Quantitative MRI assessment of joint effusion using T2-relaxometry at 3 Tesla: a feasibility and reproducibility study.

OBJECTIVE: T2-relaxometry could differentiate between physiological and haemorrhagic joint effusion (≥ 5% blood) in vitro. Are quantitative T2-relaxation time measurements of synovial fluid feasible and reproducible in vivo in clinically bleed-free joints of men with haemophilia? MATERIALS AND METHODS: In this cross-sectional study, we measured T2-relaxation times of synovial fluid in clinically bleed-free ankles, knees or elbows of men with severe haemophilia A using a T2-mapping sequence (duration ≤ 7 min) at 3 Tesla MRI. Manual and circular regions of interest (ROI) were drawn in the synovial fluid of each joint by two independent observers to measure T2-relaxation times. Measurement feasibility was expressed as the success rate of the measurements by both observers. The interobserver and intraobserver reproducibility of the measurements were evaluated by the intraclass correlation coefficient of absolute agreement (ICC) and the limits of agreement (LoA) from Bland Altman analysis. RESULTS: We evaluated 39 clinically bleed-free joints (11 ankles, 12 knees, 16 elbows) of 39 men (median age, 24 years; range 17-33) with severe haemophilia A. The success rate of the T2-measurements was ≥ 90%. Interobserver reliability was good to excellent (manual ROI: ICC = 0.92, 95% CI 0.76-0.97; circular ROI: ICC = 0.82, 95% CI 0.66-0.91) and interobserver agreement was adequate (manual ROI: LoA = 71 ms; circular ROI: LoA = 146 ms). Intraobserver reliability was good to excellent (manual ROI: ICC = 0.78, 95% CI - 0.06-0.94; circular RO: ICC = 0.99, 95% CI 0.98-0.99) and intraobserver agreement was good (manual ROI: LoA = 63 ms; circular ROI: LoA = 41 ms). CONCLUSION: T2-relaxometry of synovial fluid in haemophilia patients is feasible with good interobserver and intraobserver reproducibility.

Subclinical synovial proliferation in patients with severe haemophilia A: The value of ultrasound screening and biochemical markers.

AIM: Subclinical bleeding and inflammation play a role in progression of haemophilic arthropathy. Synovial proliferation is predictive of joint bleeding and its early detection may guide treatment changes and prevent arthropathy progression. This study evaluated the prevalence of active and inactive subclinical synovial proliferation and investigated potential biochemical blood/urine markers to identify patients with active subclinical synovial proliferation. METHODS: This cross-sectional study included patients with severe haemophilia A born 1970-2006 who were evaluated during routine clinic visits. Patients with (a history of) inhibitors or recent joint bleeding were excluded. Elbows, knees and ankles were examined for subclinical synovial proliferation by ultrasound and physical examination. Active synovial proliferation was distinguished from inactive synovial proliferation using predefined criteria. Blood/urine biochemical markers (serum osteopontin, sVCAM-1, Coll2-1, COMP, CS846, TIMP, and urinary CTX-II) were compared individually and as combined indexes between patients with and without active synovial proliferation. RESULTS: This cohort consisted of 79 patients with a median age of 31 years (range 16.5-50.8 years) with 62/79 (78%) of the patients using continuous prophylaxis. The annualized joint bleeding rate over the last 5 years was .6 (.2-1.1). Active (17/79, 22%) and inactive subclinical synovial proliferation (17/79, 22%) were both prevalent in this cohort. Biochemical markers were not correlated with active subclinical synovial proliferation. CONCLUSION: Subclinical synovial proliferation, both active and inactive, was prevalent in patients with severe haemophilia A with access to prophylaxis and would be overlooked without routinely performed ultrasounds. Biochemical markers were unable to identify patients with active subclinical synovial proliferation.

Pre-operative synovial hyperaemia in haemophilia patients undergoing total knee replacement and the effects of genicular artery embolization: A retrospective cohort study.

AIM: Haemophilia is characterized by recurrent joint bleeding caused by a lack of clotting factor VIII or IX. Due to repeated joint bleeding, end-stage arthropathy occurs in relatively young patients. A total knee replacement (TKR) can be a solution. However, TKR may be complicated by perioperative and postoperative bleeds despite clotting factor therapy. The aim of this study was to evaluate the prevalence of pre-operative synovial hyperaemia and the effects of Genicular Artery Embolization on synovial hyperaemia and 3-month postoperative joint bleeding. METHODS: In this retrospective cohort study, all patients with haemophilia who underwent periarticular catheter angiography between 2009 and 2020 were evaluated after written informed consent. Synovial hyperaemia on angiography was scored by an interventional radiologist. RESULTS: Thirty-three angiography procedures in 24 patients were evaluated. Median age was 54.4 years (IQR 48.4-65.9). Preoperative synovial hyperaemia was observed in 21/33 joints (64%). Moderate and severe synovial hyperaemia was observed in 10/33 joints (30%). Synovial hyperaemia decreased in 13/15 (87%) joints after embolization. Three-month postoperative joint bleeding occurred in 5/32 joints: in 2/18 joints (11%) without synovial hyperaemia and in 3/14 joints (21%) with mild synovial hypertrophy. Non-embolized and embolized joints did not differ regarding 3-month postoperative bleeding (P = .425). No complications were observed after embolization. CONCLUSION: One-third of patients with haemophilia requiring a TKR had moderate or severe synovial hyperaemia which can be reduced safely by Genicular Artery Embolization prior to TKR. Three-month postoperative bleeding appears to occur independently of the presence of residual mild synovial hyperaemia.

Monitoring recovery of joints after bleeding: Physical examination and ultrasound are complementary.

AIM: Traditionally, recovery after a joint bleed in people with bleeding disorders is evaluated by clinical symptoms. Following a bleed, however, asymptomatic joints may still show synovial hypertrophy and effusion on ultrasound. We evaluated the duration of full recovery from a joint bleed. Additionally, we determined how recovery differed when assessed by physical examination and ultrasound. METHODS: In this retrospective cohort study, we investigated joint bleeds in elbows, knees and ankles of people with haemophilia or Von Willebrand disease who attended the Van Creveldkliniek between 2016 and 2021. Physical examination (warmth, swelling, range of motion and gait) and ultrasound (effusion and synovial hypertrophy) were performed within 7 days after the onset of the bleed, 1 week after the first examination and monthly thereafter until patients had recovered fully. Joint bleeds were treated in line with the current international treatment guidelines. RESULTS: We evaluated 30 joint bleeds in 26 patients. The median recovery time was 1 month (range 0.3-5 months). In 47% of the joint bleeds, the recovery took longer than 1 month. The moment of recovery based on physical examination and ultrasound differed in 27% of bleeds. Both persistent abnormalities at physical examination in joints with normalized ultrasounds and persistent ultrasound findings in clinically recovered joints occurred. CONCLUSION: Joint bleed recovery can take long and recovery times differed per bleed. Recovery differed when assessed by physical examination or ultrasound. Therefore, both should be used to closely monitor recovery of joint bleeds and offer personalized care.

Magnetic resonance imaging evidence for subclinical joint bleeding in a Dutch population of people with severe hemophilia on prophylaxis.

BACKGROUND: Previous studies suggest that subclinical bleeding occurs in persons with hemophilia. OBJECTIVES: The aim of this study was to investigate whether patients with lifelong access to prophylaxis showed signs of previous subclinical bleeding on magnetic resonance imaging (MRI) in joints without a history of joint bleeding. METHODS: This single-center cross-sectional study included persons with severe hemophilia A on prophylaxis, aged 16 to 33 years, with lifetime bleeding records available. Per participant, 1 index joint without a history of joint bleeding was evaluated with 3-Tesla MRI, including hemosiderin sensitive sequences. MRI scans were reviewed according to the International Prophylaxis Study Group (IPSG) additive MRI scale (range, 0-17/joint). Hemosiderin deposits with/without synovial hypertrophy were considered signs of previous subclinical bleeding. Additionally, physical examination was performed, followed by ultrasound examination according to the Hemophilia Early Arthropathy Detection with Ultrasound protocol. RESULTS: In 43 patients with a median age of 23.5 years, 43 joints (16 elbows, 13 knees, 14 ankles) without reported bleeds were evaluated with MRI. The median IPSG MRI score was 1 (range, 0-9). Signs of previous subclinical bleeding were observed in 7 of 43 joints (16%; 95% CI, 7-30): 7 of 7 joints showed hemosiderin deposits, with concomitant synovial hypertrophy in 2 of 7 joints. MRI changes were accompanied by swelling and ultrasound-detected synovial hypertrophy in 1 ankle only. None of the other joints showed abnormalities at physical examination and ultrasound. CONCLUSION: In this study, 16% of the joints without reported bleeds showed signs of previous subclinical bleeding, providing evidence for subclinical bleeding in people with severe hemophilia with lifelong access to prophylaxis.

Screening for subclinical synovial proliferation in haemophilia: A systematic review and meta-analysis comparing physical examination and ultrasound.

INTRODUCTION: Ultrasound is increasingly used as addition to physical examination for detection of subclinical joint changes in haemophilia. However, the added value of ultrasound to physical examination for detecting synovial proliferation is not fully established. AIM: To determine the diagnostic accuracy of swelling at physical examination for ultrasound-detected synovial proliferation in haemophilia. METHODS: PubMed and EMBASE were searched up to 2 August 2022. Studies reporting original data on occurrence of swelling at physical examination and synovial proliferation on ultrasound of index joints in persons with haemophilia were included. Risk of bias and applicability were assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Diagnostic accuracy parameters of swelling at physical examination for ultrasound-detected synovial proliferation were determined. Summary sensitivity and specificity were calculated using a bivariate random-effects model. RESULTS: Fifteen studies reporting on swelling at physical examination and synovial proliferation on ultrasound in 2890 joints of 627 patients were included. Prevalence of subclinical synovial proliferation ranged between 0% and 55%. Sensitivity of swelling was low [summary estimate .34; 95% confidence interval (CI) .24-.46], while specificity was high (summary estimate .97; CI .92-.99). Predictive values varied widely due to inter-study differences in prevalence of synovial proliferation. CONCLUSION: Joint swelling has low sensitivity for presence of ultrasound-detected synovial proliferation in haemophilia, suggesting underestimation of synovial proliferation by physical examination alone. Consequently, ultrasound screening may generate important information on synovial changes which would otherwise remain undetected.

Detecting low blood concentrations in joints using T1 and T2 mapping at 1.5, 3, and 7 T: an in vitro study.

BACKGROUND: Intra-articular blood causes irreversible joint damage, whilst clinical differentiation between haemorrhagic joint effusion and other effusions can be challenging. An accurate non-invasive method for the detection of joint bleeds is lacking. The aims of this phantom study were to investigate whether magnetic resonance imaging (MRI) T1 and T2 mapping allows for differentiation between simple and haemorrhagic joint effusion and to determine the lowest blood concentration that can be detected. METHODS: Solutions of synovial fluid with blood concentrations ranging from 0 to 100% were scanned at 1.5, 3, and 7 T. T1 maps were generated with an inversion recovery technique and T2 maps from multi spin-echo sequences. In both cases, the scan acquisition times were below 5 min. Regions of interest were manually drawn by two observers in the obtained T1 and T2 maps for each sample. The lowest detectable blood concentration was determined for all field strengths. RESULTS: At all field strengths, T1 and T2 relaxation times decreased with higher blood concentrations. The lowest detectable blood concentrations using T1 mapping were 10% at 1.5 T, 25% at 3 T, and 50% at 7 T. For T2 mapping, the detection limits were 50%, 5%, and 25%, respectively. CONCLUSIONS: T1 and T2 mapping can detect different blood concentrations in synovial fluid in vitro at clinical field strengths. Especially, T2 measurements at 3 T showed to be highly sensitive. Short acquisition times would make these methods suitable for clinical use and therefore might be promising tools for accurate discrimination between simple and haemorrhagic joint effusion in vivo.

The Potential of Fasting and Caloric Restriction to Mitigate Radiation Damage-A Systematic Review.

Detrimental health effects from ionizing radiation to living organisms is one of the key concerns identified and addressed by Radiation Protection institutions, nationally and internationally on Earth and for human spaceflight. Thus, new methods for mitigating the adverse effects of ionizing radiation are urgently needed for terrestrial health and deep space exploration. Caloric restriction and (intermittent-) fasting have been reported to elicit a variety of immediate and long-term physiological effects. The rapidly growing body of evidence of research studies investigating the effects of caloric restriction and dietary fasting points toward a multitude of benefits affecting numerous physiological systems. Therefore, a systematic review was performed to evaluate the evidence of caloric restriction and dietary fasting on the physiological response to ionizing radiation in humans and animals. All experimental studies of humans, animals, and eukaryotic cell lines available in PubMed, Cochrane library, and specialized databases were searched comparing irradiation post-caloric restriction or fasting to a non-nutritionally restricted control group on a broad range of outcomes from molecular to clinical responses. The initial search yielded 2,653 records. The final analysis included 11 studies. Most studies investigated survival rate or cancer occurrence in animals. Included studies did not reveal any benefit from pre exposure caloric restriction, except when performed with post radiation caloric restriction. However, the effects of pre-exposure fasting suggest increased resilience to ionizing radiation.