Material and Method: The MRE images and files of 28 patients diagnosed with or suspected of having Crohn's disease were reviewed. Colonoscopy was performed in all subjects. This study included 17 patients with both colonoscopic findings and histological evidence of active CD. All patients underwent dynamic contrast-enhanced MRE. The following semiquantitative parameters were derived from the time-intensity curve: the maximum contrast enhancement, maximum relative enhancement, wash-in rate, time to peak, dynamic and static enhancement ratios, slope of enhancement, and area under the curve (AUC).

Results: In total, 43 bowel segments (26 involved, 17 normal) in the 17 patients with active disease were analyzed. Of the semiquantitative parameters, only the AUC differed significantly (p<0.05) between involved and normal bowel segments.

Conclusion: No one semiquantitative parameter alone can identify active inflammation more reliably than colonoscopy and pathological confirmation.

The evaluation of disease activity and severity is a difficult process that requires a combination of histological, endoscopic and conventional radiological techniques². This is especially important when directing treatment strategies and monitoring disease activity. To evaluate the treatment efficacy, frequent monitoring is needed. Consequently, the monitoring technique must be noninvasive and patient-friendly. Magnetic resonance imaging (MRI) has the potential to meet the needs of CD patients safely and noninvasively.

Magnetic resonance enterography (MRE) not only enables an evaluation of the segments proximal to strictures that cannot be reached by colonoscopy but also helps to assess extraluminal complications and disease extension and activity^3,4. Many investigators have examined the role of the contrast pattern and diffusion restriction parameters in differentiating active and chronic disease both qualitatively and quantitatively. The increase in local vascularity is directly proportional to the severity of disease. This increases not only the contrast enhancement, but also the enhancement ratio (ER) and the slope of enhancement assessed in dynamic studies. We assessed the benefits of adding dynamic studies to conventional MRI in CD patients.

Patients younger than 18 years of age, with incomplete work-ups, or whose diagnosis changed after the MRE studies were excluded. The patients with no colonoscopic recordings or histopathological investigations were excluded. Two patients were later diagnosed with gastrointestinal tuberculosis and lymphoma, and were excluded. Nine patients who had no signs of active disease on colonoscopic examination and histopathology were also excluded. Ultimately, 17 patients with both colonoscopic and histological signs of active CD were studied.

The C-reactive protein (CRP) level and sedimentation rates were noted. Colonoscopic findings indicative of active disease were mucosal erosion, ulceration, granularity, and fragility. The histopathological findings of disease activity were crypt abscesses, mucosal ulceration, neutrophilic infiltration, and edema.

MR Imaging protocol
The MRE was carried out after a minimum of 4 h of fasting. All patients followed the same protocol. In the hour before imaging, the subjects were instructed to drink 150 mL of mannitol mixed with 1.5 L of water. Before drinking the mixture, the patients were given 10 mg of metoclopramide orally. A glass of the contrast medium was given every 5 min, until just before the patient lay down for imaging. MRI was performed in the prone position at 1.5 T (Philips Achieva) using a phased-array body coil with a dynamic contrast-enhanced MRE protocol.

Coronal turbo spin echo (TSE) T2-weighted (repetition time/echo time (TR/TE) 401/80, turbo factor 75, echo planar imaging (EPI) factor 1, slice thickness 4.5 mm, slice gap 1.0 mm, field of view (FOV) 392 mm, matrix 246×400), coronal balanced turbo field echo (BTFE) (TR/TE 3.6/1.8, flip angle 60°, turbo factor 1, EPI factor 1, slice thickness 4.5 mm, slice gap 1.0 mm, FOV 377 mm, matrix 257×288), coronal TSE long TE T2- weighted (TR/TE 531/217, turbo factor 113, EPI factor 1, slice thickness 4.5 mm, slice gap 1.0 mm, FOV 397 mm, matrix 49/560), coronal fat suppressed TSE T2-weighted spectral adiabatic inversion recovery (SPAIR) (TR/TE 445/80, turbo factor 70, EPI factor 1, slice thickness 5.0 mm, slice gap 1.0 mm, FOV 431 mm, matrix 238×640), axial BTFE (TR/TE 3.1/1.5, turbo factor 1, slice thickness 7.0 mm, slice gap 1.0 mm, FOV 314 mm, matrix 215×224), axial TSE long TE T2-weighted (TR/TE 489/200, slice thickness 7.0 mm, slice gap 1.0 mm, FOV 312 mm, matrix 196×432), axial fat suppressed TSE T2-weighted SPAIR (TR/TE 379/8, slice thickness 7.0 mm, slice gap 1.0 mm, FOV 316 mm, matrix 175×432) were performed. Before intravenous contrast administration to reduce bowel peristalsis a 10 mg hyoscine butilbromide was given intravenously. Coronal and axial fat suppressed gradient echo T1-weighted dynamic contrast enhanced high-resolution isotropic volume examination (THRIVE) (coronal dynamic TR/TE 4.4/2.1, turbo factor 44, EPI factor 1, slice thickness 4.0 mm, slice gap 1.0 mm, FOV 375 mm, matrix, 190×192, axial dynamic matrix 160×176, slice thickness 4.0 mm, slice gap 2.0 mm, FOV 320 mm) protocols were performed.

The dynamic studies were performed in four phases: non-contrast T1-weighted, arterial, portal, and venous phases. The studies took approximately 20 min. After contrast administration, all patients were observed for 45 min. Using dynamic images, the time-intensity curves (TIC) were plotted automatically with the workstation software and semiquantitative measurements were calculated.

MR imaging analysis
Conventional MRI
Mural hyperenhancement (segmentally increased signal intensity compared with normal bowel segments), mural thickening (>3 mm), increased T2 signal of the bowel wall, mural striation (two or three layered appearance of the bowel wall), fatty proliferation, enlarged lymph nodes (short axis >5 mm), penetrating disease (sinus tract, abscess, phlegmon, or fistula), and the comb sign (prominent vasa recta) were evaluated in all patients. Two segments that could be used in the quantitative analysis were chosen: an involved ileal segment with maximal contrast enhancement as the study group and an ileal segment that appeared normal as a control group.

Dynamic contrast-enhanced MRI
Dynamic contrast-enhanced MR (DCE-MR) analysis included an evaluation of the contrast enhancement of normal and involved ileal segments. A single region of interest (ROI) drawn freehand, measuring approximately 3-45 mm², was placed on the thickest, most strongly enhancing bowel wall. Signal intensities and dynamic scans were calculated and displayed in a graph. The graphs showed typical a contrast-enhancement pattern with the baseline intensity (SI_base) increasing following the bolus injection, and then stabilizing and decreasing slightly (SI_end). The times when the contrast injection started (t_inject = t₀), when the contrast enhancement started (tstart), and of maximum contrast enhancement (tend) were recorded, with ∆t = t_end – t_start.

In the dynamic series, the dynamic contrast ratio (ER_dynamic) and slope of enhancement (SoE) were measured using published formulae⁵.

ER_dynamic= SI_end/ SI_base
SoE= (SI_end- SI_base ) / SI_base × ∆t

In the static series, the static contrast ratio (ER_static) was measured using mesenteric fat as a reference.

ER_static= (SI_postbowel/ SI_{postfat) / (SI prebowel / SIprefat)}

where SI_postbowel and SI_postfat refer to the signal intensities of the bowel wall and mesenteric fat after contrast enhancement, respectively, and SI _prebowel and SI_prefat are the values before contrast enhancement. Using these formulas, ER_dynamic, SoE, and ER_static were determined. Other semiquantitative parameters studied were the maximum enhancement, maximum relative enhancement, wash-in rate, time to peak (t_peak), and area under the curve (AUC).

Statistical analysis
All data were analyzed using the Statistical Package for the Social Sciences (SPSS ver. 17.0). The parameters for 26 involved ileal segments and 17 normal ileal segments in the 17 patients diagnosed with active Crohn’s disease colonoscopically and histopathologically were compared using the Mann–Whitney U-test. Values of p<0.05 were considered to indicate statistical significance.

Conventional MRI findings
All of the patients had findings of active inflammation in the terminal ileum (Figure 1). Wall thickening (>3 mm) and increased contrast enhancement were found in all 17 patients. Fibro-fatty proliferation was evident in 9 patients, mesenteric lymph nodes in 12, fistulas in 3 (Figure 2), and an abscess in 1 patient. Nine patients had similar findings of active inflammation in both the terminal ileum and distal ileal segment.

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Figure 1: Contrast enhanced dynamic MR enterography imaging of 30 years old male patient (a) contrast enhancement of terminal ileum in coronal image (b) coronal long TE T2 weighted image: thickened terminal ileum and milimetric lymph nodes in mesentery. (c) time-intensity curve after placing ROI on terminal ileum (L1) and neighbouing inflammatory mesenteric fat (L2).

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Figure 2: Contrast enhanced dynamic MR enterography imaging of 42 years old male patient (a) contrast enhancement of terminal ileum in coronal images (b) coronal long TET2 weighted image: thickened terminal ileum and ileoileal anastomoses.

Semiquantitative analysis findings
The semiquantitative parameters of normal and involved bowel segments from the time–intensity curve are summarized in Table 1.

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Table 1: Semiquantitative parameters of contrast enhancement

There was no significant (p=0.228) difference in the maximum contrast enhancement between the involved and normal segments. The mean±SD maximum contrast enhancement was 1027.5±453.586 in the 26 involved segments and 837.24±340.091 in 17 the control segments.

The mean maximum relative enhancement of the 26 involved segments and 17 normal segments was 156.46±82.327 and 226.06±145.458, respectively (p=0.054).

For the involved and normal segments, the mean t_peak was 19.12±38.589 and 120.82±44.911 (p=0.486), respectively, the mean wash-in rate was 14.538±7.865 and 12.235±7.2761 (p=0.392), the mean ER_dynamic was 1.19±0.402 and 1.47±1.007 (p=0.398), the mean SoE was 1.04±1.341 and 1.88±2.233 (p=0.223), and the mean ER_static was 0.92±0.688 and 1.47±1.505 (p=0.203).

For the involved and normal segments, the mean tpeak was 19.12±38.589 and 120.82±44.911 (p=0.486), respectively, the mean wash-in rate was 14.538±7.865 and 12.235±7.2761 (p=0.392), the mean ERdynamic was 1.19±0.402 and 1.47±1.007 (p=0.398), the mean SoE was 1.04±1.341 and 1.88±2.233 (p=0.223), and the mean ERstatic was 0.92±0.688 and 1.47±1.505 (p=0.203).

Angiogenesis is an important factor in contrast enhancement of the intestinal wall. The microvascularization of the intestinal wall initiates inflammation-dependent angiogenesis in Crohn’s disease. Brahme et al.¹⁴ demonstrated increased vascularity and edema corresponding to the degree of inflammation using in vitro angiography of resected intestinal segments.

Previous studies of dynamic contrast-enhanced MRE in the assessment of Crohn’s disease activity evaluated quantitative measures using semiquantitative parameters^15,16.

In 18 patients with active Crohn’s disease, Oto et al. determined the transfer constant (Ktrans) and extravascular extracellular space volume per unit tissue volume (ve). Both measurements were significantly higher in inflamed terminal ileum than in normal ileal segments¹⁵. In another study, Oto et al. observed 32 normal and 19 involved intestinal segments with dynamic contrast-enhanced MRE and made both quantitative and semiquantitative measurements¹⁶. Ktrans and ve were significantly higher in the involved segments. The AUC, contrast intake (A), and slope of contrast enhancement (slopeinitial) were higher in the involved segments in the semiquantitative analysis. The ROC analysis of the significant values showed that these parameters could be used to differentiate normal and involved segments. However, the contrast intake ratio, wash-out rate, and tpeak were not useful.

Florie et al.⁵ studied the enhancement ratio (ER) and SoE in 52 patients to evaluate the disease activity with dynamic contrast-enhanced MRE. They also compared ERdynamic and ERstatic, and assessed the intestinal wall thickness, tstart, and ∆t. As a reference, they used the Crohn’s disease activity index (CDAI)^17, clinical grade, and Van Hees Activity Index¹⁸.

We investigated whether it was possible to use objective, quantitative data to evaluate the disease activity, instead of subjective clinical findings and activity determination scales or invasive procedures such as colonoscopy. We searched for a parameter that can differentiate active from inactive ileal segments in dynamic contrast-enhanced MRE, in patients whose disease activity has been verified by colonoscopy. We calculated only semiquantitative measures in this study, and only the AUC was statistically significant, although the maximum relative enhancement approached statistical significance. In a larger study group, this parameter might also be significant.

To make correct measurements, it is important to visualize the intestinal wall clearly. Adequate filling of the intestinal lumen is essential. Some authors favor the use of oral contrast^19,20, although Shoenut et al.²¹ achieved acceptable results without any oral contrast. We used an oral contrast agent dissolved in 1.5 L of water and managed to fill the intestines sufficiently.

Colonoscopy and pathological evaluation were used to verify active disease in this study. The signal intensity measurements were higher in the involved segments, as in other studies. However, there were significant differences in the values among the pathological segments. Patients with greater inflammation had higher contrast intensity. Patients with intra-abdominal abscesses and fistulas had very high intensities. Measurements were very low in patients with mild contrast enhancement in the terminal ileum and with lower CRP levels. These differences likely hindered the achievement of statistical significance. With a homogenous study group involving patients of similar disease activity, we might have obtained more comparable results.

Unlike other studies of this subject, the ER_dynamic, ER_static, and contrast enhancement curve were lower in the involved segments in eight patients. Although the signal intensity has been found to be higher in involved segments, the calculations prove otherwise, so the formulas seem unreliable.

The small number of subjects and heterogeneity of the patients’ disease activities were the major limitations of this study. In addition to this heterogeneity, the patients who had been diagnosed with Crohn’s disease before the study have already been receiving medical treatment. The inevitable pulsation and peristalsis artifacts were present, although the MRE protocol we use includes a breath-holding maneuver and anti-peristaltic medication.

The reproducibility of the study was not considered in the study design. ROI were placed manually on the intestinal walls by the same radiologist. The thinness of the normal distended intestinal wall complicated the assessment of the partial volume artifact. We did not prove the normality of the segments histopathologically; we only considered them to be normal. This is another study weakness.

Our study showed that conventional MRE findings are more valuable than semiquantitative measurements. Dynamic studies are not superior to the single-phase technique for contrast enhancement patterns at showing active inflammation, disease extent, or the degree of inflammation. Moreover, no single semiquantitative parameter distinguishes active inflammation more reliably than colonoscopy and pathological confirmation.

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