Quantitative Chemical Shift Imaging Research Articles

Investigating the efficacy of acupuncture in treating patients with metabolic-associated fatty liver disease: a protocol for a randomised controlled clinical trial

IntroductionAcupuncture is widely used for metabolic-associated fatty liver disease (MAFLD) treatment; however, the clinical efficacy has not been confirmed due to the lack of high-level evidence-based clinical practice. The purpose...

The Bone Biomarker of Quantitative Chemical Shift Imaging in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long-Term Enzyme Replacement Therapy

Quantitative chemical shift imaging (QCSI) is the most sensitive imaging biomarker to assess bone marrow involvement in Gaucher disease. Widespread QCSI use is limited by test availability. Anecdotal reports describe two patients demonstrating significant improvement in fat fraction (FF) assessed by QCSI following a switch from imiglucerase to taliglucerase alfa. This analysis evaluated bone marrow involvement in adults with Type 1 Gaucher disease receiving low-dose enzyme replacement therapy (ERT) with imiglucerase and/or velaglucerase alfa. We report baseline data for 30 patients meeting eligibility criteria. Median (range) duration and dose of ERT were 18 (5-26) years and 30 (30-60) U/kg/month, respectively. Low FF scores (<0.30) were observed for seven patients (23%; 95% confidence interval, 10-42%) and were more common in females (n = 6) versus males (n = 1; p < 0.025); one female was menopausal. These baseline data demonstrate that prolonged low-dose ERT with imiglucerase or velaglucerase alfa led to an adequate bone response, assessed by QCSI, in the majority of patients. A minority of such patients with suboptimal bone response require therapeutic change. The next phase of the study will address the effect of switching to taliglucerase alfa on bone status for patients with less than optimal QCSI scores (<0.30).

Fat fraction quantification of bone marrow in the lumbar spine using the LiverLab assessment tool in healthy adult volunteers and patients with Gaucher disease.

Magnetic Resonance Imaging is used for evaluation of bone in Gaucher disease (GD), but a widely available quantitative scoring method remains elusive. The study purpose was to assess the reproducibility of the LiverLab tool for assessing bone marrow fat fraction (FF) and determine whether it could differentiate GD patients from healthy subjects. Ten healthy volunteers and 18 GD patients were prospectively recruited. FF was calculated at L3, L4 and L5. GD patient bone marrow burden (BMB) score assessed by one observer. Inter and intra-rater agreement assessed with Bland-Altman data plots. Differences in FF between healthy volunteers versus GD patients and between subjects treated versus not treated assessed using two-sample t-tests. In GD patients, the relationship between FF, BMB and glucosylsphingosine was determined using the Pearson's correlation coefficient. Healthy volunteer mean FF was 0.36, standard deviation (SD) 0.10 (range 0.20-0.57). Intra and inter-rater SD were both 0.02. GD patient mean FF was 0.40, SD 0.13 (range 0.09-0.57). No statistical difference was shown between healthy volunteers and GD patients (P=0.447) or between GD patients whether on enzyme replacement therapy or not (P=0.090). No significant correlation between mean FF and total BMB (r=-0.525, P=0.253) or between FF and glucosylsphingosine levels (r=0.287, P=0.248). Excellent reproducibility of LiverLab FF measurements across studies and observers is comparable to Dixon quantitative chemical shift imaging (QCSI). Lack of statistical difference between GD patients and controls may be explained by limited patient numbers, active treatment or mild disease severity in untreated patients.

Enhancement patterns of adrenal nodules on magnetic resonance imaging.

ABSTRACTObjective:To compare enhancement patterns of typical adrenal adenomas, lipid-poor adenomas, and non-adenomas on magnetic resonance imaging (MRI).Materials and Methods:Evaluation of adrenal nodules larger than 1.0 cm, with at least 2-year follow-up, evaluated on MRI in January 2007 and December 2016. Two different protocols were included - upper abdomen MRI (delayed phase after 3 minutes) and abdomen and pelvis MRI (delayed phase after 7 minutes) – and nodules were divided in typical adenomas (characterized on out-of-phase MRI sequence), lipid-poor adenomas (based on follow-up imaging stability) and non-adenomas (based on pathological finding or follow-up imaging). T2-weighted and enhancement features were analyzed (absolute and relative washout and enhancement curve pattern), similarly to classic computed tomography equations.Results:Final cohort was composed of 123 nodules in 116 patients (mean diameter of 1.8 cm and mean follow up time of 4 years and 3 months). Of them, 98 (79%) nodules had features of typical adenomas by quantitative chemical shift imaging, and demonstrated type 3 curve pattern in 77%, mean absolute and relative washout of 29% and 16%, respectively. Size, oncologic history and T2-weighted features showed statistically significant differences among groups. Also, a threshold greater than 11.75% for absolute washout on MRI achieved sensitivity of 71.4% and specificity of 70.0%, in differentiating typical adenomas from non-adenomas.Conclusion:Calculating absolute washout of adrenal nodules on MRI may help identifying proportion of non-adenomas.

MRI-derived proton density fat fraction.

Reflecting the growing interest in early diagnosis of nonalcoholic fatty liver disease in recent years, the development of noninvasive and reliable fat quantification methods is required. Fat quantification by magnetic resonance imaging (MRI), especially MRI-derived proton density fat fraction (MRI-PDFF) obtained by quantitative chemical shift imaging such as the multi-point Dixon method, is highly correlated with histological evaluation and fat quantification with MR spectroscopy (MRS). In recent years, MRI-PDFF has been increasingly used as a reference standard for image-based fat quantification instead of MRS because it is possible to evaluate the whole liver with a single breath-hold. Furthermore, recent advances in MR imaging have led to the application of multiparametric MRI for the diagnosis of nonalcoholic fatty liver disease with specific liver tissue quantification of fat, iron, and fibrosis. One of the advantages of multiparametric MRI is that whole organ imaging to exclude sampling variability and organ-specific tissue quantification can be done simultaneously. Therefore, multiparametric MRI methods offer an attractive option for noninvasive and comprehensive liver assessment beyond the quantitative assessment of liver steatosis. In this review article, we mainly focus on a technical explanation and clinical interpretation of MRI-PDFF in the quantitative assessment of liver steatosis. Furthermore, we would like to mention future perspectives of MR imaging of the liver in relation to elastography and other specific multiparametric MRI methods such as R2* and T1 mapping.

Multi-parametric MR in Becker muscular dystrophy patients.

Quantitative MRI and MRS of muscle are increasingly being used to measure individual pathophysiological processes in Becker muscular dystrophy (BMD). In particular, muscle fat fraction was shown to be highly associated with functional tests in BMD. However, the muscle strength per unit of contractile cross‐sectional area is lower in patients with BMD compared with healthy controls. This suggests that the quality of the non‐fat‐replaced (NFR) muscle tissue is lower than in healthy controls. Consequently, a measure that reflects changes in muscle tissue itself is needed. Here, we explore the potential of water T 2 relaxation times, diffusion parameters and phosphorus metabolic indices as early disease markers in patients with BMD. For this purpose, we examined these measures in fat‐replaced (FR) and NFR lower leg muscles in patients with BMD and compared these values with those in healthy controls. Quantitative proton MRI (three‐point Dixon, multi‐spin‐echo and diffusion‐weighted spin‐echo echo planar imaging) and 2D chemical shift imaging 31P MRS data were acquired in 24 patients with BMD (age 18.8‐66.2 years) and 13 healthy controls (age 21.3‐63.6 years). Muscle fat fractions, phosphorus metabolic indices, and averages and standard deviations (SDs) of the water T 2 relaxation times and diffusion tensor imaging (DTI) parameters were assessed in six individual leg muscles. Phosphodiester levels were increased in the NFR and FR tibialis anterior, FR peroneus and FR gastrocnemius lateralis muscles. No clear pattern was visible for the other metabolic indices. Increased T 2 SD was found in the majority of FR muscles compared with NFR and healthy control muscles. No differences in average water T 2 relaxation times or DTI indices were found between groups. Overall, our results indicate that primarily muscles that are further along in the disease process showed increases in T 2 heterogeneity and changes in some metabolic indices. No clear differences were found for the DTI indices between groups.

Bone Marrow Involvement in Patients with Type 1 Gaucher Disease Receiving Low-Dose Long Term Enzyme Replacement Therapy (median 18 years)

Bone complications are the most dramatic and life-impairing outcomes of type 1 Gaucher disease (GD1), a common lysosomal storage disorder. Bone marrow infiltration by Gaucher cells substantially decreases the bone marrow fat fraction (FF), and the extent of this reduction correlates with the overall severity of skeletal manifestations in this disorder. Previous studies have demonstrated that the degree of infiltration can best be estimated by magnetic imaging resonance (MRI)-based quantitative chemical shift imaging (QCSI) and that the fat fraction (FF) score so derived can predict the risk of clinically important bone events. The aim of this study was to evaluate bone marrow involvement in GD1 patients who had received enzyme replacement therapy (ERT) for at least 5 years. Methods: Patients from SZMC Gaucher unit, ≥ 18 years, who were treated with ERT for ≥ 5 years, with a stable dose in the previous 6 months, were recruited. Patients taking another experimental drug, with past exposure to taliglucerase-alfa, presence of any medical, emotional, behavioral or psychological condition were excluded. Energy x-ray absorptiometry (DEXA) was performed at SZMC and the QSCI was performed at the Academic Medical Center in Amsterdam, Netherlands as previously described [Mass et al, Am J Radiol 2002:179:961-965]. A QCSI score of &lt;0.30 was indicative of bone at risk. This investigator initiated clinical trial was approved IRB at SZMC and AMC and sponsored by Pfizer. Study number registration- MOH-2017-04-000351. Results: Thirty patients (13 females) at a median (range) age of 46 (19-71) years consented to participate in this study and to perform the QCSI test. GBA mutations of study patients included N370S homozygote (n=12), N370S compound heterozygote (n=17), and T431 homozygote (n=1). The median (range) duration of ERT was 18 (5-26) years. Thirteen patients were receiving imiglucerase as the primary ERT [median (range) duration, 19 (9-26) years], five patients were receiving velaglucerase alfa [median (range) duration, 11 ( 5-12) years], and 12 patients converted from imiglucerase to velaglucerase alfa [median (range) duration, 7 (6-10) years]. The majority of patients received low-dose regimen, i.e. 15 Units/kg/2 weeks (Table 1). The median (range) T score for lumbar spine from DEXA scans, available for 26 of 30 patients, was −1.3 (−2.8-0.0). The median (range) QCSI score was 0.42 (0.24-0.66). Seven patients, 23% (95% confidence interval 10%-42%), had abnormal QCSI FF scores (&lt;0.30). Abnormal QSCI score was more common in female compared to male (Table 1) (p=0.025). Only one of these was menopausal. No differences were found in age, gender, genotype, history of splenectomy, duration and type of ERT and GD-related parameters between those with QSCI score of bone at risk to those with normal score (Table 1). In summary, these findings demonstrate that, despite prolonged treatment with imiglucerase and/or velalgucerase alfa, 23% of patients still had QCSI scores indicative of an inadequate response in bones. Nevertheless, most patients with prolonged low-dose ERT maintain a normal QCSI, indicative of a positive bone status. The higher prevalence of women in the cohort with low FF is not related to menopausal phase and remains unexplained. As no other patient-related nor GD-related parameter predicted abnormal bone marrow infiltration, a more widely available, quantitative measure of bone marrow infiltration is required for the assessment of response in bones to ERT for patients with GD1. The second phase of this study will evaluate the impact of a switch to a third ERT in those patients from this study with QCSI scores of &lt;0.30. These patients will be offered treatment with taliglucerase alfa at equivalent doses and subsequent reassessment of any impact on clinical symptoms and QCSI scores evaluated. Disclosures Revel-Vilk: Takeda: Honoraria, Other: Travel, Research Funding; Prevail therapeutics: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding. Szer:Alexion: Honoraria, Other: Travel, Research Funding; Amgen: Honoraria, Other: Travel, Research Funding; Celgene: Honoraria, Other: Travel, Research Funding; MSD: Honoraria, Other: Travel, Research Funding; Novartis: Honoraria, Other: Travel, Research Funding; Pfizer: Honoraria, Other: Travel, Research Funding; Takeda: Honoraria, Other: Travel, Research Funding; Sanofi: Honoraria, Other: Travel, Research Funding; Prevail Therapeutics: Honoraria, Other: Travel, Research Funding. Zimran:Centogene: Other: research grant; Shire: Consultancy, Honoraria, Research Funding; TAKEDA: Honoraria; Pfize: Honoraria, Research Funding; Bio-events: Honoraria; Targeted Cell Therapies: Consultancy; Prevail Therapeutics: Consultancy.

Value of assessment of multivoxel proton chemical shift imaging to predict long term outcome in patients after out-of-hospital cardiac arrest: A preliminary prospective observational study

BackgroundExisting methods to predict recovery after out-of-hospital cardiac arrest (OHCA) lack of accuracy. The aim of this study was to determine whether quantitative proton chemical shift imaging (1H-CSI) during the subacute stage of OHCA can predict neurological outcome of such patients. MethodsThis monocentric prospective observational study was conducted in a Intensive Care Unit of a teaching hospital. Forty consecutive patients with OHCA were enrolled between January 1st 2011–December 31st 2013. Multivoxel 1H-CSI values were compared to structural magnetic resonance imaging (MRI) sequences (fluid-attenuated inversion recovery and diffusion-weighted imaging). Ratios of N-acetyl-aspartate (NAA) to creatine (Cr) and choline compounds were analyzed using region of interest in bilateral lenticular cores and thalami. The outcome evaluated was the Cerebral Performance Category (CPC) at 6 months, dichotomized as favorable (CPC 1-2) and unfavorable outcome (CPC 3-5). The performance was compared by area under the receiver operating characteristic (ROCAUC) curves analysis. ResultsTwenty nine OHCA had an interpretable MRI. Eight patients (28%) had favorable outcome at 6 months. The worst NAA/Cr in lenticular cores was the best 1H-CSI marker, with 80% sensitivity (95% confidence interval (CI), 57–94) and a 100% specificity (95% CI, 63–100) with a positive predictive value of 100%. Prognostic accuracy, as quantified by the ROCAUC, was higher with the worst NAA/Cr in lenticular cores (ROCAUC 0.88; 95% CI, 0.70–0.97) than with the structural MRI sequences. ConclusionIn this preliminary study we found that multivoxel 1H-CSI in lenticular cores was highly predictive of unfavorable outcome at 6 months.

Improvement in bone marrow infiltration in patients with type I Gaucher disease treated with taliglucerase alfa

Preliminary data suggest a positive effect of taliglucerase alfa on the bone marrow infiltration of Gaucher cells. In this investigator-initiated study, we report the impact of taliglucerase alfa on the bone marrow fat fraction (FF) in 26 patients assessed by quantitative chemical shift imaging (QCSI). Of 15 treatment-naïve patients (median age 48 [range 24–68] years), eight had baseline FF ≤ 0.3, six of those with a FF ≤ 0.23 (‘bone at risk’). All significantly improved from a median baseline FF of 0.24 (0.15–0.32) to 1st year FF of 0.37 (0.25–0.54) and 2nd year FF of 0.42 (0.27–0.59) (p = 0.01). Among the 11 ‘switch-over’ patients (median age 42 [range 33–69] years; median imiglucerase exposure 8 [range 1–17] years), eight had baseline FF ≤ 0.3, five of those with FF < 0.23. All, but one, significantly improved from a median baseline FF of 0.17 (0.08–0.28) to 1st year FF of 0.3 (0.05–0.34) and 2nd year FF of 0.34 (0.08–0.44) (p = 0.03). Two elderly female patients (age 43 and 58 years, with 17 years imiglucerase exposure) who remained at the same enzyme replacement therapy dose, increased from baseline FF of 0.13 and 0.19 to 0.26 at 1 year. Although the number of observations is small, we hypothesize that switching to taliglucerase may result in an improved bone marrow response. A larger study is needed to assess the early benefit of taliglucerase alfa in adult patients with type 1 Gaucher disease on the bone marrow compartment.

QCSI (quantitative chemical shift imaging) for assessment of bone marrow involvement in patients with Gaucher disease

QCSI (quantitative chemical shift imaging) for assessment of bone marrow involvement in patients with Gaucher disease

Significant and continuous improvement in quantitative chemical shift imaging (QCSI) in patients with Gaucher disease treated with taliglucerase alfa during the early access program

Significant and continuous improvement in quantitative chemical shift imaging (QCSI) in patients with Gaucher disease treated with taliglucerase alfa during the early access program

Successful and uncomplicated transfer of MRI Quantitative Chemical Shift Imaging (QCSI) technology for the detection of bone marrow fat signal fraction in type I Gaucher disease

Background and study aim: Dixon Quantitative Chemical Shift Imaging (QCSI) to measure lumbar spine bone marrow fat signal fraction (FF), is considered the ‘gold standard’ for the determination and follow up of bone involvement in type I Gaucher disease (GD). Since there used to be only one centre in Europe (AMC, Amsterdam, the Netherlands) offering this technique, we transferred the Amsterdam QCSI technology to the University Hospital Gasthuisberg (Leuven, Belgium) and tested it on 9 Belgian patients. Patients and methods: 9 GD patients entered the study from November 2006 till April 2010. Installation of the QCSI technique in Leuven required a visit of the Amsterdam MRI physicist (E.M.A.) for one day, to install software and train the local team. Requirements for running the technique are: a 1.5 Tesla MRI-scanner, Siemens or General Electric, with access to sequence programming and a dedicated physicist. A total of 22 scans were performed in Leuven and in 2 patients parallel scans were performed at the AMC, to determine reproducibility. The critical cut-off value of FF for bone disease is 23%, according to data published by the Amsterdam group. Results: Four patients were scanned once and five patients at least 3 times. Two parallel scans in Leuven and Amsterdam were each performed within one week and showed good reproducibility (40.7% vs. 43.8% and 41% vs. 39% ). Due to a shortage of enzyme, enzyme replacement therapy ceased from August 2009 till January 2010, causing a detectable decrease in FF in 3 patients. This confirms that QCSI is useful in clinical follow-up. Conclusion: This study shows that Dixon QCSI MRI technology is successfully transferable from one centre to another, offering the potential for spreading this technique to Gaucher MRI expert centres throughout the world.

Evaluation of an imaging biomarker, Dixon quantitative chemical shift imaging, in Gaucher disease: lessons learned.

Gaucher disease (GD) is the first lysosomal storage disorder for which specific therapy became available. The infiltration of bone marrow by storage cells plays an important part in the pathophysiology of skeletal complications and can be quantified by measurements of bone marrow fat fraction (Ff). Ff measurements by Dixon quantitative chemical shift imaging (QCSI) are standard for the follow-up care of GD patients at the Academic Medical Center. Several criteria should be met in order for these measurements to qualify as an imaging biomarker. These include: 1) The presence of the imaging biomarker is closely coupled or linked to the presence of the target disease or condition; 2) The detection and/or quantitative measurement of the biomarker is accurate, reproducible, and feasible over time, and; 3) The changes measured over time in the imaging biomarker are closely coupled, or linked, to the success or failure of the therapeutic effect and the true end point for the medical therapy being evaluated. This review assesses the use of Ff measurements by QCSI as a biomarker for GD in light of these criteria. In addition potential pitfalls are discussed including: degenerative disc disease; vertebral collapse and infection; haematological malignancies; focal fatty deposits; age; menopause; phase and repositioning errors, and; fat surrounding the basivertebral vein.QCSI measurements of Ff can be used as an imaging biomarker for GD taking these pitfalls into account. It is one of the first biomarkers, in particular imaging biomarkers, for GD that has been systematically evaluated and could be a valuable tool in clinical trials comparing different treatments or dosing regimens.

Taliglucerase alfa leads to favorable bone marrow responses in patients with type I Gaucher disease

Taliglucerase alfa (Protalix Biotherapeutics, Israel) is a carrot-cell-expressed recombinant human beta-glucocerebrosidase recently approved in the United States for the treatment of type 1 Gaucher disease (GD). As bone disease is one of the most debilitating features of GD, quantification of bone marrow involvement is important for monitoring the response to treatment. Therefore, bone marrow fat fraction (Ff) measured by quantitative chemical shift imaging (QCSI) was included as exploratory parameter to evaluate bone marrow response in treatment naïve GD patients participating in a double-blind, randomized phase III study. Eight GD patients with intact spleens were treated with 30 or 60U/kg biweekly. Ff results were compared to outcomes in 15 untreated Dutch GD patients with a follow-up interval of 1year. Five taliglucerase alfa treated patients had a Ff below the threshold that relates to complication risk (<0.23) at baseline (median (n=8) 0.19, range 0.11-0.35). Ff significantly increased compared to baseline (p=0.012) and compared to untreated patients (p=0.005), already after 1year of follow-up with further improvement up to 36months. In four patients with the lowest Ff, the higher dose resulted in increases above 0.23 within 1year. All patients had sustained improvements in all other parameters. There was no influence of antibodies on response parameters. Treatment with taliglucerase alfa results in significant increases in lumbar spine fat fractions, which indicates clearance of Gaucher cells from the bone marrow.

Comparison of Qualitative and Quantitative Evaluation of Diffusion-Weighted MRI and Chemical-Shift Imaging in the Differentiation of Benign and Malignant Vertebral Body Fractures

The objective of our study was to compare the diagnostic value of qualitative diffusion-weighted imaging (DWI), quantitative DWI, and chemical-shift imaging in a single prospective cohort of patients with acute osteoporotic and malignant vertebral fractures. The study group was composed of patients with 26 osteoporotic vertebral fractures (18 women, eight men; mean age, 69 years; age range, 31 years 6 months to 86 years 2 months) and 20 malignant vertebral fractures (nine women, 11 men; mean age, 63.4 years; age range, 24 years 8 months to 86 years 4 months). T1-weighted, STIR, and T2-weighted sequences were acquired at 1.5 T. A DW reverse fast imaging with steady-state free precession (PSIF) sequence at different delta values was evaluated qualitatively. A DW echo-planar imaging (EPI) sequence and a DW single-shot turbo spin-echo (TSE) sequence at different b values were evaluated qualitatively and quantitatively using the apparent diffusion coefficient. Opposed-phase sequences were used to assess signal intensity qualitatively. The signal loss between in- and opposed-phase images was determined quantitatively. Two-tailed Fisher exact test, Mann-Whitney test, and receiver operating characteristic analysis were performed. Sensitivities, specificities, and accuracies were determined. Qualitative DW-PSIF imaging (delta = 3 ms) showed the best performance for distinguishing between benign and malignant fractures (sensitivity, 100%; specificity, 88.5%; accuracy, 93.5%). Qualitative DW-EPI (b = 50 s/mm(2) [p = 1.00]; b = 250 s/mm(2) [p = 0.50]) and DW single-shot TSE imaging (b = 100 s/mm(2) [p = 1.00]; b = 250 s/mm(2) [p = 0.18]; b = 400 s/mm(2) [p = 0.18]; b = 600 s/mm(2) [p = 0.39]) did not indicate significant differences between benign and malignant fractures. DW-EPI using a b value of 500 s/mm(2) (p = 0.01) indicated significant differences between benign and malignant vertebral fractures. Quantitative DW-EPI (p = 0.09) and qualitative opposed-phase imaging (p = 0.06) did not exhibit significant differences, quantitative DW single-shot TSE imaging (p = 0.002) and quantitative chemical-shift imaging (p = 0.01) showed significant differences between benign and malignant fractures. The DW-PSIF sequence (delta = 3 ms) had the highest accuracy in differentiating benign from malignant vertebral fractures. Quantitative chemical-shift imaging and quantitative DW single-shot TSE imaging had a lower accuracy than DW-PSIF imaging because of a large overlap. Qualitative assessment of opposed-phase, DW-EPI, and DW single-shot TSE sequences and quantitative assessment of the DW-EPI sequence were not suitable for distinguishing between benign and malignant vertebral fractures.

Long Term Bone Marrow Responses, as Measured by Quantitative Chemical Shift Imaging (QCSI) MRI, Following Treatment With Taliglucerase Alfa in Patients with Type 1 Gaucher Disease

Long Term Bone Marrow Responses, as Measured by Quantitative Chemical Shift Imaging (QCSI) MRI, Following Treatment With Taliglucerase Alfa in Patients with Type 1 Gaucher Disease

Aspectos óseos de la enfermedad de Gaucher

The exposition aims, is to review the pathophysiological mechanisms of bone marrow involvement and the patterns of marrow infiltration by Gaucher cells. We have reviewed the different methods of assessment of bone marrow infiltration and its temporal development. Qualitative methods include simple radiography, magnetic resonance imaging (MRI), computed tomography (CT) and radioisotope. The simple radiography is the basic element, but its sensitivity is limited and only allows for assessing changes and trabecular bone remodeling MRI allows us to appreciate the bone marrow infiltration, detection of complications and response to therapy. Radioisotopes can contribute to the differential diagnosis of osteomyelitis and bone crises. Among the quantitative methods are the QCSI (quantitative chemical shift imaging) and the dual-energy X-ray absorptiometry (DEXA), as well as new quantitative techniques of CT, MRI and ultrasound densitometry. The QCSI performed an assessment of fat content of bone marrow in the spine. DEXA quantifies bone density by measuring the attenuation coefficient. The semiquantitative methods have various “scores” to establish criteria for generalized bone disease endpoints of disease progression and response to therapy.

Spontaneous regression of disease manifestations can occur in type 1 Gaucher disease; results of a retrospective cohort study

Gaucher disease (GD) is a lysosomal storage disorder, caused by deficient activity of the enzyme glucocerebrosidase. GD is classically divided into three major phenotypes. The most prevailing form is type 1, which presents with variable hepatosplenomegaly, cytopenia, and/or bone disease. In adult patients with mild manifestations, progress of disease might be slow or even absent. As a consequence, treatment with intravenous enzyme replacement or substrate reduction is not always necessary. In the Netherlands, the follow-up of GD patients is centralized, which allows detailed investigation of untreated patients. A retrospective study was conducted in 18 type 1 GD patients, (2 teenagers: 15 and 16 years of age at first visit) who were not treated for at least one year. The chitotriosidase activity, platelet count, hemoglobin level, lumbar bone marrow fat content measured with quantitative chemical shift imaging (QCSI), liver ratio (ml/kg body weight), and spleen volume were recorded. Criteria were developed to score regression, stability or progression of disease. During a mean follow up of 4.5 years (range 1.1–12.2) seven patients (39%) showed spontaneous regression of GD. Eight patients (44%) were stable. Two patients had progressive disease, solely based upon a sustained increase in chitotriosidase activity. A pediatric patient had an increase in splenomegaly but an improvement in bone marrow fat fraction, probably due to aging. Nine patients fulfilled the local criteria to start treatment at first visit, of whom six started treatment within 1.1 to 6.8 years. The other three refused therapy, but nevertheless showed stability or even regression of the disease during a follow up of 4.6, 9.5 and 11.4 years respectively. None of the parameters was predictive of progression or regression of disease. In conclusion, GD in adults can, in some cases, regress spontaneously. No parameters for accurately predicting future disease course exist.

Gaucher Disease: A Systematic Review and Meta-Analysis of Bone Complications and Their Response to Treatment.

Gaucher disease (GD) is an inherited lysosomal storage disease, which is often managed by enzyme replacement therapy (ERT). While the response to ERT is gratifying in terms of hepatosplenomegaly, cytopenias, and general well-being, the response of bony disease is very slow, and in some cases non-existent. Skeletal manifestations are the most painful and debilitating components of GD type 1, and have a negative impact on the patient's quality of life. Whether an increase in the dose of ERT has a beneficial effect, and whether substrate reduction therapy (SRT) stabilizes and/or ameliorates bony disease, is controversial. The aim of our study was to determine whether or not there is enough evidence to make a definitive statement about the effects of ERT and SRT on bony complications of Gaucher disease. We conducted a systematic review of all studies examining the effects of ERT and SRT on bony complications of Gaucher disease published before July 2008. The studies were identified by a computerized search using Medline, Embase, The Cochrane Database of Systematic Reviews, The Cochrane Central Register of Control Trials (CCTR), and bibliographies of papers subsequently retrieved from the search. Three hundred studies were grouped according to whether they deal with the natural history of GD or therapeutic issues and 17 studies were included in the review. Meta analyses were done using a random effects model and the studies compared baseline versus after-treatment values. Quantitative Chemical Shift Imaging (QCSI) of vertebral bone marrow (BM) fat fraction, Magnetic Resonance Imaging (MRI) T1-weighted signal, semi-quantitative MRI bone marrow burden (BMB) score, and bone mineral density (BMD) Z scores of spine and femur were used to assess the effects of ERT and SRT on bony complications. Of the 4 studies that measured BM fat fraction, 3 showed that fat fraction significantly increased after ERT (Weighted Mean Difference [WMD] of 0.17, 95 % CI of 0.13 to 0.2, n= 36, p < 0.00001) and one study showed a non-significant increase in fat fraction after SRT (n = 2, p = 1.23). MRI T1-weighted signal was measured in 6 studies (5 studies on ERT and one on SRT), and 44/78 (56%) of GD1 patients were responders to ERT versus 20/78 (25.6%) who did not respond to ERT. One study showed that BM infiltration generally decreased after SRT. Of the 3 studies that measured BMB score, 2 showed that BMB score significantly decreased after ERT (WMD of −4.98, 95 % CI of −8.38 to −1.57, n= 27, p = 0.004) and one study showed a stable BMB score after SRT (n = 6, p = 0.82).The 4 studies in which BMD Z score of lumbar spine (LS) was measured showed an increase in Z score after ERT (WMD of 0.37, 95 % CI of −0.05 to 0.79, n= 54, p = 0.09) and one study showed a significant increase in LS Z score after 6 months of SRT. Of the 3 studies that measured BMD Z score of femurs, 2 showed a non-significant increase in Z score after ERT (WMD of 0.16, 95 % CI of −0.29 to 0.61, n= 43, p = 0.48) and one study showed a significant increase in femur Z score after 6 months of SRT. These studies suggest that ERT may be more effective in ameliorating BM involvement than in increasing BMD Z scores. SRT may stabilize the BM involvement and generally increase the BMD Z scores. However, further investigations are needed on the effects of SRT on bony complications of GD.

Low frequency maintenance therapy with imiglucerase in adult type I Gaucher disease: a prospective randomized controlled trial

Gaucher disease type I can be successfully treated with enzyme replacement therapy (ERT). In order to reduce the burden of the intravenously administered enzyme, a low frequency of administration was prospectively studied in patients with stable and minor disease following ERT. Eleven patients were randomly assigned either to continue their original regimen of a dose of ERT once every week or fortnight (five patients) or to lower the frequency of administration to once every 4 weeks, at the same cumulative dose (six patients). The primary end-point was change in liver ratio (mL/kg body weight). Secondary end-points were spleen volume, hemoglobin level, platelet count, lumbar bone marrow fat content measured with quantitative chemical shift imaging (QCSI), white cell count, and plasma levels of ferritin, chitotriosidase, liver enzymes and angiotensin-converting enzyme (ACE). There were no significant mean differences between the two treatment arms in liver ratio or any of the other end-points. However, there were two treatment failures in the low frequency of administration group. These patients showed progression of disease as evidenced by a reduction of QCSI in one patient and an increase in liver ratio as well as a slow decrease in QCSI in the other. Both patients already had relatively low baseline QCSI values. One patient switched back to the original regimen at 6 months because of subjective complaints. Low frequency ERT in adult Gaucher type I patients maintains stable disease in most, but not all patients with stable and minimal disease. Close monitoring of all disease parameters remains mandatory.