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1 All authors: Department of Diagnostic and Interventional Radiology, University Hospital Essen, Hufelandstrasse 55, Essen 45122, Germany.
Received May 19, 2003;
accepted after revision June 30, 2004.
Address correspondence to S. C. Goehde.
Abstract
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SUBJECTS AND METHODS. The study group was composed of 331 subjects. The MRI protocol (mean examination time, 63 min) encompassed the target organs: the brain, arterial system, heart, and colon. Diagnoses were deemed relevant if the physician had to inform the subject about the findings. Subjects with a history of serious illnesses were excluded from subsequent analysis (n = 33). All analyses were performed for the resulting subgroup of 298 subjects (247 men, 51 women; mean age, 49.7 years).
RESULTS. All 298 examinations were diagnostic excluding eight MR colonography components in which remaining stool hampered reliable diagnosis. Follow-up or radiologic confirmation could be obtained in 75% of all cases with relevant findings (128/169); only one false-positive result was encountered. Of the study group, 21% exhibited signs of atherosclerotic disease. Two cerebral infarctions and one myocardial infarction, previously unknown, were encountered; 12% had peripheral vascular disease. Twelve colonic polyps and nine pulmonary lesions were correctly detected. Of all MRI examinations, 29% revealed relevant additional findings in nontargeted organs. Only one minor allergoid reaction was encountered.
CONCLUSION. The presented data point toward an increased use of MRI for screening in the future, but to date screening MRI should not be performed outside a research setting because the cost–benefit relation is unclear.
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Risks associated with high radiation doses inherent to CT cast a shadow on the future of CT-based screening. Although with recent low-dose protocols the total radiation dose to the subject is minimized and radiation-induced individual risk might be far less than the risk of subsequent diagnostic and therapeutic interventions, the U.S. Food and Drug Administration has issued radiation alerts [6], and the European Union has passed legislation prohibiting the use of examinations based on ionizing radiation for screening purposes except mammography [7]. Recognition thereof has focused attention on an imaging technique void of ionizing radiation or other harmful side effects: MRI.
On the basis of the inherently high soft-tissue contrast in conjunction with high spatial and temporal resolution, MRI emerged as the imaging technique of choice in the evaluation of many organs. Among them, the central nervous system features prominently; inflammatory, neoplastic, and vascular disease are reliably detected or excluded using MRI [8, 9].
Similarly, the arterial system is accurately assessed with MR angiography. Compared with catheter-based angiography, MR angiography has been shown to be equivalent in virtually all territories including the carotid [10], renal [11], and peripheral [12] arteries. Motivated by the systemic nature of atherosclerotic disease, the concept of whole-body MR angiography—encompassing the arterial tree from the carotids to the trifurcation vessels—has recently been introduced [13].
At the same time, cardiac MRI permits the evaluation of regional and global myocardial contractibility, valvular function [14], and myocardial viability and perfusion [15]. Finally, MRI has been shown to be capable of detecting mass lesions exceeding 10 mm in the lungs [16] and colon [17] with high sensitivity and specificity.
To date, cost concerns and lengthy data acquisition times have prohibited the use of MRI for screening. Recent hard- and software advances combining toward faster data acquisition over several body regions have opened new possibilities. Thus, a comprehensive 60-min MRI protocol permitting the detection of early cardiovascular disease and lung and colon cancer has been developed. The purpose of this study was to assess the technical feasibility of this MRI-based comprehensive screening strategy and to determine the frequency of findings pointing to the targeted and other diseases.
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Subsequent analysis was thus limited to a subgroup of 298 subjects encompassing 247 men and 51 women who ranged in age from 31 and 73 years with a mean age of 49.7 years. Only 2.6% of them were 65 years old or older, and only 15.8% were under 40 years old. Of the group, 20% were smokers, and the mean body mass index was 24.6. The imaging material was shown to the subjects after completion of the examination. Compliance regarding suggested treatment or follow-up diagnostic examinations was monitored by telephone interviews and review of medical records.
MRI
Imaging was performed on a 1.5-T MRI system (Magnetom Sonata, Siemens
Medical Solutions), equipped with a fully MRI-compatible rolling table
platform (AngioSURF, MR-Innovation) for whole-body coverage
[18], which allows image
acquisition using a body array surface coil. The comprehensive MRI-based
screening protocol contained five components (Tables
1 and
2).
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First, the cerebrum was assessed by fast T1- and T2-weighted spin-echo, FLAIR, and diffusion-weighted imaging. The intracerebral arterial system was directly visualized by axial 3D time-of-flight MR angiography. At a later time point (after the cardiac examination), a T1-weighted gradient-echo sequence was applied, which made use of the contrast agent that had been given for MR angiography (contrast-enhanced sequence of the brain for tumor detection). This sequence was performed for subject number 51 and all subsequent examinations; before this time point, the contrast-enhanced sequence was not part of the protocol.
Second, whole-body MR angiography based on the acquisition of five slightly overlapping 3D coronal data sets (64 sections each) acquired in immediate succession using a fast 3D fast low-angle shot (FLASH) sequence was performed. Each data set was collected over 12 sec, and the first three data sets were acquired using the breath-hold technique. The addition of a 3-sec pause for table movement from one body region to the next translates into a total acquisition time of 72 sec. After conventional test bolus timing with 1 mL at 1.2 mL/sec for individual assessment of circulation time, a 1-molar gadolinium-based contrast agent (Gadobutrol, Gadovist 1.0, Schering) was administered at a dose of 0.2 mmol/kg of body weight for arterial enhancement [19, 20] via a 19-gauge plastic IV line placed in the antecubital vein. The contrast material was diluted with saline solution to a total amount of 60 mL. Then, a biphasic contrast injection protocol was used: a first flush of 30 mL at 1.2 mL/sec and a second flush at 0.7 mL/sec, followed by a saline flush of 20 mL at 0.7 mL/sec. No venous compression was used.
Axial HASTE imaging (slice thickness, 8 mm) of the thorax was performed to depict the pulmonary parenchyma and cardiac morphology. For this purpose, two blocks of slices were acquired, both using the breath-hold technique. The former injected contrast agent (for MR angiography) does not alter the value of this T2-weighted sequence. No additional contrast material was given for this MRI examination of the lungs.
Subsequent functional assessment of the heart was based on segmented true fast imaging with steady-state free-precession (true FISP) cine measurements collected in the left ventricular short axis. Standard valvular views (four-chamber, two-chamber, and outflow) were added. A segmented inversion recovery turbo gradient-echo sequence, collected in both the short (3D) and long (2D) axes making use of the contrast administration for whole-body MR angiography, was assessed for areas of late enhancement denoting myocardial infarction. A total of 13–18 breath-holds were performed.
For MR colonography, all subjects had undergone standard preparation for bowel cleansing. Scopolamine (40 mg) was administered IV to minimize bowel motion. Glaucoma required the alternative use of glucagon in three subjects (dosage 100 mg = 1 IU). The subjects were imaged in the prone position only because air bubbles, due to their low signal, do not pose a problem in image assessment of the T1-weighted sequences. The colon was filled with 1,500–2,500 mL of warm tap water via rectal enema. The amount of water administered rectally was chosen according to the subject's acceptance. No fluoroscopic imaging was performed for guidance of the enema, because our experience shows that this approach results in sufficient colonic distention. T1-weighted 3D gradient-echo images (96 sections) of the colon were collected during breath-holding over 23 sec before and 60 and 90 sec after a second IV administration of gadobutrol at a dose of 0.1 mmol/kg of body weight.
Imaging Data Review
The in-room time—that is, the time between the subject entering the
MRI room for positioning and the subject leaving the MRI room—was
determined. All imaging data were analyzed prospectively on a workstation
(Virtuoso, Siemens Medical Solutions) and interpreted by two board-certified
radiologists with extensive MR experience (> 5 years) in consensus. The
workstation permitted 2D, 3D, and cine loop viewing and rendered maximum
intensity projections and multiplanar reformations. The reviewers were privy
to the questionnaires filled out by the subject before the examination.
MRI data of the brain were reviewed for the presence of direct or indirect signs of vascular disease as evidenced by alterations affecting the intracerebral arteries themselves or the cerebral parenchyma (infarction, white matter lesions). Additional findings within the brain or other structures such as the paranasal sinuses were also noted.
Whole-body MR angiography was analyzed for the presence of arterial luminal narrowing exceeding 50% on the basis of the most severe reduction of the arterial diameter compared with the most normal-appearing segment proximal or distal to the area of arterial compromise, arterial occlusion, arterial wall irregularities, ectasia of vessel parts, and aneurysmal disease. For this purpose, no image mask subtraction was used in any of the five angiography stations.
MRI data of the heart were reviewed qualitatively according to the following diagnostic groupings: myocardial infarction (transmural or nontransmural), regional wall motion disorders, global contractibility reduction, myocardial hypertrophy, and valvular disease. In case the diagnosis of a potentially reduced global ejection fraction was made, a subsequent quantitative analysis of the respective parameters (end-systolic and end-diastolic volume, ejection fraction) was performed using semiautomatic cardiac evaluation software (Argus, Siemens Medical Solutions).
The pulmonary parenchyma was evaluated for the presence, location, and size of pulmonary mass lesions and other incidental findings such as pleural effusions.
Similarly, MR colonography data sets were searched for the presence of enhancing colorectal masses. Reported incidental findings included diverticular disease and renal, hepatic, spinal, adrenal, gastric, pancreatic, and retroperitoneal masses.
Data Analysis
Findings were characterized as relevant or not relevant. Relevant findings
led to informing the subject of the findings, a therapeutic recommendation, or
mandated subsequent diagnostic follow-up. This definition was used according
to the routine clinical setting, in which nonmalignant findings are also
explained in the reports or, in case of self-referral, in which the subjects
are informed about possibly important findings. This includes anatomic
variations such as the retroaortic renal vein or degenerative spine disease
because these findings can lead to symptoms and hepatic hemangiomas because
this finding might pose differential diagnostic problems in the future; the
informed patient can resolve the problem.
Thus, arterial narrowing exceeding 50%; the presence of aneurysmal disease, cerebral infarctions, or extended microangiopathic white matter lesions; colorectal masses; and evidence of myocardial infarction, reduced regional or global ventricular wall motion, left ventricular hypertrophy, and valvular disease were considered relevant. Similarly, the presence of gastric herniation, renal masses, focal pulmonary lesions of potential malignancy, extensive paranasal sinusitis, heterogeneous or enlarged thyroid, adrenal masses, and frank spinal disk herniation were considered relevant. Identification of renal or hepatic cysts or hemangiomas and of light to moderate paranasal sinusitis was considered not relevant. Similarly, focal arterial irregularities or stenoses with luminal narrowing of less than 50% and diverticular disease were considered not relevant.
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Subsequent disease-oriented analysis was limited to the 298 subjects who were considered not seriously ill. Results of a cursory questionnaire focusing on medical history are summarized in Table 3. Only 69% of all subjects did not show any relevant finding in the target organs (arteries, heart, brain, or colon) (Figs. 1A, 1B, 1C, 1D, 1E, 2, 3A, 3B, 3C, 4A, 4B, 4C, 4D, 5).
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Vascular Disease
Of the 298 subjects, MRI revealed signs of cerebrovascular, peripheral
vascular, or cardiovascular disease in 21%
(Table 4). Twenty-seven
subjects (9%) had unequivocal macro- or microangiopathic changes within the
cerebrovascular system, nine of them of medium to higher degree
(Table 4 and Fig.
6A,
6B,
6C,
6D,
6E). Of those, MRI revealed
unknown cerebral infarctions in two subjects and a tandem stenosis of the
extracranial internal carotid artery in one subject.
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In 20 subjects (7%), whole-body MR angiography revealed relevant signs of atherosclerosis (Table 4), including two high-grade stenoses of the proximal internal carotid artery, a focal dissection of the infrarenal aorta in a 40-year-old smoker, and dissection of the superficial femoral artery in a 52-year-old smoker (Fig. 7). In two subjects, one intracerebral aneurysm (size, 5 mm) and one fenestration of the basilar artery were detected as a risk factor for the development of cerebral aneurysms. In 18 additional individuals, only irregularities of the vessel walls or focal calcified plaques of the peripheral arterial system were identified; those cases with multifocal extended atherosclerotic disease or plaques of the internal carotid artery (n = 8) were regarded as relevant.
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No subject had difficulties performing the repeated breath-holds (up to 18) during the cardiac part of the examination. Cardiac MRI revealed a previously unknown subendocardial infarction in a 62-year-old man, shown by late enhancement. In five individuals, all men, regional or global myocardial dyskinesia with reduced ejection fractions (< 50%) was noted. MRI revealed left myocardial hypertrophy in 17 subjects, of those 64.7% had known arterial hypertension, compared with only 23.8% of the remaining subjects. Eleven subjects had valvular disease.
Pulmonary Disease
The HASTE data sets revealed nine pulmonary lesions ranging in diameter
between 3 and 7 mm in five subjects. Of those, seven were classified as
probably benign, making use of a set of different parameters such as signal,
size, and shape. CT was performed for further evaluation in only of two
subjects (each with two pulmonary lesions); in these cases, the lesions could
be confirmed to be benign (Fig.
8A,
8B,
8C,
8D) and the single masses were
found to be partially calcified.
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Colonic Disease
In all subjects, sufficient distention of all colonic parts was obtained.
All images were of diagnostic quality, except for eight MR colonography
components in which remaining stool hampered reliable diagnosis. Twelve
examinations of the colon showed unequivocal polyps ranging in diameter from 5
to 13 mm (Fig. 9A,
9B,
9C). Diverticular disease was
diagnosed in 15 subjects, which was rated as a nonrelevant side finding.
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Other Findings
Beyond the targeted organs (arteries, brain parenchyma, heart, colon),
additional findings were reported, particularly in the abdomen. These findings
are listed in Table 5. One
renal cell carcinoma was detected, and no other malignancies were
encountered.
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Confirmation with Other Imaging Techniques
Seventy-five percent of all cases with relevant findings were corroborated
clinically at the time of treatment (polypectomy, renal surgery) or by other
dedicated forms of imaging including sonography, CT, and MRI (Tables
4 and
5). In one case, a
contrast-enhancing 10-mm vertebral lesion, judged initially as relevant, was
diagnosed as a hemangioma on dedicated spine MRI and hence was reclassified as
not relevant. Of the nine pulmonary lesions identified on MRI, four were
subsequently confirmed by MDCT in two subjects
(Table 4); they were found to
be partially calcified. All relevant arterial stenoses (except lower limb
artery stenoses in one subject) were confirmed by sonography, regional MR
angiography, or digital subtraction angiography. All colonic polyps were
confirmed at colonoscopic polypectomy.
Image Demonstration
All subjects readily accepted the offer to have the imaging material shown
to them after the examination, resulting in a high rate of compliance
regarding diagnostic examinations or therapy for findings deemed relevant.
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Cardiovascular disease is the leading cause of mortality in western societies [21]. Although the known risk factors are readily identifiable by a combination of physical examination, laboratory analysis, and patient history, the proposed MRI protocol offers a unique opportunity to assess what damage if any has already been inflicted on the cardiovascular system. Thus, the outlined protocol has been shown to be highly sensitive regarding the identification of cerebrovascular disease. The size, number, and distribution of ischemic cerebral regions permit consideration of possible causes: thus, microangiopathic changes of the cerebral white matter are highly suggestive of hypertension [22], and thromboembolic changes are most frequently induced by high-grade carotid disease.
Early diagnosis of carotid stenoses is important because patients with stenoses of the internal carotid artery that are greater than 75%, as measured by Doppler examination, are at risk for stroke, in the range of 2% to 5%, within the first year of observation; this risk can be reduced by a factor of up to 55%. Furthermore, of patients who develop stroke during the observation of an asymptomatic lesion, 83% had no warning symptoms [23, 24]. Our 2.3% prevalence of cerebral infarction and microangiopathy correlates well with the literature [25], underlining the high sensitivity of MRI for intracerebral vascular lesions.
Because screening also must consider rare but significant cerebral tumors, a contrast-enhanced cerebral sequence should be part of the protocol. This sequence was integrated at the end of the cardiac examination with no need for additional contrast agent administration because the sequence makes use of the contrast agent previously administered for MR angiography. Similarly, the proposed protocol offers a highly accurate assessment of myocardial viability. On the basis of delayed enhancement, infarcted myocardium is detected on T1-weighted images with high sensitivity and specificity [26, 27], allowing early secondary prevention strategies that have been shown to alter outcomes in high-risk, not yet symptomatic patients [28].
The cardiovascular screening component also encompasses a thorough analysis of the arterial lumen by means of intracerebral time-of-flight and contrast-enhanced multistation whole-body MR angiography. The quality of the former has been shown to be sufficient to detect small aneurysms or precursors thereof [29], as confirmed in two of the screened patients. Whole-body MR angiography mirrors the generalized nature of atherosclerotic disease from a diagnostic viewpoint. The 40-cm field of view of our scanner leads to a slight reduction in the signal-to-noise ratio at the upper and lower margins of the single source images, which is obvious in the maximum intensity projections; however, because the window and level settings can be adjusted for each of the subregions when multiplanar reformations are assessed, this lower signal-to-noise ratio does not result in problems. The technique has thus been shown to be accurate in the detection and characterization of arterial disease [13].
Early diagnosis of peripheral vascular disease plays a role in convincing patients to lower their risk profile and to extend physical activity [30]. Merely the lumen of the coronary arteries remains unassessed by MR angiography. Even though several techniques have been proposed, none has gained clinical relevance. Although the ability to analyze myocardial viability in combination with ventricular function reduces the impact of this deficit, incorporation of coronary MR angiography into a future screening protocol remains highly desirable. Until this time, it seems crucial that some form of cardiac evaluation under stress conditions be performed.
As part of the cardiac examination, the lungs are also depicted and thus have to be assessed. MRI of the lung had been handicapped by susceptibility effects at the interfaces between the pulmonary interstitium and air-filled alveoli. These artifacts can be overcome using ultrashort TEs. On the basis of such sequences, the accuracy of MRI regarding the detection of pulmonary lesions has been shown to be quite high [31, 32]. In a study involving 30 patients with known pulmonary masses, axial HASTE images revealed 1,032 of 1,102 lesions seen on CT (Schroeder T et al., 2002 European Congress of Radiology). Reflecting the lack of signal-providing protons, smaller-calcified nodules were missed. Furthermore, lesions with a diameter of less than 3 mm were also missed. This might explain the low number of pulmonary lesions found in our study. Some kind of screening for pulmonary nodules should be performed in such a multiorgan MRI examination because lung carcinoma is the leading cause of cancer death and lesion detection at an early stage leads to a significantly higher number of T1 tumors found and consecutively to a better outcome [33].
Another focus of the proposed MRI-based screening protocol relates to the detection of colorectal cancer. Colorectal cancer has been a focus of screening efforts for quite some time. Despite these efforts, the incidence of colorectal cancer continues to increase with more than 130,000 newly diagnosed cases and 50,000 deaths in the United States alone [34]. The biology of colorectal cancer, evolving from precancerous colonic polyps to carcinoma over a considerable time span, has elevated colorectal polyp screening with subsequent endoscopic polypectomy to one of the most promising preventive measures in medicine [34, 35].
MR colonography overcomes many of the shortcomings limiting the clinical impact of existing screening techniques including the gold standard conventional colonoscopy. In the setting of a dark, water-filled colonic lumen, lesion detection is based on enhancement of the colonic wall and of colorectal masses [36]. The technique has been shown to be both sensitive and specific regarding the detection of colorectal masses [36, 37]. The overall prevalence of colonic polyps of 4% in our study population is lower than the expected prevalence of 14–25% [38] for patients older than 50 years. This result certainly might reflect the limited spatial image resolution, which does not permit the diagnosis of polyps less than 5 mm; however, it also mirrors the very low prevalence (< 1%) [39] of polyps in patients younger than 50 years. Just as important as diagnostic accuracy, high patient acceptance of the examination is assured by the lack of procedural pain and the prospect of fecal tagging, which has been shown to successfully eliminate the need for colonic cleansing [40].
Detected relevant findings were not limited to the target organs. Rather, there were a number of additional relevant findings. Analysis of the parenchymal organs in the abdomen can be based on 3D gradient-echo data sets collected in the arterial, portal venous, and hepatic venous phases. The first data set is provided as part of the whole-body MR angiography examination, and the subsequent data sets are collected for MR colonography. Previous studies have shown this type of dynamic contrast-enhanced 3D imaging of the abdomen to be accurate regarding the identification of abnormalities in the parenchymal organs [41]. Similar experiences have been reported on the basis of MR colonography data sets alone [37]. Hence, it was not surprising that the featured imaging protocol did result in the identification of multiple additional findings outside the target organs with considerable specificity.
Clearly, the limited number of individuals included in this study cannot provide relevant data regarding the value of MRI-based screening from a societal perspective. This will need to be accomplished in larger-scale studies. However, the presented data are sufficient to illustrate the technical feasibility of a comprehensive MRI-based screening approach capable of assessing multiple organ systems in a single examination. Furthermore, this study does provide an overview of the kind of abnormalities that can be identified. The diagnostic accuracy of the different components making up the comprehensive MRI protocol has been established in a number of comparative examinations against gold standards. Lack of follow-up examinations in individuals lacking abnormal findings prohibits any meaningful analysis of the studied subjects in this regard.
On the basis of the available data, we are comfortable recommending therapeutic interventions or further diagnostic workup aimed at preventing disease progress. Furthermore, we found the images displaying abnormalities useful in persuading subjects to consider lowering their risk profile by quitting smoking, reducing cholesterol intake, or becoming more compliant with hypertension medication. Although this study falls short of offering conclusive evidence, immediate reactions of individuals at the time of image data presentation did indeed suggest a profound impact. The high compliance rate of individuals with suggested subsequent diagnostic and therapeutic steps supports this observation.
This study is one of the first attempts to implement and evaluate a comprehensive MRI-based screening examination. Compared with the radiation exposure caused by CT, public health concern associated with MRI is minimal. Thus, exposure to MRI as a patient has never been associated with any harmful side effects [42]. Side effects may, however, be associated with the administration of paramagnetic contrast agents, which must be considered an integral part of the proposed examination. Although rare, anaphylactoid reactions may occur. Hence, individuals need to be monitored during the examination procedure. Only one subject showed a minor allergoid reaction in this study. On the other hand, nephrotoxicity, a worry with iodinated contrast agents, is of no concern [43].
Preparation of the colon was necessary for MR colonography, which is known to be the most unpleasant part of conventional colonoscopy [44]. Because the single subjects were keen to receive the MRI examination, none complained about bowel cleansing.
This study, however, does not provide data about the potential benefits or costs that would be gained or would have to be spent for subsequent diagnostic or therapeutic procedures. Also, the potential harm due to treatment of false-positive findings cannot be addressed. This study was not designed to answer these difficult questions; rather, it presents a potential multiorgan screening design and reports about the range of diseases that one encounters in such a setting.
We conclude that the outlined MRI-based screening strategy encompassing the brain, the arterial system, the heart, and the colon was well tolerated and yielded relevant, un-suspected findings for a variety of organs. The presented data point toward an increased use of MRI for screening in the future. However, as long as the individual and socioeconomic impact are not known, screening examinations should be performed in a research setting, which would also help to collect performance and outcome data.
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