Is It Possible to Discriminate Active MS Lesions with Diffusion Weighted Imaging?

Objective: Patients with multiple sclerosis (MS) are at a risk of gadolinium deposition because of multiple control imaging. Therefore, it is important to determine biomarkers that can differentiate active and chronic lesions without using contrast agent. This study aimed to assess mean apparent diffusion coefficient (ADC) values and signal intensities (SI) on diffusion weighted imaging (DWI) values of active and nonactive lesions. Materials and Methods: We included 25 patients in this study. We measured mean ADC values and SI on DWI of the randomly selected active and nonactive lesions and normal appearing white matter (NAWM) for all patients with MS. SI on DWI and ADC values were normalized to the SI of the CSF. We compared all of the measurements between active and nonactive lesions, active lesions and NAWM, and nonactive lesions and NAWM. SI on DWI and mean ADC values of normal healthy white matter (NHWM) of control group were measured. A comparison was made between NHWM and NAWM. Results: For patients with active lesions, the mean nADC value was 0.35±0.06 for active lesions and 0.30±0.07 for nonactive lesions (p>0.050). The mean nDWI-SI value was 3.69±0.68 for active lesions was 3.39±0.68 for nonactive lesions (p<0.050). When patients with and without active lesions were compared, both nDWI values and nADC values for active and nonactive lesions were statistically insignificant (p>0.050). Discussion: In MS lesions, diffusion alternations can be quantitatively evaluated with ADC mapping. Lesions seen in patients with MS have higher mean ADC values than NAWM and NHWM.


Introduction
Multiple sclerosis (MS) is a common autoimmune neurologic disorder. Demyelination due to myelin breakdown, axonal injury, perivascular inflammation, and gliosis are seen in MS lesions [1]. Although various imaging modalities can help to diagnose MS, magnetic resonance imaging (MRI) is the most sensitive one. MRI has an important role in guiding treatment and disease prognosis by enabling early diagnosis [1,2] For the first imaging and follow-up of patients with MS, conventional sequences include T1 weighted images (WI), T2WI, FLAIR images, and contrast-enhanced T1WI [2]. Changes on diffusion WI (DWI) and apparent diffusion coefficient (ADC) maps can be seen because of the inflammatory processes causing cytotoxic and then vasogenic edema [3]. Since various pathologies can cause hyperintensities on T2WI and FLAIR images, using conventional MRI alone has low specificity. Furthermore, it is inadequate to reveal the injury of normal appearing white matter (NAWM) [4].
Recently, studies have shown gadolinium deposition in the brain after contrast-enhanced MRI. The patients with MS are at a risk of gadolinium deposition because of multiple control imaging. It is known that repeat doses of gadolinium are correlated with an increase in intensity on T1WI in the dentate nucleus of the cerebellum in patients with MS [5]. This finding is associated with secondary-progressive MS and clinical disability [6]. Therefore, it is important to determine biomarkers that can differentiate active and chronic lesions without using contrast agent [7]. DWI shows the movement of water molecules in tissues, and the ADC maps show the quantitative measurement of myelin breakdown [8]. The mean ADC values of MS lesions may show alterations depending on the type of edema during active and chronic periods [3]. The MS lesions may have higher mean ADC values than NAWM [3,8]. Even though conventional MRI cannot depict any intensity changes in NAWM, microscopic injuries may be present. The measurement of ADC values may allow the detection of NAWM injuries [8].
This study aimed to assess mean ADC values and signal intensity (SI) on DWI of active and nonactive lesions and NAWM and to compare their measurements with each other and with normal healthy white matter (NHWM) of patients with normal brain MRI findings and no clinical suspicion of MS.

Patients
The institutional review board approved this retrospective, single-center study protocol and waived informed consent.
We retrospectively evaluated 35 patients examined with brain MRI between November 2011 and November 2016. Patients who did not get contrast administration and patients without b=1000 DWI sequences were excluded from the study. Twenty-five patients were included in the study. Twenty-two patients had relapsing-remitting MS, two patients had seconder progressive MS, and one patient had primer progressive MS. For comparison, a control group consisted of 25 patients without any history of radiotherapy, chemotherapy, and hypertension; without significant abnormalities on brain MRI; and the same age and gender as the patient group.

MRI Protocol and Evaluation of Images
All images were obtained with 3 Tesla MR scanner (Siemens Magnetom Verio, Erlangen, Germany). All the patients included in the study had FLAIR images (axial plane, TSE, TR>6000, TE:100-140, TI: 2000-2500, FOV: 240, slice thickness/gap:4/0), DWI (b=1000, SS-EPI, axial plane, TSE, TR>5000, TE:min, FOV: 240, slice thickness/ gap:4/0), ADC maps, and contrast-enhanced 3d-T1WI (MPRAGE, 3D, TR>2100, TE:min, TI: 1100, FOV: 256, slice thickness/gap:4/0). For contrastenhanced imaging gadobutrol (Gadovist, Bayer Schering Pharma, Berlin, Germany) or gadoterate meglumine (dotarem; Guerbet, Aulnay-sous-Bois, France) were administered at a single dose of 0.1 mmol/kg by intravenous bolus injection at a rate of 2 mL/s. The presence of contrast-enhancing lesions and diffusion restriction was noted. Contrast-enhancing lesions were considered as active lesions. For patients with active MS lesions, mean ADC values and signal intensities (SI) on DWI of the randomly selected active and nonactive lesions were measured. In patients with MS with acute disease, 31 active lesions and 31 nonactive lesions were assessed; in patients with chronic disease, 38 nonactive lesions were assessed. These parameters were also measured from the frontal NAWM for all patients with MS. Measurements were made using region of interests (ROI). ROIs were located centrally in the lesions. SI on DWI and ADC values were normalized (n) to the signal intensities of the cerebrospinal fluid (CSF) (SI lesion /SI CSF ) for correction between examinations. SI of the CSF was measured from the body of the lateral ventricle. All of the measurements were compared between active and nonactive lesions, active lesions and NAWM, and nonactive lesions and NAWM and NAWMs of patients with active and nonac-

Discussion
In MS, alterations of water diffusion are seen because of tissue damage. Thus, DWI can be used to evaluate the quantitative assessment of tissue damage in patients with MS. The DWI and ADC maps may show changes before blood-brain barrier leakage occurs and MS lesions become evident [9]. For the evaluation of the severity and the disease extension to NAWM of MS, DWI and ADC maps are used together with routine MRI [4,8].
Larsson et al. [10] evaluated 25 patients with MS, and they reported that water diffusion is higher in MS lesions than NAWM. They also found that water diffusion is high in acute lesions compared with chronic lesions. They suggested that an increase in water diffusion might be related to an increase in extracellular space and the degree of demyelination. It was stated that measurement of water diffusion could contribute to the assessment of demyelination pathogenesis.
Some articles and case reports suggest that acute MS lesions show restriction on the ADC maps [11][12][13][14]. A restricted ADC is seen in the early stages of acute lesions, and subsequently, ADC values normalize or increase. It is assumed that restriction emerges before the contrast enhancement of lesions becomes visible and normalizes long before enhancement disappears [15]. Diffusion restriction is seen before the tissue injuries become prominent on conventional MRI. Restriction is significant in the first seven days in patients with acute MS attack. The ADC values subsequently normalize and then increase in about the fourth week. In the first seven days, contrast enhancement is subtle or absent, and in up to four weeks, enhancement becomes prominent [16]. An increase in ADC values of MS lesions is considered a result of vasogenic edema, axonal injury, and demyelination [17][18][19]. Balashov et al. [12 ] found nine acute lesions with restricted dif-  Several studies showed that ADC values of NAWM are higher than NHWM [8,9 ]. Microscopic injuries are also seen in NAWM, not merely in visible lesions [4]. Werring et al. [9] suggested that there is an increase in ADC values of prelesion NAWM (approximately six months before contrast-enhancing lesions are seen), and at the same time, ADC values of contralateral NAWM are stable. The ADC values of contralateral NAWM are initially stable and eventually increase. An increase in ADC values indicates microscopic injuries in NAWM, and MS lesions may develop from these areas in time. This shows that MS is a white matter disease with multiple involvement areas [20]. Pathological changes in NAWM include astrocyte hyperplasia, microglia activation, perivascular inflammation, and myelin breakdown [9,21]. These changes cause tissue damage and enlargement of extracellular space and lead to an increase in ADC values [9]. In a study of Caramia et al. [22] in which they evaluated clinically isolated patients with MS, they found no significant changes in ADC values on initial MRI, but after one year, follow-up imaging showed that ADC values of NAWM had increased. These data indicate that in the early stages of MS disease, microscopic injuries are not significant, but subsequently, diffusion abnormalities can occur. In our study, no statistically significant difference was found between the ADC values of NAWM and NHWM.
Almolla et al. [8] evaluated patients with MS with chronic lesions and found a significant increase in ADC values of chronic lesions compared with NAWM and NHWM. In a study in which patients with MS with acute attack were assessed, Yurtsever et al. [3] reported that ADC values of acute lesions have higher ADC values than NAWM and NHWM. Terzi et al. [20] found no significant difference between ADC values of active and chronic lesions, but they indicated that active lesions have higher ADC values than NAWM.
There are several limitations of this study. First is the small sample size. Second, when evaluating the NAWM and NHWM, ADC measurements were made from a single frontal white matter region where there were no hyperintensities seen on T2WI and FLAIR images. Taking measurements from one region instead of averaging measurements from different regions might have affected our results. Not all of the MS lesions were sampled, but they were randomly selected.
Our results also showed no statistically significant difference between active and chronic lesions, and both lesion groups had statistically significant higher ADC values than NAWM and NHWM. These findings were consistent with other studies mentioned before.
In conclusion, in MS lesions, diffusion alternations may be seen because of tissue damage caused by demyelination. These alternations in diffusion between NAWM and active/nonactive MS lesions can be quantitatively evaluated with DWI.
Ethics Committee Approval: Ethics committee approval was received for this study from the Ethics Committee of Ankara University School of Medicine.
Informed Consent: Informed consent is not necessary due to the retrospective nature of this study.
Peer-review: Externally peer-reviewed. Financial Disclosure: The authors declared that this study has received no financial support.