[Anticholinergic scales: Use in psychiatry and update of the anticholinergic impregnation scale]. / Les échelles anticholinergiques : usage en psychiatrie et mise à jour de l'échelle d'imprégnation anticholinergique.

Anticholinergic properties are well known to prescribers, notably in mental health, as a therapeutic strategy for i.e. extrapyramidal syndrome but also as a source of numerous adverse side effects. Herein, we propose a narrative literature review describing: (i) cholinergic pharmacology and anticholinergic properties; (ii) the importance of anticholinergic therapeutic properties in psychiatry; (iii) the existing anticholinergic drug scales and their usage limitations in Psychiatry and; last (iv) an update to the anticholinergic drug impregnation scale, designed for the French psychiatry practice. The anticholinergic side effects can appear both in the peripheral level (dry mouth, constipation, etc.) and in the central level (especially as cognitive deficits). Many of the so called « anticholinergic ¼ drugs are in fact entirely or mostly antimuscarinic and act essentially as parasympathetic system antagonists. Overall, anticholinergic/antimuscarinic side effects are usually attributed to psychotropic medications: to certain antipsychotics, notably classical neuroleptics such as phenothiazine and also to tricyclic antidepressants. In practice, the impact of anticholinergic toxicity treatments is often highlighted due to their excessively prolonged use in patients on antipsychotics. Interestingly, these antipsychotic treatments are better known for their anticholinergic side effects, especially cognitive ones, with an early onset specially in elder patients and/or in the case of polymedication. In order to evaluate anticholinergic side effects, metrics known as anticholinergic burden scales were created in the last few decades. Nowadays, 13 different scales are documented and accepted by the international academic community, but only three of them are commonly used: the Anticholinergic Drug Scale (ADS), the Anticholinergic Risk Scale (ARS) and the Anticholinergic Burden Scale (ACB). All of them are based on a similar principle, consisting of grading treatments individually, and they are normally scored from 0 - no presence of side effects - to 3 - anticholinergic effects considered to be strong or very strong. Using these scales enables the calculation of the so-called "anticholinergic burden", which corresponds to the cumulative effect of using multiple medications with anticholinergic properties simultaneously. The application of anticholinergic scales to patients with psychiatric disorders has revealed that schizophrenic patients seem to be especially sensitive to anticholinergic cognitive side effects, while elder and depressed patients were more likely to show symptoms of dementia when exposed to higher anticholinergic burden. Unfortunately, these tools appear to have a low parallel reliability, and so they might induce large differences when assessing side effects predictability. In addition, the capacity of these scales to predict central adverse effects is limited due to the fact they poorly or do not differentiate, the ability of treatments to cross the blood-brain barrier. Finally, one last limitation on the validity of these scales is prescription posology is not accounted for side effects considered to be dose dependent. Recently, the MARANTE (Muscarinic Acetylcholine Receptor ANTagonist Exposure) scale has incorporated an anticholinergic burden weighting by posology. Nevertheless, this new model can be criticized, due to the limited number of medications included and due to testing a limited number of potency ranges and dosages for each treatment. Herein, we propose an update to the Anticholinergic Impregnation Scale, developed specifically for the French Psychiatry practice. The scale validation was based on an evaluation of the prescriptions correcting anticholinergic peripheral side effects (constipation, xerostomia and xeropthalmia). This indirect evaluation allowed us to show patients with an anticholinergic impregnation score higher than 5 received significantly more treatments for constipation and xerostomia. This strategy bypasses the bias of a cognitive evaluation in patients with severe mental health disorders. Moreover, the relevance of a tool developed specifically for French psychiatry is justified by the fact that some highly prescribed treatments for mental illness in France (cyamemazine and tropatemine) are strong anticholinergics, and also by the fact they are rarely included in the existing anticholinergic scales. This update of the original scale, published in 2017, includes information whether prescribed drugs cross the blood-brain barrier and thus makes possible a more accurate assessment when evaluating anticholinergic central side effects. Finally, the anticholinergic impregnation scale will soon be integrated into a prescription help software, which is currently being developed to take into consideration dose dependent adverse effects.

Ankylosing spondylitis: correlations between clinical and MRI indices of sacroiliitis activity.

AIM: To analyse the correlations between clinical and MRI sacroiliitis activity indices in ankylosing spondylitis (AS). MATERIALS AND METHODS: Sixteen normal volunteers and 52 patients were enrolled. The clinical AS activity indices included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score, serum high-sensitivity C-reactive protein, and erythrocyte sedimentation rate. The MRI sacroiliitis activity indices included apparent diffusion coefficient (ADC) values of bone and the Spondyloarthritis Research Consortium of Canada (SPARCC) score. RESULTS: The mean SPARCC score of the control group was 0 and of the AS group was 9.9 ± 9.1 (range 0-36). The mean ADC value of the AS group was statistically significantly higher than that of the control group (49.7 ± 20.2 × 10(-5)mm(2)/s versus 38.9 ± 5.3 × 10(-5)mm(2)/s, p < 0.05). The BASDAI score showed a statistically significant correlation with the SPARCC score (r = 0.685, p < 0.05) and with ADC values (r = 0.329, p < 0.05). ADC values correlated with the SPARCC score (r = 0.390, p < 0.05). CONCLUSION: ADC values and the SPARCC index may be useful activity indices in AS.

Whole-Body Diffusion Imaging Applying Simultaneous Multi-Slice Excitation.

PURPOSE: The purpose of this study was to examine the feasibility of a fast protocol for whole-body diffusion-weighted imaging (WB-DWI) using a slice-accelerated echo-planar sequence, which, when using comparable image acquisition parameters, noticeably reduces measurement time compared to a conventional WB-DWI protocol. MATERIALS AND METHODS: A single-shot echo-planar imaging sequence capable of simultaneous slice excitation and acquisition was optimized for WB-DWI on a 3 T MR scanner, with a comparable conventional WB-DWI protocol serving as the reference standard. Eight healthy individuals and one oncologic patient underwent WB-DWI. Quantitative analysis was carried out by measuring the apparent diffusion coefficient (ADC) and its coefficient of variation (CV) in different organs. Image quality was assessed qualitatively by two independent radiologists using a 4-point Likert scale. RESULTS: Using our proposed protocol, the scan time of the WB-DWI measurement was reduced by up to 25.9 %. Both protocols, the slice-accelerated protocol and the conventional protocol, showed comparable image quality without statistically significant differences in the reader scores. Similarly, no significant differences of the ADC values of parenchymal organs were found, whereas ADC values of brain tissue were slightly higher in the slice-accelerated protocol. CONCLUSION: It was demonstrated that slice-accelerated DWI can be applied to WB-DWI protocols with the potential to greatly reduce the required measurement time, thereby substantially increasing clinical applicability. KEY POINTS: •Whole-body diffusion-weighted imaging (WB-DWI) using simultaneous multi-slice and blipped-CAIPIRINHA reduces the measurement time strongly without having a significant impact on image quality. •The reduction in measurement time might strongly contribute to the clinical applicability of WB-DWI. •However, further refinement of the slice-accelerated EPI sequence, and the WB-DWI protocol applying this sequence type seems necessary; and the value of such WB-DWI protocols for assessment of systemic oncological diseases needs to be investigated in further clinical studies.

Metal artefact reduction in MRI at both 1.5 and 3.0 T using slice encoding for metal artefact correction and view angle tilting.

OBJECTIVE: To compare metal artefact reduction in MRI at both 3.0 T and 1.5 T using different sequence strategies. METHODS: Metal implants of stainless steel screw and plate within agarose phantoms and tissue specimens as well as three patients with implants were imaged at both 1.5 T and 3.0 T, using view angle tilting (VAT), slice encoding for metal artefact correction with VAT (SEMAC-VAT) and conventional sequence. Artefact reduction in agarose phantoms was quantitatively assessed by artefact volume measurements. Blinded reads were conducted in tissue specimen and human imaging, with respect to artefact size, distortion, blurring and overall image quality. Wilcoxon and Friedman tests for multiple comparisons and intraclass correlation coefficient (ICC) for interobserver agreement were performed with a significant level of p < 0.05. RESULTS: Compared with conventional sequences, SEMAC-VAT significantly reduced metal artefacts by 83% ± 9% for the screw and 89% ± 3% for the plate at 1.5 T; 72% ± 7% for the screw and 38% ± 13% for the plate at 3.0 T (p < 0.05). In qualitative analysis, SEMAC-VAT allowed for better visualization of tissue structures adjacent to the implants and produced better overall image quality with good interobserver agreement for both tissue specimen and human imaging (ICC = 0.80-0.99; p < 0.001). In addition, VAT also markedly reduced metal artefacts compared with conventional sequence, but was inferior to SEMAC-VAT. CONCLUSION: SEMAC-VAT and VAT techniques effectively reduce artefacts from metal implants relative to conventional imaging at both 1.5 T and 3.0 T. ADVANCES IN KNOWLEDGE: The feasibility of metal artefact reduction with SEMAC-VAT was demonstrated at 3.0-T MR. SEMAC-VAT significantly reduced metal artefacts at both 1.5 and 3.0 T. SEMAC-VAT allowed for better visualization of the tissue structures adjacent to the metal implants. SEMAC-VAT produced consistently better image quality in both tissue specimen and human imaging.

Magnetic resonance imaging and other techniques in the diagnosis of multiple sclerosis.

We evaluated 35 patients with multiple sclerosis (MS) by magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis, evoked potential testing, and computed tomographic (CT) scanning. As classified by the McAlpine et al and McDonald and Halliday criteria, 27 patients had definite MS, three had probable MS, and five had possible MS. All of the patients had multiple white matter lesions detectable by MRI that were evident predominantly in the periventricular areas but also in the cerebral or cerebellar white matter. The severity of the MRI abnormality, as judged by the number and size of the lesions, correlated with the likelihood of a positive CT scan but not with the duration of disease, the degree of disability, or positive CSF oligoclonal banding. Magnetic resonance imaging successfully demonstrated brain-stem lesions in 15 patients (none were seen on CT scans). Magnetic resonance imaging seems to be a sensitive indicator of MS lesions, but clinical assessment will continue to be crucial to the diagnosis of MS.

A review of contrast media research in 1999-2000.

Contrast media research published during the years 1999 and 2000 is reviewed in this article, in terms of relevance to developments within the field of diagnostic radiology. The primary focus is on publications from the journal Investigative Radiology, which publishes much of the clinical and laboratory research performed in this field. The journals Radiology and the American Journal of Roentgenology are dominant in the field of diagnostic radiology and together publish more than 10 times the number of articles as appear each year in Investigative Radiology. However, in 1999 for example, these two journals together published fewer articles than did Investigative Radiology alone that concerned basic (animal) research with contrast media. Thirty-six percent of the articles in Investigative Radiology in 1999 had a primary focus on contrast media and 18% on basic (animal) research with contrast media. To make this review more complete, articles from other major journals are cited and discussed, as needed, to provide supplemental information in the few areas not well covered by articles in Investigative Radiology. The safety of contrast media is always an important topic and research continues to be performed in this area, both to explore fundamental issues regarding iodinated contrast media and also to establish the overall safety profile of new magnetic resonance (MR) and ultrasound agents. In regard to preclinical investigations, most of the work performed in the last 2 years has been with MR and ultrasound. In MR, research efforts continue to be focused on the development of targeted agents. In ultrasound, research efforts are split between studies looking at new imaging methods and early studies of targeted agents. In regard to the clinical application of contrast media, the published literature continues to be dominated by MR. Investigations include the study of disease in clinical trials and in animal models. A large number of studies continue to be published in regard to new techniques and applications within the field of contrast-enhanced magnetic resonance angiography. This field represents the single, largest new clinical application of contrast media in MR to emerge in the last decade. New clinical research continues to be published regarding the use of contrast media in computed tomography (CT), ultrasound, and x-ray angiography. The introduction of spiral CT (together with the multidetector scanners) has led to greater utilization of this modality, as well as intravenous iodinated contrast media. The number of publications regarding clinical applications of intravenously injected ultrasound contrast agents remains low, with the high expectations in regard to growth (in terms of number of exams using contrast) of the last decade yet to be fulfilled.

Evaluation of standard and high-dose contrast-enhanced breath-hold liver magnetic resonance for visualization of metastatic disease in an animal model.

RATIONALE AND OBJECTIVES: The ability of dynamic contrast-enhanced magnetic resonance imaging to improve detection of liver metastases was evaluated in an experimental rabbit model. Scans using two different contrast doses, 0.1 and 0.3 mmol/kg, of a gadolinium chelate with extracellular distribution were compared to precontrast T2- and T1-weighted scans. METHODS: Seven New Zealand White rabbits with VX-2 adenocarcinoma metastases to the liver were imaged at 1.5 tesla. Each animal was studied twice, on different days, to evaluate both contrast doses. Precontrast T2- and T1-weighted scans were compared to dynamic postcontrast T1-weighted scans obtained at 1, 2, 3, 4, and 5 minutes after intravenous injection. All scans were acquired during suspended respiration. The contrast agent, Gd HP-DO3A (gadoteridol or ProHance), was administered as a bolus. Images were analyzed by region of interest measurements. RESULTS: Injection of 0.3 mmol/kg Gd HP-DO3A produced liver enhancement which was statistically superior to 0.1 mmol/kg at all time points postcontrast. Enhancement of the paraspinous musculature at the higher dose was also statistically superior at all time points, with one exception (5 minutes postcontrast). Lesion detectability, evaluated by the signal difference over noise ratio, peaked at one minute postcontrast and was substantially greater at the higher contrast dose (31.4 +/- 8.3 at 0.3 mmol/kg versus 16.8 +/- 4.2 at 0.1 mmol/kg, P = 0.02). CONCLUSIONS: Using a rabbit model and breath-hold imaging technique, metastatic lesions in the liver were best visualized on early (1 minute) dynamic high dose (0.3 mmol/kg) postcontrast scans. Contrast dose and timing of image acquisition are critical issues for optimal liver lesion detection on magnetic resonance imaging.

Contrast media research.

This selective review highlights research in contrast media development and application in the field of diagnostic radiology in 1998 and 1999. The focus is on research published in Investigative Radiology, supplemented with work from other publications in the few areas not extensively covered by the journal. Studies continue to be performed, although at a low level, examining safety issues. Most preclinical investigations have focused on MR and ultrasound agents. In MR, the research effort is concentrated on the development of targeted agents; in ultrasound, work is focused on the characterization of basic contrast mechanisms. The demonstration of clinical applications is still dominated by work with MR, both in disease models and human investigations. The use of extracellular gadolinium chelates to enhance visualization of blood vessels (the field of contrast-enhanced MR angiography) is the largest single new clinical application of contrast media to emerge in several years. New clinical applications continue to be pursued with contrast media in CT, ultrasound, and x-ray angiography. As intravenously injected ultrasound contrast agents come to market, trials demonstrating clinical applications and subsequent scientific publications will increase in number.

Choice of metal ion and formulation concentration for first-pass brain perfusion studies with magnetic resonance imaging at 1.5 tesla.

RATIONALE AND OBJECTIVES: Gadolinium (Gd) and dysprosium (Dy) analogues, chelated with HP-DO3A, were compared at both 0.5- and 1.0-mol/L concentrations for efficacy in first-pass brain studies on magnetic resonance (MR) imaging at 1.5 tesla (T). METHODS: Ten healthy cats were examined with a dose of 0.3 mmol/kg, using two concentrations of each agent (0.5 mol/L and 1.0 mol/L, 20 examinations). Gadolinium-HP-DO3A (gadoteridol or ProHance) or Dy-HP-DO3A was injected at 9 mL/second, with acquisition of 64 sequential steady-state free precession (SSFP) images at a rate of one each 0.6 second. RESULTS: The change in white matter signal intensity, at the peak of the first pass of the contrast agent bolus in the brain, was -231 +/- 68 for the 0.5-mol/L formulation of Gd-HP-DO3A, compared with -267 +/- 57 for the 1.0-mol/L formulation. Using the 0.5-mol/L formulation of Dy-HP-DO3A, the change at peak was -318 +/- 42, a result statistically improved compared with both the 0.5-mol/L (P < 0.02) and 1.0-mol/L (P < 0.04) Gd-HP-DO3A formulations. A further improvement was observed with the 1.0-mol/L Dy-HP-DO3A formulation, with the change being -368 +/- 33. CONCLUSIONS: First-pass brain MR studies at 1.5 T are improved by use of higher concentration Gd chelate formulations (1.0 versus 0.5 mol/L) and by substitution of the Dy ion for the Gd ion in the chelate. Injection of higher-concentration formulations results in higher initial arterial metal ion concentration. Incomplete blood mixing on transit during first pass causes the higher initial concentration, which then results in a greater susceptibility effect on imaging. The superiority of the Dy formulation compared with the Gd formulation is anticipated because of the higher magnetic moment of Dy. The curves for tissue signal intensity versus time during first pass return artifactually to near baseline after Gd chelate injection (when SSFP imaging techniques are used), a differentiating feature from results with the Dy chelate. This difference can be explained by a substantial T1 effect of the Gd chelate, despite acquisition of images that are predominantly susceptibility weighted.

Dynamic contrast-enhanced magnetic resonance imaging in a model of splenic metastasis.

RATIONALE AND OBJECTIVES: The use of rapid dynamic magnetic resonance (MR) imaging after bolus intravenous contrast injection, to improve detection and delineation of parenchymal disease, was evaluated in an experimental model of splenic metastasis. METHODS: An experimental model for splenic metastasis was first developed in the New Zealand White rabbit. Magnetic resonance studies were then obtained at 1.5 tesla in six animals. A 25 ga needle was used to penetrate the spleen and inject 0.1 mL of minced, screened VX2 adenocarcinoma (obtained from a carrier rabbit). The injections were performed by two techniques, percutaneously using ultrasound guidance (n = 3) and at the time of abdominal laparotomy (n = 3). The animals were imaged at 1.5 tesla on day 10 after implantation. Breath-hold T2-weighted and T1-weighted scans were acquired prior to contrast injection. A dose of 0.3 mmol/kg gadoteridol (ProHance) was then administered intravenously using an MR-compatible power injector, with both dynamic and delayed postcontrast scans obtained. The lesion was confirmed in each animal by gross pathologic and microscopic exam. RESULTS: On region of interest analysis of T2-weighted scans, the lesions could not be differentiated by signal intensity (with any statistical significance) from normal surrounding splenic parenchyma. Lesion conspicuity, assessed by signal difference/noise ratio on dynamic turbo-FLASH scans, increased from 6+/-5 precontrast to a peak of 16+/-5 at 31 seconds postcontrast, with P < 0.003 (n = 6). Lesion conspicuity steadily diminished from this time to 5 minutes postinjection, although it was still improved at 5 minutes over precontrast scans. CONCLUSIONS: On early dynamic contrast enhanced breath-hold MR, marked improvement in the differentiation of splenic metastases from surrounding normal parenchyma is achieved. The capability of dynamic MR in this regard is analogous to that demonstrated for helical computed tomography.

Detectability of small liver metastases with gadolinium BOPTA.

RATIONALE AND OBJECTIVES: The ability to detect small liver metastases was evaluated with both gadolinium Gd BOPTA and Gd HP-DO3A on high-field (1.5 tesla [T]) magnetic resonance (MR) imaging using a rabbit tumor model. METHODS: Five New Zealand White rabbits with metastatic liver disease (VX-2 adenocarcinoma) were imaged on a 1.5 T Siemens Vision MR system. Magnetic resonance studies were obtained in each animal on days 8 and 9 after tumor implantation. Each animal was studied twice, once after injection of 0.3 mmol/kg Gd HP-DO3A (gadoteridol or ProHance) and once after injection of 0.1 mmol/kg Gd BOPTA (gadobenate dimeglumine or MultiHance). The order of injection for the two agents was randomized with the two studies in any one animal separated by 24 hours to allow for clearance. Magnetic resonance image acquisition was performed in all cases with suspended respiration. Baseline two-dimensional FLASH T1-weighted and turbo-spin echo T2-weighted scans were acquired first. The contrast was then administered as an intravenous bolus. T1-weighted scans were acquired at 1, 5, 15, 30, 45, and 60 minutes after administration of Gd BOPTA and 1, 5, and 15 minutes after administration of Gd HP-DO3A. Each rabbit was killed after completion of imaging, their liver removed and taken to the veterinarian at the University's animal disease diagnostic laboratory for lesion confirmation. RESULTS: Despite acquisition of precontrast T2-weighted scans, lesions could not be identified with certainty in four of five animals in the Gd HP-DO3A study. Normal liver signal intensity increased from 895 +/- 17 to a peak of 1384 +/- 50 at 1 minute after Gd HP-DO3A administration. After Gd BOPTA administration, normal liver signal intensity increased from 899 +/- 105 to a peak of 1433 +/- 76 at 15 minutes. Liver enhancement thereafter decreased gradually to 1297 +/- 84 at 60 minutes. The injection of 0.3 mmol/kg Gd HP-DO3A resulted in parenchymal enhancement, which was statistically superior (P < 0.01) to an injection of 0.1 mmol/kg Gd BOPTA at 1 minute, not statistically different at 5 minutes, and inferior (P < 0.02) at 15 minutes. From region of interest measurements, lesion detectability was statistically superior on scans at 15 to 60 minutes after Gd BOPTA administration compared with precontrast T1- and T2-weighted scans (P values: < 0.03- < 0.005). Lesion detectability was maximum at 30 minutes postcontrast (15.2 +/- 4.5), markedly superior to that precontrast on both T1- (5.7 +/- 5.0) and T2-weighted scans (7.2 +/- 1.5). On masked film review of the Gd BOPTA case set, no lesions were noted prospectively on T2-weighted scans. Lesions in all five animals were well visualized on scans 45 to 60 minutes after Gd BOPTA administration. The Gd HP-DO3A case set was not read masked, as lesions could be identified only in one of the five animals with all films available for inspection. An additional feature of scans with Gd BOPTA (used at a dose of 0.1 mmol/kg), in distinction to those with Gd HP-DO3A (used at a dose of 0.3 mmol/kg), was the diminished enhancement of hepatic vessels. CONCLUSIONS: Using a rabbit model, small metastatic lesions (diameter, 2-4 mm) were well visualized on delayed postcontrast Gd BOPTA scans. These lesions could not be diagnosed prospectively on T2-weighted images. In only one of five animals were lesions detected on early dynamic post-contrast high-dose Gd HP-DO3A scans.

Magnetic resonance imaging of an experimental model of intracranial metastatic disease. A study of lesion detectability.

RATIONALE AND OBJECTIVES: The detectability of brain metastases was evaluated in a rabbit model, with attention to magnetic resonance contrast dose and timing of image acquisition after injection of contrast medium. METHODS: Five New Zealand white rabbits were studied at 1.5 T 6 to 7 days and 11 to 12 days after surgical implantation of an adenocarcinoma tumor nidus. T1- and T2-weighted spin-echo images (0.9 x 0.9 x 2 mm3 voxel size) were obtained before administration of contrast medium. T1-weighted images were repeated 5, 15, and 30 minutes after intravenous injection of 0.1 mmol/kg gadoteridol. At 40 minutes, a supplemental dose of 0.2 mmol/kg (0.3 mmol/kg cumulative dose) was administered, with T1-weighted images repeated at 5, 15, and 30 minutes after the second injection. RESULTS: Six to 7 days after tumor implantation, lesion enhancement (percent change, with normalization to baseline and equilibrium values) was 42 +/- 9% at 5 minutes, 48 +/- 9% at 15 minutes, and 42 +/- 10% at 30 minutes after administration of 0.1 mmol/kg gadoteridol. After administration of 0.3 mmol/kg gadoteridol, lesion enhancement was 111 +/- 13% at 5 minutes, 116 +/- 8% at 15 minutes, and 100% at 30 minutes. On film review, 2 of 5 lesions were not detectable at 6 to 7 days after tumor implantation with 0.1 mmol/kg gadoteridol. Administration of 0.3 mmol/kg gadoteridol provided for lesion identification in each instance. Eleven to 12 days after tumor implantation, one lesion was not detectable with 0.1 mmol/kg gadoteridol. Administration of 0.3 mmol/kg gadoteridol again provided for lesion identification in all cases. Mean lesion enhancement increased from 39 +/- 15% to 104 +/- 10%. CONCLUSIONS: The administration of 0.3 mmol/kg gadoteridol (high dose) compared with 0.1 mmol/kg gadoteridol (conventional dose) improves metastatic lesion detectability in the brain. The lesions identified only at high dose were confirmed by histopathology. Smaller lesions were not detected at a dose of 0.1 mmol/kg.

Magnetization transfer and high-dose contrast in early brain infection on magnetic resonance.

RATIONALE AND OBJECTIVES: The authors studied the effect of contrast dose, use of magnetization transfer (MT), and temporal delay on the visualization of contrast enhancement with gadoteridol (Gd HP-DO3A) in a canine brain abscess model. METHODS: Alpha streptococcus brain abscesses were studied in five dogs at 1.5 tesla (T) 1 and 5 days after implantation. Scans were performed 1, 11, and 21 minutes after contrast was administered, using an initial dose of 0.1 mmol/kg. A supplemental contrast injection of 0.2 mmol/kg was given (for a cumulative dose of 0.3 mmol/kg), with scans repeated at 31, 41, and 51 minutes. RESULTS: Lesion conspicuity on day 1 was greater at high-contrast doses (0.3 mmol/kg) compared with standard doses (0.1 mmol/kg), regardless of whether imaging was performed without (0.89 +/- 0.02 compared with 0.26 +/- 0.08) or with (0.97 +/- 0.04 compared with 0.28 +/- 0.06) MT. High-dose, MT, and a delay after contrast was injected all produced a statistically significant improvement. On blinded review of films obtained 11 and 14 minutes after injection, enhancement of the lesion could not be identified with certainty in two of five dogs at a dose of 0.1 mmol/kg, regardless of whether MT was used. Enhancement was seen consistently in all lesions at 0.3 mmol/kg. On day 5, results were comparable, with greater absolute enhancement. CONCLUSIONS: In early brain infection, high-contrast doses (0.3 mmol/kg), MT, and a moderate delay after injection all improve visualization of lesion enhancement.

Comparison of gadolinium Cy2DOTA, a new hepatobiliary agent, and gadolinium HP-DO3A, an extracellular agent, in healthy liver and metastatic disease.

RATIONALE AND OBJECTIVES: A new gadolinium (Gd) chelate with preferential hepatobiliary uptake, Gd Cy2DOTA, was compared in two animal species with Gd HP-DO3A (gadoteridol), a clinically approved contrast agent with extracellular distribution. Liver enhancement was evaluated for these two contrast agents using magnetic resonance imaging, whereas an experimental model of metastatic disease was used to evaluate the agents' efficacy for liver-lesion delineation. METHODS: The two agents were compared in four healthy Rhesus monkeys (eight studies) and five New Zealand White rabbits with implanted VX-2 liver tumors (ten studies). The contrast dose was 0.1 mmol/kg, with the agents given in random order and at least 72 hours between contrast injections. Breathhold T1-weighted spin echo scans were obtained at 1.5 tesla (T) before and after contrast was administered. Postcontrast scans were obtained 1 to 90 minutes after injection in the monkeys and 1 to 240 minutes after injection in the rabbits. RESULTS: Prolonged hepatic enhancement, superior in degree to that with Gd HP-DO3A, was noted in both monkeys and rabbits after injection of Gd Cy2DOTA. Two minutes after contrast, liver SI was 1.94 +/- 0.05 with Gd Cy2DOTA compared with 1.51 +/- 0.05 with Gd HP-DO3A in monkeys. Sixty minutes after contrast, liver SI was 1.60 +/- 0.09 compared with 1.20 +/- 0.02. The difference between agents was significant at all times from 2 to 60 minutes after contrast injection (P < 0.01). Excretion of contrast into the gall bladder was observed in both animal species with Gd Cy2DOTA but not with Gd HP-DO3A. The maximum improvement in lesion conspicuity (rabbit) occurred 45 minutes after injection of Gd Cy2DOTA and 5 minutes after injection of Gd HP-DO3A. Sixty minutes after injection, liver-lesion contrast was 246 +/- 61 with Gd Cy2DOTA and 106 +/- 28 with Gd HP-DO3A, with a significant difference (P < 0.02). CONCLUSIONS: Gd Cy2DOTA provides greater enhancement of the liver parenchyma on immediate and delayed magnetic resonance scans than does Gd HP-DO3A. On delayed scans, Gd Cy2DOTA provides superior delineation of metastatic liver lesions.

Evaluation of gadolinium 2,5-BPA-DO3A, a new macrocyclic hepatobiliary chelate, in normal liver and metastatic disease on high field magnetic resonance imaging.

RATIONALE AND OBJECTIVES: A new hepatobiliary gadolinium chelate, gadolinium (Gd) 2,5-BPA-DO3A, was compared in two animal species with Gd HP-DO3A (gadoteridol), a clinically approved extracellular contrast agent, and Gd Cy2-DOTA, a second hepatobiliary chelate in preclinical development. The ligand in Gd 2,5-BPA-DO3A is macrocyclic in nature, as opposed to the linear structure of Gd DTPA. Gadolinium 2,5-BPA-DO3A was evaluated on magnetic resonance imaging at 1.5 T, examining specifically liver parenchymal enhancement and lesion delineation, the latter in metastatic disease. METHODS: Gadolinium 2,5-BPA-DO3A was evaluated in five normal rhesus monkeys and four New Zealand White rabbits with implanted VX-2 liver tumors. These studies were compared with magnetic resonance exams in the same animals using Gd HP-DO3A and Gd Cy2-DOTA. A contrast dose of 0.1 mmol/kg intravenous was employed in each instance, with the sequence of administration (for the three agents) randomized and at least 72 hours between injections. Spin echo breathhold T1-weighted scans were obtained before and at multiple times after contrast administration. Postcontrast scans were acquired from 1 to 60 minutes after injection in the monkeys and from 1 to 240 minutes in the rabbits. RESULTS: Enhancement of normal liver parenchyma was markedly superior with Gd 2,5-BPA-DO3A compared with Gd HP-DO3A and Gd Cy2-DOTA in both monkeys and rabbits. At 2 and 60 minutes after contrast administration, the liver signal intensity in the monkey was 452 +/- 56 and 440 +/- 69 with Gd 2,5-BPA-DO3A compared with 295 +/- 34 and 256 +/- 38 with Gd HP-DO3A. The difference between agents was statistically significant at all postcontrast time points in the rhesus monkey. Excretion of contrast into the gall bladder was consistently observed after Gd 2,5-BPA-DO3A injection in both animal species. Maximum lesion conspicuity occurred in the rabbit at 45 minutes after Gd 2,5-BPA-DO3A administration. At 45 minutes postinjection, liver-lesion contrast was 0.60 +/- 0.15 with Gd 2,5-BPA-DO3A, 0.35 +/- 0.11 with Gd Cy2-DOTA, and 0.12 +/- 0.04 with Gd HP-DO3A, with the differences between agents being statistically significant. CONCLUSIONS: Gadolinium 2,5-BPA-DO3A is superior to both Gd Cy2-DOTA and Gd HP-DO3A in the degree of enhancement of normal liver parenchyma achieved after intravenous injection. This leads to improved liver lesion delineation with Gd 2,5-BPA-DO3A on delayed postcontrast magnetic resonance scans.

Early dynamic magnetic resonance imaging of liver metastases with 0.3 and 0.6 mmol/kg gadoteridol injection.

RATIONALE AND OBJECTIVES: The potential for improvement in liver-lesion conspicuity on early dynamic scans after bolus intravenous gadolinium (Gd) chelate administration was evaluated using gadoteridol (Gd-HP-DO3A; Prohance) at doses of 0.3 and 0.6 mmol/kg. METHODS: Five New Zealand white rabbits with focal VX-2 adenocarcinoma liver metastases were studied on a 1.5-tesla Siemens Vision scanner. Each rabbit was imaged twice (on two separate days), after injections of 0.3 mmol/kg and 0.6 mmol/ kg Gd-HP-DO3A. The contrast dose (0.3 or 0.6 mmol/kg) was given as a single intravenous injection. The order of injection for the two doses was randomized, with the two studies (in any one rabbit) separated by 24 hours to allow for clearance. Contrast was administered using an autoinjector at a rate of 1.5 mL/second. Turbo-fast low-angle shot scans were obtained before and at 6, 12, 19, 25, 31, 60, 120, 180, 240, 300, and 600 seconds after contrast injection. The lesions were confirmed, after killing the rabbit, by gross and microscopic examination. RESULTS: The enhancement of normal liver parenchyma, assessed by (SIt-SIo)/SIo.100, (SI = signal intensity) peaked at 32% +/- 4% 19 seconds after injection of 0.3 mmol/kg and at 38% +/- 5% 31 seconds after injection of 0.6 mmol/kg. The difference in maximum parenchymal enhancement achieved, comparing the 0.3 and 0.6 mmol/kg doses, was statistically significant (P < 0.03). Lesion conspicuity, specifically (SIliver-SIlesion/noise), increased from 4.5 +/- 2.3 precontrast to a maximum of 6.8 +/- 1.2 at 19 seconds postcontrast using a dose of 0.3 mmol/kg, with the difference statistically significant (P < 0.03). The increase with a dose of 0.6 mmol/kg was from 4.2 +/- 0.7 to 6.5 +/- 1.9 with this difference also statistically significant (P < 0.02). There was no statistically significant difference in lesion conspicuity between the doses of 0.3 and 0.6 mmol/kg. CONCLUSIONS: Conspicuity of liver metastases can be improved substantially with dynamic magnetic resonance imaging and rapid intravenous bolus contrast injection with a dose of 0.3 mmol/kg. No further improvement is noted at a dose of 0.6 mmol/kg, despite greater positive contrast enhancement of normal liver parenchyma.

Magnetic resonance imaging of experimental pyelonephritis in rabbits.

RATIONALE AND OBJECTIVES: An experimental model of acute focal pyelonephritis was developed in the New Zealand White rabbit, with initial imaging evaluation performed using high-field contrast-enhanced magnetic resonance (MR) in six animals. METHODS: The left kidney was visualized fluoroscopically after intravenous injection of iodinated contrast. A 0.1 mL mixture of agarose/Streptococcus faecalis was then injected percutaneously into the kidney at the corticomedullary junction with a 25-gauge needle. The animals were imaged at 1.5 tesla on day 5 after injection of bacteria. Breathhold T2-weighted and T1-weighted scans were acquired prior to contrast injection. Using an MR-compatible power injector, 0.3 mmol/kg gadoteridol was then administered, with both dynamic and delayed postcontrast scans obtained. The lesion was confirmed in each animal by gross and microscopic exam. RESULTS: The area of acute focal pyelonephritis was somewhat difficult to identify on precontrast scans. The lesion was mildly hyperintense on T2-weighted scans and slightly hypointense to isointense on T1-weighted scans relative to normal surrounding renal parenchyma. On early dynamic turbo-fast low-angle shot scans, the lesion could be identified due to differential tissue enhancement. Direct visualization of the lesion, with increased conspicuity relative to precontrast scans, was possible because of delayed positive enhancement at 60 seconds postcontrast. Lesion conspicuity, assessed by signal difference/noise ratio, increased from 0 +/- 5 precontrast to a peak of 12 +/- 6 at 60 seconds postcontrast (P = 0.003; n = 6). CONCLUSIONS: On dynamic contrast-enhanced MR, acute focal pyelonephritis can demonstrate transient positive contrast enhancement (using a contrast dose of 0.3 mmol/kg) relative to surrounding normal renal parenchyma. This appearance is due to hyperconcentration of the contrast agent in normal parenchyma and T2 effects. The pattern is opposite that seen in spiral computed tomography.

Contrast-enhanced magnetic resonance imaging in a spinal epidural tumor model.

RATIONALE AND OBJECTIVES: A spinal epidural tumor model was developed, using the VX-2 adenocarcinoma in rabbits, to assess the strengths and weaknesses of magnetic resonance (MR) as a cross-sectional imaging modality for the evaluation of epidural neoplastic disease. High-resolution MR images were acquired both before and after intravenous gadolinium chelate injection, assessing lesion detectability and efficacy of imaging technique. METHODS: An adenocarcinoma tumor (VX-2) was produced in the epidural space of six New Zealand White rabbits and subsequently studied on a 1.5 tesla whole body MR scanner. VX-2 tumor tissue was removed from the thigh of a carrier rabbit, minced, and screened. Under fluoroscopic guidance, 0.2 mL of the tumor preparation was then injected into the epidural space of the experimental rabbits. The injection was performed at the L5-6 level using an epidural needle and polyethylene tubing sleeved within the needle. The rabbits were imaged using a circular small parts surface coil 5 to 15 days after the epidural injection. In all six animals, one complete MR exam was obtained within the time frame of days 9 to 11. T1- and T2-weighted axial scans were obtained before contrast injection, with the T1 scans acquired both with and without fat saturation. Postcontrast T1 scans also were obtained, using fat saturation, after the injection of 0.1 and 0.3 (cumulative dose) mmol/kg gadoteridol (Gd HP-DO3A; ProHance) in all animals. The film images were interpreted in a prospective fashion by a single neuroradiologist who was masked to imaging technique and contrast dosing. The digital data was analyzed by region of interest measurement. At the end of the imaging studies, the animals were sacrificed and the epidural lesion confirmed by gross and microscopic exam. RESULTS: On a prospective masked read of the MR films, epidural tumor was depicted best on postcontrast fat saturation T1-weighted scans using a cumulative contrast dose of 0.3 mmol/kg. Substantial contrast enhancement of the tumor was observed in all instances on postcontrast scans. The precontrast T1-weighted scan was least efficacious for lesion identification and differentiation from the compressed spinal cord. Depending on the pulse sequence used, one (T2-weighted) to three (T1-weighted without fat saturation) of the lesions could not be identified prospectively on precontrast scans. Lesion growth with time after implantation was chronicled by MR imaging, accompanied by progression of symptoms. On region of interest analysis, differentiation of epidural tumor from normal cord was greatest (11.6 +/- 6.1) on postcontrast scans using a cumulative contrast dose of 0.3 mmol/kg. The level of differentiation achieved was twice that of postcontrast scans using a contrast dose of 0.1 mmol/kg (5.9 +/- 3.6). These results were superior on statistical analysis to that with all other scan techniques (P = 0.002-0.0005). Cord and tumor could not be differentiated on the basis of signal intensity, with any statistical significance, using precontrast T1 and T2 scans. The lesions were confirmed in each animal by gross and microscopic exam. On inspection of the gross specimen, the tumors were noted to be located in the epidural space and to cause cord compression. On microscopic exam, the tumor was composed of epithelial cells that were moderately pleomorphic. CONCLUSIONS: In the New Zealand White rabbit, an epidural tumor could be created consistently using the described percutaneous approach. These lesions are suitable for MR imaging studies, examining lesion detectability and efficacy of imaging technique. The lesions created in the current study could not be diagnosed prospectively in all cases on precontrast T1 and T2 scans images. Postcontrast scans were most efficacious for diagnosis and lesion delineation, with high-dose (0.3 mmol/kg) scans superior to standard dose (0.1 mmol/kg).

Magnetic resonance imaging in a spinal abscess model. Preliminary report.

RATIONAL AND OBJECTIVES: Magnetic resonance (MR) scan technique and lesion detectability were evaluated using a newly developed spinal abscess model in the New Zealand White rabbit. METHODS: To create the lesion, an epidural needle was inserted under fluoroscopic guidance in the lumbar region and advanced to penetrate the ligamentum flavum. Next, polyethylene tubing was fed through the needle into the epidural space. A mixed suspension of Staphylococcus aureus (Cowan I) and blue polystyrene microspheres then was injected. Lesions were evaluated by MR imaging in four animals at multiple time points (3, 6, and 9 days). Imaging was performed at 1.5 tesla using a surface coil. Precontrast T2-and T1-weighted scans were first obtained. The T1-weighted scans were acquired both with and without fat saturation, and were repeated after intravenous contrast administration. The contrast agent used was gadoteridol (gadolinium HP-DO3A or ProHance) at a dose of 0.3 mmol/kg. RESULTS: On prospective film review, postcontrast scans proved superior for lesion detection. A spinal abscess could be identified postcontrast in all cases, irrespective of the use of fat saturation. The next best imaging technique for lesion detection was the T2-weighted scan, with 5 of 8 lesions noted thereon. Visualization of lesion margins proved to be a primary factor in prospective lesion identification. Region of interest image analysis demonstrated the postcontrast scans to be superior to all precontrast scan techniques for conspicuity of the interface between the abscess and the compressed spinal cord, with these results statistically significant. The lesions were characterized histologically by infiltrates of heterophils into the meninges and outer spinal cord with accompanying mild hemorrhage, fibrin exudation, and bacterial colonies. The lesions in three animals were confirmed to be in the epidural space, with the lesion in one animal in the subdural space. CONCLUSIONS: The current animal model was developed to study spine infection and, specifically, imaging characteristics and lesion detectability on MR. With the increased use of epidural catheters for pain management and the large number of acquired immunodeficiency syndrome cases, epidural infection is becoming an increasingly important clinical problem. Imaging technique, in particular the use of intravenous contrast, is critical for lesion detection and evaluation.

Hepatic abscesses. Magnetic resonance imaging findings using gadolinium-BOPTA.

RATIONALE AND OBJECTIVES: Gadolinium (Gd)-BOPTA was evaluated in a rabbit liver abscess model and compared with Gd-HP-DO3A, examining lesion conspicuity and characterization. METHODS: Five New Zealand White rabbits with a liver abscess were studied on a 1.5-tesla Siemens Vision magnetic resonance unit. The disease model was created by surgically implanting a gel capsule filled with fusobacterium into the central or left lobe of the liver. For imaging, the animals were ventilated using a Harvard pump. Pancuronium bromide (0.12 mg/kg) was administered to allow acquisition of breath-hold scans. Magnetic resonance scans were obtained in each animal on days 2 and 3 after surgery. Every animal was studied twice, once after intravenous injection of 0.3 mmol/kg Gd-HP-DO3A (gadoteridol; ProHance) and once after intravenous injection of 0.1 mmol/kg Gd-BOPTA (gadobenate dimeglumine; MultiHance). The order of injection for the two agents was randomized with the two studies in each animal, separated by 24 hours to permit clearance. Image acquisition was performed in each instance with respiration suspended. Baseline two-dimensional spin-echo T1-weighted and fast spin-echo T2-weighted breath-hold scans were obtained first. The voxel dimensions were 5 x 0.8 x 0.8 mm3. Imaging times were 23 seconds for the T1-weighted scan and 26 seconds for the T2-weighted scan. Postcontrast scans, using spin-echo T1-weighted technique, were obtained at 1, 3, 5, and 15 minutes after contrast injection, whether Gd-HP-DO3A or Gd-BOPTA was used. Additional scans were obtained at 30, 45, and 60 minutes after Gd-BOPTA administration. At the completion of imaging on day 3, each animal was killed and the liver was removed and taken to a veterinary pathologist at the University's animal disease diagnostic lab for gross and histologic examination. RESULTS: The enhancement of normal liver parenchyma, assessed by region of interest measurement and specifically as (SI(t) - SI0)/SI0 x 100, peaked at 119 +/- 37% 1 minute after injection of 0.3 mmol/kg Gd-HP-DO3A and at 126 +/- 30% 30 minutes after injection of 0.1 mmol/kg Gd-BOPTA. The difference in enhancement achieved, comparing results at each time point, was statistically significant only at 1 and 3 minutes postcontrast (P = 0.003 and 0.03). Lesion conspicuity, specifically (SIliver - SIlesion/noise), increased from 272 +/- 29 precontrast to a maximum of 639 +/- 73 at 30 minutes postcontrast using a dose of 0.1 mmol/kg Gd-BOPTA, with the improvement statistically significant (P = 0.0003). Lesion conspicuity on the T2-weighted scan was 137 +/- , with the Gd-BOPTA scan markedly superior (P = 0.00004). On scans at 45 and 60 minutes after Gd-BOPTA administration, a progressive increase in signal intensity in the central necrotic portion of the lesion was observed. This was most consistent with gradual diffusion of the agent from the adjacent liver into the lesion. Using Gd-HP-DO3A at 0.3 mmol/kg (three times the dose for Gd-BOPTA), lesion conspicuity increase from 305 +/- 37 precontrast to a maximum of 701 +/- 92 at 1 minute postcontrast, with this difference also statistically significant (P = 0.0004). The abscess rim exhibited moderate contrast enhancement, greater than that of normal liver parenchyma, on early postcontrast images with Gd-HP-DO3A. CONCLUSIONS: The conspicuity of an early liver abscess is improved markedly on delayed imaging after administration of 0.1 mmol/kg Gd-BOPTA. Although a similar magnitude of parenchymal enhancement can be obtained after the administration of an extracellular agent, such as Gd-HP-DO3A, high-contrast dose (0.3 mmol/kg) and early dynamic imaging are required. The appearance of a liver abscess on late scans (45 to 60 minutes) after Gd-BOPTA injection is distinct from that of nonnecrotic metastases, with diffusion of the agent into the lesion noted.