the automatic generation of the entire white matter tract in the segment of the spinal cord included in the FOV, by inbuilt software. For evaluation of quantitative indices, an ROI (size 3 mm) was drawn into the white matter column of the spinal cord. Special care was taken to avoid partial volume averaging with
underlying grey matter and overlying CSF. By means of the inbuilt software, automatic calculation of DTI indices namely FA and MD was performed within the ROI. These indices were evaluated at the level of injury, and one vertebra above and below the level of injury. In controls we evaluated the FA and MD values at all cervical vertebral levels and individually computed the average FA and average MD in each subject. The patients were reassessed clinically 1–2 months after the DTI study. Scoring of extent of clinical severity was done based on the Frankel grading system – a five point system (A–E in decreasing order of severity), which takes into account the sensory and motor deficit [11]. The data collected was statistically analyzed by SPSS (version15.0) software. Chi-square test was applied to compare sex distribution between cases and controls. Unpaired t-test was applied to compare age of cases and controls. Changes in DTI in the form of fractional anisotropy and mean diffusion were obtained. These changes were statistically compared with age and sex matched controls by unpaired t-test. Correlation of DTI changes with clinical severity (based on Frankel grading) was performed using Spearman correlation. Results A total of 20 cases and 30 healthy controls was enrolled. In Case group (n = 20), age range was from 17 to 54 yrs. (Mean age35.95 10.86 yrs). In Control group (n = 30), age range was from 19 to 54 yrs. (Mean age-35.90+/ 10.13 yrs.). The difference in age of Cases and Controls was not statistically significant (p value = 0.802) by Unpaired t-test. There were 20 males and 10 females in Control group and 14 males and 6 females in Case group. The difference in distribution based on sex in Cases and Controls was not statistically significant (p value = 0.292) by Chi-square test. Of the 20 cases of cervical trauma, there was evidence of vertebral fracture in 4, spondylolisthesis in 4, bone-marrow edema in 4, reduced disc height in 4, disc bulge in 9, secondary spinal canal stenosis in 8., cord compression in 10, nerve- root compression in 7, cord signal changes in 10 and hemorrhagic changes in the form of extradural hematoma seen in 1. MR study of controls revealed no significant finding (Table 1). In the study group involving cases of cervical injury (n = 20), the Mean FA value at the level of injury (0.43+/ 0.08) was less than the Mean FA value of cervical spine (0.62+/ 0.06) in controls (n = 30), which was statistically significant (p value <0.001). However no significant difference was found in Mean FA value above the level of injury or below the level of injury in comparison to controls (Table 2). Further, the Mean MD value at the level of injury (1.30+/ 0.24) in cases (n = 20) was higher than the Mean MD value of controls (1.07+/ 0.12), which was statistically significant (p value <0.001). However no significant difference was found in Mean MD value above or below the level of injury between Cases and Controls (Table 2). Statistically significant (p < 0.01) positive Spearman’s correlation
Table 1 Conventional MRI findings in cases of injury of cervical spine. S. No
MRI findings
No. of Cases of Cervical spine
1 2 3 4 5 6 7 8 9 10
Vertebral fracture Spondylolisthesis Bone-marrow edema Reduced disc height Disc bulge Secondary spinal canal stenosis Cord compression Nerve root compression Cord signal changes Hemorrhagic changes (extradural hematoma)
4 4 4 10 9 8 10 7 10 1
Please cite this article in press as: M.M. D’souza, et al., Diffusion tensor MR imaging in spinal cord injury, Injury (2017), http://dx.doi.org/ 10.1016/j.injury.2017.02.016
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M.M. D’souza et al. / Injury, Int. J. Care Injured xxx (2016) xxx–xxx
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Table 2 Comparison of DTI parameters between cases of cervical injury and controls. DTI Parameter
Above injury
At the level of injury
Below injury
Controls
FA
0.64 0.07 (p value 0.461) 1.03 0.12 (p value 0.270)
0.43 0.08 (p value <0.001) 1.30 0.24 (p value <0.001)
0.61 0.06 (p value 0.422) 1.12 0.14 (p value 0.130)
0.62 0.06
MD
(r value = 0.86) was found between FA values at the level of injury and clinical grading (Frankel score – A, B, C, D, E in order of decreasing sensorimotor deficit). In contrast, negative correlation was found between mean MD at the level of injury and the Frankel score (r value = 0.38) which was however statistically not significant. (p value 0.09). Qualitative tractographic analysis was performed in all cases and controls. Normal orientation of white matter tracts in the cord was visualized in all 30 controls in the form of homogenous blue color suggestive of preservation of integrity of white matter tracts (Fig. 1). In 10 cases, routine MRI scanning depicted changes in cord signal intensity. On tractography, changes in cord integrity could be observed in 12 cases in the form of distortion of homogenous blue color with or without flecks of green color interspersed within, thereby suggesting disruption in cord integrity (Fig. 2). In the remaining 8 cases, the spinal cord appeared grossly normal on qualitative tractographic analysis. Discussion MR imaging, owing to its excellent soft-tissue resolution, has played an important role in the assessment of spinal cord injury. However, subtle cord injuries are often missed on conventional MR sequences, and the association between clinical severity of injury and pathology depicted on MR has been found to be less than satisfactory in several cases [12]. In the present study, conventional MR sequences revealed abnormality in the spinal cord and associated soft tissue in 10 cases, of a total of 20 cases included in the study. In the remaining cases, the cord appeared normal, despite the presence of neurological deficit as determined by the low Frankel score. Development of a reliable, objective and quantitative measure for assessment of spinal cord injury is essential, without which we would be unable to provide a reliable prognosis or consistency in management [13].
1.07 0.12
This study was an attempt to assess the diagnostic performance of a novel method, namely DTI in the evaluation of spinal cord injury. DTI assesses the microstructural integrity of nerve fiber tracts, based on the simple principle of diffusion of water molecules in vivo. The changes in diffusion on DTI can be assessed either qualitatively by ‘fiber tracking techniques’ (tractography) or quantitatively by calculating DTI anisotropy indices (datametrics) [14]. Tractography gives a visual representation and assessment of the diffusion status of the evaluated structure, which allows tracking of the longitudinal structure of the axons. The direction of diffusion can also be color-coded and traditionally, diffusion from left to right is represented by red, antero-posterior direction by green and cranio-caudal by blue. In the spine, as the fibers are mainly cranio-caudal, the tracts are always represented in blue. Spinal tractography can show the macroscopic orientation of fibers with dramatic representation of the disruption of tracts, which can be poorly seen on plain MRI. Clinically, this information allows better delineation of damaged fiber tracts in the injured spinal cord [15]. Anisotropy indices or DTI datametrics provide a quantitative perspective and a numerical value to the diffusion in any particular voxel. Among the different indices described, the most commonly used are Fractional anisotropy (FA) and Mean diffusivity (MD), often called the Apparent diffusion coefficient (or ADC). Fractional anisotropy measures the fraction of the ‘magnitude’ of total diffusion which occurs in one particular voxel that can be attributed to anisotropic diffusion. FA varies between 0 for diffusion in a perfect sphere (isotropic diffusion) and 1 for diffusion in a perfect thinnest cylinder (infinite anisotropy). Usually, in intact neurons, the FA value is closer to 1 because of the high degree of anisotropy. When there is any damage to the axonal membrane, the diffusion at that level becomes unrestricted and isotropic. The other important index is the mean diffusivity which is a measure of the average diffusion in all directions. A low
Fig. 1. T2 sagittal image in healthy control (A) shows normal cervical spinal cord. Axial diffusion tensor image with ROI (B) and diffusion tensor tractography image (C) in same subject shows intact white matter tract of cervical spinal cord.
Please cite this article in press as: M.M. D’souza, et al., Diffusion tensor MR imaging in spinal cord injury, Injury (2017), http://dx.doi.org/ 10.1016/j.injury.2017.02.016
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Fig. 2. T2 sagittal and axial image (A, B) in a case of cervical spinal injury (Frankel grade D) shows early degenerative changes in spine with intact spinal cord. Axial DTI (C) and diffusion tensor tractography image (D) show white matter disruption at level of injury.
value for MD indicates that the imaged structure (e.g. nerve fibers) is organized, whereas a high value indicates disorganization within the fiber tracts [8]. The present study incorporated both qualitative and quantitative assessment of the spinal cord. Tractography revealed a disruption in the neuronal integrity in 12 cases. On quantitative assessment, a significant decrease in FA was noted in the acute phase at the level of injury in patients compared to controls (mean 0.43 vs 0.62, p value <0.001). Further, patients demonstrated a significant increase in MD injury, compared to controls (mean 1.3 vs 1.07, p value <0.001). This rise in MD with an accompanying fall in FA at the site of spinal cord injury has been observed in other studies as well [13,16,17]. A similar pattern of reduced FA with increased MD has been observed in cases of non-traumatic spinal cord pathology also [18–21]. In our study, the patients who had neurological deficits despite a normal conventional MR study, revealed a fall in FA and increase in MD levels on DTI studies. The superiority of DTI over conventional MRI in determining the presence and extent of cord pathology has been reported in the past also. A study by Demir et al. [22] on cervical compressive myelopathy revealed significant reduction in FA and increase in MD at sites which appeared normal on conventional MR sequences, which correlated well with the clinical data. The cause for the increased ADC values and decreased FA values at the level of injury is still uncertain. Tsuchiya et al. [23] explained it was possible that the elevated ADC values indicated edema and necrosis, with myelomalacia in the chronic phase. According to Ting Song et al. [24], intervertebral disk herniation and canal stenosis compressing the spinal cord could cause decreasing perfusion which might lead to ischemia and anoxemia and cellular membrane injury that could increase cellular membrane penetrability. Long-term compression of spinal cord may cause CSF to flow turbulently and to penetrate into spinal cord and to form intramedullary microcysts which cannot be displayed on conventional MR examination [21]. The decreased FA values have been attributed to the restricted anisotropic diffusion of water molecule in the injured cord. Because FA measures the degree of myelination, with higher FA values suggesting more intact spinal nerves, the positive correlation between FA and sensori-motor performance may be expected. Likewise, because MD measures the degree of molecular water movement with lower values
suggesting more intact spinal cord, the negative correlation between MD and sensori-motor status may also be expected [13]. Currently, several neurological tests are in vogue for the assessment of clinical severity of injury and its prognostication. However, assessment of clinical severity is challenging in the acute phase due to spinal shock. An objective, quantitative imaging tool could be of great clinical utility in this scenario. An excellent correlation was observed between FA and the ultimate clinical severity of injury in our study. We adopted the Frankel scoring system to assess the clinical severity of injury, as it is robust, easy to apply and has been validated in previous studies [11]. There was significant positive correlation (r value 0.86, p value <0.01) between FA indices at the site of injury and the Frankel score obtained 1–2 months after injury. Although negative correlation was found between Frankel score and mean MD at the level of injury (r value = 0.38) it was however statistically not significant. (p value 0.09). Statistically significant correlation between the FA values and clinical severity of injury as determined by the ISNCSCI scores were documented even in the pediatric population in previous studies, wherein performance of DTI is known to pose additional technical challenges, largely owing to the smaller field of view (FOV) of the spinal cord [13]. In our study we found that DTI was superior to conventional MRI scans in depicting changes in spinal cord integrity after traumatic injury. Qualitative tractography enabled the delineation of changes in the white matter tract of spinal cord, both obvious as well as subtle. Quantitative indices in the form of FA and MD were a more useful parameter for detection of spinal cord injury. FA value was significantly decreased while MD value was significantly increased at the level of injury in cases as compared to controls. FA showed significant correlation with the Frankel score, a clinical measure of the motor and sensory status. Long-term studies would be needed to see if DTI could be used as a reliable prognostic marker of neurological outcome in spinal cord injury. Conflict of interest statement None of the authors of the manuscript titled “Diffusion Tensor MR Imaging in Spinal Cord Injury” have any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.
Please cite this article in press as: M.M. D’souza, et al., Diffusion tensor MR imaging in spinal cord injury, Injury (2017), http://dx.doi.org/ 10.1016/j.injury.2017.02.016
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M.M. D’souza et al. / Injury, Int. J. Care Injured xxx (2016) xxx–xxx
References [1] Silberstein M, Tress BM, Hennessy O. Prediction of neurologic outcome in acute spinal cord injury: the role of CT and MR. AJNR 1992;13:1597–608. [2] Katzberg RW, Benedetti PF, Drake CM, Ivanovic M, Levine RA, Beatty CS, et al. Acute Cervical spine injuries: prospective MR imaging assessment at a level 1 trauma center. Radiology 1999;213:203–12. [3] Flanders AE, Schaefer DM, Doan HT, Mishkin MM, Gonzalez CF, Northrup BE. Acute Cervical spine trauma: correlation of MR imaging findings with degree of neurologic deficit. Radiology 1990;177:25–33. [4] Kulkarni MV, McArdle CB, Kopanicky D, Miner M, Cotler HB, Lee KF, et al. Acute spinal cord injury: MR imaging at 1.5 T. Radiology 1987;164:837–43. [5] Bondurant FJ, Cotler HB, Kulkarni MV, McArdle CB, Harris Jr. JH. Acute spinal cord injury: a study using physical examination and magnetic resonance imaging. Spine 1990;15:161–8. [6] Flanders AE, Spettell CM, Tartaglino LM, Friedman DP, Herbison GJ. Forecasting motor recovery after Cervical spinal cord injury: value of MR imaging. Radiology 1996;201:649–55. [7] Matsumoto M, Toyama Y, Ishikawa M, Chiba K, Suzuki N, Fujimura Y. Increased signal intensity of the spinal cord on magnetic resonance images in Cervical compressive myelopathy. Does it predict the outcome of conservative treatment? Spine 2000;25:677–82. [8] Rajasekaran S, Kanna RM, Shetty AP. Diffusion tensor imaging of the spinal cord and its clinical applications. J Bone Joint Surg Br 2012;94:1024–31. [9] Bosma R, Stroman PW. Diffusion tensor imaging in the human spinal cord: development, limitations, and clinical applications. Crit Rev Biomed Eng 2012;40:1–20. [10] Shanmuganathan K, Gullapalli RP, Zhuo J, Mirvis SE. Diffusion tensor MR imaging in Cervical spine trauma. AJNR 2008;29:655–9. [11] Frankel HL, Hancock DO, Hyslop G, Melzak J, Michaelis LS, Ungar GH, et al. The value of postural reduction in the initial management of closed injuries of the spine with paraplegia and tetraplegia. I. Paraplegia 1969;7:179–92. [12] Kerkovsky M, Bednarik J, Dusek L, Sprlakova-Pukova A, Urbanek I, Mechl M, et al. Magnetic resonance diffusion tensor imaging in patients with Cervical spondylotic spinal cord compression: correlations between clinical and electrophysiological findings. Spine 2012;37:48–56.
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[13] Mohamed FB, Hunter LN, Barakat N, Liu CS, Sair H, Samdani AF, et al. Diffusion tensor imaging of the pediatric spinal cord at 1.5T: preliminary results. AJNR 2011;32:339–45. [14] Ries M, Jones RA, Dousset V, Moonen CT. Diffusion tensor MRI of the spinal cord. Magn Reson Med 2000;44:884–92. [15] Thomsen C, Henriksen O, Ring P. In vivo measurement of water self diffusion in the human brain by magnetic resonance imaging. Acta Radiol 1987;28:353–61. [16] Ford JC, Hackney DB, Alsop DC, Jara H, Joseph PM, Hand CM, et al. MRI characterization of diffusion coefficients in a rat spinal cord injury model. Magn Reson Med 1994;31:488–94. [17] Deo AA, Grill RJ, Hasan KM, Narayana PA. In vivo serial diffusion tensor imaging of experimental spinal cord injury. J Neurosci Res 2006;83:801–10. [18] Facon D, Ozanne A, Fillard P, Lepeintre JF, Tournoux-Facon C, Ducreux D. MR diffusion tensor imaging and fiber tracking in spinal cord compression. AJNR 2005;26:1587–94. [19] Renoux J, Facon D, Fillard P, Huynh I, Lasjaunias P, Ducreux D. MR diffusion tensor imaging and fiber tracking in inflammatory diseases of the spinal cord. AJNR 2006;27:1947–51. [20] Lee JW, Kim JH, Park JB, Park KW, Yeom JS, Lee GY, et al. Diffusion tensor imaging and fiber tractography in Cervical compressive myelopathy: preliminary results. Skeletal Radiol 2011;40:1543–51. [21] Mamata H, Jolesz FA, Maier SE. Apparent diffusion coefficient and fractional anisotropy in spinal cord: age and Cervical spondylosis-related changes. J Magn Reson Imaging 2005;22:38–43. [22] Demir A, Ries M, Moonen CT, Vital JM, Dehais J, Arne P, et al. Diffusionweighted MR imaging with apparent diffusion coefficient and apparent diffusion tensor maps in Cervical spondylotic myelopathy. Radiology 2003;229:37–43. [23] Tsuchiya K, Katase S, Fujikawa A, Hachiya J, Kanazawa H, Yodo K. Diffusionweighted MRI of the Cervical spinal cord using a single-shot fast spin-echo technique: findings innormal subjects and in myelomalacia. Neuroradiology 2003;45:90–4. [24] Song T, Chen WJ, Yang B, Zhao HP, Huang JW, Cai MJ, et al. Diffusion tensor imaging in the Cervical spinal cord. Eur Spine J 2011;20:422–8.
Please cite this article in press as: M.M. D’souza, et al., Diffusion tensor MR imaging in spinal cord injury, Injury (2017), http://dx.doi.org/ 10.1016/j.injury.2017.02.016
Injury, Int. J. Care Injured xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Original article
Diffusion tensor MR imaging in spinal cord injury Maria M. D’souza* ,a , Ajay Choudharyb , Mahesh Pooniaa , Pawan Kumara , Subash Khushua a b
INMAS, Brig SK Majumdar Marg, Delhi, 110054, India Dept. of Neurosurgery, RML Hospital, New Delhi, India
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 20 February 2017
Background: The ability of diffusion tensor imaging (DTI) to complement conventional MR imaging by diagnosing subtle injuries to the spinal cord is a subject of intense research. We attempted to study change in the DTI indices, namely fractional anisotropy (FA) and mean diffusivity (MD) after traumatic cervical spinal cord injury and compared these with corresponding data from a control group of individuals with no injury. The correlation of these quantitative indices to the neurological profile of the patients was assessed. Material and methods: 20 cases of acute cervical trauma and 30 age and sex matched healthy controls were enrolled. Scoring of extent of clinical severity was done based on the Frankel grading system. MRI was performed on a 3T system. Following the qualitative tractographic evaluation of white matter tracts, quantitative datametrics were calculated. Results: In patients, the Mean FA value at the level of injury (0.43+/ 0.08) was less than in controls (0.62+/ 0.06), which was statistically significant (p value <0.001). Further, the Mean MD value at the level of injury (1.30+/ 0.24) in cases was higher than in controls (1.07+/ 0.12, p value <0.001). Statistically significant positive correlation was found between clinical grading (Frankel grade) and FA values at the level of injury (r value = 0.86). Negative correlation was found between clinical grade and Mean MD at the level of injury (r value = 0.38) which was however statistically not significant. Conclusion: Quantitative DTI indices are a useful parameter for detection of spinal cord injury. FA value was significantly decreased while MD value was significantly increased at the level of injury in cases as compared to controls. Further, FA showed significant correlation with clinical grade. DTI could thus serve as a reliable objective imaging tool for assessment of white matter integrity and prognostication of functional outcome. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Diffusion tensor imaging Spinal cord injury Neurological outcome
Introduction Spinal trauma can result in devastating medical, social, emotional and financial consequences, especially when associated with neurological damage. Diagnostic imaging plays a crucial role in evaluating and detecting spinal trauma. The imaging assessment of these patients has undergone dramatic changes over the past several years. Today, conventional MR imaging is performed routinely to demonstrate soft tissue and spinal cord injuries in spinal trauma [1–3]. Many advantages of MRI such as higher contrast resolution, absence of bony artifacts, multiplanar capability, and choice of various pulse sequences make it possible to diagnose spinal trauma more accurately. Conventional MRI relies heavily on changes in signal intensity for depiction of pathology.
* Corresponding author. E-mail address: [email protected] (M.M. D’souza).
However, the literature is ambivalent about the relationship between MRI findings and extent of neurological damage. According to certain reports, edema and hemorrhage in the spinal cord following trauma are well demonstrated by MR imaging and may help to predict neurologic outcome [4–6]. However, some studies suggest that although spinal cord edema, hemorrhage and interstitial fibrosis will appear as changes in signal intensity on conventional MRI, they may not always be successful in the prediction of functional deficit [7]. Diffusion tensor imaging (DTI) is a novel MR imaging technique which assesses the microstructural integrity of nerve fiber tracts. It is based on the simple principle of diffusion of water molecules in tissue. In neuronal tissue, this mobility is restricted to one particular direction by the presence of biological barriers such as cell membranes and myelin sheath, hence the diffusion is termed anisotropic. Interruption or alteration of this linear molecular diffusion at any point along the neuron can be the first sign of a
http://dx.doi.org/10.1016/j.injury.2017.02.016 0020-1383/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: M.M. D’souza, et al., Diffusion tensor MR imaging in spinal cord injury, Injury (2017), http://dx.doi.org/ 10.1016/j.injury.2017.02.016
G Model JINJ 7094 No. of Pages 5
2
M.M. D’souza et al. / Injury, Int. J. Care Injured xxx (2016) xxx–xxx
physiological disturbance, which makes DTI more sensitive to early change even before gross structural changes are evident [8]. DTI is currently the only means for non-invasive in vivo assessment of white matter tract integrity [9]. The two most widely used quantitative DTI indices are fractional anisotropy (FA) and mean diffusivity (MD). The ability of DTI to complement conventional MR imaging by diagnosing subtle injuries to the spinal cord in humans, or predict the need for early therapeutic intervention for optimal clinical outcome is a subject of intense research [10]. We hypothesized that there would be changes in DTI indices in spinal cord injury, which could correlate with the ultimate neurological deficit. Our purpose was to study changes in the DTI indices, namely FA and MD in patients with traumatic spinal cord injury and assess the correlation of these quantitative data metrics to the neurological profile of the patients. Material and methods 20 cases of cervical trauma, with/without neurologic deficit diagnosed clinically or/and by radiological imaging were recruited for the study from the neurosurgery department of a reputed hospital, within 7 days of sustaining trauma. 30 age and sex matched healthy controls were also included. Written, informed consent was obtained from all subjects. Subjects with concomitant spinal pathology (eg. old Pott’s spine) were excluded. Subjects with non MR compatible metallic implants and those with claustrophobia were excluded from the study. The institutional review board approved of the study. Following a detailed history and clinical examination, radiographs and CT scan were taken where indicated. MRI of cervical spine was performed on a three tesla (3T) MR system (Siemen’s Skyra). The MR protocol was as follows: (a) Sagittal T1: repetition time in milliseconds (msec) [TR]/echotime in msec [TE] – 450/9.5, (b) Sagittal T2:TR/TE – 3630/104, (c) Axial T1: TR/TE – 450/9.6 and (d) Axial T2: TR/TE 500/15. For DTI, we used a single shot echo planar imaging (EPI) sequence (b-value = 0,700 s/mm2) using 20 diffusion encoding directions with scan time of approximately 6 min. The image was acquired in axial plane with image matrix of 128 128, slice thickness of 5 mm with no inter-slice gap, and a field of view (FOV) of 280 280 mm. To enhance the signal-tonoise ratio and reduce the phase fluctuations, magnitudeconstructed images were repeated (averages = 4) and temporally averaged. Following image acquisition, the data was analyzed quantitatively and qualitatively. For qualitative analysis, a region of interest (ROI) was drawn in the region of the spinal cord. This became a seed-point for the automatic generation of the entire white matter tract in the segment of the spinal cord included in the FOV, by inbuilt software. For evaluation of quantitative indices, an ROI (size 3 mm) was drawn into the white matter column of the spinal cord. Special care was taken to avoid partial volume averaging with
underlying grey matter and overlying CSF. By means of the inbuilt software, automatic calculation of DTI indices namely FA and MD was performed within the ROI. These indices were evaluated at the level of injury, and one vertebra above and below the level of injury. In controls we evaluated the FA and MD values at all cervical vertebral levels and individually computed the average FA and average MD in each subject. The patients were reassessed clinically 1–2 months after the DTI study. Scoring of extent of clinical severity was done based on the Frankel grading system – a five point system (A–E in decreasing order of severity), which takes into account the sensory and motor deficit [11]. The data collected was statistically analyzed by SPSS (version15.0) software. Chi-square test was applied to compare sex distribution between cases and controls. Unpaired t-test was applied to compare age of cases and controls. Changes in DTI in the form of fractional anisotropy and mean diffusion were obtained. These changes were statistically compared with age and sex matched controls by unpaired t-test. Correlation of DTI changes with clinical severity (based on Frankel grading) was performed using Spearman correlation. Results A total of 20 cases and 30 healthy controls was enrolled. In Case group (n = 20), age range was from 17 to 54 yrs. (Mean age35.95 10.86 yrs). In Control group (n = 30), age range was from 19 to 54 yrs. (Mean age-35.90+/ 10.13 yrs.). The difference in age of Cases and Controls was not statistically significant (p value = 0.802) by Unpaired t-test. There were 20 males and 10 females in Control group and 14 males and 6 females in Case group. The difference in distribution based on sex in Cases and Controls was not statistically significant (p value = 0.292) by Chi-square test. Of the 20 cases of cervical trauma, there was evidence of vertebral fracture in 4, spondylolisthesis in 4, bone-marrow edema in 4, reduced disc height in 4, disc bulge in 9, secondary spinal canal stenosis in 8., cord compression in 10, nerve- root compression in 7, cord signal changes in 10 and hemorrhagic changes in the form of extradural hematoma seen in 1. MR study of controls revealed no significant finding (Table 1). In the study group involving cases of cervical injury (n = 20), the Mean FA value at the level of injury (0.43+/ 0.08) was less than the Mean FA value of cervical spine (0.62+/ 0.06) in controls (n = 30), which was statistically significant (p value <0.001). However no significant difference was found in Mean FA value above the level of injury or below the level of injury in comparison to controls (Table 2). Further, the Mean MD value at the level of injury (1.30+/ 0.24) in cases (n = 20) was higher than the Mean MD value of controls (1.07+/ 0.12), which was statistically significant (p value <0.001). However no significant difference was found in Mean MD value above or below the level of injury between Cases and Controls (Table 2). Statistically significant (p < 0.01) positive Spearman’s correlation
Table 1 Conventional MRI findings in cases of injury of cervical spine. S. No
MRI findings
No. of Cases of Cervical spine
1 2 3 4 5 6 7 8 9 10
Vertebral fracture Spondylolisthesis Bone-marrow edema Reduced disc height Disc bulge Secondary spinal canal stenosis Cord compression Nerve root compression Cord signal changes Hemorrhagic changes (extradural hematoma)
4 4 4 10 9 8 10 7 10 1
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Table 2 Comparison of DTI parameters between cases of cervical injury and controls. DTI Parameter
Above injury
At the level of injury
Below injury
Controls
FA
0.64 0.07 (p value 0.461) 1.03 0.12 (p value 0.270)
0.43 0.08 (p value <0.001) 1.30 0.24 (p value <0.001)
0.61 0.06 (p value 0.422) 1.12 0.14 (p value 0.130)
0.62 0.06
MD
(r value = 0.86) was found between FA values at the level of injury and clinical grading (Frankel score – A, B, C, D, E in order of decreasing sensorimotor deficit). In contrast, negative correlation was found between mean MD at the level of injury and the Frankel score (r value = 0.38) which was however statistically not significant. (p value 0.09). Qualitative tractographic analysis was performed in all cases and controls. Normal orientation of white matter tracts in the cord was visualized in all 30 controls in the form of homogenous blue color suggestive of preservation of integrity of white matter tracts (Fig. 1). In 10 cases, routine MRI scanning depicted changes in cord signal intensity. On tractography, changes in cord integrity could be observed in 12 cases in the form of distortion of homogenous blue color with or without flecks of green color interspersed within, thereby suggesting disruption in cord integrity (Fig. 2). In the remaining 8 cases, the spinal cord appeared grossly normal on qualitative tractographic analysis. Discussion MR imaging, owing to its excellent soft-tissue resolution, has played an important role in the assessment of spinal cord injury. However, subtle cord injuries are often missed on conventional MR sequences, and the association between clinical severity of injury and pathology depicted on MR has been found to be less than satisfactory in several cases [12]. In the present study, conventional MR sequences revealed abnormality in the spinal cord and associated soft tissue in 10 cases, of a total of 20 cases included in the study. In the remaining cases, the cord appeared normal, despite the presence of neurological deficit as determined by the low Frankel score. Development of a reliable, objective and quantitative measure for assessment of spinal cord injury is essential, without which we would be unable to provide a reliable prognosis or consistency in management [13].
1.07 0.12
This study was an attempt to assess the diagnostic performance of a novel method, namely DTI in the evaluation of spinal cord injury. DTI assesses the microstructural integrity of nerve fiber tracts, based on the simple principle of diffusion of water molecules in vivo. The changes in diffusion on DTI can be assessed either qualitatively by ‘fiber tracking techniques’ (tractography) or quantitatively by calculating DTI anisotropy indices (datametrics) [14]. Tractography gives a visual representation and assessment of the diffusion status of the evaluated structure, which allows tracking of the longitudinal structure of the axons. The direction of diffusion can also be color-coded and traditionally, diffusion from left to right is represented by red, antero-posterior direction by green and cranio-caudal by blue. In the spine, as the fibers are mainly cranio-caudal, the tracts are always represented in blue. Spinal tractography can show the macroscopic orientation of fibers with dramatic representation of the disruption of tracts, which can be poorly seen on plain MRI. Clinically, this information allows better delineation of damaged fiber tracts in the injured spinal cord [15]. Anisotropy indices or DTI datametrics provide a quantitative perspective and a numerical value to the diffusion in any particular voxel. Among the different indices described, the most commonly used are Fractional anisotropy (FA) and Mean diffusivity (MD), often called the Apparent diffusion coefficient (or ADC). Fractional anisotropy measures the fraction of the ‘magnitude’ of total diffusion which occurs in one particular voxel that can be attributed to anisotropic diffusion. FA varies between 0 for diffusion in a perfect sphere (isotropic diffusion) and 1 for diffusion in a perfect thinnest cylinder (infinite anisotropy). Usually, in intact neurons, the FA value is closer to 1 because of the high degree of anisotropy. When there is any damage to the axonal membrane, the diffusion at that level becomes unrestricted and isotropic. The other important index is the mean diffusivity which is a measure of the average diffusion in all directions. A low
Fig. 1. T2 sagittal image in healthy control (A) shows normal cervical spinal cord. Axial diffusion tensor image with ROI (B) and diffusion tensor tractography image (C) in same subject shows intact white matter tract of cervical spinal cord.
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Fig. 2. T2 sagittal and axial image (A, B) in a case of cervical spinal injury (Frankel grade D) shows early degenerative changes in spine with intact spinal cord. Axial DTI (C) and diffusion tensor tractography image (D) show white matter disruption at level of injury.
value for MD indicates that the imaged structure (e.g. nerve fibers) is organized, whereas a high value indicates disorganization within the fiber tracts [8]. The present study incorporated both qualitative and quantitative assessment of the spinal cord. Tractography revealed a disruption in the neuronal integrity in 12 cases. On quantitative assessment, a significant decrease in FA was noted in the acute phase at the level of injury in patients compared to controls (mean 0.43 vs 0.62, p value <0.001). Further, patients demonstrated a significant increase in MD injury, compared to controls (mean 1.3 vs 1.07, p value <0.001). This rise in MD with an accompanying fall in FA at the site of spinal cord injury has been observed in other studies as well [13,16,17]. A similar pattern of reduced FA with increased MD has been observed in cases of non-traumatic spinal cord pathology also [18–21]. In our study, the patients who had neurological deficits despite a normal conventional MR study, revealed a fall in FA and increase in MD levels on DTI studies. The superiority of DTI over conventional MRI in determining the presence and extent of cord pathology has been reported in the past also. A study by Demir et al. [22] on cervical compressive myelopathy revealed significant reduction in FA and increase in MD at sites which appeared normal on conventional MR sequences, which correlated well with the clinical data. The cause for the increased ADC values and decreased FA values at the level of injury is still uncertain. Tsuchiya et al. [23] explained it was possible that the elevated ADC values indicated edema and necrosis, with myelomalacia in the chronic phase. According to Ting Song et al. [24], intervertebral disk herniation and canal stenosis compressing the spinal cord could cause decreasing perfusion which might lead to ischemia and anoxemia and cellular membrane injury that could increase cellular membrane penetrability. Long-term compression of spinal cord may cause CSF to flow turbulently and to penetrate into spinal cord and to form intramedullary microcysts which cannot be displayed on conventional MR examination [21]. The decreased FA values have been attributed to the restricted anisotropic diffusion of water molecule in the injured cord. Because FA measures the degree of myelination, with higher FA values suggesting more intact spinal nerves, the positive correlation between FA and sensori-motor performance may be expected. Likewise, because MD measures the degree of molecular water movement with lower values
suggesting more intact spinal cord, the negative correlation between MD and sensori-motor status may also be expected [13]. Currently, several neurological tests are in vogue for the assessment of clinical severity of injury and its prognostication. However, assessment of clinical severity is challenging in the acute phase due to spinal shock. An objective, quantitative imaging tool could be of great clinical utility in this scenario. An excellent correlation was observed between FA and the ultimate clinical severity of injury in our study. We adopted the Frankel scoring system to assess the clinical severity of injury, as it is robust, easy to apply and has been validated in previous studies [11]. There was significant positive correlation (r value 0.86, p value <0.01) between FA indices at the site of injury and the Frankel score obtained 1–2 months after injury. Although negative correlation was found between Frankel score and mean MD at the level of injury (r value = 0.38) it was however statistically not significant. (p value 0.09). Statistically significant correlation between the FA values and clinical severity of injury as determined by the ISNCSCI scores were documented even in the pediatric population in previous studies, wherein performance of DTI is known to pose additional technical challenges, largely owing to the smaller field of view (FOV) of the spinal cord [13]. In our study we found that DTI was superior to conventional MRI scans in depicting changes in spinal cord integrity after traumatic injury. Qualitative tractography enabled the delineation of changes in the white matter tract of spinal cord, both obvious as well as subtle. Quantitative indices in the form of FA and MD were a more useful parameter for detection of spinal cord injury. FA value was significantly decreased while MD value was significantly increased at the level of injury in cases as compared to controls. FA showed significant correlation with the Frankel score, a clinical measure of the motor and sensory status. Long-term studies would be needed to see if DTI could be used as a reliable prognostic marker of neurological outcome in spinal cord injury. Conflict of interest statement None of the authors of the manuscript titled “Diffusion Tensor MR Imaging in Spinal Cord Injury” have any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work.
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Please cite this article in press as: M.M. D’souza, et al., Diffusion tensor MR imaging in spinal cord injury, Injury (2017), http://dx.doi.org/ 10.1016/j.injury.2017.02.016