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J Neurosurg Sci. Author manuscript; available in PMC 2017 November 05.
Fractional Anisotropy to Quantify Cervical Spondylotic Myelopathy Severity Rory K.J. Murphy1, Peng Sun2, Rowland H. Han3, Kim J. Griffin2, Joanne Wagner4, Chester K. Yarbrough1, Neill M. Wright1, Ian G. Dorward1, K. Daniel Riew5, Michael P. Kelly6, Paul Santiago1, Lukas P. Zebala6, Kathryn Trinkaus7, Wilson Z. Ray1, and Sheng-Kwei Song2
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1Department
of Neurosurgery, Washington University, St. Louis
2Department
of Radiology, Washington University, St. Louis
3Washington
University School of Medicine, St. Louis
4Department
of Physical Therapy and Athletic Training, Saint Louis University, St. Louis
5Department
of Orthopedic Surgery, Columbia University, New York
6Department
of Orthopedic Surgery, Washington University, St. Louis
7Division
of Biostatistics, Washington University School of Medicine, St. Louis
Abstract Study Design—Prospective Cohort Study
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Object/Summary of Background Data—A number of clinical tools exist for measuring the severity of cervical spondylotic myelopathy (CSM). Several studies have recently described the use of non-invasive imaging biomarkers to assess severity of disease. These imaging markers may provide an additional tool to measure disease progression and represent a surrogate marker of response to therapy. Correlating these imaging biomarkers with clinical quantitative measures is critical for accurate therapeutic stratification and quantification of axonal injury.
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Methods—Fourteen patients and seven healthy control subjects were enrolled. Patients were classified as mildly (7) or moderately (7) impaired based on mJOA. All patients underwent diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI) analyses. In addition to standard neurological examination, all participants underwent 30 meter walking test, 9-hole peg test, grip strength, key pinch, and vibration sensation thresholds in the index finger and great toe. Differences in assessment scores between controls, mild and moderate CSM patients were correlated with DTI and DBSI derived fractional anisotropy (FA). Results—Clinically, 30-meter walking times were significantly longer in the moderately impaired group than in the control group. Maximum 9-hole peg test times were significantly longer in both the mildly and moderately impaired groups as compared to normal controls. Scores
Corresponding Author: Wilson Z. Ray, MD, Department of Neurosurgery, 660 South Euclid Ave, Box 8057, St. Louis, MO 63110, Phone: 314-747-6145, Fax: 314-362-2107, [email protected]. Conflicts of Interest: The authors report no conflict of interest concerning the material or methods used in this study or the findings specified in this paper.
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on great toe vibration sensation thresholds were lower in the mildly impaired and moderately impaired groups as compared to controls. We found no clear evidence for any differences in minimum grip strength, minimum key pinch, or index finger vibration sensation thresholds. There were moderately strong associations between DTI and DBSI FA values and 30-meter walking times and 9-hole peg test. Conclusion—The 30-meter walking test and 9-hole peg test were both moderately to strongly associated with DTI/DBSI FA values. FA may represent an additional measure to help differentiate and stratify patients with mild or moderate CSM. Keywords Diffusion Magnetic Resonance Imaging/methods; Cervical Spondylosis; Myelopathy
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Introduction
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Cervical spondylotic myelopathy (CSM) refers to a syndrome of spinal cord dysfunction resulting from compression due to progressive age-related degeneration of the cervical vertebral bodies and intervertebral discs.1–3 It is a leading cause of progressive disability, as well as the most common cause of spinal cord dysfunction in adults over 55 years.4–6 Although there is no well-defined pattern of deficits in CSM, common manifestations include gait disturbance, clumsiness and paresthesia of the hands, sensory loss, and urinary or rectal sphincter dysfunction.7–9 Modified Japanese Orthopaedic Association (mJOA) scale is the most widely utilized and accepted measure of clinical disability.10 Because CSM can vary widely in its presentation, several measures have been proposed to quantify disease severity across multiple motor and sensory domains.11 Many of these measurements are underused or understudied;12 in particular, few studies have correlated patient or physician reported outcome scales with objective measures of functional impairment.13, 14
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Advanced MRI techniques, specifically diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI) have recently been reported to provide quantification of axonal loss and disease severity.15–17 DTI and DBSI provide both information regarding anatomical connectivity and objective metrics for axonal and myelin injury. DTI fractional anisotropy (FA) values of the cervical cord have been shown previously to correlate with CSM severity.18–21 This finding is expected because DTI-derived FA values reflect the overall spinal cord white matter integrity. In contrast, DBSI-derived axial and radial diffusivity and FA provide a neuronal fiber-specific assessment by modeling and accounting for potential confounding extra-axonal pathologies such as infiltrating cells, edema, and axonal loss. Thus, DBSI-derived FA reflects the integrity of residual axons that could signify ongoing functional impairment and/or predict long-term outcome. The main goal of this work is coupling quantifiable non-invasive imaging metrics with clinical assessments of disease severity, this relationship is critical for future accurate therapeutic stratification and response to therapy. We present our results utilizing both DTI and DBSI metrics to assess more detailed quantitative functional measures of CSM severity.
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Materials and Methods The Washington University Human Research Protection Office/Institutional Review Board and the Saint Louis University Institutional Review Board approved this study, and all subjects provided written informed consent. Subjects
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Inclusion criteria: (1) Age 18–65; (2) Clinical evidence of CSM as determined by gait abnormalities, spasticity, hyperreflexia, ankle clonus, positive Babinski and/or positive Hoffman sign; (3) With or without other signs and symptoms of myelopathy including, but not limited to, loss of manual dexterity, extremity weakness, muscle atrophy, sensory abnormalities, proprioceptive loss in the legs, paraparesis or frank quadriparesis. Subjects with clinical conditions such as amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, spine tumor, or HIV-related myelopathy, concomitant thoracic and/or lumbar stenosis were excluded to prevent confounding clinical tests. Patients with medical illnesses and extremity orthopedic conditions that might affect ability to assess neurologic function were also excluded. Fourteen patients (6 males and 8 females) and seven healthy control subjects (3 males and 4 females) were enrolled. The average age of patients was 48 ± 15 (50 ± 14 for controls; mean ± SD). Seven patients with mild (mJOA ≥ 15, mean age 45), five patients with moderate (14 ≥ mJOA ≥ 11, mean age 52.5), and two patients with severe (mJOA < 11, mean age 59) CSM were enrolled. Due to the low number of severe patients, moderate and severe patients were combined (labeled “moderate”) for further analysis. Clinical Assessment
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All participants underwent a neurologic examination by a board-certified neurosurgeon or orthopedic surgeon. A standard neurological examination was performed and included index finger and great toe vibration sensation thresholds, grip strength, and key pinch. For the walking test, subjects walked on a flat surface for a total of 30 meters including one turn. Patients were requested to walk at their maximum comfortable speed, and time taken was recorded with a stopwatch. Next, 9 hole peg test (9HPT) was performed as previously described,22 and each participant’s maximum time for completion was recorded. Finally, mJOA scores were collected using a standard questionnaire. All clinical assessments were completed during each participant’s first office visit or at the time of study scanning. MRI acquisition
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Diffusion MRI data acquisition and pre-processing was performed as previously reported23, 24. Briefly, twice refocused spin-echo diffusion-weighted (DW) images were collected with a multi-b-value scheme (25 directions with unique b-value in each direction and minimum/mean/maximum b-values = ~400/600/800 s/mm2 and two b0 images) at 3T (Trio; Siemens, Erlangen, Germany) with slice-by-slice cardiac-gating, reduced field-ofview, 2D single-shot spin-echo echo planar imaging sequence, and voxel size of 0.9 × 0.9 × 5 mm3. Three separate slice groups (C1–C2, C3–C4, and C5–C6), each consisting of 6 axial slices, were acquired in around 45 minutes. After 2D rigid-body registration restricted to translation of all DW and b0 images, DTI and DBSI analyses were performed.
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DBSI analysis was performed on averaged white matter voxels from each slice group (e.g., C3–C4, including the compression epi-center slices). The regions of white matter tracts were delineated using Factional Anisotropy (FA) map and b0 image. The DBSI metrics from the 3 slice groups were further averaged to yield aggregate DBSI metrics for each subject. Similarly, aggregate DTI metrics for each subject were derived from all white matter regions of interest from all measured slices. (Figure 1) Statistical Analysis
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30 meter walking test scores and maximum 9HPT scores were approximately Gaussian on a log scale. Grip strength, key pinch and vibration sensation thresholds were approximately Gaussian on the original scale. Because the measures contained areas of sparse data, both nonparametric Kruskal-Wallis tests (comparing the ranked distribution of values) and rank correlations were performed. These correlations are interpreted in the same fashion as the usual Pearson correlations, although they describe a wider range of associations that may not be strictly linear.
Results There was no difference in the age or sex of controls and test subjects. DBSI FA, DTI FA, 30 meter walking test scores, maximum 9HPT scores, minimum grip strength and key pinch, and vibration sensation thresholds in index finger and great toe were compared in 7 controls and 14 CSM patients with mild (N=7) or moderate/severe (N=7) impairment. Means and distributions of scores for DTI/DBSI FA values and the 6 neurological assessments, stratified by subject group, are summarized in Table 1.
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FA values DTI FA values for patients with moderate to severe CSM were significantly lower than controls and mild CSM patients (p < 0.001). DTI FA values were strongly correlated with mJOA scores (r = 0.77 p < 0.001). DBSI FA values were lower than those of controls, values were only moderately correlated with mJOA (r = 0.54 p = 0.011). 30 meter walking test
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Walking times were longer in the moderate/severely impaired group as compared to the controls (p = 0.018). There was one patient in the mildly impaired group with an unusually long walking time, and the model failed to find evidence for a difference between mild and moderate impairment groups. The nonparametric test did not find evidence for a difference between all three groups taken as a whole. As depicted in Figure 2A, the association between DTI FA and 30m walking test was strong (r = 0.69 p = 0.004). DBSI FA was also moderately associated (r = 0.62 p = 0.014) (Figure 2B).
9HPT maximum times were longer in the moderately impaired group than in the control (p = 0.010) or mildly impaired (p = 0.022) groups. Times on this test varied considerably in the moderate group (27.90 – 57.19 seconds), with some patients having times as short as those seen in the mild group (16.18 – 30.74 seconds). All times in the moderate group were longer than those in the control group (14.72 – 27.96 seconds). As depicted in Figure 3A and 3B,
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there was a strong correlation for both DTI FA (r = 0.87 p < 0.0001) and DBSI FA (r = 0.74 p = 0.003). Grip strength minimum We found no clear evidence for a difference in minimum grip strength between any of our groups. Median strength appeared to decline with increasing CSM severity, but some patients in the control and mildly impaired groups also demonstrated low age and gender expected strength scores. Additionally, some scores in the moderately impaired group fell within the range of scores in the mild and control groups. While DTI and DBSI FA were moderately correlated to grip strength and disease severity (r = 0.68 and 0.67), our study failed to demonstrate significant clinical differences in this measure between any of the groups.
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Key pinch minimum There was no clear evidence for a difference in minimum key pinch scores. Controls generally had higher scores, while mildly and moderately impaired patients had lower scores. However, there was considerable overlap in scores from the three groups. Key pinch did not demonstrate meaningful correlation between either DTI or DBSI FA values (r = 0.49 and 0.49). Vibration sensation threshold (index finger)
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We also found no clear evidence for a difference in index finger vibration sensation thresholds between the groups. Controls generally had higher scores than mildly or moderately impaired patients, but there was considerable overlap in scores from the three groups. Vibration sensation did not demonstrate any correlation between DTI or DBSI measures of FA (r = 0.32 and 0.23). Vibration sensation threshold (great toe) Scores were lower in the moderately impaired group than in the control (p = 0.015) or mildly impaired (p = 0.042) groups. However, scores varied considerably within the moderately impaired group. Both DTI and DBSI FA measures failed to demonstrate strong correlations (r = 0.56 and 0.48).
Discussion
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Although mJOA and similar instruments are considered standard assessment tools for CSM,25 they are subject to physician bias and patient reported ability and therefore might be supplemented by more objective and/or quantitative measures. Increasing use of DTI to quantify axonal/myelin injury in CSM patients has provided clinicians with an additional tool to help stratify patients that may benefit from surgical decompression. Despite the more widespread use of DTI, little data exists on how these imaging metrics correlate with objective clinical assessments such as 30 meter walk and the 9HPT, especially in patients with a mild presentation. While the mJOA assesses gait, balance, and hand function, it may lose granularity for meaningful improvement, particularly in patients with mild CSM.26 A number of clinical examination findings (grip strength, 30 m walk, etc) have been suggested
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to guide diagnosis and treatment of CSM, but few of these measures have been validated in the same patient population.14 The combination of objective and quantitative outcome measures is important to more clearly define clinical presentation in a standardized manner, establish efficacy of interventions, and enable clinicians to time their interventions appropriately.
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Kalsi-Ryan et al.27 discussed the importance of ancillary measures including grip strength and 30 meter walking test,11 and we agree that objective clinical measures can effectively supplement standard scales in the care and stratification of disease severity of CSM patients. The 30-meter walking test is the best studied of the physical tests to date in CSM patients,13, 28 and provides an assessment of the degree of gait impairment. This measure has been validated against the Myelopathy Disability Index (MDI) and Nurick Scale with reproducible results.11 Although we did find that the walking test distinguishes between controls and moderately impaired patients, in this small cohort of patients it was not sensitive enough to detect mildly impaired patients or to distinguish mild from moderate disease. The 9HPT is already used routinely to measure hand dexterity in multiple sclerosis,29 and has been previously found to distinguish healthy subjects from CSM patients.30
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DTI FA has been reported by several groups20, 31–34 to correlate with CSM severity and may represent an adjunct marker to help guide surgical intervention. Ellingson et al.21 reported a significant correlation between FA measurements and mJOA score in forty-eight CSM patients (the majority of patients presented with gait and/or hand coordination difficulties, while formal assessment with 30 meter walk and 9HPT was not performed). Guan et al.32 recently analyzed DTI metrics collected on patients with CSM from 14 studies with a total of 479 patients and 278 controls revealing that FA was significantly reduced at the most compressed level in CSM patients. Our results also suggest a strong correlation between DTI FA and mJOA, as well as other quantitative functional assessments.
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The use of DTI FA as an adjunct measure to assess myelopathy severity is reasonable since it reflects the overall effect of axonal injury, demyelination, inflammation, and axonal loss, i.e., an integrated metric of tissue integrity. In the present study, we found that DTI FA strongly correlated with mJOA scores, supporting that DTI FA provides value as a metric to reflect ongoing neurological impairments. However, this is insufficient to predict outcome of treatment or disease progression since it is not a definitive measure to distinguish reversible from irreversible spinal cord injury. DBSI detects, distinguishes, and quantifies axonal injury, demyelination, and inflammation from the irreversible axonal loss. Thus, a progression of axon/myelin damage could be accurately assessed using DBSI. A larger prospective study is currently underway to further delineate the clinical usefulness in DBSI and potential for predicting functional outcomes following surgical decompression. To our knowledge, vibration sensation threshold in the great toe has not been previously evaluated for ability to determine CSM severity. Interestingly, we found that this measure was able to distinguish moderately impaired patients from both controls and those with milder forms of disease, but was again unable to detect mildly impaired patients from controls. We also failed to show significant differences in grip strength, key pinch, and index
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finger vibration sensation threshold among our groups. In light of these results, further studies with larger group sizes might be warranted to clarify the role of great toe vibration sensation thresholds in CSM management and to reveal any correlations between the other three measures with disease severity that we failed to demonstrate with our dataset. Limitations The authors acknowledge this study has several limitations including; small number of patients, the lack of a gold standard for the diagnosis of CSM for image comparison, and the current requirement for research specific specialized diffusion weighted imaging sequence.
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The combination of quantifiable measures of axonal integrity combined with clinical assessments may allow for earlier detection of CSM and allow more appropriate patient treatment stratification. Consistent with literature reports, DTI FA correlate with CSM severity. In our small cohort the 30-meter walking test and 9HPT differentiated those with mild or moderate/severe CSM and healthy controls. These measures also correlated well with both DTI and DBSI FA and may be the most suitable quantitative clinical function measures to incorporate into clinical care and research evaluation.
Acknowledgments Disclosures: Dr. Wagner is an employee of and stockholder of Acorda Therapeutics. Dr. Kelly receives research support from the Orthopedic Research and Education Fund, The Cervical Spine Research Society, the Barnes Jewish Foundation, The Fox Family Foundation, and the Patient-Centered Outcomes Research Institute, and fellowship support from AO Spine. Dr. Zebala receives consulting fees from K2M, Orthofix, Ulrich Medical, and fellowship support from AO Spine and OMEGA.
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Disclosure of funding: This study was supported in part by National Institute of Health (grant NS047592). Missouri SCIRP. NIH NINDs K23NS084932.
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Figure 1.
Standard sagittal T2 weighted image from a normal control subject (A). DTI derived FA maps and DBSI derived fiber FA maps were obtained at the location between C1–2 (B & E), C3–4 (C & F), and C5–6 (D & G) from the control. Standard sagittal T2 weighted imaging demonstrating focal spinal cord compression with T2 signal change in a CSM patient with focal compression at C5/6 (H). DTI derived FA and DBSI derived fiber FA maps were at the location between C1–2 (I & L), C3–4 (J & M), and C5–6 (K & N) from the CSM patient. (Modified and used with permission from Spine (Phila Pa 1976). 2015 Dec 8. Magnetic Resonance Imaging Biomarker of Axon Loss Reflects Cervical Spondylotic Myelopathy Severity)
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Figure 2.
Depicted is the correlation of 30 Meter Walking Test with DTI FA (A) and DBSI FA (B). Rank correlations suggest 30m walking test was correlated with both DTI FA (r = 0.69 and p = 0.004) and DBSI FA (r = 0.62 and p = 0.014).
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Figure 3.
Depicted is the correlation of maximum 9 Hole Peg Test with DTI FA (A, r = 0.87 and p < 0.0001) and DBSI FA (B, r = 0.74 and p = 0.003). Rank correlations suggest 30m walking test was correlated with both DTI FA (r = 0.69 and p = 0.004) and DBSI FA (r = 0.62 and p = 0.014).
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Author Manuscript 20.29 41.58 8.50 6.60 6.60
9HPT maximum (s)
Grip strength minimum (kg)
Key pinch minimum (kg)
VST Index finger
VST Great toe
(5.09 – 8.11)
(5.30 – 7.90)
(4.63 – 12.37)
(29.68 – 53.48)
(14.72 – 27.96)
(12.35 – 22.49)
6.00
7.10
4.44
27.12
22.30
19.27
s=seconds. kg=kilograms. VST=vibration sensation threshold.
For vibration sensation threshold, values are scores from 0 – 8.
16.67
30 meter walking test (s)
Control
(4.49 – 7.51)
(5.80 – 8.40)
(1.99 – 6.88)
(15.22 – 39.02)
(16.18 – 30.74)
(14.66 – 25.33)
Mild
3.62
5.38
4.28
22.40
39.94
29.34
(1.94 – 5.31)
(3.92 – 6.82)
(1.54 – 7.01)
(9.091 – 35.71)
(27.90 – 57.19)
(20.99 – 41.02)
Moderate
Means (and 95% Confidence Intervals) of Clinical Function Measures by CSM Severity
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Table 1 Murphy et al. Page 13
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Fractional Anisotropy to Quantify Cervical Spondylotic Myelopathy Severity Rory K.J. Murphy1, Peng Sun2, Rowland H. Han3, Kim J. Griffin2, Joanne Wagner4, Chester K. Yarbrough1, Neill M. Wright1, Ian G. Dorward1, K. Daniel Riew5, Michael P. Kelly6, Paul Santiago1, Lukas P. Zebala6, Kathryn Trinkaus7, Wilson Z. Ray1, and Sheng-Kwei Song2
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1Department
of Neurosurgery, Washington University, St. Louis
2Department
of Radiology, Washington University, St. Louis
3Washington
University School of Medicine, St. Louis
4Department
of Physical Therapy and Athletic Training, Saint Louis University, St. Louis
5Department
of Orthopedic Surgery, Columbia University, New York
6Department
of Orthopedic Surgery, Washington University, St. Louis
7Division
of Biostatistics, Washington University School of Medicine, St. Louis
Abstract Study Design—Prospective Cohort Study
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Object/Summary of Background Data—A number of clinical tools exist for measuring the severity of cervical spondylotic myelopathy (CSM). Several studies have recently described the use of non-invasive imaging biomarkers to assess severity of disease. These imaging markers may provide an additional tool to measure disease progression and represent a surrogate marker of response to therapy. Correlating these imaging biomarkers with clinical quantitative measures is critical for accurate therapeutic stratification and quantification of axonal injury.
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Methods—Fourteen patients and seven healthy control subjects were enrolled. Patients were classified as mildly (7) or moderately (7) impaired based on mJOA. All patients underwent diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI) analyses. In addition to standard neurological examination, all participants underwent 30 meter walking test, 9-hole peg test, grip strength, key pinch, and vibration sensation thresholds in the index finger and great toe. Differences in assessment scores between controls, mild and moderate CSM patients were correlated with DTI and DBSI derived fractional anisotropy (FA). Results—Clinically, 30-meter walking times were significantly longer in the moderately impaired group than in the control group. Maximum 9-hole peg test times were significantly longer in both the mildly and moderately impaired groups as compared to normal controls. Scores
Corresponding Author: Wilson Z. Ray, MD, Department of Neurosurgery, 660 South Euclid Ave, Box 8057, St. Louis, MO 63110, Phone: 314-747-6145, Fax: 314-362-2107, [email protected]. Conflicts of Interest: The authors report no conflict of interest concerning the material or methods used in this study or the findings specified in this paper.
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on great toe vibration sensation thresholds were lower in the mildly impaired and moderately impaired groups as compared to controls. We found no clear evidence for any differences in minimum grip strength, minimum key pinch, or index finger vibration sensation thresholds. There were moderately strong associations between DTI and DBSI FA values and 30-meter walking times and 9-hole peg test. Conclusion—The 30-meter walking test and 9-hole peg test were both moderately to strongly associated with DTI/DBSI FA values. FA may represent an additional measure to help differentiate and stratify patients with mild or moderate CSM. Keywords Diffusion Magnetic Resonance Imaging/methods; Cervical Spondylosis; Myelopathy
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Introduction
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Cervical spondylotic myelopathy (CSM) refers to a syndrome of spinal cord dysfunction resulting from compression due to progressive age-related degeneration of the cervical vertebral bodies and intervertebral discs.1–3 It is a leading cause of progressive disability, as well as the most common cause of spinal cord dysfunction in adults over 55 years.4–6 Although there is no well-defined pattern of deficits in CSM, common manifestations include gait disturbance, clumsiness and paresthesia of the hands, sensory loss, and urinary or rectal sphincter dysfunction.7–9 Modified Japanese Orthopaedic Association (mJOA) scale is the most widely utilized and accepted measure of clinical disability.10 Because CSM can vary widely in its presentation, several measures have been proposed to quantify disease severity across multiple motor and sensory domains.11 Many of these measurements are underused or understudied;12 in particular, few studies have correlated patient or physician reported outcome scales with objective measures of functional impairment.13, 14
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Advanced MRI techniques, specifically diffusion tensor imaging (DTI) and diffusion basis spectrum imaging (DBSI) have recently been reported to provide quantification of axonal loss and disease severity.15–17 DTI and DBSI provide both information regarding anatomical connectivity and objective metrics for axonal and myelin injury. DTI fractional anisotropy (FA) values of the cervical cord have been shown previously to correlate with CSM severity.18–21 This finding is expected because DTI-derived FA values reflect the overall spinal cord white matter integrity. In contrast, DBSI-derived axial and radial diffusivity and FA provide a neuronal fiber-specific assessment by modeling and accounting for potential confounding extra-axonal pathologies such as infiltrating cells, edema, and axonal loss. Thus, DBSI-derived FA reflects the integrity of residual axons that could signify ongoing functional impairment and/or predict long-term outcome. The main goal of this work is coupling quantifiable non-invasive imaging metrics with clinical assessments of disease severity, this relationship is critical for future accurate therapeutic stratification and response to therapy. We present our results utilizing both DTI and DBSI metrics to assess more detailed quantitative functional measures of CSM severity.
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Materials and Methods The Washington University Human Research Protection Office/Institutional Review Board and the Saint Louis University Institutional Review Board approved this study, and all subjects provided written informed consent. Subjects
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Inclusion criteria: (1) Age 18–65; (2) Clinical evidence of CSM as determined by gait abnormalities, spasticity, hyperreflexia, ankle clonus, positive Babinski and/or positive Hoffman sign; (3) With or without other signs and symptoms of myelopathy including, but not limited to, loss of manual dexterity, extremity weakness, muscle atrophy, sensory abnormalities, proprioceptive loss in the legs, paraparesis or frank quadriparesis. Subjects with clinical conditions such as amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, spine tumor, or HIV-related myelopathy, concomitant thoracic and/or lumbar stenosis were excluded to prevent confounding clinical tests. Patients with medical illnesses and extremity orthopedic conditions that might affect ability to assess neurologic function were also excluded. Fourteen patients (6 males and 8 females) and seven healthy control subjects (3 males and 4 females) were enrolled. The average age of patients was 48 ± 15 (50 ± 14 for controls; mean ± SD). Seven patients with mild (mJOA ≥ 15, mean age 45), five patients with moderate (14 ≥ mJOA ≥ 11, mean age 52.5), and two patients with severe (mJOA < 11, mean age 59) CSM were enrolled. Due to the low number of severe patients, moderate and severe patients were combined (labeled “moderate”) for further analysis. Clinical Assessment
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All participants underwent a neurologic examination by a board-certified neurosurgeon or orthopedic surgeon. A standard neurological examination was performed and included index finger and great toe vibration sensation thresholds, grip strength, and key pinch. For the walking test, subjects walked on a flat surface for a total of 30 meters including one turn. Patients were requested to walk at their maximum comfortable speed, and time taken was recorded with a stopwatch. Next, 9 hole peg test (9HPT) was performed as previously described,22 and each participant’s maximum time for completion was recorded. Finally, mJOA scores were collected using a standard questionnaire. All clinical assessments were completed during each participant’s first office visit or at the time of study scanning. MRI acquisition
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Diffusion MRI data acquisition and pre-processing was performed as previously reported23, 24. Briefly, twice refocused spin-echo diffusion-weighted (DW) images were collected with a multi-b-value scheme (25 directions with unique b-value in each direction and minimum/mean/maximum b-values = ~400/600/800 s/mm2 and two b0 images) at 3T (Trio; Siemens, Erlangen, Germany) with slice-by-slice cardiac-gating, reduced field-ofview, 2D single-shot spin-echo echo planar imaging sequence, and voxel size of 0.9 × 0.9 × 5 mm3. Three separate slice groups (C1–C2, C3–C4, and C5–C6), each consisting of 6 axial slices, were acquired in around 45 minutes. After 2D rigid-body registration restricted to translation of all DW and b0 images, DTI and DBSI analyses were performed.
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DBSI analysis was performed on averaged white matter voxels from each slice group (e.g., C3–C4, including the compression epi-center slices). The regions of white matter tracts were delineated using Factional Anisotropy (FA) map and b0 image. The DBSI metrics from the 3 slice groups were further averaged to yield aggregate DBSI metrics for each subject. Similarly, aggregate DTI metrics for each subject were derived from all white matter regions of interest from all measured slices. (Figure 1) Statistical Analysis
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30 meter walking test scores and maximum 9HPT scores were approximately Gaussian on a log scale. Grip strength, key pinch and vibration sensation thresholds were approximately Gaussian on the original scale. Because the measures contained areas of sparse data, both nonparametric Kruskal-Wallis tests (comparing the ranked distribution of values) and rank correlations were performed. These correlations are interpreted in the same fashion as the usual Pearson correlations, although they describe a wider range of associations that may not be strictly linear.
Results There was no difference in the age or sex of controls and test subjects. DBSI FA, DTI FA, 30 meter walking test scores, maximum 9HPT scores, minimum grip strength and key pinch, and vibration sensation thresholds in index finger and great toe were compared in 7 controls and 14 CSM patients with mild (N=7) or moderate/severe (N=7) impairment. Means and distributions of scores for DTI/DBSI FA values and the 6 neurological assessments, stratified by subject group, are summarized in Table 1.
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FA values DTI FA values for patients with moderate to severe CSM were significantly lower than controls and mild CSM patients (p < 0.001). DTI FA values were strongly correlated with mJOA scores (r = 0.77 p < 0.001). DBSI FA values were lower than those of controls, values were only moderately correlated with mJOA (r = 0.54 p = 0.011). 30 meter walking test
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Walking times were longer in the moderate/severely impaired group as compared to the controls (p = 0.018). There was one patient in the mildly impaired group with an unusually long walking time, and the model failed to find evidence for a difference between mild and moderate impairment groups. The nonparametric test did not find evidence for a difference between all three groups taken as a whole. As depicted in Figure 2A, the association between DTI FA and 30m walking test was strong (r = 0.69 p = 0.004). DBSI FA was also moderately associated (r = 0.62 p = 0.014) (Figure 2B).
9HPT maximum times were longer in the moderately impaired group than in the control (p = 0.010) or mildly impaired (p = 0.022) groups. Times on this test varied considerably in the moderate group (27.90 – 57.19 seconds), with some patients having times as short as those seen in the mild group (16.18 – 30.74 seconds). All times in the moderate group were longer than those in the control group (14.72 – 27.96 seconds). As depicted in Figure 3A and 3B,
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there was a strong correlation for both DTI FA (r = 0.87 p < 0.0001) and DBSI FA (r = 0.74 p = 0.003). Grip strength minimum We found no clear evidence for a difference in minimum grip strength between any of our groups. Median strength appeared to decline with increasing CSM severity, but some patients in the control and mildly impaired groups also demonstrated low age and gender expected strength scores. Additionally, some scores in the moderately impaired group fell within the range of scores in the mild and control groups. While DTI and DBSI FA were moderately correlated to grip strength and disease severity (r = 0.68 and 0.67), our study failed to demonstrate significant clinical differences in this measure between any of the groups.
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Key pinch minimum There was no clear evidence for a difference in minimum key pinch scores. Controls generally had higher scores, while mildly and moderately impaired patients had lower scores. However, there was considerable overlap in scores from the three groups. Key pinch did not demonstrate meaningful correlation between either DTI or DBSI FA values (r = 0.49 and 0.49). Vibration sensation threshold (index finger)
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We also found no clear evidence for a difference in index finger vibration sensation thresholds between the groups. Controls generally had higher scores than mildly or moderately impaired patients, but there was considerable overlap in scores from the three groups. Vibration sensation did not demonstrate any correlation between DTI or DBSI measures of FA (r = 0.32 and 0.23). Vibration sensation threshold (great toe) Scores were lower in the moderately impaired group than in the control (p = 0.015) or mildly impaired (p = 0.042) groups. However, scores varied considerably within the moderately impaired group. Both DTI and DBSI FA measures failed to demonstrate strong correlations (r = 0.56 and 0.48).
Discussion
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Although mJOA and similar instruments are considered standard assessment tools for CSM,25 they are subject to physician bias and patient reported ability and therefore might be supplemented by more objective and/or quantitative measures. Increasing use of DTI to quantify axonal/myelin injury in CSM patients has provided clinicians with an additional tool to help stratify patients that may benefit from surgical decompression. Despite the more widespread use of DTI, little data exists on how these imaging metrics correlate with objective clinical assessments such as 30 meter walk and the 9HPT, especially in patients with a mild presentation. While the mJOA assesses gait, balance, and hand function, it may lose granularity for meaningful improvement, particularly in patients with mild CSM.26 A number of clinical examination findings (grip strength, 30 m walk, etc) have been suggested
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to guide diagnosis and treatment of CSM, but few of these measures have been validated in the same patient population.14 The combination of objective and quantitative outcome measures is important to more clearly define clinical presentation in a standardized manner, establish efficacy of interventions, and enable clinicians to time their interventions appropriately.
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Kalsi-Ryan et al.27 discussed the importance of ancillary measures including grip strength and 30 meter walking test,11 and we agree that objective clinical measures can effectively supplement standard scales in the care and stratification of disease severity of CSM patients. The 30-meter walking test is the best studied of the physical tests to date in CSM patients,13, 28 and provides an assessment of the degree of gait impairment. This measure has been validated against the Myelopathy Disability Index (MDI) and Nurick Scale with reproducible results.11 Although we did find that the walking test distinguishes between controls and moderately impaired patients, in this small cohort of patients it was not sensitive enough to detect mildly impaired patients or to distinguish mild from moderate disease. The 9HPT is already used routinely to measure hand dexterity in multiple sclerosis,29 and has been previously found to distinguish healthy subjects from CSM patients.30
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DTI FA has been reported by several groups20, 31–34 to correlate with CSM severity and may represent an adjunct marker to help guide surgical intervention. Ellingson et al.21 reported a significant correlation between FA measurements and mJOA score in forty-eight CSM patients (the majority of patients presented with gait and/or hand coordination difficulties, while formal assessment with 30 meter walk and 9HPT was not performed). Guan et al.32 recently analyzed DTI metrics collected on patients with CSM from 14 studies with a total of 479 patients and 278 controls revealing that FA was significantly reduced at the most compressed level in CSM patients. Our results also suggest a strong correlation between DTI FA and mJOA, as well as other quantitative functional assessments.
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The use of DTI FA as an adjunct measure to assess myelopathy severity is reasonable since it reflects the overall effect of axonal injury, demyelination, inflammation, and axonal loss, i.e., an integrated metric of tissue integrity. In the present study, we found that DTI FA strongly correlated with mJOA scores, supporting that DTI FA provides value as a metric to reflect ongoing neurological impairments. However, this is insufficient to predict outcome of treatment or disease progression since it is not a definitive measure to distinguish reversible from irreversible spinal cord injury. DBSI detects, distinguishes, and quantifies axonal injury, demyelination, and inflammation from the irreversible axonal loss. Thus, a progression of axon/myelin damage could be accurately assessed using DBSI. A larger prospective study is currently underway to further delineate the clinical usefulness in DBSI and potential for predicting functional outcomes following surgical decompression. To our knowledge, vibration sensation threshold in the great toe has not been previously evaluated for ability to determine CSM severity. Interestingly, we found that this measure was able to distinguish moderately impaired patients from both controls and those with milder forms of disease, but was again unable to detect mildly impaired patients from controls. We also failed to show significant differences in grip strength, key pinch, and index
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finger vibration sensation threshold among our groups. In light of these results, further studies with larger group sizes might be warranted to clarify the role of great toe vibration sensation thresholds in CSM management and to reveal any correlations between the other three measures with disease severity that we failed to demonstrate with our dataset. Limitations The authors acknowledge this study has several limitations including; small number of patients, the lack of a gold standard for the diagnosis of CSM for image comparison, and the current requirement for research specific specialized diffusion weighted imaging sequence.
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The combination of quantifiable measures of axonal integrity combined with clinical assessments may allow for earlier detection of CSM and allow more appropriate patient treatment stratification. Consistent with literature reports, DTI FA correlate with CSM severity. In our small cohort the 30-meter walking test and 9HPT differentiated those with mild or moderate/severe CSM and healthy controls. These measures also correlated well with both DTI and DBSI FA and may be the most suitable quantitative clinical function measures to incorporate into clinical care and research evaluation.
Acknowledgments Disclosures: Dr. Wagner is an employee of and stockholder of Acorda Therapeutics. Dr. Kelly receives research support from the Orthopedic Research and Education Fund, The Cervical Spine Research Society, the Barnes Jewish Foundation, The Fox Family Foundation, and the Patient-Centered Outcomes Research Institute, and fellowship support from AO Spine. Dr. Zebala receives consulting fees from K2M, Orthofix, Ulrich Medical, and fellowship support from AO Spine and OMEGA.
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Disclosure of funding: This study was supported in part by National Institute of Health (grant NS047592). Missouri SCIRP. NIH NINDs K23NS084932.
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Figure 1.
Standard sagittal T2 weighted image from a normal control subject (A). DTI derived FA maps and DBSI derived fiber FA maps were obtained at the location between C1–2 (B & E), C3–4 (C & F), and C5–6 (D & G) from the control. Standard sagittal T2 weighted imaging demonstrating focal spinal cord compression with T2 signal change in a CSM patient with focal compression at C5/6 (H). DTI derived FA and DBSI derived fiber FA maps were at the location between C1–2 (I & L), C3–4 (J & M), and C5–6 (K & N) from the CSM patient. (Modified and used with permission from Spine (Phila Pa 1976). 2015 Dec 8. Magnetic Resonance Imaging Biomarker of Axon Loss Reflects Cervical Spondylotic Myelopathy Severity)
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Figure 2.
Depicted is the correlation of 30 Meter Walking Test with DTI FA (A) and DBSI FA (B). Rank correlations suggest 30m walking test was correlated with both DTI FA (r = 0.69 and p = 0.004) and DBSI FA (r = 0.62 and p = 0.014).
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Figure 3.
Depicted is the correlation of maximum 9 Hole Peg Test with DTI FA (A, r = 0.87 and p < 0.0001) and DBSI FA (B, r = 0.74 and p = 0.003). Rank correlations suggest 30m walking test was correlated with both DTI FA (r = 0.69 and p = 0.004) and DBSI FA (r = 0.62 and p = 0.014).
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Author Manuscript 20.29 41.58 8.50 6.60 6.60
9HPT maximum (s)
Grip strength minimum (kg)
Key pinch minimum (kg)
VST Index finger
VST Great toe
(5.09 – 8.11)
(5.30 – 7.90)
(4.63 – 12.37)
(29.68 – 53.48)
(14.72 – 27.96)
(12.35 – 22.49)
6.00
7.10
4.44
27.12
22.30
19.27
s=seconds. kg=kilograms. VST=vibration sensation threshold.
For vibration sensation threshold, values are scores from 0 – 8.
16.67
30 meter walking test (s)
Control
(4.49 – 7.51)
(5.80 – 8.40)
(1.99 – 6.88)
(15.22 – 39.02)
(16.18 – 30.74)
(14.66 – 25.33)
Mild
3.62
5.38
4.28
22.40
39.94
29.34
(1.94 – 5.31)
(3.92 – 6.82)
(1.54 – 7.01)
(9.091 – 35.71)
(27.90 – 57.19)
(20.99 – 41.02)
Moderate
Means (and 95% Confidence Intervals) of Clinical Function Measures by CSM Severity
Author Manuscript
Table 1 Murphy et al. Page 13
J Neurosurg Sci. Author manuscript; available in PMC 2017 November 05.
