Comparison between diffusion-weighted imaging and post-contrast enhanced T1-weighted sequence in brain MRI of patients with an acute attack of multiple sclerosis and the role of serum vitamin D3 level in its diagnosis

doi:10.21203/rs.3.rs-1656385/v1

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Comparison between diffusion-weighted imaging and post-contrast enhanced T1-weighted sequence in brain MRI of patients with an acute attack of multiple sclerosis and the role of serum vitamin D3 level in its diagnosis

https://doi.org/10.21203/rs.3.rs-1656385/v1

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Background and purpose. – Identifying multiple sclerosis (MS) lesions is cornerstone in the diagnosis and prognosis of the disease activity. Application of contrast-enhanced magnetic resonance imaging (CE-MRI) is vital but the alternative use of diffusion-weighted imaging (DWI) and biomarkers is most appropriate when the injection of contrast agents is contraindicated. The present study investigated the possible substitution of CE-MRI with DWI and determined a vitamin D3 cutoff point for MS patients with positive MRI.

Materials and Methods. – 5 ml of peripheral venous blood was collected from all patients and DWI and post-contrast T1-weighted MRI were performed on 85 patients with acute attacks of MS from April 2018 to November 2019. Contrast-enhanced lesions were considered the gold standard of activity in MRI in evaluating the relation between CE-MRI and DWI.

Results. – The accuracy of CE-MRI was higher (63.5%) compared to DWI (27.1%). Majority of patients (54) showed positive results in CE-MRI. The difference between patients with and without positive CE-MRI was statistically significant in terms of vitamin D3 deficiency (P=0.001). The optimal cutoff of vitamin D₃ for CE-MRI positive patients was 23.33 ng/ml with 83.33% sensitivity and 61.29% specificity.

Conclusions. – Combination of CE-MRI and DWI yields more positive imaging results; DWI sequence alone, without using T1 with contrast in MRI, is not enough to assess brain lesion activity in patients with MS. Furthermore, vitamin D₃ levels of <23.33 ng/ml correlate well with a positive result in CE-MRI where the MS activity is most likely to be present.

Multiple sclerosis

DW-MRI

Contrast-enhanced T1-weighted

Vitamin D3

Multiple Sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS). It is the most common cause of non-traumatic disability in young and middle-aged people [1]. Inflammation, myelin destruction, axonal degeneration, edema, neurons destruction, and gliosis are the main pathologic features of MS plaques [2]. During an MS attack, patients may experience new symptoms or exacerbation of previous symptoms. The common presentations in MS include sensory abnormalities, changes in vision, motor weakness, imbalance and dizziness, bladder dysfunction, and memory dysfunction [3–5].

In the 2017 revision of McDonald's criteria, the diagnosis of MS is confirmed when demyelinating lesions of CNS are detected by magnetic resonance imaging (MRI) [6, 7]. MRI study as a standard and highly sensitive modality can characterize MS lesion in terms of number of lesions, size, shape, and location in the brain as well as therapeutic response [8]. Several studies have investigated and compared the sensitivity of different MRI modalities in the diagnosis of MS lesions and plaques [9–11]. The diagnosis and follow-up of MS patients is usually carried out with conventional MRI techniques including T1-weighted, T2-weighted, and fluid-attenuated inversion recovery (FLAIR) images [12–15]. Pathologically, MS is linked to inflammatory injuries to the blood-brain barrier (BBB). The standard tool for monitoring BBB inflammatory injuries and disease activity in MS patients is post-contrast-enhanced T1-weighted imaging [10, 16]. However, this method is expensive and even contraindicated in patients with sensitivity to contrast agents and renal impairment [12–16]. Quantitative magnetic resonance (MR) imaging, an advancement in MRI, enables scientists to study the histopathology of MS. In this regard, diffusion-weighted magnetic resonance imaging (DWI or DW-MRI) for quantifying water diffusion in the brain lesions of MS patients is a new functional imaging substitute [17]. Considering the disadvantages of conventional MRI, finding an alternative imaging technique with less contraindications may be of utmost value.

In addition to imaging studies, laboratory tests are essential for diagnosing MS. Vitamin D₃ is key in physiologic bone metabolism but it is also implicated in the progression and severity of various autoimmune diseases [18, 19]. Deficiency of vitamin D₃ has been addressed in most MS patients [20, 21], and a reverse association has been found between serum level of vitamin D3 and MS risk [22, 23]. Smolders et al. (2008) reported that low level of serum vitamin D₃ is associated with disability and a greater relapse rate in MS patients [21]. Hence, comparison between serum level of vitamin D₃ and MRI methods hold merit to be studied in patients with an acute attack of MS.

The present study aimed at first to evaluate the difference between post-contrast-enhanced T1 and DW-MRI sequences in detection of acute MS lesions, and then to discover possible correlation between findings of different MRI sequences and serum level of vitamin D₃. In other words, the possibility of alternative use of DWI instead of post-contrast-enhanced T1 with gadolinium was investigated to provide another imaging modality for patients with history of contrast sensitivity or other contraindications.

Study Population and Sampling

This cross-sectional study was conducted on 85 patients suffering from acute attacks of MS who were referred to Shahid Faqihi Hospital from April 2018 to November 2019. A definitive diagnosis of multiple sclerosis was the inclusion criterion; patients with other neurologic, systemic, or autoimmune disorders and with a history of sensitivity to gadolinium-based contrast agents, and MS patients using vitamin D supplements were excluded from the study. The demographic and clinical characteristics of patients including sex, age, disease duration, family history, rate of MS attack, underlying illness, and type of medication used were registered by a neurologist. This study was approved by the ethics committee of Shiraz University of Medical Science (SUMS). Written informed consents were obtained from all participants.

MRI Sequences

A 1.5 Tesla MR system (Siemens, Magnetum Avantto) was used to capture brain MRI of all MS patients with acute attacks referring to our center; the images were taken on a 384×225 matrix. The conventional MRI protocol comprised of an axial T1-weighted sequence (repetition time (TR)/echo time (TE) = 420/10 ms; slice thickness = 7 mm) with and without gadolinium-based contrast agent, an axial T2-weighted sequence (TR/ TE = 3740/90 ms; slice thickness= 7 mm), and an axial and sagittal 3-dimensional FLAIR sequence (TR/TE = 6000/360 ms; flip angle = 120 degrees; slice thickness = 1 mm) of whole-brain. In addition, sagittal and axial images of the spinal cord were taken for T1-weighted, T2-weighted, and STIR prior to and after applying contrast agent. Whole-brain DWI images were taken as well (TR/TE = 3500/135ms; flip angle= 90 degrees; field of view (FOV) =150-230; slice thickness = 7 mm). MS plaques with iso-intense to hypo-intense signals in the apparent diffusion coefficient (ADC) map were defined as diffusion restricted (DR) lesions. The number and location of MS plaques were evaluated by an expert neuroradiologist.

Assessment of Vitamin D₃ Status

Before MRI scanning, venous blood samples were obtained from each participant after 10-12 hours of fasting. Five ml samples of blood were transferred to tubes containing K₂EDTA and then centrifuged at 1,200 × g for 15 min at 4°C to separate the serum. Finally, a commercially available ELISA kit (Monobind Inc., Lake Forest, CA, USA) was used to quantify the serum concentration of 25-(OH) vitamin D₃. All laboratory measurements were performed in standard laboratory conditions under the supervision of an expert. For this study serum 25(OH) vitamin D levels less than 20 ng/mL (50 nmol/L) was defined as vitamin D₃ deficiency.

Patient Categorization

An MS lesion showing contrast enhancement in T1WI post-contrast sequence was labeled “Contrast⁺ plaque”, and diffusion with greater restriction than expected for a lesion in DWI was labeled “Diffusion⁺ plaque”. By the same token, the term CE⁺-MRI was used when a sequence showed Contrast⁺ plaques, and DW⁺-MRI when a sequence showed Diffusion⁺ plaques. Furthermore, patients with either CE⁺-MRI, or DW⁺-MRI, or both were categorized in the group of positive MRIs.

According to the 2017 McDonald criteria, contrast-MRI can determine the activity of brain lesions. Hence, we considered Gad⁺(gadolinium-enhanced) plaques as the gold standard for detection of lesion activity in MRI. After patients’ evaluation with DWI, ADC maps representing abnormal restricted diffusion was used to confirm the high signal on isotropic images. Findings of conventional MRI and DWI were then evaluated to make a comparison between Contrast⁺plaques and Diffusion⁺plaques.

Statistical Analysis

All data was analyzed using SPSS software (SPSS 19.0; SPSS Inc., Chicago, IL, USA). The data was expressed as mean ± standard deviation (SD) and analyzed by receiver-operating characteristic (ROC) curve, Youden index, and Mann-Whitney U-test. The range used to classify the accuracy of the area under ROC curve (AUC) are: 0.5-0.6=fail; 0.6-0.7=poor; 0.7-0.8=fair; 0.8-0.9=good; 0.9-1=excellent. A P-value less than 0.05 was considered statistically significant.

Of 85 MS-diagnosed patients with MS acute attack, 21 (24.7 %) and 64 (75.3%) were male and female, respectively. The mean age of patients was 41±1.6 with a range of 15–67 years. Findings of the present study revealed that MS lesions develop mainly in the supra-tentorial region (cerebral hemispheres) (74%) and only two cases (3%) demonstrated infra-tentorial (brainstem and cerebellum) lesions. Also, thirteen cases (23%) had lesions in both supra- and infra-tentorial regions.

Table 1

MS patients’ frequency and level of vitamin D₃ across the groups of imaging modalities

MRI Methods	Imaging Result	N	levels of Vitamin D3*
MRI Methods	Imaging Result	N	Mean	SD
CE-MRI	Negative	31	28.15	16.44
CE-MRI	Positive	54	20.60	17.37
DWI	Negative	62	24.01	18.05
DWI	Positive	23	21.58	15.42
CE-MRI: contrast enhanced magnetic resonance imaging DWI or DW-MRI: diffusion weighted magnetic resonance imaging (Positive) implies either contrast-enhancement or diffusion with restriction (Negative) implies non-enhanced contrast or diffusion without restriction *levels of vitamin D3 are expressed in ng/ml

A total of 57 MS patients (67 %) had positive MRI (positive results either in CE-MRI or DW-MRI). Based on enhancement and diffusion patterns, majority of the patients (n=34) had only Contrast⁺ plaques, 28 patients had neither Contrast⁺ nor Diffusion⁺ plaques, and 20 patients had both Contrast⁺ and Diffusion⁺ plaques. Patients with the negative and positive results of CE-MRI had mean vitamin D3 levels of 28.15±16.44 and 20.6±17.33 ng/ml, respectively. On the other hand, patients with negative and positive results of DWI reported mean vitamin D3 levels of 24.01±18.05 and 21.58±15.42 ng/ml, respectively which is shown in Table 1.

Table 2

Frequency of vitamin D₃ deficiency based on new cutoff

MRI Method	Optimal vitamin D₃ cutoff	Frequency
MRI Method	Optimal vitamin D₃ cutoff	Vitamin D₃ < Optimal vitamin D3 cutoff (Expected deficient patients)	Vitamin D₃≥ Optimal vitamin D3 cutoff (Expected sufficient patients)
CE-MRI	23.33	56	29
DW-MRI	13.8	18	67

According to the cutoff points obtained in Table 2, the patients were categorized into groups of < or ≥ Optimal vitamin D₃ cutoff. Hence, 65.8% (56) of all patients were vitamin D₃ deficient based on the threshold of <23.33 ng/ml, while 21.17% of all patients (with the cutoff of 13.8 ng/ml) showed evidence of vitamin D₃ deficiency.

Table 3

Accuracy of imaging modalities in detection of MS lesions of CNS

MRI Method	Accuracy	95% confidence interval
MRI Method	Accuracy	Accuracy Lower	Accuracy Upper
CE-MRI	0.635	0.524	0.737
DW-MRI	0.271	0.18	0.378

In this study, presentation of contrast-enhancedplaques was considered the gold standard of activity in MRI and not all the contrast-enhanced plaques were diffusion-restricted. Hence, the accuracy of the two imaging modalities was evaluated according to the receiver-operating characteristic (ROC) curve analysis. The accuracy of the imaging methods assuming a confidence interval of 95% is demonstrated in Table 3. In this regard, contrast-enhanced MRI was more accurate (63.5%) in the detection of MS plaques than diffusion-weighted MRI (27.1%).

Table 4

The relationship between vitamin D3 deficiency and the imaging modalities using Independent-Samples Mann-Whitney U Test

Null Hypothesis	Total N	Mann-Whitney U	Z	p-value	Decision
The distribution of vitamin D₃ is the same across of CE-MRI groups	85	477	-3.287	0.001	Reject the null hypothesis
The distribution of vitamin D₃ is the same across DWI groups	85	646.5	-0.658	0.511	Retain the null hypothesis

To investigate the effect of serum vitamin D₃ level on detection of MS lesions independent samples Mann-Whitney U test was used to test the hypothesis that the distribution of vitamin D₃ is the same across the groups of patients with positive or negative MRI result. Table 4 presents data on the z-values of -3.287 and -0.658 and the approximately calculated significant statistical differences. The results showed statistically significant differences (P=0.001) between the CE⁺-MRI patients and CE^--MRI group in levels of vitamin D₃. Hence, a significant correlation is seen between positive contrast-enhanced MRI and serum level of vitamin D₃. On the other hand, the patients of DW⁺-MRI and DW^--MRI did not show a significant difference with respect to vitamin D₃ deficiency. Thus, no evidence of significant correlation between positive DWI and serum level of vitamin D₃ (P=0.511) can be inferred.

Table 5

The effect of vitamin D₃ based on the patterns of lesions detected

MRI Method	AUC	n	₊imaging	- imaging	Optimal vitamin D3 cutoff	youden	acc	sensitivity	specificity
CE-MRI	0.715	85	54	31	23.33	0.4462	0.753	0.8333	0.6129
DW-MRI	0.546	85	23	62	13.8	0.1704	0.694	0.3478	0.8226

Furthermore, the effect of vitamin D3 level on the imaging-based MS diagnosis was assessed via receiver-operating characteristic (ROC) curve, accuracy analysis, and threshold level of vitamin D3. The area corresponding to MS diagnosis with CE-MRI under the ROC curve (AUC) was 0.71, while that of MS diagnosis with DW-MRI yielded 0.54. To measure the optimal cutoff of vitamin D₃, the Youden index was employed to balance between sensitivity and specificity of the cutoff obtained. When CE-MRI had been the method of choice, an optimal threshold of 23.33 ng/ml was measured for vitamin D₃ with 83.33% sensitivity and 61.29% specificity. For the patients diagnosed with DW-MRI, an optimal vitamin D3 cutoff of 13.8 was obtained with low sensitivity (34.78%) and relatively high specificity (82.26%) that was shown in Table 5. The optimal threshold level of vitamin D₃ was further measured specifically for men and women of each modality (Supplementary Data). Only the female group of CE-MRI showed AUC>0.7 and an optimal vitamin D₃ cutoff of 23.33 ng/ml was measured for this group (refer to supplementary data for more information).

MS is classified as an inflammatory disease of CNS targeting myelin sheath and the formation of white matter and disrupts the blood-brain barrier [24]. Till date, the precise diagnosis of MS is still challenging in spite of numerous imaging modalities [15, 25, 26]. Advances in MRI has transformed MS diagnosis and makes it possible for early and definite diagnosis. Routinely, contrast-enhanced T1-Weighted MRI is used to diagnose and follow-up on MS patients [12, 27]. Standard sequence post-contrast T1 weighted imaging can detect active plaque. The major disadvantage of the gadolinium-enhanced T1-weighted MRI (Gd-T1w MRI) technique is the need for injection of contrast media, which makes MRI less minimally invasive, more time consuming, more expensive and contraindicated in patients with sensitivity to contrast agents and renal impairment. The development of quantitative MRI techniques launched a new era in better appreciating the histopathology of MS [28, 29]. DWI is a non-invasive method based on local water motion in the tissue which was introduced by Larsson et al. (1993) for detecting acute MS lesions [30].

The present study investigated the effectiveness of DWI as an acceptable alternative technique for T1-Weighted MRI for diagnosing MS patients with acute attack. Comparing the accuracy of CE-MRI and DW-MRI, we found that the contrast-enhanced T1 plaques were more commonly detected than diffusion-restricted plaques in the study population. Our statistical analysis demonstrated higher accuracy of contrast-enhanced MRI in the detection of MS plaques, whereas that of DWI was relatively low (63.5% vs 27.1%). However, Meftahi et al. reported an AUC of 84% for 12 directional DWI and concluded the diagnostic significance of DWI 12 when CE-MRI is worried [31]. The data obtained showed that contrast T1-Weighted MRI is effective for monitoring MS activity, but DW-MRI is not a suitable alternative in patients suffering from an acute attack of MS and can be used only as an additive sequence. In this study three patients presented with a positive DW-MRI without any evidence of contrast-enhanced plaques in CE-MRI. Similarly, Davoudi et al. expressed concerned about DWI positive cases that showed CE-MRI negative results [24]. The diagnostic capability of DWI in MS is still under debate. Consistent with findings in the present study, several studies concluded that DWI findings are nonspecific and cannot differentiate lesions of acute MS attacks from other lesions [7, 28, 32]. Therefore, DWI could not substitute for contrast MRI; however, concomitant use of these two modalities could increase the probability of correct detection of active MS plaques [33]. Nevertheless, the diagnosis of another differential diagnosis of acute demyelinating lesions such as acute ischemia was shown to improve with DW-MRI [34].

In the 1970s vitamin D was identified as a key factor in MS development and various types of studies have been conducted to quantify and clarify how vitamin D influences MS [35]. The present study also investigated the association between different MRI sequences and serum level of vitamin D3 in patients suffering from acute attack of MS. MRI is an accepted modality for the diagnosis and monitoring of MS and it is more reliable in the prediction of the disease course [36]. Hence, if the MRI evidence of disease activity correlates with vitamin D, careful monitoring of serum vitamin D may help in providing a better treatment strategy for the prevention of MS attacks. Vitamin D₃ deficiency, serum 25-hydroxyvitamin D (25(OH)D), has been known as a widespread health problem, affecting approximately one billion people worldwide [37]. Vitamin D₃ deficiency is associated with higher risk of MS disease [22, 23].

In the present study, patients with Contrast⁺ plaques showed significant differences from patients without contrast-enhanced lesions in terms of serum vitamin D₃ levels (P = 0.001). Conversely, the patients of DW⁺-MRI and DW⁻-MRI were not significantly different from one another in terms of vitamin D₃ deficiency (P = 0.51). Martínez-Lapiscina EH et al. [38] in a systematic review and meta-analysis reviewed 13 studies and 3498 patients. They showed that higher serum levels of vitamin D₃ are associated with a marginal decrease in rate of relapse and radiological inflammatory activities in patients with MS. Furthermore, Weinstock-Guttman B et al. [39] demonstrated that vitamin D3 metabolites protect MS patients against brain atrophy and disability.

Despite the established significance of vitamin D3 in MS, the clinical definition of vitamin D deficiency and what constitutes optimal levels has been the subject of debate. The blood levels of 25(OH)D as suggested by the Endocrine Society for categories of deficient, insufficient, and sufficient are ≤ 20 ng/ml, 21–29 ng/ml, and ≥ 30 ng/ml, respectively [35]. However, a sharp cutoff point of vitamin D3 for MS has not been addressed yet in the literature. In this study, we have determined a vitamin D3 cutoff in relation to CE-MRI and DW-MRI. Based on the Youden index, an optimal cutoff of 23.33 ng/ml was obtained where we perform contrast-based imaging on the patients. Hence, patients with vitamin D3 levels < 23.33 ng/ml are most likely to show Contrast⁺ lesions with a sensitivity of 83.33% and specificity of 61.29% in their CE-MRI study. Through DW-MRI, we measured a vitamin D3 threshold of 13.8 ng/ml with low specificity (34.78%), but relatively high specificity (82.26%). However, our statistical analyses proved that there is no significant correlation between vitamin D₃ deficiency and positive DW-MRI (P = 0.51) and the AUC of the cutoff obtained (AUC = 0.546) fails to discriminate between the DWI groups. Therefore, the cutoff obtained for DWI in terms of vitamin D3 deficiency is of little importance and further investigation is required in this regard.

Furthermore, we performed a gender-based analysis to study the vitamin D3 threshold level in male and female patients. Through CE-MRI study, the discrimination of female patients with positive and negative results of CE-MRI was acceptable (AUC = 0.71) based on calculated vitamin D₃ cutoff; however, the effect of vitamin D₃ in the detection of MS plaques across a male group of CE-MRI, and male and female groups of DW-MRI suggested no discrimination (AUC < 0.7). An optimal cutoff of 23.33 in the female group of CE-MRI had 90.7% sensitivity and 52.38% specificity which was the same cutoff measured in CE-MRI regardless of the gender. This may be due to the fact that the majority of our patients were female and the cutoff obtained is more realistic. (Supplementary data)

In this study, we showed that what threshold of vitamin D₃ deficiency is associated with the imaging activity of MS disease. This finding may favor the protective effect of vitamin D₃ in inflammatory activities of the disease. Also, if MS patient reports serum vitamin D levels less than 23.33 ng/ml, the CE-MRI detection of MS lesion is possible with the highest sensitivity and specificity. The difference in age and sex distribution, lacking a control group, and absence of patients’ follow-up were the major limitations of the current study. Hence, we recommend the scientists conduct unbiased studies with a larger sample size in this regard.

Use of DWI sequence alone and without using gadolinium-enhanced T1-weighted MRI is not enough to assess brain lesions activity in patients with MS; however, there are cases with a positive result of DWI and negative result of CE-MRI. We suggest that the combination of CE-MRI and DW-MRI might yield more positive results in the diagnosis of active MS attacks and allow for a more accurate diagnosis. Additionally, a threshold vitamin D₃ level of < 23.33 ng/ml strongly correlates with a positive result in CE-MRI. Therefore, clinicians are recommended to remember the strong correlation between vitamin D₃ concentrations < 23.33 ng/ml and positive findings of CE-MRI in MS patients.

Ethics approval and consent to participate

This article has used human date. All ethical obligations were observed, informed consent was obtained from all subjects and/or their legal guardians, and all experiments were performed in accordance with relevant guidelines and regulations. This study was approved by the ethics committee of Shiraz University of Medical Science (SUMS).

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

This work was supported by grant number 97-01-94-17984, awarded to M Nazery from the Shiraz University of Medical Sciences.

Authors’’ contributions

All authors have contributed equally. All authors read and approved the final manuscript.

Acknowledgments

Not applicable

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Comparison between diffusion-weighted imaging and post-contrast enhanced T1-weighted sequence in brain MRI of patients with an acute attack of multiple sclerosis and the role of serum vitamin D3 level in its diagnosis

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Abstract

Introduction

Materials And Methods

Study Population and Sampling

MRI Sequences

Assessment of Vitamin D₃ Status

Patient Categorization

Statistical Analysis

Results

Discussion

Conclusion

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors’’ contributions

Acknowledgments

References

Additional Declarations

Supplementary Files

Status:

Version 1

Comparison between diffusion-weighted imaging and post-contrast enhanced T1-weighted sequence in brain MRI of patients with an acute attack of multiple sclerosis and the role of serum vitamin D3 level in its diagnosis

Status:

Version 1

Abstract

Introduction

Materials And Methods

Study Population and Sampling

MRI Sequences

Assessment of Vitamin D3 Status

Patient Categorization

Statistical Analysis

Results

Discussion

Conclusion

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Authors’’ contributions

Acknowledgments

References

Additional Declarations

Supplementary Files

Status:

Version 1

Assessment of Vitamin D₃ Status