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Magnetic resonance imaging and clinical correlations in multiple sclerosis
Journal of the Neurological Sciences, 1988, 86:1-12 Elsevier
1
JNS 03013
Magnetic resonance imaging and clinical correlations in multiple sclerosis Steven J. Huber l, George W. Paulson ~, Donald Chakeres 2, A n n Pakainis 1, Martha Brogan 2, Barbara L.Philfips ~, Mary A n n Myers I and Kottil W. R a m m o h a n ~ Departments of INeurology and 2Raa~ology, Ohio State University College of Medicine, Columbus, Ohio
(U.S.A.) (Received 26 November, 1987) (Revised, received 23 February, 1988) (Accepted 23 February, 1988)
SUMMARY
We examined the relationship between magnetic resonance imaging (MRI) cerebral findings and clinical evaluations in 66 patients with clinically definite multiple sclerosis (MS). MRI observations included total number and location of lesions visualized, degree of periventricular involvement, degree of degeneration of the corpus callosum, and extent of generalized parenchymal atrophy. Overall physical disability was evaluated by the Kurtzke Expanded Disability Status Scale (EDSS) and individual symptoms were rated according to the Kurtzke Functional Systems (FS) scale. Our results suggest that MRI brain abnormalities are siLmificantly related to the overall severity of disease, but MRI is not particularly useful to predict the presence or absence of individual symptoms. These findings do suggest that the MRI may provide useful information to monitor clinical progression of patients with MS, but the lesions visualized need not always be symptomatic nor are we sure that all symptomatic lesions, particularly in the spinal cord and optic nerves, will be visualized.
Key words: Multiple sclerosis; Magnetic resonance imaging; Disability ratings
Correspondenceto: Steven £ Huber, Ph.D., Department of Neurology, Ohio State University, 425 Means Hall, 1655 Upham Drive, Columbus, OH 43210, U.S.A. 0022-510X/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
INTRODUCTION Magnetic resonance imaging (MRI) is a well-established imaging technique for identification of lesions in multiple sclerosis (MS), and is superior to computed tomography (CT) for staging purposes (Young et al. 1981, 1983; Buonanno et al. 1983; Lukes et al. 1983; Gebarski et al. 1985; Jackson et al. 1985; Sheldon et al. 1985). The clinical significance of the MS lesions visualized by MRI is, however, often uncertain. Some patients have a plethora of lesions and mild clinical disease whereas others have few lesions but suffer from advanced clinical MS. A better understanding of the relationship between the MRI findings and the disease severity may facilitate assessment of disease progression and prognosis. We investigated the relationship between the number and the distribution of brain lesions that are detected by MRI and the overall severity of disease as well as the presence or absence of major signs and symptoms.
METHODS Patients Sixty-six patients with clinically definite MS (Poser et al. 1983) and an abnormal MRI were evaluated. This group had a mean age of 41.12 years (19-69 years). There was a mean duration of disease of 8.14 years with a range of 1-23 years. Disease evaluations Patients were evaluated for overall disability using the Expanded Disability Status Scale (EDSS) (Kurtzke 1983). The EDSS has a range of 1-9 with higher numbers indicative of more severe disability. This group had a mean of 4.7 with a range of 1-9. Individual symptoms were rated according to the Kurtzke Functional Systems (FS) scale (Kurtzke et al. 1965). The FS evaluates pyramidal, cerebellar, brainstem, sensory, bowel/bladder, visual, and cerebral function. Symptoms are rated on a scale of 0-5 (or 6 for some symptoms). A score of 0 represents absence of the symptom and higher numbers reflect severity of involvement. Magnetic resonance imaging MRI was performed on a General Electric Signa unit operating at a field strength of 1.5 T. MRI section thickness was 5 mm. Axial studies were performed using spin echo pulse sequences. A more proton density weighted scan was performed with a repetition time (TR) of 2500 msec and echo delay time (TE) of 20-30 msec. Relative T2-weighted axial images utilized a TR of 2500-3000 msec and TE of 75-80 msec. All patients were evaluated by more T1 weighted sagittal partial saturation images using a TR of 600 and TE of 20 msec. A field of vision of 20 cm was used. MRI scans were evaluated by two blinded neuroradiologists and four measures were calculated. Interobserver interpretations were averaged. These measures included:
(I) Total number and size of plaque lesions. Total number of plaque lesions were first counted and the size of each plaque was graded from 1 to 5, with higher numbers indicative of larger size. A score of 1 was given to a lesion less than 0.5 cm, 2 = 1 cm, 3 = 1.5 cm, 4 = 2 cm, and 5 = plaque size greater than 2 cm. Total scores reflect combined number and size of lesions. Total number of lesions were also divided into two separate anatomic regions including those located in the posterior fossa or supratentorial area. (2) Generalparenchymal atrophy. General parenchymal atrophy was evaluated relative to age rather than on an absolute scale. Atrophy was rated on a scale of 1-5, with higher numbers indicative of increasing severity based on the observers experience of normals. A score of 1 indicates normally appearing ventricles and cisterns for age with no evidence of parenchymal atrophy with widening of sulci. Higher values represent decreased gyral prominence. This scale was the most subjective of the scales used. (3) Atrophy of the corpus callosum. Presence of corpus callosum degeneration was rated on a scale of 1-5. A score of 1 reflects normal size without atrophic changes or parenchymal lesions and higher scores indicate diminution in size or visualization of more lesions within the corpus callosum. A score of 1 was given if the callosum had a thickness of 10-7 mm and no lesions; 2, 7-5 mm thickness or 1-4 lesions; 3, 5-3 mm thickness or 4 - 8 lesions; 4, 3-2 mm thickness or more than 8 lesions; 5, 2 - 0 mm thickness or more than 8 lesions. Most plaque lesions involved the inner surface of the corpus and produced a freely corrugated contour. (4) Severity of periventricular plaque lesions. Periventricular involvement was rated on a scale of 1-5, with higher scores indicative of more diffuse periventdcular demyelination. A score of 5 reflected complete encasement of the'lateral ventricles by plaque disease. A score of 1 reflects 0-20~o involvement, 2 = 20-40~o, 3 = 40-60~/o, 4 = 60-80%, and 5 = 80-100~o. Statistical analysis Correlations between overall severity of disease and MRI parameters were analyzed by Spearman's rank-order correlation procedure. This non-parametric procedure was chosen because disease evaluation and MRI measures (except number of lesions) are categorical data. Correlations between duration of disease and both severity of physical disability and MRI parameters were analyzed in the same fashion. Differences in MRI parameters as a function of the presence or absence of individual symptoms on the FS scale were tested by the Wilcoxon rank-sum procedure for independent samples. A score of 0 indicates absence of a symptom and 1 or above the presence of a symptom.
RESULTS
Magnetic resonance imaging There was a variety of high signal circumscribed lesions on the long TR TE images in the cerebral and brainstem white matter that could be detected by MRI (Figs. 1-6). The average number of lesions per patient was 46.6 with a range of 1-134. Lesions above
Fig. 1. Spin echo axial magnetic resonance image at the level of the lateral ventricles (repetition time, 2500 msec; echo delay time, 75 msec). Severe diffuse periventricular white matter disease is present. This is a 38-year-old male patient with a Kurtzke score of 7.
the tentorium accounted for 935/o of total lesions, while lesions in the posterior fossa region represented 70~ of total lesions. The majority of the cerebral lesions were in the periventricular area, and 89~ of the patients had some abnormality in this region (Figs. 1,3,4,5). This is consistent with previous research which found the majority of lesions detected by MRI to be in the periventricular area (Young et al. 1981; Buonanno et al. 1983; Lukes et al. 1983; Stewart etal. 1987) and indeed if none is seen then the diagnosis might be questioned. Generalized atrophy of the gyral folds beyond that expected by age alone was seen in 27 ~o of the patients (Figs. 5 and 6). Atrophy of the corpus callosum was a striking abnormality and lesions on the callosum often produced a serrated border (Fig. 6). Abnormal MRI findings in the corpus callosum was seen in 53 ~o of the patients. All lesions were quantified in the manner previously described and analyzed with respect to overall severity of disease and with presence or absence of specific symptoms.
Fig. 2. Spin echo axial magnetic resonanceimage through the midhrain (repetitiontime, 2500reset; echo delay time, 75 msec). This scan shows a 5 mm lesion in the left cerebral peduncle (arrow). This is a 47-year-oldfemale patient with a Kurtzke score of 8.
Duration of disease and MRI abnormalities The correlation between duration of disease and severity of physical disability as measured by the EDSS did not quite reach statistical significance (rho = 0.22). None of the correlations between duration of disease and MRI parameters including parenchymal atrophy (rho = 0.06), periventricular involvement (rho = 0.04), total number of lesions (rho = 0.16) or degeneration of the corpus callosum (rho = 0.05) was statistically significant. These results are consistent with the previous research which also reports that MRI is poorly associated with the duration of disease (Jacobs et al. 1984; Kirshner et al. 1985; Edwards et al. 1986; Stevens et al. 1986). Two studies did report a positive correlation, however (Sheldon et al. 1985; Stewart et al. 1987). MRI and disease severity We found a generalized relationship between severity of disease and the extent of MRI abnormalities. There was a significant correlation between disease severity and
Fig. 3. Spin echo axial magnetic resonance image at the level of the midbraln (repetition time, 2500 msec; echo delay time, 75 msec). This scan shows high signal changes in the right midbrain region (arrow) and a large number of periventricular lesions in the temporal lobes. This is a 42-year-old female patient with a Kurtzke score of 6.
extent of parenchymal atrophy (rho = 0.37, P < 0.01), periventricular involvement (rho = 0.28, P < 0.05), and callosal degeneration (rho = 0.53, P < 0.01). Total number and size of lesions (rho = 0.34, P < 0.01) and the number of lesions above the tentorium (rho = 0.35, P < 0.01) were significantly correlated with disease severity. N u m b e r of lesions visualized in the region of the posterior fossa did not correlate with severity of disease (rho --- - 0.02). These results suggest that the extent of M R I abnormalities, either in total number or distribution, are generally associated with more severe disability. M R I and presence or absence of symptoms Seven major signs and symptoms of MS were evaluated by the Kurtzke Functional Systems (FS) scale (Kurtzke et al. 1965). A score of 0 represents absence of a particular s y m p t o m and a score of I or above represents a positive symptom. Bowel
Fig. 4. Spin echo axial magneticresonanceimage above the lateral ventricles(repetitiontime, 2500msec; echo delaytime,20 reset). Multiplehigh signalwhitematter lesions are present.This is a 33-year-oldfemale patient with a Kurtzke score of 2.
or bladder dysfunction was the most common symptom (73 ~o) seen in this group. Cerebellar (70 ~o) and pyramidal dysfunction (68 ~o) were also quite common. Sensory findings (62 ~ ) and brainstem involvement (61 ~o) were seen in the majority of patients, and visual and mental symptoms were the least common (55~o). MRI findings with respect to presence or absence of individual symptoms are presented in Table 1. Our findings suggest that parenchymal atrophy was the most consistent MRI indicator related to presence or absence of the major symptoms of MS. Generalized atrophy was significantly more extensive in patients who had pyramidal, cerebellar, brainstem, and mental symptoms. Atrophy would not appear to be a useful measure related to sensory, bowel/bladder, or visual symptoms. Periventricular involvement successfully predicted the presence of pyramidal and cerebellar signs, but no other symptoms. Callosal degeneration was sensitive to the presence of pyramidal and cerebellar signs, and was sensitive to the presence of mental dysfunction,
Fig. 5. Spin echo axial magnetic resonance image at the level of the lateral ventricles (repetition time, 2500 msec; echo delay time, 20 msec). There is diffuse white matter disease seen as high signal matter in this pulse sequence. Normal white matter tracts should be lower in signal than the gray matter structures. A cystic region (arrow) is seen which may reflect greater tissue injury. This is a 45-year-old female patient with a Kurtzke score of 9.
The higher the total number of total lesions the greater the probability of pyramidal, cerebellar, and sensory signs and symptoms. Total lesions in the supratentorial area had the same pattern, whereas lesions in the posterior fossa region were not sensitive to any of the symptoms.
DISCUSSION
MRI is clearly the most sensitive measure for the diagnosis of MS and is superior to CT in visualizing brain lesions in MS (Young et al. 1981; Sheldon et al. 1985). Beyond diagnosis, MRI is potentially useful for follow-up assessment of disease progression. Previous investigations which have examined the relationship of MRI findings and overall disease severity or clinical symptoms in MS have been inconsistent.
Fig. 6. Spin echo axial magnetic resonance image of the midline (repetition time, 600 msec; echo delay time, 20 msec). The corpus callosum is thin and has an inferior serrated border. Generalized brain atrophy is also present. This is a 44-year-old female patient with a Kurtzke score of 7, and severe dementia.
We found a significant correlation between severity of disease as measured by the Kurtzke Expanded Disability Status Scale (EDSS) and the total number of lesions. While this was generally the case (Fig. 1), sporadic instances of mild disease with a large number of lesions were identified (Fig. 4). Two other studies have previously examined this same relationship. One report (Stevens et al. 1986) found a significant correlation while the other (Stewart et al. 1987) found a positive, but not a significant correlation. There are several possible reasons why there is only moderate correlation between the number of lesions visualized by MRI and severity of disease. Many of the lesions detected by MRI may be asymptomatie (Kirshner et al. 1985), perhaps as high as 75~ of lesions are clinically silent (Jacobs et al. 1984) (Fig. 4). On the other hand, it seems probable that truly symptomatic lesions are not always detected by MRI. It is logical that the greater the number of lesions visualized by MRI, the higher the probability of detecting clinically significant lesions. There are, at present, no good MRI criteria for identification of acute or active lesions without the use of gadolinium or other paramagnetic agents.
n.s. = not significant.
Pyramidal CerebeUar Brainstem Sensory Bowel/bladder Visual Mental
Symptoms
2.26, P = 1.97, P = 2.40, P = 1.59, n.s. 1.14, n.s. 1.64, n.s. 2.30, P =
Atrophy
0.02
0.024 0.049 0.016
MRI measures
COMPARISON OF MRI ABNORMALITIES
TABLE 1
2.23, 2.76, 1.92, 1.41, 1.13, 1.53, 1.36,
P = 0.026 P = 0.006 n.s. n.s. n.s. n.s. n.s.
Periventricular 3.50, 2.22, 1.33, 1.45, 1.45, 1.20, 2.72,
P = 0.0001 P = 0.027 n.s. n.s. n.s. n.s. P = 0.007
CaUosum
3.03, 3.31, 0.27, 2.36, 1.05, 0.75, 1.88,
Total
P = 0.002 P = 0.001 n.s. P = 0.02 n.s. n.s. n.s.
3.06, 3.41, 0.28, 2.40, 1.20, 0.76, 1.91,
P = 0.002 P = 0.001 n.s. P = 0.017 n.s. n.s. n.s.
Supratentorial
SYMPTOMS IN MS (z-SCORE)
No. o f lesions
WITH PRESENCE OR ABSENCE OF INDIVIDUAL
1.06, 0.99, 0.20, 0.13, - 1.30, 0.36, 0.62,
n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Posterior fossa
11 We also found that the distribution of MRI abnormalities including cortical atrophy, periventricular involvement, and callosal degeneration do correlate with overall disease severity. No one area was particularly more sensitive to overall disability. As was the case when total number of lesions was examined, it appears that the greater the number of perceptible lesions within a specific region, the greater the chance that they are clinically significant. For some symptoms, such as internuclear ophthalmoplegia, it would seem relatively easy to correlate specific clinical symptoms with MRI findings. However, there are specific problems in associating certain symptoms in patients with MS and their MRI images. The optic nerves, for example, are difficult to visualize by MRI (Gebarski et al. 1985; Sheldon et al. 1985) and special dedicated techniques would be needed to see some lesions. The spinal cord is a frequent site of symptomatic lesions (Gebarski et al. 1985; Jackson et al. 1985; Sheldon et al. 1985), but is not commonly examined in patients with MS. These lesions are small and difficult to document. Finally, lesions in the midbrain may be relatively small (Stewart et al. 1987) and difficult to detect by MRI (Lumsden et al. 1970), and yet can be very important clinically (Figs. 2 and 3). We found only 7 ~ of the total number of lesions visualized to be in the midbrain regions. MRI fmdings other than high signal regions have been reported such as low signal on T2 weighted images of the thalamus, spinal cord, and brainstem atrophy. These may be important, but difficult to quantify. The MRI findings of MS are not pathognomonic, but can also be seen with many other disorders such as lacunar infarcts, vasculitis, leukodystrophies, post-infection syndromes, and radiation and chemotherapy reactions. Therefore, in older patients in particular, the etiology of any specific lesion is unclear even when there is a solid clinical diagnosis of MS. As was noted in previous research (Lukes et al. 1983; Young et al. 1983; Jacobs et al. 1984; Gebarski et al. 1985; Sheldon et al. 1985; Edwards et al. 1986), there is variability in the ability of MRI parameters to predict major signs and symptoms of MS. In our study generalized cerebral atrophy is a non-specific indicator of many symptoms of MS including pyramidal, cerebellar, brainstem, and mental symptoms. Periventricular lesions, caliosal degeneration, and the total number of lesions were certainly associated with the presence of pyramidal and cerebellar signs and symptoms. Presence of brainstem, sensory, bowel/bladder, and visual symptoms are not, however, welldetected by any of the MRI measures. Callosal degeneration is associated with the presence of significant mental dysfunction (Fig. 6). Their finding is consistent with a previous clinicopathologic report which found extensive degeneration of the caHosum at autopsy in patients with MS and intellectual disturbance (Bamard et al. 1974). We recently reported that patients with MS who meet criteria for a dementia syndrome do indeed have significantly greater atrophy of the callosum on MRI compared to patients who were not demented (Huber et al. 1987). This relationship was unique for callosal degeneration, and is not totally explained. In summary, our findings and previous research confirms that the extent of MRI abnormalities are related to severity of overall disability in patients with MS. Certain
12
symptoms including pyramidal and cerebellar signs correlate well with MRI findings, while brainstem, visual, bowel/bladder and sensory symptoms are difficult to predict by review of the MRI. The presence of intellectual dysfunction appears consistently related to the extent of degeneration of the corpus callosum. Our findings suggest that MRI may be useful to monitor progression of MS, but longitudinal studies have not been performed. It is not usually possible to state how acute a lesion is, nor indeed how destructive it may be. Thus, at the present time MRI findings should be used with caution as a prognostic indicator for the individual patient.
REFERENCES Barnard, R.O. and M. Triggs (1974) Corpus callosum in multiple sclerosis. J. Neurol. Neurosurg. Psychiat., 37: 1259-1264. Buonanna, F. S., J.P. Kistler, J.R. Lehrich et al. (1983) Nuclear magnetic resonance imaging in multiple sclerosis. Neurol. Clin., 1: 757-764. Edwards, M.K., M.R. Farlow and J.C. Stevens (1986) Multiple sclerosis: MRI and clinical correlations. Amer. J. Neuroradiol., 7: 595-598. Gebarski, S. S., T. O. Gabrielson, S. Gilman et al. (1985) The initial diagnosis of multiple sclerosis: Clinical impact of MRI. Ann. NeuroL, 17: 469-474. Huber, S.J., G.W. Paulson, Shuttleworth et al. (1987) Magnetic resonance imaging correlate of dementia in multiple sclerosis. Arch. Neurol., 44: 732-736. Jackson, J. A., D. R. Leake, N.J. Schneiders et al. (1985) Magnetic resonance imaging in multiple sclerosis: results in 32 cases. Amer. J. Neuroradiol,, 6: 171-176. Jacobs, L., W.R. Kinkel, I. Polachini and R.P. Kinkel (1984) Clinical-nuclear magnetic resonance (NMR) correlation in multiple sclerosis (abstract). Neurology, 34 (Suppl. 1): 141. Kirshner, H.S., S.I. Tsai, V.M. Runge and A.C. Price (1985) Magnetic resonance imaging and other techniques in the diagnosis of multiple sclerosis. Arch. Neurol., 42: 859-863. Kurtzke, J.F. (1965) Further notes on disability evaluation in multiple sclerosis with scale modification. Neurology, 15: 654-661. Kurtzke, J.F. (1983) Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDDS). Neurology, 33: 1444-1452. Lukes, S.A., L.E. Crooks, M.J. Aminoff et al. (1983) Nuclear magnetic resonance imaging in multiple sclerosis. Ann. Neurol., 13: 592-601. Lumsden, C.E. (1970) The neuropathology of multiple sclerosis. In: P.J. Vinken and G.W. Bruyn (Eds.), Handbook of Clinical Neurology, Vol. 9, American Elsevier Publishing Company, New York, NY, pp. 217-309. Maramiller, K. R., J. C. Weinreb, R. Suss and R.C. Nunnally (1984) Magnetic resonance demonstration of multiple sclerosis plaques in the cervical cord. Amer. J. Neuroradiol., 5: 685-689. Poser, C.M., D. Paty, L. Scheinberg, W.I. McDonald et al. (1983) New diagnostic criteria for multiple sclerosis. Ann. Neurol., 13: 227-231. Sheldon, J.J, R. Siddharthan, J. Tobias et al. (1985) MR imaging of multiple sclerosis: comparison with clinical and CT examinations in 74 patients. Amer. J. Neuroradiol., 45: 957-964. Stevens, J.C., M.R. Farlow, M.K. Edwards and Y. Pao-lo (1986) Magnetic resonance imaging: clinical correlation in 64 patients with multiple sclerosis. Arch. Neurol., 43:1145-1148. Stewart, J.M., O.W. Houser, H.C. Baker, P.C. O'Brien and M. Rodriguez (1987) Magnetic resonance imaging and clinical relationships in multiple sclerosis. Mayo Clinic Proc., 62: 174-184. Young, I. R., A. S. Hall, C. A. Pallis et al. (1981) Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet, 2: 1063-1066. Young, I. R., C.P. Randell, P.W. Kaplan et al. (1983) Nuclear magnetic resonance imaging in white matter disease of the brain using spin-echo sequences. J. Comput. Assist. Tomogr., 13: 592-601.
1
JNS 03013
Magnetic resonance imaging and clinical correlations in multiple sclerosis Steven J. Huber l, George W. Paulson ~, Donald Chakeres 2, A n n Pakainis 1, Martha Brogan 2, Barbara L.Philfips ~, Mary A n n Myers I and Kottil W. R a m m o h a n ~ Departments of INeurology and 2Raa~ology, Ohio State University College of Medicine, Columbus, Ohio
(U.S.A.) (Received 26 November, 1987) (Revised, received 23 February, 1988) (Accepted 23 February, 1988)
SUMMARY
We examined the relationship between magnetic resonance imaging (MRI) cerebral findings and clinical evaluations in 66 patients with clinically definite multiple sclerosis (MS). MRI observations included total number and location of lesions visualized, degree of periventricular involvement, degree of degeneration of the corpus callosum, and extent of generalized parenchymal atrophy. Overall physical disability was evaluated by the Kurtzke Expanded Disability Status Scale (EDSS) and individual symptoms were rated according to the Kurtzke Functional Systems (FS) scale. Our results suggest that MRI brain abnormalities are siLmificantly related to the overall severity of disease, but MRI is not particularly useful to predict the presence or absence of individual symptoms. These findings do suggest that the MRI may provide useful information to monitor clinical progression of patients with MS, but the lesions visualized need not always be symptomatic nor are we sure that all symptomatic lesions, particularly in the spinal cord and optic nerves, will be visualized.
Key words: Multiple sclerosis; Magnetic resonance imaging; Disability ratings
Correspondenceto: Steven £ Huber, Ph.D., Department of Neurology, Ohio State University, 425 Means Hall, 1655 Upham Drive, Columbus, OH 43210, U.S.A. 0022-510X/88/$03.50 © 1988 Elsevier Science Publishers B.V. (Biomedical Division)
INTRODUCTION Magnetic resonance imaging (MRI) is a well-established imaging technique for identification of lesions in multiple sclerosis (MS), and is superior to computed tomography (CT) for staging purposes (Young et al. 1981, 1983; Buonanno et al. 1983; Lukes et al. 1983; Gebarski et al. 1985; Jackson et al. 1985; Sheldon et al. 1985). The clinical significance of the MS lesions visualized by MRI is, however, often uncertain. Some patients have a plethora of lesions and mild clinical disease whereas others have few lesions but suffer from advanced clinical MS. A better understanding of the relationship between the MRI findings and the disease severity may facilitate assessment of disease progression and prognosis. We investigated the relationship between the number and the distribution of brain lesions that are detected by MRI and the overall severity of disease as well as the presence or absence of major signs and symptoms.
METHODS Patients Sixty-six patients with clinically definite MS (Poser et al. 1983) and an abnormal MRI were evaluated. This group had a mean age of 41.12 years (19-69 years). There was a mean duration of disease of 8.14 years with a range of 1-23 years. Disease evaluations Patients were evaluated for overall disability using the Expanded Disability Status Scale (EDSS) (Kurtzke 1983). The EDSS has a range of 1-9 with higher numbers indicative of more severe disability. This group had a mean of 4.7 with a range of 1-9. Individual symptoms were rated according to the Kurtzke Functional Systems (FS) scale (Kurtzke et al. 1965). The FS evaluates pyramidal, cerebellar, brainstem, sensory, bowel/bladder, visual, and cerebral function. Symptoms are rated on a scale of 0-5 (or 6 for some symptoms). A score of 0 represents absence of the symptom and higher numbers reflect severity of involvement. Magnetic resonance imaging MRI was performed on a General Electric Signa unit operating at a field strength of 1.5 T. MRI section thickness was 5 mm. Axial studies were performed using spin echo pulse sequences. A more proton density weighted scan was performed with a repetition time (TR) of 2500 msec and echo delay time (TE) of 20-30 msec. Relative T2-weighted axial images utilized a TR of 2500-3000 msec and TE of 75-80 msec. All patients were evaluated by more T1 weighted sagittal partial saturation images using a TR of 600 and TE of 20 msec. A field of vision of 20 cm was used. MRI scans were evaluated by two blinded neuroradiologists and four measures were calculated. Interobserver interpretations were averaged. These measures included:
(I) Total number and size of plaque lesions. Total number of plaque lesions were first counted and the size of each plaque was graded from 1 to 5, with higher numbers indicative of larger size. A score of 1 was given to a lesion less than 0.5 cm, 2 = 1 cm, 3 = 1.5 cm, 4 = 2 cm, and 5 = plaque size greater than 2 cm. Total scores reflect combined number and size of lesions. Total number of lesions were also divided into two separate anatomic regions including those located in the posterior fossa or supratentorial area. (2) Generalparenchymal atrophy. General parenchymal atrophy was evaluated relative to age rather than on an absolute scale. Atrophy was rated on a scale of 1-5, with higher numbers indicative of increasing severity based on the observers experience of normals. A score of 1 indicates normally appearing ventricles and cisterns for age with no evidence of parenchymal atrophy with widening of sulci. Higher values represent decreased gyral prominence. This scale was the most subjective of the scales used. (3) Atrophy of the corpus callosum. Presence of corpus callosum degeneration was rated on a scale of 1-5. A score of 1 reflects normal size without atrophic changes or parenchymal lesions and higher scores indicate diminution in size or visualization of more lesions within the corpus callosum. A score of 1 was given if the callosum had a thickness of 10-7 mm and no lesions; 2, 7-5 mm thickness or 1-4 lesions; 3, 5-3 mm thickness or 4 - 8 lesions; 4, 3-2 mm thickness or more than 8 lesions; 5, 2 - 0 mm thickness or more than 8 lesions. Most plaque lesions involved the inner surface of the corpus and produced a freely corrugated contour. (4) Severity of periventricular plaque lesions. Periventricular involvement was rated on a scale of 1-5, with higher scores indicative of more diffuse periventdcular demyelination. A score of 5 reflected complete encasement of the'lateral ventricles by plaque disease. A score of 1 reflects 0-20~o involvement, 2 = 20-40~o, 3 = 40-60~/o, 4 = 60-80%, and 5 = 80-100~o. Statistical analysis Correlations between overall severity of disease and MRI parameters were analyzed by Spearman's rank-order correlation procedure. This non-parametric procedure was chosen because disease evaluation and MRI measures (except number of lesions) are categorical data. Correlations between duration of disease and both severity of physical disability and MRI parameters were analyzed in the same fashion. Differences in MRI parameters as a function of the presence or absence of individual symptoms on the FS scale were tested by the Wilcoxon rank-sum procedure for independent samples. A score of 0 indicates absence of a symptom and 1 or above the presence of a symptom.
RESULTS
Magnetic resonance imaging There was a variety of high signal circumscribed lesions on the long TR TE images in the cerebral and brainstem white matter that could be detected by MRI (Figs. 1-6). The average number of lesions per patient was 46.6 with a range of 1-134. Lesions above
Fig. 1. Spin echo axial magnetic resonance image at the level of the lateral ventricles (repetition time, 2500 msec; echo delay time, 75 msec). Severe diffuse periventricular white matter disease is present. This is a 38-year-old male patient with a Kurtzke score of 7.
the tentorium accounted for 935/o of total lesions, while lesions in the posterior fossa region represented 70~ of total lesions. The majority of the cerebral lesions were in the periventricular area, and 89~ of the patients had some abnormality in this region (Figs. 1,3,4,5). This is consistent with previous research which found the majority of lesions detected by MRI to be in the periventricular area (Young et al. 1981; Buonanno et al. 1983; Lukes et al. 1983; Stewart etal. 1987) and indeed if none is seen then the diagnosis might be questioned. Generalized atrophy of the gyral folds beyond that expected by age alone was seen in 27 ~o of the patients (Figs. 5 and 6). Atrophy of the corpus callosum was a striking abnormality and lesions on the callosum often produced a serrated border (Fig. 6). Abnormal MRI findings in the corpus callosum was seen in 53 ~o of the patients. All lesions were quantified in the manner previously described and analyzed with respect to overall severity of disease and with presence or absence of specific symptoms.
Fig. 2. Spin echo axial magnetic resonanceimage through the midhrain (repetitiontime, 2500reset; echo delay time, 75 msec). This scan shows a 5 mm lesion in the left cerebral peduncle (arrow). This is a 47-year-oldfemale patient with a Kurtzke score of 8.
Duration of disease and MRI abnormalities The correlation between duration of disease and severity of physical disability as measured by the EDSS did not quite reach statistical significance (rho = 0.22). None of the correlations between duration of disease and MRI parameters including parenchymal atrophy (rho = 0.06), periventricular involvement (rho = 0.04), total number of lesions (rho = 0.16) or degeneration of the corpus callosum (rho = 0.05) was statistically significant. These results are consistent with the previous research which also reports that MRI is poorly associated with the duration of disease (Jacobs et al. 1984; Kirshner et al. 1985; Edwards et al. 1986; Stevens et al. 1986). Two studies did report a positive correlation, however (Sheldon et al. 1985; Stewart et al. 1987). MRI and disease severity We found a generalized relationship between severity of disease and the extent of MRI abnormalities. There was a significant correlation between disease severity and
Fig. 3. Spin echo axial magnetic resonance image at the level of the midbraln (repetition time, 2500 msec; echo delay time, 75 msec). This scan shows high signal changes in the right midbrain region (arrow) and a large number of periventricular lesions in the temporal lobes. This is a 42-year-old female patient with a Kurtzke score of 6.
extent of parenchymal atrophy (rho = 0.37, P < 0.01), periventricular involvement (rho = 0.28, P < 0.05), and callosal degeneration (rho = 0.53, P < 0.01). Total number and size of lesions (rho = 0.34, P < 0.01) and the number of lesions above the tentorium (rho = 0.35, P < 0.01) were significantly correlated with disease severity. N u m b e r of lesions visualized in the region of the posterior fossa did not correlate with severity of disease (rho --- - 0.02). These results suggest that the extent of M R I abnormalities, either in total number or distribution, are generally associated with more severe disability. M R I and presence or absence of symptoms Seven major signs and symptoms of MS were evaluated by the Kurtzke Functional Systems (FS) scale (Kurtzke et al. 1965). A score of 0 represents absence of a particular s y m p t o m and a score of I or above represents a positive symptom. Bowel
Fig. 4. Spin echo axial magneticresonanceimage above the lateral ventricles(repetitiontime, 2500msec; echo delaytime,20 reset). Multiplehigh signalwhitematter lesions are present.This is a 33-year-oldfemale patient with a Kurtzke score of 2.
or bladder dysfunction was the most common symptom (73 ~o) seen in this group. Cerebellar (70 ~o) and pyramidal dysfunction (68 ~o) were also quite common. Sensory findings (62 ~ ) and brainstem involvement (61 ~o) were seen in the majority of patients, and visual and mental symptoms were the least common (55~o). MRI findings with respect to presence or absence of individual symptoms are presented in Table 1. Our findings suggest that parenchymal atrophy was the most consistent MRI indicator related to presence or absence of the major symptoms of MS. Generalized atrophy was significantly more extensive in patients who had pyramidal, cerebellar, brainstem, and mental symptoms. Atrophy would not appear to be a useful measure related to sensory, bowel/bladder, or visual symptoms. Periventricular involvement successfully predicted the presence of pyramidal and cerebellar signs, but no other symptoms. Callosal degeneration was sensitive to the presence of pyramidal and cerebellar signs, and was sensitive to the presence of mental dysfunction,
Fig. 5. Spin echo axial magnetic resonance image at the level of the lateral ventricles (repetition time, 2500 msec; echo delay time, 20 msec). There is diffuse white matter disease seen as high signal matter in this pulse sequence. Normal white matter tracts should be lower in signal than the gray matter structures. A cystic region (arrow) is seen which may reflect greater tissue injury. This is a 45-year-old female patient with a Kurtzke score of 9.
The higher the total number of total lesions the greater the probability of pyramidal, cerebellar, and sensory signs and symptoms. Total lesions in the supratentorial area had the same pattern, whereas lesions in the posterior fossa region were not sensitive to any of the symptoms.
DISCUSSION
MRI is clearly the most sensitive measure for the diagnosis of MS and is superior to CT in visualizing brain lesions in MS (Young et al. 1981; Sheldon et al. 1985). Beyond diagnosis, MRI is potentially useful for follow-up assessment of disease progression. Previous investigations which have examined the relationship of MRI findings and overall disease severity or clinical symptoms in MS have been inconsistent.
Fig. 6. Spin echo axial magnetic resonance image of the midline (repetition time, 600 msec; echo delay time, 20 msec). The corpus callosum is thin and has an inferior serrated border. Generalized brain atrophy is also present. This is a 44-year-old female patient with a Kurtzke score of 7, and severe dementia.
We found a significant correlation between severity of disease as measured by the Kurtzke Expanded Disability Status Scale (EDSS) and the total number of lesions. While this was generally the case (Fig. 1), sporadic instances of mild disease with a large number of lesions were identified (Fig. 4). Two other studies have previously examined this same relationship. One report (Stevens et al. 1986) found a significant correlation while the other (Stewart et al. 1987) found a positive, but not a significant correlation. There are several possible reasons why there is only moderate correlation between the number of lesions visualized by MRI and severity of disease. Many of the lesions detected by MRI may be asymptomatie (Kirshner et al. 1985), perhaps as high as 75~ of lesions are clinically silent (Jacobs et al. 1984) (Fig. 4). On the other hand, it seems probable that truly symptomatic lesions are not always detected by MRI. It is logical that the greater the number of lesions visualized by MRI, the higher the probability of detecting clinically significant lesions. There are, at present, no good MRI criteria for identification of acute or active lesions without the use of gadolinium or other paramagnetic agents.
n.s. = not significant.
Pyramidal CerebeUar Brainstem Sensory Bowel/bladder Visual Mental
Symptoms
2.26, P = 1.97, P = 2.40, P = 1.59, n.s. 1.14, n.s. 1.64, n.s. 2.30, P =
Atrophy
0.02
0.024 0.049 0.016
MRI measures
COMPARISON OF MRI ABNORMALITIES
TABLE 1
2.23, 2.76, 1.92, 1.41, 1.13, 1.53, 1.36,
P = 0.026 P = 0.006 n.s. n.s. n.s. n.s. n.s.
Periventricular 3.50, 2.22, 1.33, 1.45, 1.45, 1.20, 2.72,
P = 0.0001 P = 0.027 n.s. n.s. n.s. n.s. P = 0.007
CaUosum
3.03, 3.31, 0.27, 2.36, 1.05, 0.75, 1.88,
Total
P = 0.002 P = 0.001 n.s. P = 0.02 n.s. n.s. n.s.
3.06, 3.41, 0.28, 2.40, 1.20, 0.76, 1.91,
P = 0.002 P = 0.001 n.s. P = 0.017 n.s. n.s. n.s.
Supratentorial
SYMPTOMS IN MS (z-SCORE)
No. o f lesions
WITH PRESENCE OR ABSENCE OF INDIVIDUAL
1.06, 0.99, 0.20, 0.13, - 1.30, 0.36, 0.62,
n.s. n.s. n.s. n.s. n.s. n.s. n.s.
Posterior fossa
11 We also found that the distribution of MRI abnormalities including cortical atrophy, periventricular involvement, and callosal degeneration do correlate with overall disease severity. No one area was particularly more sensitive to overall disability. As was the case when total number of lesions was examined, it appears that the greater the number of perceptible lesions within a specific region, the greater the chance that they are clinically significant. For some symptoms, such as internuclear ophthalmoplegia, it would seem relatively easy to correlate specific clinical symptoms with MRI findings. However, there are specific problems in associating certain symptoms in patients with MS and their MRI images. The optic nerves, for example, are difficult to visualize by MRI (Gebarski et al. 1985; Sheldon et al. 1985) and special dedicated techniques would be needed to see some lesions. The spinal cord is a frequent site of symptomatic lesions (Gebarski et al. 1985; Jackson et al. 1985; Sheldon et al. 1985), but is not commonly examined in patients with MS. These lesions are small and difficult to document. Finally, lesions in the midbrain may be relatively small (Stewart et al. 1987) and difficult to detect by MRI (Lumsden et al. 1970), and yet can be very important clinically (Figs. 2 and 3). We found only 7 ~ of the total number of lesions visualized to be in the midbrain regions. MRI fmdings other than high signal regions have been reported such as low signal on T2 weighted images of the thalamus, spinal cord, and brainstem atrophy. These may be important, but difficult to quantify. The MRI findings of MS are not pathognomonic, but can also be seen with many other disorders such as lacunar infarcts, vasculitis, leukodystrophies, post-infection syndromes, and radiation and chemotherapy reactions. Therefore, in older patients in particular, the etiology of any specific lesion is unclear even when there is a solid clinical diagnosis of MS. As was noted in previous research (Lukes et al. 1983; Young et al. 1983; Jacobs et al. 1984; Gebarski et al. 1985; Sheldon et al. 1985; Edwards et al. 1986), there is variability in the ability of MRI parameters to predict major signs and symptoms of MS. In our study generalized cerebral atrophy is a non-specific indicator of many symptoms of MS including pyramidal, cerebellar, brainstem, and mental symptoms. Periventricular lesions, caliosal degeneration, and the total number of lesions were certainly associated with the presence of pyramidal and cerebellar signs and symptoms. Presence of brainstem, sensory, bowel/bladder, and visual symptoms are not, however, welldetected by any of the MRI measures. Callosal degeneration is associated with the presence of significant mental dysfunction (Fig. 6). Their finding is consistent with a previous clinicopathologic report which found extensive degeneration of the caHosum at autopsy in patients with MS and intellectual disturbance (Bamard et al. 1974). We recently reported that patients with MS who meet criteria for a dementia syndrome do indeed have significantly greater atrophy of the callosum on MRI compared to patients who were not demented (Huber et al. 1987). This relationship was unique for callosal degeneration, and is not totally explained. In summary, our findings and previous research confirms that the extent of MRI abnormalities are related to severity of overall disability in patients with MS. Certain
12
symptoms including pyramidal and cerebellar signs correlate well with MRI findings, while brainstem, visual, bowel/bladder and sensory symptoms are difficult to predict by review of the MRI. The presence of intellectual dysfunction appears consistently related to the extent of degeneration of the corpus callosum. Our findings suggest that MRI may be useful to monitor progression of MS, but longitudinal studies have not been performed. It is not usually possible to state how acute a lesion is, nor indeed how destructive it may be. Thus, at the present time MRI findings should be used with caution as a prognostic indicator for the individual patient.
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