I Clinical and Community Studies

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1 I Clinical and Community Studies Magnetic resonance imaging for detecting lesions of multiple sclerosis: comparison with computed tomography and clinical assessment Lionel Reese, MD, FRCSC, FRCPC Thomas J. Carr, MD, FRCPC Richard L. Nicholson, MD, FRCPC Eric K. Lepp, MD, FRCPC Eighty-two patients with known or suspected multiple sclerosis (MS) were examined by means of magnetic resonance imaging (MRI) with a 0.15-T resistive scanner. The diagnosis could be made by MRI in 34 (97%) of the 35 patients with chronic, well-documented, stable MS and by high-volume delayed x-ray computed tomography (HVD CT) in only 6 (54%) of 11 patients in this group. The stage of the disease as judged from the MRI scans correlated poorly with the clinical status of the patient and with the known duration of the disease. MRI identified 28 (88%) of the 32 patients in whom MS was subsequently diagnosed by a neurologist, whereas regular contrast or HVD CT identified only 11 (52%) of 21 such patients. MRI is the most sensitive imaging modality for MS but is of little value in assessing the severity of the disease: many of the lesions seen on MRI scans are clinically "silent", and MRI does not usually detect small lesions in the brainstem, cerebellum or spinal cord that may be clinically significant. On pratique l'imagerie par resonance magnetique (RM) avec un appareil de 0,15 Tesla sur 82 sujets prdsentant une sclerose en plaques (SP) confirmee ou soupconnde. Parmi 35 sujets dont From the Department of Nuclear Medicine, St. Joseph's Health Centre, London, Ont. Reprint requests to: Dr. Thomas J. Carr, Department of Nuclear Medicine, St. Joseph's Health Centre, 268 Grosvenor St., London, Ont. N6A 4V2 la maladie est prouvee, chronique et stable, cette methode fait le diagnostic de 34 d'entre eux (soit 97%), alors que la tomodensitomdtrie (TDM) retardee avec fort volume de substance de contraste (RFV) ne reconnaft que 6 (soit 54%) de 11 tels sujets. Le stade evolutif de la maladie tel que demontre par RM n'est en bonne correlation ni avec l'etat clinique ni avec la duree connue de la maladie. La RM fait le diagnostic de 28 (88%) des 32 malades chez qui il sera pose subsdquemment par des neurologues; ce n'a dte le cas de la TDM (banale ou RFV) que chez 11 (52%) de 21 tels sujets. Bien que la RM se revele ainsi la meilleure imagerie pour le diagnostic d'une SP, elle renseigne peu sur sa gravite: si d'une part elle demontre beaucoup de lesions qui sont cliniquement silencieuses, d'autre part elle ne met pas ordinairement en dvidence de petites lesions du tronc cerebral, du cervelet ou de la moelle epiniere qui peuvent avoir un grande importance clinique. n most cases the diagnosis of multiple sclerosis (MS) is based on the history and the results of physical examination and examination of cerebrospinal fluid. The role of imaging of the central nervous system (CNS) has primarily been to exclude other possible causes of the patient's symptoms. However, with the introduction of magnetic resonance imaging (MRI), the role of CNS imaging in the diagnosis of MS has become more positive. Several investigatorsl-6 have shown that MRI is useful in detecting CNS abnormalities in patients with MS, but some of their studies involved relatively few patients, lacked suitable control groups and used a variety of MRI pulse sequences. CMAJ, VOL. 135, SEPTEMBER 15,

2 We set out to determine the following. * Whether the results of scoring the MR images of patients with chronic, well-documented, stable MS using a modification of the system of Runge and colleagues4 correlate with the clinical status (Kurtzke disability score7) and the known duration of the disease. * Whether MRI is useful in the diagnosis of MS in patients suspected of having the disease. * Whether MRI is more or less sensitive than regular contrast x-ray computed tomography (CT) or high-volume delayed (HVD) CT8 in the diagnosis of MS. Methods The study involved 102 subjects: 35 patients with chronic, well-documented, stable MS who had been referred for MRI as part of a therapeutic trial;9 47 patients who had been referred by neurologists for evaluation of probable or possible MS; and 20 subjects who had been selected as a control group - 10 patients with temporal lobe epilepsy and 10 healthy young adults. All the subjects were screened prior to MRI for possible contraindications, such as the presence of aneurysm clips or pacemakers, and all gave informed consent for the scans. The study was approved by the Human Experimentation Committee of the University of Western Ontario. MRI was done with a 0.15-T resistive unit (Technicare Corporation, Solon, Ohio). Upgrades to both hardware and software components of the imager were made over the duration of the study. The theory of MRI is reviewed in recent publications.10"1 All the subjects were initially studied by means of a 32-slice, spin-echo (SE) anisotropic volume technique with a repetition time (TR) of 1000 ms and an echo time (TE) of 60 ms. To help confirm that there were indeed lesions rather than other causes of increased signal such as hemorrhage, additional single slices were taken through suspicious areas by an inversion-recovery technique with a TR of 1600 ms, an inversion time (TI) of 450 ms and a TE of 30 ms or by an SE technique with a TR of 1000 ms and a TE of 120 ms. If the clinical findings suggested brainstem lesions a midline sagittal SE slice with a TR of 1000 ms and a TE of 60 ms was also taken. Slices were an average of 1.7 cm thick, and the volume acquisition gave contiguous slices. After a major technical improvement in the equipment, multislice multiecho acquisitions became possible. Subjects were then evaluated by means of 15 contiguous 1-cm-thick SE slices with a TR of 2120 ms and a TE of 60 and 120 ms. Again, sagittal slices were also done when indicated clinically. All images were acquired in a 128-line X 256-point matrix and formatted in a 256 X 256 matrix onto a cathode ray tube for photographing. The pixel size was 1.1 X 2.2 mm before formatting. 640 CMAJ, VOL. 135, SEPTEMBER 15, 1986 Assessment ofpatients with chronic, stable MS The scans of these subjects were read independently by the four investigators, who were unaware of the clinical stage of the disease and scored the scans according to a slight modification of the system of Runge and colleagues. A normal scan is shown in Fig. 1A. Abnormalities were scored as follows. * Stage I: periatrial and a few small supraventricular lesions (Fig. 1B). * Stage II: definite periventricular white matter lesions or supraventricular lesions greater than 0.25 cm in diameter that were well separated from the ventricle and more numerous than in stage I (Fig. 1C). * Stage III: involvement of the frontal horn separate from the ventricle and numerous supraventricular lesions greater than 0.5 cm in diameter or subcortical lesions (Fig. 1D). * Stage IV: brainstem lesions or more n4merous and very large white matter lesions distant from the ventricles (Fig. 2). The between-examiner reliability was assessed by means of the kappa statistic."2 When the same score was assigned to a scan by three of the four examiners, that score was used. In the five cases in which fewer examiners agreed, the four came to a consensus. The scores were compared with the Kurtzke disability score for each patient and the Fig. 1A - Normal magnetic resonance imaging (MRI) scan of brain at midventricular level. Repetition time (TR) 2000 ms, echo time (TE) 60 ms. Scale and rightleft orientation apply to all figures.

3 known duration of the disease by determination of correlation coefficients. Fig. 1B - MRI scan at midventricular level demonstrating stage I multiple sclerosis (MS): periatrial and a few small supraventricular lesions (arrow). TR 2120 ms, TE 60 ms. Assessment ofpatients suspected of having MS and controls The scans of these subjects were studied by one of the investigators and reported as being positive for MS if lesions with a bright signal were seen in the white matter with T2 (transverse or spin-spin relaxation time)-weighted pulse sequences with a long TR (e.g., 2000 ms) and a long TE (e.g., 120 ms). The final diagnosis by the referring neurologist was accepted as the "gold standard". None of these scans were scored by the system of Runge and colleagues. Comparison ofmri with regular HVD CT Both types of CT were done within a few weeks of the MRI, and the radiologists' reports on the CT scans were compared with the scores for the MRI scans. HVD CT was performed on 11 patients randomly selected from the group with chronic, stable MS. In the group suspected of having MS, regular contrast or HVD CT, at the discretion of the attending neurologist, was performed on 21 of the 32 patients with a final diagnosis of MS; 11 underwent regular contrast CT and 10 HVD CT. Ten of the control subjects underwent one or the other form of CT. Results In all cases all the examiners agreed that lesions were present or absent, and there was substantial agreement between the examiners in the scoring of the MRI scans of the patients with Fig. 1C - MRI scan at midventricular level demonstrating stage II MS: definite periventricular white matter lesions and supraventricular lesions greater than 0.25 cm in diameter, separated from ventricle and more numerous than in stage I (arrows). TR 1530 ms, TE 60 ms. Fig. 1D - MRI scan at supraventricular level demonstrating stage III MS: larger supraventricular and subcortical lesions (arrows). TR 1530 ms, TE 60 ms. CMAJ, VOL. 135, SEPTEMBER 15,

4 chronic, stable MS (x = 0.627). The scores finally' assigned to these 35 patients correlated poorly, however, with the Kurtzke disability scores and the known duration of the disease (r2 < 0.002). Of the 35 patients with chronic, stable MS, 34 (97%) were identified by MRI as having MS; of the 11 in this group that underwent HVD CT, only 6 (54%) were identified by this technique as having MS. Of the 47 patients referred for evaluation of suspected MS, 32 were ultimately considered by the referring neurologists as having the disease; of these 32, 28 (88%) were identified by MRI as having MS, but only 5 (45%) of the 11 that underwent regular contrast CT and 6 (60%) of the 10 that underwent HVD CT were identified by these techniques as having MS. Of the 15 ultimately considered as not having MS, 2 (13%) were falsely identified by MRI as having the disease. None of the 20 controls had MRI scans that were positive for MS, and none of the 10 controls that underwent regular contrast or HVD CT showed evidence of MS on these scans. Discussion The same 0.15-T magnet was used for all the MR imaging, but the hardware and software changes during the study transformed it into an almost completely different machine. Nevertheless, throughout the study MRI was superior to both regular contrast and HVD CT in detecting lesions of MS, and at all stages of the study the lesions showed up well on the MRI scans. We believe that the improvements in the imager resulted in concurrent improvements in the quality of the images, and there may have been greater sensitivity for the lesions as the signal/noise ratio and the ability to image thinner slices increased. However, this is difficult to assess, because different patients were scanned before and after the improvements to the imager. Among the patients with known or suspected MS the ability of MRI to detect lesions of MS was clearly superior to the ability of the two types of CT. Even excluding the high sensitivity of MRI in the patients with known MS, the sensitivity of the technique (28/32, or 88%) in this study compares well with the sensitivity reported by Sheldon and associates13 (55/65, or 85%) and by Runge and colleagues4 (33/42; or 78%). The sensitivity of regular contrast or HVD CT in this study was also similar to that found by Runge and colleagues4 and by Vinuela and coworkers8 but was higher than that found by Sheldon and associates.13 The two false-positive scans were made early in the study and likely reflect our own learning more than anything else. One of the patients had undergone a brain biopsy several days before the MRI and was found to have Jakob-Creutzfeldt disease. The scan showed dilated ventricles and a confluent paraventricular increased signal and was 642 CMAJ, VOL. 135, SEPTEMBER 15, 1986 Fig. 2 MRI scans demonstrating stage IV MS: numerous subcortical (top panel) and periventricular (middle panel) lesions, as well as brainstem lesions (bottom panel). TR 2120 ms, TE 60 ms.

5 reported to be "possibly compatible with MS". In the other case MRI showed a single lesion with a long T2. It now appears certain that a single lesion would not likely be diagnostic of MS: therefore, "multiple" should apply not only to the clinical manifestations of the disease but also to the interpretation of the scans. All the patients in our study with positive MRI scans who were known or subsequently proven to have MS had more than two lesions, and only 2 of Sheldon and associates' 62 patients had only one lesion on their MRI scans. None of our controls were reported to have positive MRI scans, but MRI does lack specificity, because most CNS abnormalities cause an increase in the T2. Indeed, the pattern of periventricular white matter lesions is the most useful feature of MS for making the diagnosis by MRI. The failure of MRI scores to correlate with the Kurtzke disability scores has been observed in other studies. Gebarski and collaborators14 reported that 18 (69%) of 26 patients with positive MRI scans had clinically "silent" lesions. Sheldon and associates13 have shown that MRI does not usually detect lesions in the brainstem or cerebellum, even when they are suspected on the basis of clinical manifestations, but a lesion found in the posterior fossa is usually clinically significant. There may be small lesions of the brainstem or spinal cord that cause greater disability than would be predicted by the extent of the lesions seen on the scans. We made no attempt to view the cord beyond the brainstem, because we found that with the body coil as a receiver the images of the cord were very poor. New surface-coil technology may solve the problem. Perhaps patients who have no intracranial lesions should have scans of the cord if the exact site of the lesions is clinically important. We have found that patients often have more lesions on the MRI scans than are clinically significant at the time of scanning. Most periventricular lesions found on MRI scans are clinically silent.3'5'13'14 The scan protocols that we initially used were based on only a few patients and on the capabilities of the imager at that time. Early studies suggested that T, (longitudinal or spin-lattice relaxation time)-weighted inversion-recovery pulse sequences were useful in identifying lesions of MS,' but we soon discarded these sequences and used the spin-echo volume technique. Later reports suggested that T2-weighted pulse sequences demonstrated more lesions; others have also shown that T2-weighted spin-echo sequences are most sensitive for detecting MS lesions.3'4'6"1415 After the major improvements in our imager, we used multislice sequences with a TR of 2120 ms and a TE of 60 and 120 ms, which increased the signal/noise ratio and, therefore, the contrast of the lesions with white matter. Conclusions MRI is very sensitive in detecting the lesions of MS and is superior to both regular contrast and HVD CT. The stage of MS according to the MRI scans correlates poorly with the clinical status of the patient according to the Kurtzke disability score and with the known duration of the disease; this may be because small lesions in the brainstem or cord are beyond the limits of MRI resolution or because a large number of lesions seen on MRI scans are clinically silent. Finally, we have found that the most useful technique for detecting MS lesions is a T2-weighted spin-echo pulse sequence with a TR of 1500 ms or greater and a TE of 60 ms or greater. We thank Helen Cheung for performing the statistical analysis, Carol Milliken for typing the manuscript, and our neurology colleagues who referred the patients for scans Ṫhis study was funded by Physicians' Services Incorporated Foundation, Toronto, and by Ontario Ministry of Health grant References 1. Young IR, Hall AS, Pallis CA et al: Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet 1981; 2: Young IR, Randell CP, Kaplan PW et al: Nuclear magnetic resonance (NMR) imaging in white matter disease of the brain using spin-echo sequences. J Comput Assist Tomogr 1983; 7: Lukes SA, Crooke LE, Amenoff MJ et al: Nuclear magnetic resonance imaging in multiple sclerosis. Ann Neurol 1983; 13: Runge VM, Price AC, Kirshner HS et al: Magnetic resonance imaging of multiple sclerosis: a study of pulse-technique efficacy. AJNR 1984; 5: Johnson MA, Li DKB, Bryant DJ et al: Magnetic resonance imaging: serial observations in multiple sclerosis. Ibid: Maravilla KR, Weinreb JC, Suss R et al: Magnetic resonance demonstration of multiple sclerosis plaques in the cervical cord. Ibid: Kurtzke JF: Further notes on disability evaluation in multiple sclerosis with scale modifications. Neurology 1965; 15: Vinuela FV, Fox AJ, Debrun GM et al: New perspectives in computed tomography of multiple sclerosis. AJR 1982; 139: Harpur GD, Suke R, Bass BH et al: Hyperbaric oxygen therapy in chronic stable multiple sclerosis: double blind study. Neurology 1986; 36: Pykett IL: NMR imaging in medicine. Sci Am 1982; 246 (5): Johnston DL, Liu P, Wismer CL et al: Magnetic resonance imaging: present and future applications. Can Med Assoc J 1985; 132: Landis JR, Koch CC: The measurement of observer agreement for categorical data. Biometrics 1977; 33: Sheldon JJ, Sidebottom R, Tobias J et al: MR imaging of multiple sclerosis. Comparison with clinical and CT examinations in 74 patients. AJNR 1985; 6: Cebarski SS, Gabrielsen TO, Gilman S et al: The initial diagnosis of multiple sclerosis: clinical impact of magnetic resonance imaging. Ann Neurol 1985; 17: Brant-Zawadzki M, Davis PL, Crooks LE et al: NMR demonstration of cerebral abnormalities: comparison with CT. AIR 1983; 140: CMAJ, VOL. 135, SEPTEMBER 15,