Using synovial volume measurement by MRI to evaluate the effect of 32 P Radiation synovectomy on hemophilic arthropathy patients

2.1. General information

HA patients treated and hospitalized at the Hemophilia diagnosis and treatment Center of Henan Provincial People’s Hospital from May 2011 to January 2015 were selected in this study. Inclusion criteria were: (1) Hemophilia patients who were diagnosed with FVIIIC activity below 50% complicated with FVIII or IX coagulation factor deficiency by clinical and laboratory examinations; (2) patients with one or more HA have been clinically observed or X-ray identified, and they had more than one bleeding event in the past 6 months. There were 38 patients/cases of type A and 4 patients/cases of type B hemophilia, and a total of 63 joints were studied, including 10 hips (all are bilateral), 22 ankle (12 left ankles, 10 right ankles), 25 knee (17 left knees and 8 right knees) and 6 elbow (3 on each side) joints. All patients were male of 5 to 36 years old, and the mean age is (19.3±1.6). 16 patients (21 joints) received PRS in the center of hemophilia. PRS inclusion criteria were: (1) joint bleeding ≥3 times per year. (2) Joint continued bleeding and swelling ≥3 months. (3) Joint discontinuous swelling pain ≥6 months. Exclusion criteria of PRS included: (1) Bone and joint fusion. (2) Acute joint bleeding. (3) Infection of the skin near the joints. The study was approved by the Hospital Ethics Committee (2016) ethics Censor No. (32). All patients or their agents signed informed consent and MR enhanced examination protocol. Patients were followed up for 3 months to 2 years, each case was visited 1 to 2 times, and the frequency of bleeding before and after treatment was recorded.

2.2. Equipment and examination methods

MR unenhanced and enhanced scans were performed on all of the 63 joints in 42 patients one week before the surgery using the DISCOVERY 750 3.0T MR (American GE Healthcare) instrument. Ankle, knee and elbow scans used head, special knee and body coils, respectively. Unenhanced sequences and parameters are: spin-echo sequence of T₁-weighted images (T₁WI) on sagittal plane and coronal plane, fast spin echo sequence on T₂-weighted images (T₂WI) on sagittal plane, sagittal proton density weighted imaging (PDWI) scanning (scan parameters are shown in Table 1). The enhanced scanning sequence is sagittal fat suppression T₁WI and coronal fat suppression PDWI, and the parameters were the same as those used in the unenhanced scan. The contrast media for enhanced scanning was Gadodiamide (Gadolinium content of 287  mg, GE Healthcare Ireland). Standard dose of 0.1  mmol/kg BMI (body mass index) was administrated using a high-pressure syring with a flow rate of 1.5∼2.5 ml/s. After the injection, the same amount of saline flushing was used. The enhanced scan was completed within 10 minutes after injecting contrast media. 16 cases of surgical patients were followed up for 1 or 2 times after treatment using the same methods as pre-treatment MR scans described above.

Before the treatment, the intravenous injection surrogate factor was used to adjust the serum coagulation factor concentration to normal levels. The joint effusion was extracted and injected with radionuclide ³²P and followed routinely injected with 3∼5 mg of dexamethasone in the joint cavity. The exposure energy has the depth of 2∼5 mm, and its peak radiation reached 2∼3 mm under the synovium. The dose of the joint injection depended on the joint size and patient’s age. For 12-year-old or older, the knee, ankle and elbow joints were subject to 37.00, 18.50 and 18.50 MBq; respectively. For patients under 12 years old, the knee, ankle and elbow joints were subject to 18.50, 9.25 and 9.25 MBq; respectively. Patients were instructed to avoid weight-bearing and surgical limb activities within 24 to 48 hours and best to immobilize for 1 week after surgery.

2.4. Joint synovial membrane volume measurement

MRI data were processed on post-processing workstation (GE Advantage Workstation 4.5). We used Functool software to obtain hand-drawn region of interest (ROI) in the lesion layer. Three continuous layers with the most obvious synovial hyperplasia lesion in sagittal images were selected as ROIs. For example, for knee joint, the most prominent hyperplasia synovium sites in suprapatellar bursa area, posterior femoral lateral condyle, intercondylar or tibial plateau region were used for analysis (Fig 1). Synovial hyperplasia showed low or medium signal nodular soft tissue shadows on T₁WI and T₂WI. In the T₂WI and PDWI sequences, there were slightly lower signal shadows in comparison with the joint effusion high signal. Enhanced sequence was characterized with moderate and high enhancement. The volume of synovial membrane was measured by two senior radiologists. The disputed areas of synovial hyperplasia were determined by unanimous consultation. The ROIs of corresponding layers were measured and then superimposed. Each lesion area was measured three times to produce the average value. For the same joint, the ROI was selected on the same anatomical site before and after operation. The unenhanced and enhanced synovial signal intensities were measured and recorded directly, and the enhancement ratio was calculated as (enhanced synovial signal intensity - unenhanced synovial signal intensity)/ unenhanced synovial signal intensity. Considering the obvious contrast between the T₂WI or PDWI sequence and the effusion signal, the images used for synovial volume measurement were mainly T₂WI or PDWI. All the monitoring process were guided by hematologist. Effectiveness of therapy is usually monitored by multi-variable parameters including joint pain score, annual bleeding frequency and joint range of motion.

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Fig.1

ROI diagram of joint synovial volume measurement. ROI was selected the most obvious enhancement sites for synovial hyperplasia in sagittal joints, such as suprapatellar bursa (green), intercondylar or around tibial plateau (purple).

We used SPSS 19.0 statistical analysis software to analyze the data. We conducted the normality and homogeneity test of variance on the measurements, and then used two sample matching t test to compare the unenhanced and enhanced synovial membrane volumes of the same joint, as well as change of MR enhancement ratio after treatments. A p value of 0.05 or lower indicated statistical significance.

3.1. Comparison of synovial membrane volumes before and after MRI unenhanced and enhanced scanning

The results of MR scans showed that 63 joints of 42 patients with HA were characterized by abnormal imaging findings such as joint effusion or exudation, subchondral cystic degeneration, joint erosion, and cartilage loss. Both unenhanced and enhanced scans showed varying degrees of synovial hyperplasia within the joint capsule (Fig. 2a, b). The difference of synovial volume measured by unenhanced (3104.38±60.19 mm³) versus enhanced (2995.19±59.14 mm³) MRI was not statistically significant (t = 0.191, p > 0.05).

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Fig.2

(M 22Y) The joint bleeds repeatedly for half a year. Unenhanced coronal T₁ (Fig. 2a) and enhanced T₁ fs (Fig. 2b) of HA patients showed nodular thickening of the lateral synovium. The synovial enhancement showed more clearly defined (arrow), and diffuse enhancement of the femur and tibia end can also be seen.

Among the 16 patients with PRS, 3 patients were followed up in 3 months after surgery, and the other 13 patients finished the first post-operative MRI more than 6 months. 21 joints of 16 patients suffered from obviously less hemorrhage in follow-up visits during the period of 3-month to 2-year after treatment. The frequency of hemorrhage before treatment was 4.98 times per half a year, and that after treatment was 0.85 times per half a year. After treatment, the synovial membrane volume of 19 joint was reduced to various degrees and the degree of enhancement was reduced after treatment (Fig. 3a–d). In two cases (2 joints), the volume of synovial membrane was slightly larger than before, but the degree of enhancement decreased (Fig. 4 a, b). The differences of both synovium volume and enhancement ratio before and after treatment were statistically significant. (p < 0.05, Table 2).

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Fig.3

(M 18Y) Comparison of before and after radiation synovectomy in 3 months in HA patients. Sagittal PDWI fat suppression before (Fig. 3a) and after treatment (Fig. 3b), and T₁WI fat suppression enhanced scan before (Fig. 3c) and after treatment (Fig. 4d) shows that after treatment, the volume of nodular synovium hyperplasia was reduced (arrow) and the degree of enhancement was also decreased.

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Fig.4

(M 15Y) The intermittent joint bleeding for 2 years. Comparison of before (Fig. a) and after (Fig. b) radiation synovectomy in HA patients. The volume of synovium increased (arrow) after radiation synovectomy, but the degree of enhancement decreased compared with that before treatment in HA patients.

4.1. Significance of unenhanced and enhanced scanning sequences in synovial hyperplasia measurement in HA Patients

The results showed that the volume of synovium measured without enhancement was slightly larger than that measured with enhanced scanning, but without statistical significance. This finding suggests that if physicians are only interested in observing the thickening and severity of synovium, unenhanced examinations are likely to be satisfactory, which can reduce the cost of MR examination and the risk of local hemorrhage caused by intravenous injection. In this study, unenhanced scans mainly used T₂WI or PDWI images for synovial volume measurements because the hyperplastic synovium appeared as nodular soft tissue with low or moderate signal. The signal of the synovial effusion was relatively high, and the contours of the synovium proliferate was easily delineated. However, the hypointensity of synovium was similar to that of joint effusion in some cases, so the volume of synovium in unenhanced sequence was slightly larger than that in enhanced sequence. After injection of the contrast agent, the synovial membrane of abnormal hyperplasia was strengthened but not the joint effusion. As a result, the synovial boundary and the edges were more clearly displayed. Our experimental results are consistent with those reported by Lundin et al. [9], which showed that the enhanced scanning had limited value for synovial volume measurements.

MRI enhancement of rheumatoid arthritis has been extensively reported by other researchers [10]. It has been found that 30 to 60 seconds after the injection of the contrast agent is the most optimal time point to evaluate the increased rate of the synovial membrane. Within 10 minutes post-injection, the contrast agent has not reached the synovial fluid, leading to high synovial membrane to synovial fluid imaging contrast and clear boundary between them. We therefore completed enhanced scanning within 10 minutes after injection of contrast agent. Li et al. [6] and Jelbert et al. [11] reported that enhanced scanning could differentiate HA synovial fibrosis from acute synovitis, and fibrotic thickened synovial membrane will show delayed enhancement. It is of great clinical significance to evaluate whether the arthritis of HA patients is in the active stage of inflammatory bleeding or the inactive stage of synovial fibrosis after hemorrhage. The results of PRS treatment group showed that all the HA joints showed different degrees of synovial hyperplasia within the capsule, suggesting the active period of inflammatory hemorrhage. The synovial enhancement ratio changed after the proliferative synovial PRS treatment, indicating that the synovial membrane fibrotic may occur in the inflammatory process, which was consistent with a reduced joint bleedings and effective treatment in the clinic.

Comparison of the synovial volumes before and after PRS treatment in patients with HA showed that the synovial membrane volume was significantly reduced after treatment, along with reduced signal intensity. The frequency of hemorrhage during the period of 3-month to 2-year after PRS treatment was also notably lessened. This shows that the reduced synovium volume and signal intensity are consistent with the decreased clinical bleeding frequency, indicating that MRI can be used as an important method to evaluate the patient response to PRS. In previous literature reports [12–15], the evaluation of post-operative therapeutic effect of PRS in HA patients was mainly based on clinical pain scores and MRI Denver scores.

In our study, the synovial volume increased and the signal intensity decreased in 2 patients after treatment, but the bleeding frequency did not decrease significantly. One case may be due to the fact that the synovial membrane edema during the period of inflammatory hyperplasia had not subsided due to shorter post-operative follow-up visit time, leading to larger synovial membrane volumes after treatment; whereas the other case may be caused by poor therapeutic effect. Previous studies (e.g., [16]) reported that bleeding frequencies did not change significantly in a small number of patients after surgery, who may need secondary synovectomy; however, few studies have been reported using imaging analyses, which will be the focus of our further studies. Specifically, we are interested in using MRI examination to identify patients who are more suitable for PRS surgery.

The limitations of this study include that the sample size was relatively small, most patients selected had high bleeding frequency of recent bleedings, and only routine sequences were performed without DWI or SWI sequence. Whether other MRI sequences can better display the changes of synovial membrane needs to be further explored in future studies.