Relationship between cervical spinal cord morphometry and clinical disability in patients with multiple sclerosis

SUMMARY

OBJECTIVE:  Multiple sclerosis is an autoimmune disease that commonly affects the cervical part of the spinal cord. The aim of this study was to evaluate the relationship between cervical spinal cord atrophy and clinical disability in multiple sclerosis patients.

METHODS:  We examined the cervical spinal cord area measurements of 64 multiple sclerosis patients and 64 healthy control groups over the images obtained by a T2-weighted magnetic resonance imaging device.

RESULTS:  The C2-3, C3-4, C4-5, and C6-7 axial cross-sectional surface area values of the patient group were statistically lower than those of the control group (p<0.05). A negative correlation was found between patients’ Expanded Disability Status Scale scores and C4-5, C5-6, and C6-7 axial area (axial area p<0.05; r1=-0.472, r2=-0.513, and r3=-0.415).

CONCLUSION:  When all parameters were evaluated, the data of our control group were found to be higher than the multiple sclerosis groups. There appears to be a significant relationship between patients with cervical spinal cord atrophy and an increase in Expanded Disability Status Scale scores.

KEYWORDS: Atrophy; Cervical cord; Magnetic resonance imaging; Multiple sclerosis

INTRODUCTION

Multiple sclerosis (MS) is a common chronic inflammatory and demyelinating disease of the brain and spinal cord¹. The onset of MS can be sudden or insidious². The estimated value is found to be 2.2 million MS patients worldwide³.

The clinical course of the disease is highly variable and neurological, with a diverse spectrum². The spinal cord is frequently affected pathologically and clinically in MS. Spinal cord atrophy occurs early in the disease and is often progressive⁴.

Spinal cord atrophy results from destructive pathological changes in normal-appearing white matter and lesions⁵. Therefore, magnetic resonance imaging (MRI) findings are essential, highly sensitive, and frequently used in imaging lesions⁶.

Clinical symptoms such as lower extremity weakness, urinary and fecal sphincter control loss, and progressive motor and sensory disorders may generally be observed in individuals with spinal cord pathology⁷,⁸. In addition, these focal structural abnormalities in the spinal cord also significantly affect the patient’s functional status⁹.

Many studies show a clinicopathological correlation between the spinal cord atrophy measurement of the stages of MS and clinical disability¹⁰,¹¹. Clinical disability levels of patients with MS are evaluated with the Expanded Disability Status Scale (EDSS), which mainly deals with neurological and psychiatric symptoms¹².

In this study, we aimed to evaluate the relationship between cervical spinal cord measurements and EDSS scale results of individuals diagnosed with MS and the degree of clinical disability in the individual.

METHODS

This study was carried out in compliance with the Declaration of Helsinki. Before the inclusion of the patients, ethical approval was obtained from the Local Ethics Committee of the Medical Faculty of Selcuk University (approval number: 2019/189). Our study was carried out at one center.

Participants

Magnetic resonance (MR) images of 64 MS patients (23 males and 41 females), comprising 38 with Relapsing–Remitting Multiple Sclerosis (RRMS), 16 with Primary Progressive Multiple Sclerosis (PPMS), and 10 with Secondary Progressive Multiple Sclerosis (SPMS), and the control group consisting of 64 healthy individuals (24 males and 40 females), were analyzed retrospectively.

Inclusion criteria for the study were as follows: not having undergone cervical trauma or surgery, having a diagnosis of MS, and having EDSS value, duration, and disease subtypes simultaneously made and obtained by neurologists. For the control group, no systemic disease was diagnosed and no history of demyelinating disease was recorded.

Magnetic resonance imaging technique and clinical evaluation

The examinations of cervical MR were performed in the Radiology Department using a 1.5 T MR device (Siemens, Magnetom Area, Germany). The measurements were performed retrospectively in sagittal and axial planes with T2-weighted (TR/TE: 17/555 ms; slice thickness: 3 mm; field of view (FOV): 270 mm; and matrix: 512×512) (Figure 1).

Figure 1
(A) Display of the C2-3 range over a sagittal image (red arrow). (B) Area measurement over the axial section from level C2-3 (red circle).

Statistical analysis

The data were evaluated with the IBM SPSS Statistics Standard Concurrent User V 25 (IBM Corp., Armonk, New York, USA) statistical package program. Descriptive statistics were given as the number of units (n), percentage (%), and mean±standard deviation ($\overline{\text{x}}\pm \text{sd}$). The Shapiro-Wilk normality test and Q-Q graphics were used to evaluate the normal distribution of the data for numerical variables. The exact method of the chi-square test was used to compare the groups in terms of gender. A one-way analysis of covariance (ANCOVA) was used, after adjusting the age and gender variables, to compare axial area according to the groups. If there was a statistically significant difference from the ANCOVA, the Bonferroni correction multiple comparison tests were used to identify the different groups. The results of the two-sample independent t-test and one-way analysis of variance (ANOVA) were also given for uncorrected data to see the effects of correction. p<0.05 was considered statistically significant. Furthermore, ANOVA was also used to compare the numerical variables according to age groups. The Levene test evaluated the homogeneity of the variances. If a difference was found as a result of the one-way ANOVA, the Tukey’s test was used as a multiple comparison test.

RESULTS

Demographic characteristics of the participants

A total of 128 participants, 64 in the patient group and 64 in the control group, were included in the study. The patient and control groups were statistically similar in gender (p=1.000). The mean age of the patient group and control group was 44.14±10.26 and 34.90±10.90, respectively. The mean age of the patient group was statistically higher than the control group (p<0.001). The duration of the disease ranges from 1 to 31 years. Disease groups are similar in terms of gender, age, and disease duration (p>0.05). EDSS scores are statistically different according to disease groups (p=0.012).

Comparison of axial area values of the groups

There is a difference between the ages of the groups. In this case, axial area values are affected by age and sex variables. These values were corrected for age and sex, and analyses and interpretations were made according to the results of the one-way ANCOVA. The C2-3, C3-4, C4-5, and C6-7 axial area values of the patient group were statistically lower than those of the control group (p<0.05) (Table 1).

Table 1
Comparison of the axial area values of the groups.

Parameters (axial area)	Groups				Test statistics
	Patients		HC
	$\overline{x}$	se	$\overline{x}$	se	t*	p	F**	p
C2-3	0.732	0.012	0.925	0.012	13.701	<0.001	4.070	0.046
C3-4	0.720	0.012	0.941	0.012	14.462	<0.001	9.326	0.003
C4-5	0.753	0.013	0.968	0.013	13.193	<0.001	4.798	0.030
C5-6	0.744	0.012	0.943	0.012	13.709	<0.001	1.006	0.318
C6-7	0.697	0.012	0.881	0.012	12.076	<0.001	5.291	0.023

• x¯ values corrected for age and sex
• ^*
  independent two-sample t-test
• ^**
  one-way analysis of covariance; se: standard error.
• Bold indicates statistically significant p-value.

Magnetic resonance measurements of the cervical spinal cord and differences between groups

The axial area values for all participants, i.e., the patient group and the control group, were compared according to gender variable. The C2-3, C3-4, and C4-5 axial area values of men were statistically higher than those of women in the whole group (p<0.05). In the patient group, all axial area values except for axial area C5-6 were statistically higher in men (p<0.05). In the control group, the C3-4 and C4-5 axial area values of men were statistically higher than those of women (p=0.047 and p=0.015). Other axial area values were statistically similar in terms of sex (Table 2).

Table 2
Comparison of axial area values according to gender variable.

Parameters (axial area)	The whole group				Patients				HC
	M		F		M		F		M		F
	$\overline{x}$	sd	$\overline{x}$	sd	$\overline{x}$	sd	$\overline{x}$	sd	$\overline{x}$	sd	$\overline{x}$	sd
C2-3	0.849	0.113	0.800	0.148	0.766	0.079	0.681	0.089	0.930	0.076	0.921	0.084
	t=2.145; p=0.034				t=3.783; p<0.001				t=0.433; p=0.666
C3-4	0.854	0.134	0.802	0.140	0.747	0.076	0.691	0.095	0.957	0.089	0.916	0.070
	t=2.061; p=0.041				t=2.445; p=0.017				t=2.025; p=0.047
C4-5	0.889	0.137	0.825	0.145	0.780	0.072	0.716	0.103	0.994	0.096	0.937	0.082
	t=2.458; p=0.015				t=2.645; p=0.010				t=2.511; p=0.015
C5-6	0.855	0.128	0.818	0.142	0.754	0.077	0.709	0.100	0.951	0.087	0.930	0.076
	t=1.458; p=0.147				t=1.882; p=0.065				t=1.016; p=0.314
C6-7	0.808	0.120	0.765	0.133	0.720	0.092	0.668	0.100	0.892	0.075	0.866	0.075
	t=1.498; p=0.137				t=2.089; p=0.041				t=1.371; p=0.175

• HC: healthy control; sd: standard deviation; F: female; M: male. Bold indicates statistically significant p-value.

Comparison of axial area values of the cervical spinal cord by age variable

There was a negative correlation between the ages of the whole group (n=128) and all axial areas measured. There was a negative correlation between the ages of the patient group and the C2-3 axial area (p<0.05; r=-0.378). There was no statistically significant relationship between the age of the control group and the axial area (p>0.05).

Comparison of axial area values of cervical spinal cord according to subtypes of multiple sclerosis

Axial area values are affected by age and sex variables. Thesevalues were corrected for age and sex, and analyses and interpretations were made according to the results of the one-way ANCOVA. Axial area C2-3 values differed statistically according to the groups (p<0.048). PPMS, RRMS, and SPMS values were similar, and the control group values were statistically higher than the patient groups. The group closest to the control group in terms of the mean value was the PPMS group. The C3-4, C4-5, and C6-7 axial area values differed statistically according to the groups (p<0.05). The PPMS, RRMS, and SPMS values were similar, and the control group values were statistically higher than the patient groups. The group closest to the control group in terms of the mean value was the RRMS group (Table 3).

Table 3
Comparison of axial area of the groups according to types of disease.

Parameters (axial area)	Groups								Test statistics
	PPMS		RRMS		SPMS		HC
	$\overline{x}$	se	$\overline{x}$	se	$\overline{x}$	se	$\overline{x}$	se	F*	p	F**	p
C2-3	0.741a	0.022	0.725a	0.016	0.714a	0.035	0.925b	0.012	63.027	<0.001	2.117	0.048
C3-4	0.716a	0.022	0.726a	0.016	0.703a	0.035	0.941b	0.012	68.619	<0.001	3.455	0.019
C4-5	0.743a	0.024	0.751a	0.017	0.742a	0.037	0.968b	0.013	57.489	<0.001	2.077	0.043
C5-6	0.736	0.022	0.756	0.016	0.703	0.035	0.943	0.012	61.899	<0.001	1.163	0.327
C6-7	0.701a	0.022	0.704a	0.016	0.621a	0.034	0.881b	0.012	47.903	<0.001	3.100	0.003

• HC: healthy control; PPMS: primary progressive multiple sclerosis; RRMS: relapsing–remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; x¯: values adjusted for age and gender.
• ^*
  one-way analysis of variance
• ^**
  one-way covariance analysis results;
• and the superscripts “a” and “b” show differences between groups.
• The groups with the same letters are statistically similar. Bold indicates statistically significant p-value.

Correlation of Expanded Disability Status Scale scores and duration of disease with cervical spinal cord axial area values

A negative correlation was found between patients’ EDSS scores and C4-5, C5-6, and C6-7 axial area (axial area p<0.05; r1=-0.472, r2=-0.513, and r3 =-0.415). The relationship between disease duration and axial area values was not statistically significant (p>0.05). A positive correlation was found between PPMS, RRMS, and SPMS disease group EDSS scores and disease duration (p<0.05; r1=0.522, r2=0.438, and r3=0.711, respectively). In the RRMS group, a negative correlation was found between EDSS scores and axial area C3-4 (p<0.05; r=-0.394). There was a negative correlation between EDSS scores and C2-3 axial area values in the SPMS group (p<0.05; r=-0.668).

DISCUSSION

The reduction in the cross-sectional area of the spinal cord is considered an indirect measure of axonal degeneration¹³. MRI predicts spinal cord pathologies in 90% of MS patients¹⁴. In addition, a significant correlation was reported between cervical cord atrophy and EDSS values¹⁵,¹⁶.

In the literature, the measurement of spinal cord segments, area, length, and volume have been examined with different techniques in many studies. In these studies, the subtypes of the disease, cord areas, duration of the disease, and their relationship with the EDSS value were evaluated. Our study compared axial area measurements in MS patients and healthy individuals. In addition, the relationship between atrophy due to disease duration, age, gender, and clinical disability was investigated in patient groups. This study showed that as a result of cord area measurements, cervical spinal cord atrophy in MS patients could be evaluated.

In the study by Rocca et al.¹⁷, the C6-7 axial area measurement results of the RRMS group were lower than those in our study, but the C2-3, C3-4, C4-5, and C5-6 axial area measurements were higher. PPMS and SPMS values were lower than our measurements. The differences might be related to the disease duration and EDSS value.

In a study by Bernitsas et al.⁹, the C2 axial area measurements of the PPMS group were lower than those in our study. On the other hand, RRMS group values were found to be higher than in our study. The reason for the difference in the area measurements is due to the mean EDSS value, the difference in the measurement region, the number of samples, or the measurement method.

Cortese et al.¹⁸ measured the C2-3 axial area in a 3-year cohort study of patients with PPMS. While our results were lower than the measurement results at the beginning and the end of the first year, they were higher than those at the end of the third year. This difference is thought to be due to the duration of the disease and the lower mean EDSS compared to our group. It is thought that the fact that our study is a longitudinal study will affect the results. Our measurements were higher when healthy groups were compared in the same study. The differences are due to the mean young age of our sample group.

Biberacher et al.¹⁹ measured the C2-3 axial area of the patient group with Clinical Isolated Syndrome (CIS) and RRMS and detected the lesions in this segment. Our study is similar to the measurement results of the RRMS group. This study reported that the cord area did not differ between patients with and without lesions in CIS and RRMS. Bussas et al.²⁰ stated that there was no significant difference between the spinal cord areas of MS patients with active lesions. It has been reported in different studies that no relationship was found between spinal cord lesions and spinal cord atrophy²⁰,²¹.

It has been shown that the morphometric measurements of the spinal cord, age, gender, height, weight, ethnicity or region of residence, measurement methods, and MRI devices affect the results for MS patients. All parameters in the control group of our study were higher than those in the MS group. There was no statistically significant difference between the axial area measurements of disease duration. There is a negative correlation between the EDSS score of the patient group and the measurement parameters. This condition is thought to be related to cervical spinal cord atrophy, a significant marker of spinal cord pathology.

CONCLUSION

Spinal cord pathology in MS is a complex process. It is thought that clear information will be obtained by knowing the exact etiology and physiopathology of MS and using radiological imaging devices. We aimed to systematically record the data we have obtained as a result of this study and present it for the use of science.

• ETHICAL APPROVAL
  This study was carried out in compliance with the Declaration of Helsinki. Before the inclusion of the patients, ethical approval was obtained from the Local Ethics Committee of the Medical Faculty of Selcuk University (approval number: 2019/189).
• Funding: none.

REFERENCES

• ¹ Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018;378(2):169-80. https://doi.org/10.1056/NEJMra1401483
  » https://doi.org/10.1056/NEJMra1401483
• ² Huang WJ, Chen WW, Zhang X. Multiple sclerosis: pathology, diagnosis and treatments. Exp Ther Med. 2017;13(6):3163-6. https://doi.org/10.3892/etm.2017.4410
  » https://doi.org/10.3892/etm.2017.4410
• ³ GBD 2016 Multiple Sclerosis Collaborators. Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the global burden of disease study 2016. Lancet Neurol. 2019;18(3):269-85. https://doi.org/10.1016/S1474-4422(18)30443-5
  » https://doi.org/10.1016/S1474-4422(18)30443-5
• ⁴ Daams M, Weiler F, Steenwijk MD, Hahn HK, Geurts JJ, Vrenken H, et al. Mean upper cervical cord area (MUCCA) measurement in long-standing multiple sclerosis: relation to brain findings and clinical disability. Mult Scler. 2014;20(14):1860-5. https://doi.org/10.1177/1352458514533399
  » https://doi.org/10.1177/1352458514533399
• ⁵ Miller DH, Barkhof F, Frank JA, Parker GJ, Thompson AJ. Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance. Brain. 2002;125(Pt 8):1676-95. https://doi.org/10.1093/brain/awf177
  » https://doi.org/10.1093/brain/awf177
• ⁶ Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292-302. https://doi.org/10.1002/ana.22366
  » https://doi.org/10.1002/ana.22366
• ⁷ Miller JR. Demyelinating diseases, multiple sclerosis. In: Merritt’s HH, Rowland P, editors. Merritt’s neurology. Lippincott Williams-Wilkins Publishers; 2000. p. 586-94.
• ⁸ Noort S. Signs and symptoms of multiple sclerosis. In: Olek MJ, editor. Multiple sclerosis etiology, diagnosis, and new treatment strategies. New Jersey: Humana Press, Totowa; 2005. p. 1-11.
• ⁹ Bernitsas E, Bao F, Seraji-Bozorgzad N, Chorostecki J, Santiago C, Tselis A, et al. Spinal cord atrophy in multiple sclerosis and relationship with disability across clinical phenotypes. Mult Scler Relat Disord. 2015;4(1):47-51. https://doi.org/10.1016/j.msard.2014.11.002
  » https://doi.org/10.1016/j.msard.2014.11.002
• ¹⁰ Valsasina P, Aboulwafa M, Preziosa P, Messina R, Falini A, Comi G, et al. Cervical cord T1-weighted hypointense lesions at MR imaging in multiple sclerosis: relationship to cord atrophy and disability. Radiology. 2018;288(1):234-44. https://doi.org/10.1148/radiol.2018172311
  » https://doi.org/10.1148/radiol.2018172311
• ¹¹ Tsagkas C, Magon S, Gaetano L, Pezold S, Naegelin Y, Amann M, et al. Preferential spinal cord volume loss in primary progressive multiple sclerosis. Mult Scler. 2019;25(7):947-57. https://doi.org/10.1177/1352458518775006
  » https://doi.org/10.1177/1352458518775006
• ¹² Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-52. https://doi.org/10.1212/wnl.33.11.1444
  » https://doi.org/10.1212/wnl.33.11.1444
• ¹³ Petrova N, Carassiti D, Altmann DR, Baker D, Schmierer K. Axonal loss in the multiple sclerosis spinal cord revisited. Brain Pathol. 2018;28(3):334-48. https://doi.org/10.1111/bpa.12516
  » https://doi.org/10.1111/bpa.12516
• ¹⁴ Bot JC, Barkhof F, Polman CH, Lycklama à Nijeholt GJ, Groot V, Bergers E, et al. Spinal cord abnormalities in recently diagnosed MS patients: added value of spinal MRI examination. Neurology. 2004;62(2):226-33. https://doi.org/10.1212/wnl.62.2.226
  » https://doi.org/10.1212/wnl.62.2.226
• ¹⁵ Song X, Li D, Qiu Z, Su S, Wu Y, Wang J, et al. Correlation between EDSS scores and cervical spinal cord atrophy at 3T MRI in multiple sclerosis: a systematic review and meta-analysis. Mult Scler Relat Disord. 2020;37:101426. https://doi.org/10.1016/j.msard.2019.101426
  » https://doi.org/10.1016/j.msard.2019.101426
• ¹⁶ Evangelou N, Luca GC, Owens T, Esiri MM. Pathological study of spinal cord atrophy in multiple sclerosis suggests limited role of local lesions. Brain. 2005;128(Pt 1):29-34. https://doi.org/10.1093/brain/awh323
  » https://doi.org/10.1093/brain/awh323
• ¹⁷ Rocca MA, Valsasina P, Meani A, Gobbi C, Zecca C, Rovira À, et al. Clinically relevant cranio-caudal patterns of cervical cord atrophy evolution in MS. Neurology. 2019;93(20):e1852-66. https://doi.org/10.1212/WNL.0000000000008466
  » https://doi.org/10.1212/WNL.0000000000008466
• ¹⁸ Cortese R, Tur C, Prados F, Schneider T, Kanber B, Moccia M, et al. Ongoing microstructural changes in the cervical cord underpin disability progression in early primary progressive multiple sclerosis. Mult Scler. 2021;27(1):28-38. https://doi.org/10.1177/1352458519900971
  » https://doi.org/10.1177/1352458519900971
• ¹⁹ Biberacher V, Boucard CC, Schmidt P, Engl C, Buck D, Berthele A, et al. Atrophy and structural variability of the upper cervical cord in early multiple sclerosis. Mult Scler. 2015;21(7):875-84. https://doi.org/10.1177/1352458514546514
  » https://doi.org/10.1177/1352458514546514
• ²⁰ Bussas M, Husseini M, Harabacz L, Pineker V, Grahl S, Pongratz V, et al. Multiple sclerosis lesions and atrophy in the spinal cord: distribution across vertebral levels and correlation with disability. Neuroimage Clin. 2022;34:103006. https://doi.org/10.1016/j.nicl.2022.103006
  » https://doi.org/10.1016/j.nicl.2022.103006
• ²¹ Nijeholt GJ, Walderveen MA, Castelijns JA, Waesberghe JH, Polman C, Scheltens P, et al. Brain and spinal cord abnormalities in multiple sclerosis correlation between MRI parameters, clinical subtypes and symptoms. Brain. 1998;121(Pt 4):687-97. https://doi.org/10.1093/brain/121.4.687
  » https://doi.org/10.1093/brain/121.4.687

Publication Dates

• Publication in this collection
  13 Nov 2023
• Date of issue
  2023

History

• Received
  15 Aug 2023
• Accepted
  22 Aug 2023