Clinical and MRI analyses of dorsal spinal column function in compressive cervical myelopathy

doi:10.21203/rs.3.rs-1967473/v1

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Clinical and MRI analyses of dorsal spinal column function in compressive cervical myelopathy

https://doi.org/10.21203/rs.3.rs-1967473/v1

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This study aimed to evaluate whether the somatosensory functions of the upper (UE) and lower extremities (LE) were correlated with the degree of fasciculus cuneatus (FC) and fasciculus gracilis (FG) degeneration based on magnetic resonance imaging in patients with compressive cervical myelopathy (CCM). We prospectively recruited 32 patients with CCM. Median nerve somatosensory evoked potentials (SEPs) and the Semmes–Weinstein monofilament (SWM) test were employed to test UE somatosensory function. Tibial nerve SEPs, the foot SWM test, and Romberg ratio were used to evaluate LE somatosensory function. We imaged FC and FG using three-dimensional anisotropy contrast diffusion magnetic resonance axonography. Diffusion tensor invariant of fractional anisotropy (FA) was used to measure the degree of degeneration in FC and FG. FA values of FC degeneration were significantly correlated with the median nerve SEPs (Spearman’s rank correlation coefficient [rs] = − 0.66) and hand SWM tests (rs = − 0.52). FA values of FG degeneration were correlated with the tibial nerve SEPs (rs = − 0.66), foot SWM tests (rs = − 0.70), and Romberg ratio (rs = − 0.60). Our study demonstrates that in patients with CCM, UE and LE somatosensory examinations are correlated with the degree of degeneration in the FC and FG, respectively.

Cervical compressive myelopathy (CCM) occurs after cervical spinal cord compression due to disc herniation, stenosis, spondylosis, ossification of the posterior longitudinal ligament, or intradural extramedullary tumors^1–3. Somatosensory information is conveyed via the fasciculus cuneatus (FC) and fasciculus gracilis (FG) within the dorsal spinal column^4,5. The transmission of somatosensory-related information has been investigated in these tracts using somatosensory evoked potentials (SEPs), the Semmes–Weinstein monofilament (SWM) test, or the Romberg ratio^6–9. Although a decline in somatosensory function has been reported in patients with CCM, only one study has investigated the degeneration of FC and FG in vivo¹⁰. In a previous study, FC and FG were visualized in normal healthy volunteers using three-dimensional anisotropy contrast magnetic resonance axonography (3DAC-MRX), a diffusion contrast imaging technique^11,12, and the degenerated tracts were visualized in patients with CCM. Furthermore, the earlier study demonstrated that the degree of degeneration could be quantified by measuring the diffusion tensor invariant of fractional anisotropy (FA) of the imaged spinal tracts¹⁰.

At present, reports that examine the relationship between somatosensory functions and the degree of degeneration in FC and FG in patients with CCM are lacking. In this study, we used FA to measure the degree of degeneration in patients with CCM, and examined a) whether upper extremity (UE) somatosensory examinations of the median nerve, using SEPs and the SWM test, correlated with FA values in FC; and b) whether lower extremity (LE) somatosensory examinations of the tibial nerve, using SEPs, the foot SWM test, and Romberg ratio, correlated with FA values in FG.

Subjects

For this study, we recruited 32 patients with CCM who visited our hospital from October 2017 to October 2019 and a normal healthy volunteer. Patient diagnoses were verified by clinical investigations and by evaluating the compression of the cervical spinal cord on magnetic resonance imaging (MRI). The patients did not have other neurologic diseases, such as cerebral infarction or Parkinson’s disease. The severity of cervical myelopathy was assessed according to the Japanese Orthopedic Association (JOA) score.

Standard protocol approvals, registrations, and patient consents

Informed consent

was obtained from all subjects before study participation, and the study was approved by the Ethics Committee of Niigata University [approval number: 2016-0084]. All methods were performed in accordance with the relevant guidelines and regulation.

SEP

A Neuropack S1 EMG/Evoked Potential Measuring System (Nihon Kohden Co., Tokyo, Japan) was employed. The median and tibial nerves were stimulated at the wrist and at the posterior to the medial malleolus using a pair of surface bar electrodes, with 0.2 ms square wave electrical pulses at 3.0 Hz¹³. The stimulus intensity of the median nerve was adjusted to produce a visible thumb twitch without causing discomfort. For recordings of the tibial nerve, stimulus intensity was adjusted to twice the threshold for radiating paresthesia towards the toes. The recording electrodes for the median nerve SEPs were placed at the spinous processes of the second and seventh cervical vertebrae, C3 and C4, according to the international 10–20 system, with the reference electrode at Fz. Another electrode was placed at the ipsilateral Erb’s point with the reference electrode at the contralateral Erb’s point. The recording electrodes for the tibial nerve SEPs were placed at the spinous processes of the second and seventh cervical vertebrae, CPz, according to the international 10–20 system, with the reference electrode at Fz. Another electrode was placed at the spinous process of the 12th thoracic vertebra with the reference electrode at 5 cm cranial to the 12th thoracic vertebra. Low- and high-pass filters were applied, and the average of 500 responses for median nerve SEPs and 800 responses for tibial nerve SEPs were obtained. To ensure reproducibility of the identified peaks, two repetitions of each waveform were acquired.

We measured the latencies of the N9 and N20 peaks for the median nerve SEPs and those of the N21 and P38 peaks for the tibial nerve SEPs and calculated the interval N9 − N20, and N21 − P38 as equivalent to central conduction time (CCT) (Fig. 1). Putative sources of the N9, N20, N21, and P38 peaks are the proximal brachial plexus, the primary somatosensory cortex in the posterior wall of the central fissure, the post-synaptic response in the dorsal gray matter of the lumbosacral spinal cord, and the post-central somatosensory cortex, respectively¹³.

SWM test

Using a graded set of 20 monofilaments (Aesthesio®; Precision Tactile Sensory Evaluator, Danmic Global LLC, San Jose CA, USA), light-touch and pressure sensation were measured⁸. Measured locations are shown in Fig. 2. The SWM scores for each hand and foot were defined as the worst sensation at these locations.

Romberg ratio

Center of pressure (CoP) path length was measured using the WalkWay MW1000 system (Anima Co., Tokyo, Japan). CoP path length is the absolute length of the CoP path movement throughout the testing period⁹. The Romberg ratio was calculated by dividing CoP path length with the eyes closed by that with the eyes open. A high value indicates a great amount of postural sway due to dorsal column degeneration.

MRI

A MAGNETOM Prisma 3T magnetic resonance system with a 64-channel phased-array head neck coil (Siemens Healthineers, Erlangen, Germany) was used for all imaging studies.

Three orthogonal directional, x-, y-, and z-axes, and six directional anisotropic diffusion weighted axial images from 5 mm cranial to the most compressed spinal cord level were obtained based on a reduced field of view (FOV) readout-segmented echo-planar imaging sequence with peripheral gating^14–16. Parameters were as follows: FOV, 12.4 × 5.0–6.2 cm; matrix, 168 × 68–84; slice thickness (ST), 5.0 mm; gap, 5.0 mm; minimum repetition time (TR), 4500 ms; echo time (TE), 90–109 ms; number of excitations (NEX), 8; readout segments, 5; readout partial Fourier, 5/8. The b-value was 750 s/mm². Additionally, a reference image of b = 0 s/mm² was acquired.

Conventional T2 weighted axial and sagittal images were obtained utilizing a fast spin echo sequence with the following parameters: FOV, 18.0, 25.0 cm; matrix, 384 × 250, 512 × 256 (zero filling into 384 × 384, 512 × 512); ST, 5.0, 3.0 mm; gap, 2.5, 0.0 mm; TR, 4000, 4000 ms; TE, 91, 93 ms; echo-train length, 19, 17; NEX, 1, 1.

Regions of interest (ROIs)

All imaging analyses and calculations were performed using MATLAB 2018b (The MathWorks Inc., Natick, MA, USA). Initially, all diffusion-weighted images (DWIs) were resized to a matrix size of 512 × 207–256 while maintaining the aspect ratio. Eddy current-induced distortions and subject motion for each of the 10 images of each patient, which included three orthogonal and six directional anisotropic diffusion weighted images and a reference image of b = 0 s/mm², were corrected using rigid transformation, including translation and rotation. Subsequently, 3DAC-MRX images were created using three orthogonal directional anisotropic DWIs according to a previously reported method¹⁰ (Fig. 3). ROIs were set separately at the unilateral FCs on the 3DAC-MRX images, whereas a single ROI was set at the bilateral FG due to difficulty in visualizing the separate FG tracts within the dorsal spinal column (Fig. 4). Another ROI was set at the whole spinal cord for reference. The ROIs of the whole spinal cord were automatically selected using the Chan–Vese segmentation method¹⁷, whereas those of the FCs and FG were determined on a point-by-point basis. Finally, using six directional anisotropic DWIs and a reference image of b = 0 s/mm², the FA at the unilateral FCs, bilateral FG, and whole spinal cord were calculated¹⁸. ROI analyses were independently performed by two authors. Two weeks later, one of the two observers repeated the process.

Statistics

Intraclass correlation coefficients were calculated to evaluate inter- and intra-rater reliability of ROI analyses¹⁹. The N9 − N20 intervals and SWM scores were compared with FA values of the ipsilateral FC. The average of the bilateral P21 − N38 CCTs, that of the bilateral foot SWM scores, and Romberg ratio were compared with the FA values of FG. In addition, comparisons between somatosensory evaluations and FA values of the whole spinal cord were performed for reference. Furthermore, the FA of FC, FG, and whole spinal cord were compared with the JOA scores to evaluate total cervical spinal function. Statistical Package for the Social Sciences (SPSS) version 25.0 (SPSS Inc., Chicago, IL, USA) was used for all statistical analyses. The Spearman test was used for the comparisons, and statistical significance was set at p < 0.05.

Participants

Thirty-two patients with CCM were recruited. The demographic data are listed in Table 1. We excluded seven records of median nerve SEPs and one of tibial nerve SEPs due to unstable signal or irritation, and two of the Romberg ratio due to patient difficulty in standing upright.

Table 1

Patient demographics
Patient ID	Sex	Age (year)	Diagnosis	Disease duration (months)	Most compressed spinal cord level	JOA score
1	M	53	CSM	6	C4/5	14
2	F	80	CSM	45	C3/4	13
3	M	76	CSM	7	C3/4	9
4	M	34	CSM	9	C3/4	12
5	M	34	CSM	4	C5/6	13
6	M	82	CSM	23	C5/6	9
7	F	62	CSM	26	C5/6	13
8	M	48	CSM	8	C6/7	15
9	M	58	OPLL	3	C4/5	12
10	M	71	CSM	3	C4/5	14
11	M	63	CSM	120	C3/4	16
12	M	71	OPLL	180	C2/3	7
13	M	79	CSM	15	C4/5	10
14	M	44	CSM	70	C5/6	14
15	M	75	OPLL	120	C2/3	8
16	M	79	CSM	5	C2/3	11
17	M	71	OPLL	4	C4/5	11
18	F	79	CSM	2	C3/4	11
19	M	62	OPLL	12	C3/4	10
20	M	48	OPLL	31	C3/4	13
21	M	58	OPLL	368	C4/5	15
22	F	67	CSM	6	C4/5	12
23	M	75	CSM	6	C3/4	13
24	M	52	OPLL	24	C4/5	10
25	M	70	CSM	6	C4/5	6
26	F	27	Tumor	23	C4/5	15
27	M	40	Tumor	13	C2/3	11
28	F	27	Tumor	9	C2/3	14
29	M	71	Tumor	115	C2/3	13
30	M	77	Tumor	12	C2/3	12
31	M	59	Tumor	6	C3	10
32	M	27	Tumor	2	C4	10
CSM cervical spondylotic myelopathy, JOA Japanese Orthopedic Association, OPLL ossification of the posterior longitudinal ligament, Tumor intradural extramedullary tumor.

Correlations between somatosensory examinations and FA values of the MRI

Representative high contrast resolution 3DAC-MRX images of a normal healthy volunteer and a patient with CCM are shown in Figs. 3 and 4. The intraclass correlation coefficients of intra-rater agreement of ROI analyses were 0.98 (FCs), 0.99 (FG), and 1.00 (whole spinal cord) and those of inter-rater agreement were 0.94 (FCs), 0.95 (FG), and 1.00 (whole spinal cord). The results of the correlation analyses are listed in Table 2 and illustrated in Fig. 5.

Table 2

Results of somatosensory examinations and FA values
SEPs
N9–N20 interval, median ms (IQR)	10.8 (1.6)
Bilateral N21–P38 CCTs, median ms (IQR)	20.2 (7.5)
SWM test
Hand scores, median (IQR)	3.61 (0.86)
Average of bilateral foot scores, median (IQR)	4.37 (1.19)
Romberg ratio, median (IQR)	1.25 (0.38)
FA values
FC, median (IQR)	0.68 (0.17)
FG, median (IQR)	0.65 (0.2)
Whole spinal cord, median (IQR)	0.61 (0.1)
CCTs central conduction times, FA fractional anisotropy, FC fasciculus cuneatus, FG fasciculus gracilis, IQR interquartile range, SEPs somatosensory evoked potentials, SWM Semmes–Weinstein monofilaments.

To the best of our knowledge, this is the first report to demonstrate significant correlations of imaging findings related to FC and FG degeneration with dorsal column function: significant correlations were found between the FA values of FC and FG—based on 3DAC-MRX and diffusion tensor analysis—with median/tibial nerve SEPs, hand/foot SWM scores, and the Romberg ratio.

3DAC-MRX is a recently developed MRI technique to quantify fiber tract degeneration in terms of FA values, and has been applied in a study to image the FC and FG tracts and their degeneration¹⁰. Diffusion tensor imaging and FA analysis have been traditionally used to evaluate regional degeneration in the myelopathic spinal cord²⁰, but earlier studies evaluated FA values of the whole spinal cord as a single ROI or on tract-specific ROIs based on nonvisualized anatomical location.

In our study, the FA values of tract-specific ROIs demonstrated higher correlation coefficients with somatosensory examinations than those of the whole spinal cord. This finding may imply that isolated imaging of the spinal tract with our methodology is more efficacious in evaluating spinal tract degeneration.

We expect that the method employed in our study may contribute to improved clarification of the relationships between spinal tract degeneration and the corresponding functional decline, and to the differentiation of spinal cord disorders.

Although cervical spinal cord 3DAC-MRX images can be used to differentiate between separate FCs and bilateral FG within the dorsal spinal column, they cannot be used to visualize unilateral FGs (Fig. 2). Therefore, the average of bilateral N38 − P21 CCTs and bilateral foot SWM scores were obtained, and these averages were compared with the FA values of FG. Bilateral FGs may be demarcated independently using a higher spatial resolution in 3DAC-MRX imaging, although longer MRI-scanning sessions may be required.

While the whole spinal cord was automatically segmented using the Chan–Vese method, bilateral FCs and FG could not be segmented using conventional feature extraction methods, such as the Chan–Vese method, an independent component analysis method, and a simple linear interactive clustering superpixel method^17,21,22. Despite the high intraclass correlation coefficients of intra- and inter-rater agreement of ROI analyses, it is possible that some bias was introduced due to the point-by-point ROI analyses of FCs and FG.

In conclusion, in this study, we evaluated the degeneration of the FC and FG tracts in patients with CCM using 3DAC-MRX and diffusion tensor analysis. We demonstrated that UE somatosensory examinations of median nerve SEPs and hand SWM scores were correlated with the degree of degeneration of FC, and that LE somatosensory examinations of tibial nerve SEPs, foot SWM scores, and Romberg ratio were correlated with the degree of degeneration of FG. In the future, this method can be commonly applied in clinical practice to various neurological disorders for the diagnosis and functional assessment of spinal tract degeneration.

Author contributions

T.M. and T.U. and K.W. designed the study and wrote the manuscript. T.M. and T.U. and H.M. analyzed the data set. N.Y. and S.I. revised the manuscript. T.M. and T.K. and H.S. and S.K. collected data. N.E. supervision. All authors critically revised and gave final approval to this manuscript.

Data availability

All data generated or analysed during this study are included in this published article and its supplementary information file.

Additional information

Competing interests statement

The authors declare no conflict of interest.

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No competing interests reported.

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Clinical and MRI analyses of dorsal spinal column function in compressive cervical myelopathy

Status:

Version 1

Abstract

Figures

Introduction

Methods

Subjects

Standard protocol approvals, registrations, and patient consents

SEP

SWM test

Romberg ratio

MRI

Regions of interest (ROIs)

Statistics

Results

Participants

Correlations between somatosensory examinations and FA values of the MRI

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1