Major Dflerences in the Dynamics of Primary and Secondary Progressive Multiple Sclerosis Alan J. Thompson, MD, A. G. Kermode, MRCP, D. Wicks, PhD, D. G. MacManus, DCR, B. E. Kendall, FRCR, D. P. E. Kingsley, FKCR, and W. I. McDonald, FRCP
In patients with primary and secondary progressive multiple sclerosis (MS),major differences in the pattern and extent of abnormality on cerebral magnetic resonance imaging (MRI) between the two groups have recently been demonstrated. In the present study, 24 patients, matched for age, sex, duration of disease, and disability, had serial gadolinium diethylenetriaminepentaacetic acid-enhanced MRI over a 6-month period. The 12 patients in the secondary progressive group had a total of 109 new lesions over this time (1 8.2 lesions per patient per year) and 87% of these enhanced. Enhancement also occurred within and at the edge of preexisting lesions. In contrast, only 20 new lesions were seen in the primary progressive group (3.3 lesions per patient per year) and only one of these enhanced. There was no difference in the degree of clinical deterioration between the two groups over the 6-month period. These findings may indicate a difference in the dynamics of disease activity between the two forms of progressive MS, particularly in relation to the inflammatory component of the lesions, and have important implications for the selection of patients and the monitoring of disease activity in therapeutic trials. Thompson AJ, Kermode AG, Wicks D, MacManus DG, Kendall BE, Kingsley DPE, McDonald W1 Major differences in the dynamics of primary and secondary progressive multiple sclerosis. A n n Neurol 1991;29:53-62
That multiple sclerosis (MS) may follow a progressive course has been recognized since the time of Charcot 111. A distinction between that form of the illness which is progressive from onset (primary progressive) and that which follows an initially relapsing and remitting course (secondary progressive) was made later {2], though most authors implicitly assume that the pathogenesis of the two forms is the same. Others, noting that demyelination may be the end result of quite dlfferent pathological processes, have thought it unsafe to include the primary progressive group in the category of clinically definite MS [3]. Most current practice, as reflected in clinical trials, includes both groups of patients under the heading of chronic progressive MS. If there truly are differences in pathogenesis between the two groups, it is important to distinguish them, lest a therapeutic effect be missed because of the heterogeneity of the cohort being studied. What then is the evidence that the two forms of progressive MS differ? Clinically, patients with primary progressive MS tend to present at a later age than the secondary progressive group 12, 4-7). The most common mode of presentation is a progressive parapa-
resis, though progressive hemiparesis, brainstem syndromes, and visual loss [S] have also been described. It has been suggested that patients in this group have a worse prognosis in terms of disability [5, 91 and that there may be epidemiological differences between primary and secondary progressive MS [lo]. A number of immunogenetic studies have suggested differences in the human leukocyte antigen (HLA) profile between the two groups but the evidence is not conclusive [11-13]. More recently analysis of HLA DR and HLA DQ genes by restriction fragment length polymorphism (RFLP) has suggested that primary progressive MS may be associated with a specific heterozygous Taq 1 HLA DQ p-restriction fragment, which is not seen in secondary progressive MS {14]. Pathological studies have not resolved the issue, as none have made the distinction between primary and secondary progression. Since magnetic resonance imaging (MRI) provides evidence about the distribution of pathological changes during life [15, 161 and serial gadolinium-enhanced MRI can provide evidence about the dynamics of the pathology in terms of both the evolution of new lesions and the natural history of the
From the Multiple Sclerosis NMR Research Group, Institute of Neurology, Queen Square, London, Great Britain.
Address correspondence to Dr Thompson, Lecturer in Clinical Neurology, Institute of Neurology. Queen Square, London W C l N 3BG1 Great Britain'
Received Mar 5 , 1990, and in revised form Jun 22 and Jul 18. Accepted for publication Jul 19, 1990.
Copyright
0 1991 by t h e American Neurological Association
53
disease process [17, 181, we undertook a systematic study over a 6-month period of the clinical and MRI features of the two forms of progressive MS.
Materials and Methods The study was restricted to patients with definite MS and strict criteria for the two patient groups were adhered to rigidly.
Clinical Thirty-four patients with clinically definite MS [19] were studied; 20 had secondary progressive MS and 14 had primary progressive disease. Patients were selected by one of us (A. J. T.) from the MS population attending the National Hospital for Nervous Diseases, Queen Square, London. The case notes of potential candidates were carefully studied and suitable patients reviewed. A detailed history was taken. Many patients initially thought to have primary progressive MS were found to have had either a transient episode that resolved prior to the onset of progression or a period of rapid deterioration during the progressive phase that would fulfill the criteria for a relapse; such patients were excluded from the study. Primary progressive MS was defined as disease that was progressive from onset, with no evidence of relapses or remissions. We required that the evidence of involvement of at least two anatomically separate areas of the central nervous system (CNS) was sequential, with a period of at least 1 month between them. Paraclinical findings such as an abnormal visual-evoked response, though not a new lesion on MRI, were also used as evidence of a second lesion. All patients had oligoclonal bands in the cerebrospinal fluid (CSF). Of the 14 patients studied, the progressive syndromes were: paraparesis (5), hemiparesis (3), brainstem syndromes (3), cerebellar syndromes (2), and visual syndromes (1). Patients with sccondary progressive MS had an initial relapsing and remitting phase but had developed progressive disability over at least the preceding 6 months. Superimposed relapses were allowed. Relapse was defined as the Occurrence of a symptom or symptoms of neurological dysfunction, with or without objective confirmation lasting more than 24 hours, and remission was defined as a definite improvement in signs, symptoms, or both, present for at least 24 hours and lasting for at least 1 month [19}. All patients attended the National Hospital for Nervous Diseases and had been seen close to the clinical onset of the disease. Each patient was assessed neurologically by one of us (A. J. T.) on entry into the study and at the time of each scan. Disability was measured using the Expanded Kurtzke Disability Status Scale (EDSS) and Kurtzke’s functional score 1201.
MRI T2-weighted MRI of the brain was performed in 34 patients (Picker, International, Wembley, Middlesex, UK, 0.5 tesla, spin echo (SE) 2000/60, 5-mm contiguous slices, 256 x 256 image matrix). T2-weighted MRI of the spinal cord was performed on 20 patients with secondary progressive MS and 10 patients with primary progressive MS (SE 1500/80, parasagittal, 5-mm slices of cervical and thoracic sections). Twelve patients from each clinical group were scanned
54 Annals of Neurology
Vol 29 No 1 January 1991
serially for a 6-month period: two weekly scans for 3 months and then monthly. The patients were selected on the basis of availability, and as only 12 patients in the primary progressive group were able to take part in such frequent scanning, the same number of patients were selected from the secondary progressive group, matched for age, disease duration, and disability. Scanning plane was determined by four oblique pilots (transverse, coronal, sagittal, and a final check transverse pilot) to ensure consistency of the imaging plane throughout the study. In previous serial studies 1151 repositioning had been shown to be better than t 4 degrees; this has been improved further by the current method, thus facilitating comparison between serial images [2 11. Gadolinium diethylenetriaminepentaacetic acid (GdDTPA), 0.1 mMikg, was injected intravenously and T1weighted Gd-DTPA-enhanced scans were obtained of the brain (SE 500140, 256 x 128 image matrix) in all 24 patients, and of the cervical and thoracic sections (SE 500140, 256 x 256 image matrix) in the first 12 patients, 6 from each group. Following injection of Gd-DTPA the patient was repositioned, thus delaying the imaging for 7 minutes. The 24 brain slices were done in three blocks of eight, each taking 3 minutes. The middle block was done first and was followed by the lower and finally the higher block. Thus the brain was imaged from 7 to 16 minutes after injection of Gd-DTPA. In the first 12 patients (6 with primary progressive and 6 with secondary progressive MS) Gd-DTPA was given monthly and in the second 12 patients it was given fortnightly for 3 months and then monthly. Scans were examined by two of us (D. P. E. K. and B. E. K.) who were unaware of the patients’ disease pattern. Lesions were counted and sized for 17 anatomically defined locations. An arbitrary scoring system weighted for lesion size was used to estimate total lesion load; 1 point was given for each lesion with a diameter 1-5 mm, 2 points for one 610 mm, and 3 points for one over 10 mm in size. As the dimensions of confluent lesions were often extensive, particularly in the periventricular regions, they were measured in t h e coronal plane only and scored 1 extra point.
Relaxation Times in Normal-Appeuring White Matter Single-slice scanning was used for quantitative measurements of relaxation time to minimize errors from slice profile effects 1221. An axial slice at a similar level in all patients was taken through the frontal white matter. Three sequences were performed: 1. SE 1500140, 5-mm section, two acquisitions, 128 X 256 image matrix. 2. Inversion recovery (IR) 15001401500, 5-mm section, two acquisitions, 128 X 256 image matrix. 3. A multiecho sequence, repetition time (TR) 1500 milliseconds, 16 repeated echoes at 40-millisecond intervals, 5-mm section, two acquisitions, 128 x 256 image matrix
(SE 1500/40-640). T1-weighted images were computed from SE 1500!40 and IR 1500140/500 images using algorithms provided by the manufacturer. T2-weighted images were produced from the SE 1500140-640 multiecho scan using a multipoint monoexponential curve-fitting procedure. The accuracy and preci-
Table I . M R l Abnormalities in Brain
No. of lesions per patient (mean) Confluent lesions > 5 mm (mean) Percentage of lesions < 5 mm in size Lesion load (mean)
Primary Progressive
Secondary Progressive
Level of Significance
30 1.4 78% 39
42 4.1 65 % 62
p p p p
sion of measurements made previously on our machine have been established with phantoms 1221, and also in normal control subjects where standard deviations of T1 and T 2 of 3% were found in the normal-appearing white matter [23]. Measurements were made on calculated T1- and T2weighted images on a remote Sun 4 Sparc workstation (Sun Microsystems, Inc, Mountain View, CA) running the Analyze image-processing package (Biodynamics Group, Mayo Clinic, Rochester, MN). A region of interest of equal size in both frontal lobes was selected by one of us (A. G. K.) without knowledge of the identity of each scan. Partial volume errors were minimized by selecting regions that were clearly distinct from visible lesions, gray matter, and CSF. Approval was given by the Ethics Committee of the National Hospital for Nervous Disease and all patients gave informed consent to the investigation.
Statistics Results were analyzed using chi squared, Wilcoxon rank sum, and Kurland-Wallis tests as appropriate. The Pearson correlation coefficient was used to compare the TI values in the normal-appearing white matter to the total lesion load.
=
= = =
0.08 0.025 0.009 0.028
normalities of the spinal cord were seen in 4 of the 10 patients with primary progressive MS and 9 of the 20 with secondary progressive MS.
Serial Study CLINICAL. There was no significant difference in the mean age, mean duration of disease, or mean disability score between the two groups of patients studied serially (Table 3). In the 6 months of the serial study 16 patients deteriorated clinically, while 8 remained unchanged (4 with primary progressive and 4 with secondary progressive MS). In the former 16 patients, there was mild deterioration (0.5 on the Kurtzke scale) in 10 (4 with secondary progressive, 6 with primary progressive), moderate deterioration (1 on the Kurtzke scale) in 5 patients ( 3 with secondary progressive, 2 with primary progressive), and marked deterioration (1.5 on the Kurtzke scale) in 1 patient with secondary progressive MS. There were 17 superimposed relapses in the secondary progressive group.
O n only one occasion in the serial study was a dose of Gd-DTPA missed (for technical reasons), and the patient in question had 4 new lesions on the MRI on that day. Over the 6-month period 120 new lesions were seen in the 24 patients studied. The vast majority of these occurred in the patients with secondary progressive MS; 107 were in 11 of :he 12 patients with secondary progressive MS, while only 20 new lesions were seen in 6 of the 12 patients with primary progressive MS. The rate of development of new lesions in the primary progressive group was 3.3 lesions per patient per year, while in the secondary progressive group it was 18.2 lesions per patient per year. There was great variation in the frequency of new lesions in both groups; in the secondary progressive group the variation ranged from 0 to 67 (median, 7) and in the primary progressive group it ranged from 0 to 9 (median, 0.5). Of the 109 new lesions seen in the secondary progressive group, 91 showed enhancement with Gd-DTPA (87% of the 105 new lesions scanned with Gd-DTPA enhancement), while only one of the 20 lesions in the primary progressive group showed enhancement. The difference between the two groups in terms of the development of new lesions and the frequency of enhancement was highly significant ( p = 0.041 and p = 0.001, respectively). MRI.
Results Cross-sectional Study This paper provides data on the natural history of the lesion and of the disease based on the serial enhanced scans of 24 patients with progressive MS. They were selected from a larger series of 34 patients in whom the extent and distribution of MRI abnormality were studied. These cross-sectional data for a slightly smaller group of patients have been described elsewhere [ 2 4 ] . Briefly, the mean number of lesions was higher in the secondary progressive group and there was a greater tendency for these lesions to be large and confluent ( p = 0.025). Conversely, there was a higher proportion of small lesions in the primary progressive group ( p = 0.007) and the lesion load was thus significantly greater in the patients with secondary progressive MS ( p = 0.028) (Table 1, Fig 1A and B). There was no difference in the frequency of atrophy between the two groups. The distribution of lesions was similar in the two groups (Table Z), though there was a greater number of periventricdar lesions in the secondary progressive group ( p = 0.003). Of particular relevance was the fact that there was no difference in the proportion of lesions in such potentially disabling are% as the internal capsule and brainstem. Ab-
Thompson et al: Dynamic Differences in Progressive MS 5 5
B
A Fig 1. T2-weighted MRI ISE 2000l60). (A)Forty-one-year-old man with primavy progressive MS of 15 years' duration and a score on the Expanded Disability Status Scale (EDSS) of 6.0. The scan is notable for the paucity of abnormality. (B) Fortyfive-year-old man with secondary progressiue MS of 5 years' duration and a score on the EDSS of 5.5. The scan shows multiple large discrete and confEuent lesions.
Table 2. Distribution
of
Lesion Load
Primary Secondary Level of Progressive Progressive Significance Periventricular Discrete cerebral Internal capsule Brainstem Cerebellum
rotal
19.2 15.6 1.5
34.7 22.0 1.9 3.5
3.6
1.7
1.0 37.4
p p p p p
=
0.003 0.10 0.27
=
0.74
=
0.21
= =
62.3
"Arbitrary score; see text for details.
Table 3. Clinical Features"
Age (yr) Duration (yr) EDSS
Primary Progressive (n = 12)
Secondary Progressive (n = 12)
42.4 10.0 (25-61) 7.0 -+ 3.8 4.5 2 1.2
35.0 ? 8.7 (24-53) 7.8 +- 4.7 5.2 ? 1.0
"Data are means and standard deviation with ranges in parentheses. There were no significant differences between the two groups.
EDSS
=
Expanded Disability Status Scale.
56 Annals of Neurology
Vol 27
No 1 January 1991
No new lesions and no enhancement with GdDTPA were seen in the spinal cord of any of the 12 patients studied serially. From their initial presentation, new lesions were observed to increase in size over 2 to 4 weeks: The area of abnormality on T2-weighted MRI was greater than the area of enhancement with Gd-DTPA (Fig 2). When enhancement ceased, the T2-weighted abnormality usually diminished to a size corresponding approximately with the initial area of enhancement. This waxing and waning of lesions has been previously described { 161, though its relation to enhancement reflecting active inflammation 1181 in the lesion has
Fig 2. Serial enhanced MRI from a 25-year-old woman with secondary progressive MS. The Jcans were taken at approximately 4-week intervals, and are numberedsequentially 1 to 5 . Slices 5-mm thick from three levels in the brain 1 cm apart (A,B, and C) are illustrated. Enhancement is shown in red superimposed on the unenhanced T2-weighted spin-echo scan. Thefollowing observations can be made: (1) New lesions are frequent. (2)Enhancement in the majority of lesions ceases in approximately 1 month. (3) The areas of enhancement are frequently smaller than the areas of unenhanced abnormality. The latter often increase in size and then decrease after enhancement has ceased. The residual areas of unenhanced T2weighted abnormality correspond approximately with the earlier areas of enhancement (e.g.. row B24). (4)There is a tendeng to temporal clustering of lesions (e.g., r y ~ 2ABC u and row 3ABC {multiple lesions] compared with row JABC {few lesions}).
b
Thompson et al: Dynamic Differences in Progressive MS
57
not. A small proportion of lesions disappeared completely-7 in the secondary progressive group and 2 in the primary progressive group-but this was only seen with smaller lesions. Reenhancement in preexisting lesions was seen on 14 occasions, either at the edge of the lesion giving a ringlike appearance if the entire edge was enhanced (Fig 3) or in the center of an apparently homogeneous area of abnormal signal on the unenhanced scan (Fig 4). Duration of enhancement was measured in the 86 lesions seen in the secondary progressive group. This ranged from approximately 1 month in the majority of patients (67%) (Fig 5 ) to greater than 2 months in 2 patients (Fig 6). Stated another way, with only monthly scanning we would have detected enhancement in 83 (80%) of 105 new lesions. It is of interest that 5 new lesions in the secondary progressive group were not seen to enhance, despite the patients receiving GdDTPA fortnightly; if enhancement were present, it must have been of less than 2 weeks’ duration. MRI AND CLINICAL CORRELATION. As we have previously described 1241, there was no correlation between disability on entry into the study and lesion number or lesion load. Eighteen patients showed clinical evidence of disease activity during the 6-month period: 8 in the primary progressive group and 10 in the secondary progressive group (2 had relapses but no overall deterioration). Of the 18 patients 13 had MRI evidence of disease activity and 5 did not. Four of the latter had primary progressive MS and the fifth was a patient with secondary progressive MS who did not deteriorate over the 6 months but did have a mild relapse when one of her legs became slightly weaker. Of the 6 patients who had no clinical evidence of disease activity, 5 showed changes on serial scanning. The sixth patient was in the primary progressive group. The frequency of occurrence of new lesions on MRI was clearly much greater than the frequency of clinical events in the secondary progressive group. This is well demonstrated by the patient whose scans are shown in Figure 2. During the 6-month study period, she developed 67 new lesions despite having only two clinical relapses superimposed on the progressive course, with moderate overall deterioration (increase in EDSS of 0.5). Thus clinically, it would not have been possible to predict such intense activity. There was a tendency for some patients to show clustering of lesions in time but this was not consistent. However, evidence of disease activity on MRI (new lesions, enlargement or enhancement in preexisting lesions) was more common at the time of clinical relapse in the secondary progressive group. Changes on MRI were seen in association with 11 (65%) of the 17 clinical relapses while of the 73 occasions when there was no acute deterioration clini-
58 Annals of Neurology
Vol 29
No 1 January 1991
cally, changes on MRI were seen in only 19 (26%) (x2 = 9.2, p < 0.01). In the secondary progressive group, multiple new lesions were seen often in association with a single monosymptomatic relapse, an observation previously seen with double-dose delayed computed tomography 1251. NoRMAL-APPEARING WHITE MATTER. T 1 and T2 values for normal-appearing white matter were calculated for 22 of the 24 patients in the serial study and for 12 normal control subjects (Table 4). The T1 values of the patients with secondary progressive MS were higher than those for the normal control subjects and the patients with primary progressive disease, though the difference was not significant. There was, however, a significant relationship between the lesion load and the T1 value ( p < 0.05) (Fig 7) when the two groups were combined. T2 values in the normal-appearing white matter were similar in all three groups.
Discussion If differences between the two groups of patients with progressive MS exist, they would only be detected if strict clinical criteria were adhered to, particularly in relation to the primary progressive group. All patients studied had originally been seen close to the initial clinical onset of disease. In the primary progressive group there was no evidence whatsoever of relapses or remissions. All of the patients in this group satisfied the criteria for definite MS 119) in that they all had oligoclonal bands in their CSF and had evidence, either clinical or paraclinical, of lesions in two anatomically distinct areas of the CNS that had developed over a period of not less than 1 month. In the secondary progressive group there was a clear relapsing-remitting history and a period of progression of at least 6 months’ duration prior to the study. In selecting our patients it became apparent that there were many “transitional” patients who had had a mild relapse prior to the onset of the progressive phase. Such patients have been described previously [2) and are currently under study. In an earlier cross-sectional study, we demonstrated differences in the MRI appearances between the primary and secondary progressive groups in that patients with primary progressive MS generally had fewer and smaller lesions [241. The next logical step was to see if there were differences in the dynamics of the two forms of progressive MS: in the rate of development and in the nature of the lesions. In this serial GdDTPA-enhanced study, striking differences were found in both. New lesions accrued in the secondary progressive group at a significantly greater rate than in the primary progressive group; a mean of 18.2 new lesions per patient per year compared with only 3.3 in the primary progressive group. Enhancement was
Fig 3. (A) T2-weighted MRI (SE 2000160) showing a lesion in the ldt cerebelkzrpedunck that is not enhancing. (B) One month kztw the lesion haJ enlarged on the unenhanced SE 2000160 images. (C) The same image as in (B) with rhe region of GdDTPA enhancement superimposed in red. Note the ring enhancement that coweJponds to the centrifugal enlargement of the lesion.
F i g 4. (A)T2-weightedMRI (SE 2000l60) shwing bilateral conjuent lesions in both temporal lobes. (Bj Unenhanced T2weighted image 1 month later is unchanged. (C) The same image as in (B) with the region of Gd-DTPA enhancement superimposed in red. Note that there is enhancement wzthin the conjuent region of high signal, indicating renewed disease uctivity that wouU have been missed without the u ~ of e Gd-DTPA.
A
B
C
D
F i g 5 . Serial enhanced Tl-weighted M R I (SE 50Ol40i from the patient illustrated in Figure 2. The scans are tuken at monthly intervals. No enhancement is seen in thefirrt scan (A).In the second (B) there is a cluster of lesions in the le$t parietal area and a single lesion on the right. One month later (Ci the areas of enhancement in the le$t parietal region have reduced in size and the lesion on the right has disappeared. HouiefJer,3 new lesions have appeared on the right; 2 in the posterior parietal white matter and one in the centrum semiovule. In the finulscun (Dj all previous lesions have dirappeared and the only area of enhancement is adjacent to the posterior body of the left wntricle. Time in Weeks
found in the vast majority of new lesions in the secondary progressive group (87%) and was also seen at the edge or within preexisting lesions. In contrast, as has already been suggested 126, 271, enhancement of new lesions in the primary progressive group was rare (only 1 of 20). Thus the disease process based on MRI changes appeared to be considerably more active in secondary progressive MS. Nonetheless, despite the paucity of abnormality on MRI, the primary progressive group was clinically very disabled and showed continuing deterioration. This discrepancy to which we have referred previously [24, 283 cannot be explained by the site of the cerebral lesions and may relate to greater spinal cord involvement, which is well recognized pathologically [29]. Scanning of the cord with MRI is much less satisfactory than that of the brain and it is likely that smaller lesions are being missed in both groups. However, as the same methods were used in the 12 patients who had serial spinal imaging and no significant difference was found between the two groups, technical factors alone are unlikely to account for the differences. Furthermore, many of the patients with primary progressive MS (6 of 12 patients) had evidence of clinical involvement outside the spinal cord. As many of the focal lesions in the primary progressive group were small, it is possible that many more were beyond the resolution of the scanner. The same would be true if the pathological process in this group was more diffuse rather than focal either in the brain or in the spinal cord. This would result in the appar60 Annals of Neurology
Vol 29 No 1 January 1991
F i g 6. Duration of enhancement of individuul lesions of known age (n = 86). Lesions enhancing at the sturt of the study, or still enhancing at the end of the study, are not included as their duration of enhancement is not precisely known. Each bar represents the time “window” or interval during which the lesions colrkd have been enhancing. The size o f each “window”was determined by the frequeniy of Gd-DTPA-enhanced scans. For example, the top bar ( n = 3) represents lesions that were enhancing on only one fortnightly scan; therefore. their duration of enhancement could have been anything from 1 day t o 27 day. The number of lesions in each category is listed on the y axis next to euch bar.
ently normal-appearing white matter being more abnormal in the primary progressive group than in the secondary progressive group when analyzed quantitatively. Our results suggest that the opposite is the case and the normal-appearing white matter is more abnormal in the secondary progressive group when compared to either control subjects or the primary progressive group. Moreover, there is a significant relationship between the lesion load and the alteration in T 1 values of the normal-appearing white matter (see Fig 7), suggesting that the more extensive the visible abnormality on MRI is, the more abnormal the “normal-appearing” white matter is. Another possible explanation for the disability in the primary progressive group is that the lesion itself may be different. Recent evidence based on magnetization decay curves {30, 3 11 and examination of pathological specimens {32) suggest that chronic lesions vary, at one extreme being predominantly cellular with
Table 4. Relaxation Times {Milliseconds)in Patients and Control Subjects
Number of patients with T1 measurements T1 values in NAWM ( 2 SD) Number of patients with T2 measurements T2 values in NAWM ( 2SD) NAWM
=
Primary Progressive
Secondary Progressive
Normal Control Subjects
10 422
12
12 415 12 75.7
? 21 10 75.5 -+ 2.6
? ?
22 3.0
&
?
15 2.2
normal-appearing white matter.
C
470 --
0
22 patients p < 0.05
380 370 10
432 11 77.7
20
30 40 50 60 70 80 Total Lesion Load
90 100 110 120 130
Fig 7. Graph showing the correlation between total lesion load (arbitraryunits) and TI relaxution times in nomal-appearing white matter (NAWM) in the 12 patients with seconhiy and 10 with primary pmgressive M S .
marked gliosis (“closed”), and at the other “open” with a much expanded extracellular space and severe axonal loss. Neurological deficit associated with the latter would likely be more severe with little potential for recovery 1331. We found a striking lack of enhancement in the new lesions in the primary progressive group. Why? Enhancement correlates with breakdown of the bloodbrain barrier accompanying active inflammation, as learned from studies on chronic relapsing experimental allergic encephalomyelitis [34} and from the pattern of enhancement seen in acute lesions on dynamic scanning in MS [IS}. We found enhancement in all of 23 new lesions less than 5 weeks old in patients with relapsing-remitting MS {17, 181 and more recently have shown it to be the earliest abnormality seen on MRI in acute relapse {28). The duration of enhancement in the secondary progressive group in the present study ranged from 2 weeks to greater than 2 months (see Fig 6). Further, 5 new lesions in this group were not seen to enhance despite fortnightly scans. This is of relevance when addressing the question of the lack of enhancement in the primary progressive group. Failure to enhance may not indicate lack of inflammation, because duration of enhancement may be less than the shortest interval we examined (2 weeks). Furthermore many of the lesions in this patient group were very small and enhancement may be beyond the resolution of the scanner.
There is evidence in relapsing-remitting disease that the severity of blood-brain barrier breakdown declines with time [18}, from an initial peak at which the degree of enhancement is similar to that of the choroid plexus where a blood-ussue barrier of the type seen in the brain and retina does not exist. If in primary progressive MS there were a change in the blood-brain barrier but the peak increase in permeability was much less than that in secondary progressive disease, the concentration of Gd-DTPA in the extravascular space might be too small to be visible on sequential scans. T1 measurements from these lesions and the surrounding white matter before and after Gd-DTPA injection might be capable of revealing minimal enhancement [32}, indicating blood-brain barrier disruption that is undetectable by conventional methods. Finally, detailed pathological examination of tissue from patients with primary progressive MS to look at the distribution and nature of the lesions in terms of both axonal loss and inflammation should help answer this question. Whether or not it turns out that inflammation is present in primary progressive MS, it is clear that there are important differences in the natural history of the individual lesion and in the dynamics of the disease process which have important practical implications. First, as far as diagnosis is concerned, it is important to appreciate that many patients with primary progressive MS have little abnormality on their cerebral MRIs. Indeed we have seen a number of such patients whose scans were reported as normal, but on careful examination several small lesions were visible. Second, our observations are relevant to monitoring therapy. As pointed out, Gd-DTPA enhancement in MS indicates the presence of inflammation, characteristic of lesions containing myelin breakdown products at postmortem. It is thus an index of recent events and currently provides the most direct means of monitoring disease activity, the suppression of which is the goal of long-term treatment. Simply counting the appearance of new lesions or measuring lesion area or volume runs the risk of missing new activity, since enhancement can occur within apparently homogeneous areas of abnormal signal with little or no overall change in size. Third, the rate of appearance of new lesions on cerebral MRI varied considerably from patient to patient (within the secondary progressive group it ranged from Thompson et al: Dynamic Differences in Progressive MS 61
0 to 67 over the 6-month period), suggesting that it may be necessary 10carry out serial scanning on individual patients prior to entering them into treatment trials. However, it should be noted that despite clinical deterioration, 4 of 12 patients with primary progressive MS had no new lesions on MRI. Finally, since the dynamics of the individual lesion and of the disease process overall are so different in the primary and secondary progressive groups, they should be considered separately in therapeutic trials. Indeed it could even be that therapeutic agents appropriate to relapsing-remitting disease have little effect on the primary progressive group. The Multiple Sclerosis NMR Research Group is supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland, and also by the Medical Research Council of Great Britain. Dr Thompson is supported by the Scarfe Trust. We are grateful to R. Robb, Biodynamics Group, The Mayo Clinic, for providing Analyze image-processing software, and to Dr R. Clark for statistical advice. We would like to thank Drs P. Rudge, R. S. Kocen, and J. N. Blau for referring patients for this study.
References 1. Charcot J-M. Histologe de la sclerose en plaques. Gazerte Hopital, Paris, 1868;41:554-555, 557-558, 566 2. McAlpine D. Course and prognosis of multiple sclerosis. In McAlpine D, Compston ND, Lumsden CE, eds. Multiple sclerosis. Edinburgh: ENS Livingstone, 1955:135-155 3. McDonald WI, Halliday AM. The diagnosis and classification of multiple sclerosis. Br Med Bull 1977;33:4-8 4. Muller R. Studies on disseminated sclerosis. Acra Med S c a d 1949;133(~~ppl222): 1-2 14 5. Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerised data processing of 349 patients. Brain 1980;103:281-300 6. Thompson AJ, Hutclnson M, Brazil J, et al. A clinical and laboratory study of benign multiple sclerosis. Q J Med 1986; 58:69-80 7. Weinshenker BG, Bass B, h c e GPA, et al. The natural hstory of multiple sclerosis; a geographically based study. Brain 1989; 112: 133-146 8. Ormerod IEC, McDonald WI. Multiple sclerosis presenting with progressive visual failure. J Neurol Neurosurg Psychiatry 1984;47943-946 9. Verjans E, Theys SP, Delmotte P, Carton H. Clinical parameters and intrathecal IgG synthesis as prognostic features of multiple sclerosis. Part 1. J Neurol 1983;229:155-165 10. Larsson JP, Cavaale G, Reiisc T, et al. Multiple sclerosis more than one disease. Acta Neurol Scand 1985;72:145-150 11. Madigand M, Oger JJ-F, Faucher R, et al. HLA profiles in multiple sclerosis suggest two f o r m of disease and the existence of protective haplotypes. J Neurol Sci 1982;53:519-529 12. Van Lambalgen R, Sanders EACM, DAmaro J. Sex distribution, age of onset and HLA profiles in two types of multiple sclerosis. J Neurol Sci 1986;76:13-21 13. Francis DA, Batchelor JR, McDonald WI, et al. Multiple sclerosis in North East Scotland: an association with HLA-DQW1. Brain 1987;IlO: 181-196 14. Olerup 0, Hillert J, Fredrikson S, et al. Primarily chronic progressive and relapsingiremitring multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci USA 1989;86:7113-7117
62 Annals of Neurology Vol 29 No 1 January 1991
15. Ormerod IEC, Miller D H , McDonald WI, et al. The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions: a quantitative study. Brain 1987; 110:1579-1616 16 Willoughby EW, Grochowski E, Li D, et al. Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in reiapsing patients. Ann Neurol 1989;25:43-49 1 7 Miller DH, Rudge P, Johnson G, et al. Serial gadoliniumenhanced magnetic resonance imaging in multiple sclerosis. Brain 1988;111:927-939 18. Kermode AG, Tofts PS, Thompson AJ, et al. Heterogeneity of blood brain barrier changes in multiple sclerosis: an MRI study. Neurology 1990;40:229-235 19 Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis; guidelines for research protocols. Ann Neurol 1983;13:22?-231 20 Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33: 1444-1452 21. MacManus DG, Kermode AG, Tofts PS. A repositioning technique for cerebral magnetic resonance imaging of patients with multiple sclerosis. In Book of Abstracts, Society of Magnetic Resonance Imaging in Medicine, Berkeley, CA, 1989;2:617 (Abstract) 22. Johnson G, Ormerod IEC, Barnes D, et al. Accuracy and precision in the measurement of relaxation times from nuclear magnetic rrsonauce images. Br J Kadiol 1987;60:143-153 23. Miller D H , Ormerod IEC, Gibson A, er al. MR brain scanning in patients with vasculitis: differentiation from multiple sclerosis. Neuroradiology 1987;29:226-23 1 24. Thompson AJ, Kermode AG, MacManus DG, et al. Parterns of disease activity in multiple sclerosis: a clinical and magnetic resonance imaging study. Br Med J 1990;300:631-634 25. Ebers G, Vinuela F, Feasby T, Paty D. Multifocal CT enhancement in MS. Can J Neurol Sci 1981;8:190-194 26. Thompson AJ, Kermode AG, MacManus DG, et al. Pathogenesis of progressive multiple sclerosis. Lancer 1989;1:13221323 27. Kappos L, Stadt D, Rohrbach E, Keil W. Gadolinium-DTPA enhanced magnetic resonance imaging in the evaluation of different disease courses and disease activity in MS. Neurology 1988;38(suppl 1):255 (Abstract) 28. Kermode AG, Thompson AJ, Tofts PS, et al. Breakdown of the blood-brain barrier precedes symptoms and other M N signs of new lesions in multiple sclerosis: pathogenetic and clinical implications. Brain 1990;113:1471-1489 29. Allen IV, Glover G, Anderson R. Abnormalities in the macroscopically normal white maccer in cases of mild or spinal multiple sclerosis. Acta Neuropathol (Berl) 1981;(suppl Vl1):176178
30. Barnes D, McDonald WI, Johnson G, et al. Quantitative nuclear magnetic resonance imaging: characterisation of experimental cerebral oedema. J Neurol Neurosurg Psychiatry 1987;50:125-
133 31. Larsson HBW, Frederiksen J, Kjaer L, et al. In-viw determination of T, and Tr in the brain of patients with severe but stable multiple sclerosis. Magn Reson Med 1988;7:43-55 32. Barnes D, Munro PiMG, Youl BD, et al. The longstanding MS lesion: a quantitative MRI and electron microscopic study. Brain (in press) 33. McDonald WI. Pathophysiology of multiple sclerosis. In McDonald WI, Silberberg DH, eds. Multiple sclerosis. London: Bunerworths, 1986:128-129 34. Hawkins CP, Munro PMG, Mackenzie K, et al. Duration and selectivity of blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis studied using gadolinium-DTPA and protein markers. Brain 1990;113:365-378
In patients with primary and secondary progressive multiple sclerosis (MS),major differences in the pattern and extent of abnormality on cerebral magnetic resonance imaging (MRI) between the two groups have recently been demonstrated. In the present study, 24 patients, matched for age, sex, duration of disease, and disability, had serial gadolinium diethylenetriaminepentaacetic acid-enhanced MRI over a 6-month period. The 12 patients in the secondary progressive group had a total of 109 new lesions over this time (1 8.2 lesions per patient per year) and 87% of these enhanced. Enhancement also occurred within and at the edge of preexisting lesions. In contrast, only 20 new lesions were seen in the primary progressive group (3.3 lesions per patient per year) and only one of these enhanced. There was no difference in the degree of clinical deterioration between the two groups over the 6-month period. These findings may indicate a difference in the dynamics of disease activity between the two forms of progressive MS, particularly in relation to the inflammatory component of the lesions, and have important implications for the selection of patients and the monitoring of disease activity in therapeutic trials. Thompson AJ, Kermode AG, Wicks D, MacManus DG, Kendall BE, Kingsley DPE, McDonald W1 Major differences in the dynamics of primary and secondary progressive multiple sclerosis. A n n Neurol 1991;29:53-62
That multiple sclerosis (MS) may follow a progressive course has been recognized since the time of Charcot 111. A distinction between that form of the illness which is progressive from onset (primary progressive) and that which follows an initially relapsing and remitting course (secondary progressive) was made later {2], though most authors implicitly assume that the pathogenesis of the two forms is the same. Others, noting that demyelination may be the end result of quite dlfferent pathological processes, have thought it unsafe to include the primary progressive group in the category of clinically definite MS [3]. Most current practice, as reflected in clinical trials, includes both groups of patients under the heading of chronic progressive MS. If there truly are differences in pathogenesis between the two groups, it is important to distinguish them, lest a therapeutic effect be missed because of the heterogeneity of the cohort being studied. What then is the evidence that the two forms of progressive MS differ? Clinically, patients with primary progressive MS tend to present at a later age than the secondary progressive group 12, 4-7). The most common mode of presentation is a progressive parapa-
resis, though progressive hemiparesis, brainstem syndromes, and visual loss [S] have also been described. It has been suggested that patients in this group have a worse prognosis in terms of disability [5, 91 and that there may be epidemiological differences between primary and secondary progressive MS [lo]. A number of immunogenetic studies have suggested differences in the human leukocyte antigen (HLA) profile between the two groups but the evidence is not conclusive [11-13]. More recently analysis of HLA DR and HLA DQ genes by restriction fragment length polymorphism (RFLP) has suggested that primary progressive MS may be associated with a specific heterozygous Taq 1 HLA DQ p-restriction fragment, which is not seen in secondary progressive MS {14]. Pathological studies have not resolved the issue, as none have made the distinction between primary and secondary progression. Since magnetic resonance imaging (MRI) provides evidence about the distribution of pathological changes during life [15, 161 and serial gadolinium-enhanced MRI can provide evidence about the dynamics of the pathology in terms of both the evolution of new lesions and the natural history of the
From the Multiple Sclerosis NMR Research Group, Institute of Neurology, Queen Square, London, Great Britain.
Address correspondence to Dr Thompson, Lecturer in Clinical Neurology, Institute of Neurology. Queen Square, London W C l N 3BG1 Great Britain'
Received Mar 5 , 1990, and in revised form Jun 22 and Jul 18. Accepted for publication Jul 19, 1990.
Copyright
0 1991 by t h e American Neurological Association
53
disease process [17, 181, we undertook a systematic study over a 6-month period of the clinical and MRI features of the two forms of progressive MS.
Materials and Methods The study was restricted to patients with definite MS and strict criteria for the two patient groups were adhered to rigidly.
Clinical Thirty-four patients with clinically definite MS [19] were studied; 20 had secondary progressive MS and 14 had primary progressive disease. Patients were selected by one of us (A. J. T.) from the MS population attending the National Hospital for Nervous Diseases, Queen Square, London. The case notes of potential candidates were carefully studied and suitable patients reviewed. A detailed history was taken. Many patients initially thought to have primary progressive MS were found to have had either a transient episode that resolved prior to the onset of progression or a period of rapid deterioration during the progressive phase that would fulfill the criteria for a relapse; such patients were excluded from the study. Primary progressive MS was defined as disease that was progressive from onset, with no evidence of relapses or remissions. We required that the evidence of involvement of at least two anatomically separate areas of the central nervous system (CNS) was sequential, with a period of at least 1 month between them. Paraclinical findings such as an abnormal visual-evoked response, though not a new lesion on MRI, were also used as evidence of a second lesion. All patients had oligoclonal bands in the cerebrospinal fluid (CSF). Of the 14 patients studied, the progressive syndromes were: paraparesis (5), hemiparesis (3), brainstem syndromes (3), cerebellar syndromes (2), and visual syndromes (1). Patients with sccondary progressive MS had an initial relapsing and remitting phase but had developed progressive disability over at least the preceding 6 months. Superimposed relapses were allowed. Relapse was defined as the Occurrence of a symptom or symptoms of neurological dysfunction, with or without objective confirmation lasting more than 24 hours, and remission was defined as a definite improvement in signs, symptoms, or both, present for at least 24 hours and lasting for at least 1 month [19}. All patients attended the National Hospital for Nervous Diseases and had been seen close to the clinical onset of the disease. Each patient was assessed neurologically by one of us (A. J. T.) on entry into the study and at the time of each scan. Disability was measured using the Expanded Kurtzke Disability Status Scale (EDSS) and Kurtzke’s functional score 1201.
MRI T2-weighted MRI of the brain was performed in 34 patients (Picker, International, Wembley, Middlesex, UK, 0.5 tesla, spin echo (SE) 2000/60, 5-mm contiguous slices, 256 x 256 image matrix). T2-weighted MRI of the spinal cord was performed on 20 patients with secondary progressive MS and 10 patients with primary progressive MS (SE 1500/80, parasagittal, 5-mm slices of cervical and thoracic sections). Twelve patients from each clinical group were scanned
54 Annals of Neurology
Vol 29 No 1 January 1991
serially for a 6-month period: two weekly scans for 3 months and then monthly. The patients were selected on the basis of availability, and as only 12 patients in the primary progressive group were able to take part in such frequent scanning, the same number of patients were selected from the secondary progressive group, matched for age, disease duration, and disability. Scanning plane was determined by four oblique pilots (transverse, coronal, sagittal, and a final check transverse pilot) to ensure consistency of the imaging plane throughout the study. In previous serial studies 1151 repositioning had been shown to be better than t 4 degrees; this has been improved further by the current method, thus facilitating comparison between serial images [2 11. Gadolinium diethylenetriaminepentaacetic acid (GdDTPA), 0.1 mMikg, was injected intravenously and T1weighted Gd-DTPA-enhanced scans were obtained of the brain (SE 500140, 256 x 128 image matrix) in all 24 patients, and of the cervical and thoracic sections (SE 500140, 256 x 256 image matrix) in the first 12 patients, 6 from each group. Following injection of Gd-DTPA the patient was repositioned, thus delaying the imaging for 7 minutes. The 24 brain slices were done in three blocks of eight, each taking 3 minutes. The middle block was done first and was followed by the lower and finally the higher block. Thus the brain was imaged from 7 to 16 minutes after injection of Gd-DTPA. In the first 12 patients (6 with primary progressive and 6 with secondary progressive MS) Gd-DTPA was given monthly and in the second 12 patients it was given fortnightly for 3 months and then monthly. Scans were examined by two of us (D. P. E. K. and B. E. K.) who were unaware of the patients’ disease pattern. Lesions were counted and sized for 17 anatomically defined locations. An arbitrary scoring system weighted for lesion size was used to estimate total lesion load; 1 point was given for each lesion with a diameter 1-5 mm, 2 points for one 610 mm, and 3 points for one over 10 mm in size. As the dimensions of confluent lesions were often extensive, particularly in the periventricular regions, they were measured in t h e coronal plane only and scored 1 extra point.
Relaxation Times in Normal-Appeuring White Matter Single-slice scanning was used for quantitative measurements of relaxation time to minimize errors from slice profile effects 1221. An axial slice at a similar level in all patients was taken through the frontal white matter. Three sequences were performed: 1. SE 1500140, 5-mm section, two acquisitions, 128 X 256 image matrix. 2. Inversion recovery (IR) 15001401500, 5-mm section, two acquisitions, 128 X 256 image matrix. 3. A multiecho sequence, repetition time (TR) 1500 milliseconds, 16 repeated echoes at 40-millisecond intervals, 5-mm section, two acquisitions, 128 x 256 image matrix
(SE 1500/40-640). T1-weighted images were computed from SE 1500!40 and IR 1500140/500 images using algorithms provided by the manufacturer. T2-weighted images were produced from the SE 1500140-640 multiecho scan using a multipoint monoexponential curve-fitting procedure. The accuracy and preci-
Table I . M R l Abnormalities in Brain
No. of lesions per patient (mean) Confluent lesions > 5 mm (mean) Percentage of lesions < 5 mm in size Lesion load (mean)
Primary Progressive
Secondary Progressive
Level of Significance
30 1.4 78% 39
42 4.1 65 % 62
p p p p
sion of measurements made previously on our machine have been established with phantoms 1221, and also in normal control subjects where standard deviations of T1 and T 2 of 3% were found in the normal-appearing white matter [23]. Measurements were made on calculated T1- and T2weighted images on a remote Sun 4 Sparc workstation (Sun Microsystems, Inc, Mountain View, CA) running the Analyze image-processing package (Biodynamics Group, Mayo Clinic, Rochester, MN). A region of interest of equal size in both frontal lobes was selected by one of us (A. G. K.) without knowledge of the identity of each scan. Partial volume errors were minimized by selecting regions that were clearly distinct from visible lesions, gray matter, and CSF. Approval was given by the Ethics Committee of the National Hospital for Nervous Disease and all patients gave informed consent to the investigation.
Statistics Results were analyzed using chi squared, Wilcoxon rank sum, and Kurland-Wallis tests as appropriate. The Pearson correlation coefficient was used to compare the TI values in the normal-appearing white matter to the total lesion load.
=
= = =
0.08 0.025 0.009 0.028
normalities of the spinal cord were seen in 4 of the 10 patients with primary progressive MS and 9 of the 20 with secondary progressive MS.
Serial Study CLINICAL. There was no significant difference in the mean age, mean duration of disease, or mean disability score between the two groups of patients studied serially (Table 3). In the 6 months of the serial study 16 patients deteriorated clinically, while 8 remained unchanged (4 with primary progressive and 4 with secondary progressive MS). In the former 16 patients, there was mild deterioration (0.5 on the Kurtzke scale) in 10 (4 with secondary progressive, 6 with primary progressive), moderate deterioration (1 on the Kurtzke scale) in 5 patients ( 3 with secondary progressive, 2 with primary progressive), and marked deterioration (1.5 on the Kurtzke scale) in 1 patient with secondary progressive MS. There were 17 superimposed relapses in the secondary progressive group.
O n only one occasion in the serial study was a dose of Gd-DTPA missed (for technical reasons), and the patient in question had 4 new lesions on the MRI on that day. Over the 6-month period 120 new lesions were seen in the 24 patients studied. The vast majority of these occurred in the patients with secondary progressive MS; 107 were in 11 of :he 12 patients with secondary progressive MS, while only 20 new lesions were seen in 6 of the 12 patients with primary progressive MS. The rate of development of new lesions in the primary progressive group was 3.3 lesions per patient per year, while in the secondary progressive group it was 18.2 lesions per patient per year. There was great variation in the frequency of new lesions in both groups; in the secondary progressive group the variation ranged from 0 to 67 (median, 7) and in the primary progressive group it ranged from 0 to 9 (median, 0.5). Of the 109 new lesions seen in the secondary progressive group, 91 showed enhancement with Gd-DTPA (87% of the 105 new lesions scanned with Gd-DTPA enhancement), while only one of the 20 lesions in the primary progressive group showed enhancement. The difference between the two groups in terms of the development of new lesions and the frequency of enhancement was highly significant ( p = 0.041 and p = 0.001, respectively). MRI.
Results Cross-sectional Study This paper provides data on the natural history of the lesion and of the disease based on the serial enhanced scans of 24 patients with progressive MS. They were selected from a larger series of 34 patients in whom the extent and distribution of MRI abnormality were studied. These cross-sectional data for a slightly smaller group of patients have been described elsewhere [ 2 4 ] . Briefly, the mean number of lesions was higher in the secondary progressive group and there was a greater tendency for these lesions to be large and confluent ( p = 0.025). Conversely, there was a higher proportion of small lesions in the primary progressive group ( p = 0.007) and the lesion load was thus significantly greater in the patients with secondary progressive MS ( p = 0.028) (Table 1, Fig 1A and B). There was no difference in the frequency of atrophy between the two groups. The distribution of lesions was similar in the two groups (Table Z), though there was a greater number of periventricdar lesions in the secondary progressive group ( p = 0.003). Of particular relevance was the fact that there was no difference in the proportion of lesions in such potentially disabling are% as the internal capsule and brainstem. Ab-
Thompson et al: Dynamic Differences in Progressive MS 5 5
B
A Fig 1. T2-weighted MRI ISE 2000l60). (A)Forty-one-year-old man with primavy progressive MS of 15 years' duration and a score on the Expanded Disability Status Scale (EDSS) of 6.0. The scan is notable for the paucity of abnormality. (B) Fortyfive-year-old man with secondary progressiue MS of 5 years' duration and a score on the EDSS of 5.5. The scan shows multiple large discrete and confEuent lesions.
Table 2. Distribution
of
Lesion Load
Primary Secondary Level of Progressive Progressive Significance Periventricular Discrete cerebral Internal capsule Brainstem Cerebellum
rotal
19.2 15.6 1.5
34.7 22.0 1.9 3.5
3.6
1.7
1.0 37.4
p p p p p
=
0.003 0.10 0.27
=
0.74
=
0.21
= =
62.3
"Arbitrary score; see text for details.
Table 3. Clinical Features"
Age (yr) Duration (yr) EDSS
Primary Progressive (n = 12)
Secondary Progressive (n = 12)
42.4 10.0 (25-61) 7.0 -+ 3.8 4.5 2 1.2
35.0 ? 8.7 (24-53) 7.8 +- 4.7 5.2 ? 1.0
"Data are means and standard deviation with ranges in parentheses. There were no significant differences between the two groups.
EDSS
=
Expanded Disability Status Scale.
56 Annals of Neurology
Vol 27
No 1 January 1991
No new lesions and no enhancement with GdDTPA were seen in the spinal cord of any of the 12 patients studied serially. From their initial presentation, new lesions were observed to increase in size over 2 to 4 weeks: The area of abnormality on T2-weighted MRI was greater than the area of enhancement with Gd-DTPA (Fig 2). When enhancement ceased, the T2-weighted abnormality usually diminished to a size corresponding approximately with the initial area of enhancement. This waxing and waning of lesions has been previously described { 161, though its relation to enhancement reflecting active inflammation 1181 in the lesion has
Fig 2. Serial enhanced MRI from a 25-year-old woman with secondary progressive MS. The Jcans were taken at approximately 4-week intervals, and are numberedsequentially 1 to 5 . Slices 5-mm thick from three levels in the brain 1 cm apart (A,B, and C) are illustrated. Enhancement is shown in red superimposed on the unenhanced T2-weighted spin-echo scan. Thefollowing observations can be made: (1) New lesions are frequent. (2)Enhancement in the majority of lesions ceases in approximately 1 month. (3) The areas of enhancement are frequently smaller than the areas of unenhanced abnormality. The latter often increase in size and then decrease after enhancement has ceased. The residual areas of unenhanced T2weighted abnormality correspond approximately with the earlier areas of enhancement (e.g.. row B24). (4)There is a tendeng to temporal clustering of lesions (e.g., r y ~ 2ABC u and row 3ABC {multiple lesions] compared with row JABC {few lesions}).
b
Thompson et al: Dynamic Differences in Progressive MS
57
not. A small proportion of lesions disappeared completely-7 in the secondary progressive group and 2 in the primary progressive group-but this was only seen with smaller lesions. Reenhancement in preexisting lesions was seen on 14 occasions, either at the edge of the lesion giving a ringlike appearance if the entire edge was enhanced (Fig 3) or in the center of an apparently homogeneous area of abnormal signal on the unenhanced scan (Fig 4). Duration of enhancement was measured in the 86 lesions seen in the secondary progressive group. This ranged from approximately 1 month in the majority of patients (67%) (Fig 5 ) to greater than 2 months in 2 patients (Fig 6). Stated another way, with only monthly scanning we would have detected enhancement in 83 (80%) of 105 new lesions. It is of interest that 5 new lesions in the secondary progressive group were not seen to enhance, despite the patients receiving GdDTPA fortnightly; if enhancement were present, it must have been of less than 2 weeks’ duration. MRI AND CLINICAL CORRELATION. As we have previously described 1241, there was no correlation between disability on entry into the study and lesion number or lesion load. Eighteen patients showed clinical evidence of disease activity during the 6-month period: 8 in the primary progressive group and 10 in the secondary progressive group (2 had relapses but no overall deterioration). Of the 18 patients 13 had MRI evidence of disease activity and 5 did not. Four of the latter had primary progressive MS and the fifth was a patient with secondary progressive MS who did not deteriorate over the 6 months but did have a mild relapse when one of her legs became slightly weaker. Of the 6 patients who had no clinical evidence of disease activity, 5 showed changes on serial scanning. The sixth patient was in the primary progressive group. The frequency of occurrence of new lesions on MRI was clearly much greater than the frequency of clinical events in the secondary progressive group. This is well demonstrated by the patient whose scans are shown in Figure 2. During the 6-month study period, she developed 67 new lesions despite having only two clinical relapses superimposed on the progressive course, with moderate overall deterioration (increase in EDSS of 0.5). Thus clinically, it would not have been possible to predict such intense activity. There was a tendency for some patients to show clustering of lesions in time but this was not consistent. However, evidence of disease activity on MRI (new lesions, enlargement or enhancement in preexisting lesions) was more common at the time of clinical relapse in the secondary progressive group. Changes on MRI were seen in association with 11 (65%) of the 17 clinical relapses while of the 73 occasions when there was no acute deterioration clini-
58 Annals of Neurology
Vol 29
No 1 January 1991
cally, changes on MRI were seen in only 19 (26%) (x2 = 9.2, p < 0.01). In the secondary progressive group, multiple new lesions were seen often in association with a single monosymptomatic relapse, an observation previously seen with double-dose delayed computed tomography 1251. NoRMAL-APPEARING WHITE MATTER. T 1 and T2 values for normal-appearing white matter were calculated for 22 of the 24 patients in the serial study and for 12 normal control subjects (Table 4). The T1 values of the patients with secondary progressive MS were higher than those for the normal control subjects and the patients with primary progressive disease, though the difference was not significant. There was, however, a significant relationship between the lesion load and the T1 value ( p < 0.05) (Fig 7) when the two groups were combined. T2 values in the normal-appearing white matter were similar in all three groups.
Discussion If differences between the two groups of patients with progressive MS exist, they would only be detected if strict clinical criteria were adhered to, particularly in relation to the primary progressive group. All patients studied had originally been seen close to the initial clinical onset of disease. In the primary progressive group there was no evidence whatsoever of relapses or remissions. All of the patients in this group satisfied the criteria for definite MS 119) in that they all had oligoclonal bands in their CSF and had evidence, either clinical or paraclinical, of lesions in two anatomically distinct areas of the CNS that had developed over a period of not less than 1 month. In the secondary progressive group there was a clear relapsing-remitting history and a period of progression of at least 6 months’ duration prior to the study. In selecting our patients it became apparent that there were many “transitional” patients who had had a mild relapse prior to the onset of the progressive phase. Such patients have been described previously [2) and are currently under study. In an earlier cross-sectional study, we demonstrated differences in the MRI appearances between the primary and secondary progressive groups in that patients with primary progressive MS generally had fewer and smaller lesions [241. The next logical step was to see if there were differences in the dynamics of the two forms of progressive MS: in the rate of development and in the nature of the lesions. In this serial GdDTPA-enhanced study, striking differences were found in both. New lesions accrued in the secondary progressive group at a significantly greater rate than in the primary progressive group; a mean of 18.2 new lesions per patient per year compared with only 3.3 in the primary progressive group. Enhancement was
Fig 3. (A) T2-weighted MRI (SE 2000160) showing a lesion in the ldt cerebelkzrpedunck that is not enhancing. (B) One month kztw the lesion haJ enlarged on the unenhanced SE 2000160 images. (C) The same image as in (B) with rhe region of GdDTPA enhancement superimposed in red. Note the ring enhancement that coweJponds to the centrifugal enlargement of the lesion.
F i g 4. (A)T2-weightedMRI (SE 2000l60) shwing bilateral conjuent lesions in both temporal lobes. (Bj Unenhanced T2weighted image 1 month later is unchanged. (C) The same image as in (B) with the region of Gd-DTPA enhancement superimposed in red. Note that there is enhancement wzthin the conjuent region of high signal, indicating renewed disease uctivity that wouU have been missed without the u ~ of e Gd-DTPA.
A
B
C
D
F i g 5 . Serial enhanced Tl-weighted M R I (SE 50Ol40i from the patient illustrated in Figure 2. The scans are tuken at monthly intervals. No enhancement is seen in thefirrt scan (A).In the second (B) there is a cluster of lesions in the le$t parietal area and a single lesion on the right. One month later (Ci the areas of enhancement in the le$t parietal region have reduced in size and the lesion on the right has disappeared. HouiefJer,3 new lesions have appeared on the right; 2 in the posterior parietal white matter and one in the centrum semiovule. In the finulscun (Dj all previous lesions have dirappeared and the only area of enhancement is adjacent to the posterior body of the left wntricle. Time in Weeks
found in the vast majority of new lesions in the secondary progressive group (87%) and was also seen at the edge or within preexisting lesions. In contrast, as has already been suggested 126, 271, enhancement of new lesions in the primary progressive group was rare (only 1 of 20). Thus the disease process based on MRI changes appeared to be considerably more active in secondary progressive MS. Nonetheless, despite the paucity of abnormality on MRI, the primary progressive group was clinically very disabled and showed continuing deterioration. This discrepancy to which we have referred previously [24, 283 cannot be explained by the site of the cerebral lesions and may relate to greater spinal cord involvement, which is well recognized pathologically [29]. Scanning of the cord with MRI is much less satisfactory than that of the brain and it is likely that smaller lesions are being missed in both groups. However, as the same methods were used in the 12 patients who had serial spinal imaging and no significant difference was found between the two groups, technical factors alone are unlikely to account for the differences. Furthermore, many of the patients with primary progressive MS (6 of 12 patients) had evidence of clinical involvement outside the spinal cord. As many of the focal lesions in the primary progressive group were small, it is possible that many more were beyond the resolution of the scanner. The same would be true if the pathological process in this group was more diffuse rather than focal either in the brain or in the spinal cord. This would result in the appar60 Annals of Neurology
Vol 29 No 1 January 1991
F i g 6. Duration of enhancement of individuul lesions of known age (n = 86). Lesions enhancing at the sturt of the study, or still enhancing at the end of the study, are not included as their duration of enhancement is not precisely known. Each bar represents the time “window” or interval during which the lesions colrkd have been enhancing. The size o f each “window”was determined by the frequeniy of Gd-DTPA-enhanced scans. For example, the top bar ( n = 3) represents lesions that were enhancing on only one fortnightly scan; therefore. their duration of enhancement could have been anything from 1 day t o 27 day. The number of lesions in each category is listed on the y axis next to euch bar.
ently normal-appearing white matter being more abnormal in the primary progressive group than in the secondary progressive group when analyzed quantitatively. Our results suggest that the opposite is the case and the normal-appearing white matter is more abnormal in the secondary progressive group when compared to either control subjects or the primary progressive group. Moreover, there is a significant relationship between the lesion load and the alteration in T 1 values of the normal-appearing white matter (see Fig 7), suggesting that the more extensive the visible abnormality on MRI is, the more abnormal the “normal-appearing” white matter is. Another possible explanation for the disability in the primary progressive group is that the lesion itself may be different. Recent evidence based on magnetization decay curves {30, 3 11 and examination of pathological specimens {32) suggest that chronic lesions vary, at one extreme being predominantly cellular with
Table 4. Relaxation Times {Milliseconds)in Patients and Control Subjects
Number of patients with T1 measurements T1 values in NAWM ( 2 SD) Number of patients with T2 measurements T2 values in NAWM ( 2SD) NAWM
=
Primary Progressive
Secondary Progressive
Normal Control Subjects
10 422
12
12 415 12 75.7
? 21 10 75.5 -+ 2.6
? ?
22 3.0
&
?
15 2.2
normal-appearing white matter.
C
470 --
0
22 patients p < 0.05
380 370 10
432 11 77.7
20
30 40 50 60 70 80 Total Lesion Load
90 100 110 120 130
Fig 7. Graph showing the correlation between total lesion load (arbitraryunits) and TI relaxution times in nomal-appearing white matter (NAWM) in the 12 patients with seconhiy and 10 with primary pmgressive M S .
marked gliosis (“closed”), and at the other “open” with a much expanded extracellular space and severe axonal loss. Neurological deficit associated with the latter would likely be more severe with little potential for recovery 1331. We found a striking lack of enhancement in the new lesions in the primary progressive group. Why? Enhancement correlates with breakdown of the bloodbrain barrier accompanying active inflammation, as learned from studies on chronic relapsing experimental allergic encephalomyelitis [34} and from the pattern of enhancement seen in acute lesions on dynamic scanning in MS [IS}. We found enhancement in all of 23 new lesions less than 5 weeks old in patients with relapsing-remitting MS {17, 181 and more recently have shown it to be the earliest abnormality seen on MRI in acute relapse {28). The duration of enhancement in the secondary progressive group in the present study ranged from 2 weeks to greater than 2 months (see Fig 6). Further, 5 new lesions in this group were not seen to enhance despite fortnightly scans. This is of relevance when addressing the question of the lack of enhancement in the primary progressive group. Failure to enhance may not indicate lack of inflammation, because duration of enhancement may be less than the shortest interval we examined (2 weeks). Furthermore many of the lesions in this patient group were very small and enhancement may be beyond the resolution of the scanner.
There is evidence in relapsing-remitting disease that the severity of blood-brain barrier breakdown declines with time [18}, from an initial peak at which the degree of enhancement is similar to that of the choroid plexus where a blood-ussue barrier of the type seen in the brain and retina does not exist. If in primary progressive MS there were a change in the blood-brain barrier but the peak increase in permeability was much less than that in secondary progressive disease, the concentration of Gd-DTPA in the extravascular space might be too small to be visible on sequential scans. T1 measurements from these lesions and the surrounding white matter before and after Gd-DTPA injection might be capable of revealing minimal enhancement [32}, indicating blood-brain barrier disruption that is undetectable by conventional methods. Finally, detailed pathological examination of tissue from patients with primary progressive MS to look at the distribution and nature of the lesions in terms of both axonal loss and inflammation should help answer this question. Whether or not it turns out that inflammation is present in primary progressive MS, it is clear that there are important differences in the natural history of the individual lesion and in the dynamics of the disease process which have important practical implications. First, as far as diagnosis is concerned, it is important to appreciate that many patients with primary progressive MS have little abnormality on their cerebral MRIs. Indeed we have seen a number of such patients whose scans were reported as normal, but on careful examination several small lesions were visible. Second, our observations are relevant to monitoring therapy. As pointed out, Gd-DTPA enhancement in MS indicates the presence of inflammation, characteristic of lesions containing myelin breakdown products at postmortem. It is thus an index of recent events and currently provides the most direct means of monitoring disease activity, the suppression of which is the goal of long-term treatment. Simply counting the appearance of new lesions or measuring lesion area or volume runs the risk of missing new activity, since enhancement can occur within apparently homogeneous areas of abnormal signal with little or no overall change in size. Third, the rate of appearance of new lesions on cerebral MRI varied considerably from patient to patient (within the secondary progressive group it ranged from Thompson et al: Dynamic Differences in Progressive MS 61
0 to 67 over the 6-month period), suggesting that it may be necessary 10carry out serial scanning on individual patients prior to entering them into treatment trials. However, it should be noted that despite clinical deterioration, 4 of 12 patients with primary progressive MS had no new lesions on MRI. Finally, since the dynamics of the individual lesion and of the disease process overall are so different in the primary and secondary progressive groups, they should be considered separately in therapeutic trials. Indeed it could even be that therapeutic agents appropriate to relapsing-remitting disease have little effect on the primary progressive group. The Multiple Sclerosis NMR Research Group is supported by the Multiple Sclerosis Society of Great Britain and Northern Ireland, and also by the Medical Research Council of Great Britain. Dr Thompson is supported by the Scarfe Trust. We are grateful to R. Robb, Biodynamics Group, The Mayo Clinic, for providing Analyze image-processing software, and to Dr R. Clark for statistical advice. We would like to thank Drs P. Rudge, R. S. Kocen, and J. N. Blau for referring patients for this study.
References 1. Charcot J-M. Histologe de la sclerose en plaques. Gazerte Hopital, Paris, 1868;41:554-555, 557-558, 566 2. McAlpine D. Course and prognosis of multiple sclerosis. In McAlpine D, Compston ND, Lumsden CE, eds. Multiple sclerosis. Edinburgh: ENS Livingstone, 1955:135-155 3. McDonald WI, Halliday AM. The diagnosis and classification of multiple sclerosis. Br Med Bull 1977;33:4-8 4. Muller R. Studies on disseminated sclerosis. Acra Med S c a d 1949;133(~~ppl222): 1-2 14 5. Confavreux C, Aimard G, Devic M. Course and prognosis of multiple sclerosis assessed by the computerised data processing of 349 patients. Brain 1980;103:281-300 6. Thompson AJ, Hutclnson M, Brazil J, et al. A clinical and laboratory study of benign multiple sclerosis. Q J Med 1986; 58:69-80 7. Weinshenker BG, Bass B, h c e GPA, et al. The natural hstory of multiple sclerosis; a geographically based study. Brain 1989; 112: 133-146 8. Ormerod IEC, McDonald WI. Multiple sclerosis presenting with progressive visual failure. J Neurol Neurosurg Psychiatry 1984;47943-946 9. Verjans E, Theys SP, Delmotte P, Carton H. Clinical parameters and intrathecal IgG synthesis as prognostic features of multiple sclerosis. Part 1. J Neurol 1983;229:155-165 10. Larsson JP, Cavaale G, Reiisc T, et al. Multiple sclerosis more than one disease. Acta Neurol Scand 1985;72:145-150 11. Madigand M, Oger JJ-F, Faucher R, et al. HLA profiles in multiple sclerosis suggest two f o r m of disease and the existence of protective haplotypes. J Neurol Sci 1982;53:519-529 12. Van Lambalgen R, Sanders EACM, DAmaro J. Sex distribution, age of onset and HLA profiles in two types of multiple sclerosis. J Neurol Sci 1986;76:13-21 13. Francis DA, Batchelor JR, McDonald WI, et al. Multiple sclerosis in North East Scotland: an association with HLA-DQW1. Brain 1987;IlO: 181-196 14. Olerup 0, Hillert J, Fredrikson S, et al. Primarily chronic progressive and relapsingiremitring multiple sclerosis: two immunogenetically distinct disease entities. Proc Natl Acad Sci USA 1989;86:7113-7117
62 Annals of Neurology Vol 29 No 1 January 1991
15. Ormerod IEC, Miller D H , McDonald WI, et al. The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions: a quantitative study. Brain 1987; 110:1579-1616 16 Willoughby EW, Grochowski E, Li D, et al. Serial magnetic resonance scanning in multiple sclerosis: a second prospective study in reiapsing patients. Ann Neurol 1989;25:43-49 1 7 Miller DH, Rudge P, Johnson G, et al. Serial gadoliniumenhanced magnetic resonance imaging in multiple sclerosis. Brain 1988;111:927-939 18. Kermode AG, Tofts PS, Thompson AJ, et al. Heterogeneity of blood brain barrier changes in multiple sclerosis: an MRI study. Neurology 1990;40:229-235 19 Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis; guidelines for research protocols. Ann Neurol 1983;13:22?-231 20 Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33: 1444-1452 21. MacManus DG, Kermode AG, Tofts PS. A repositioning technique for cerebral magnetic resonance imaging of patients with multiple sclerosis. In Book of Abstracts, Society of Magnetic Resonance Imaging in Medicine, Berkeley, CA, 1989;2:617 (Abstract) 22. Johnson G, Ormerod IEC, Barnes D, et al. Accuracy and precision in the measurement of relaxation times from nuclear magnetic rrsonauce images. Br J Kadiol 1987;60:143-153 23. Miller D H , Ormerod IEC, Gibson A, er al. MR brain scanning in patients with vasculitis: differentiation from multiple sclerosis. Neuroradiology 1987;29:226-23 1 24. Thompson AJ, Kermode AG, MacManus DG, et al. Parterns of disease activity in multiple sclerosis: a clinical and magnetic resonance imaging study. Br Med J 1990;300:631-634 25. Ebers G, Vinuela F, Feasby T, Paty D. Multifocal CT enhancement in MS. Can J Neurol Sci 1981;8:190-194 26. Thompson AJ, Kermode AG, MacManus DG, et al. Pathogenesis of progressive multiple sclerosis. Lancer 1989;1:13221323 27. Kappos L, Stadt D, Rohrbach E, Keil W. Gadolinium-DTPA enhanced magnetic resonance imaging in the evaluation of different disease courses and disease activity in MS. Neurology 1988;38(suppl 1):255 (Abstract) 28. Kermode AG, Thompson AJ, Tofts PS, et al. Breakdown of the blood-brain barrier precedes symptoms and other M N signs of new lesions in multiple sclerosis: pathogenetic and clinical implications. Brain 1990;113:1471-1489 29. Allen IV, Glover G, Anderson R. Abnormalities in the macroscopically normal white maccer in cases of mild or spinal multiple sclerosis. Acta Neuropathol (Berl) 1981;(suppl Vl1):176178
30. Barnes D, McDonald WI, Johnson G, et al. Quantitative nuclear magnetic resonance imaging: characterisation of experimental cerebral oedema. J Neurol Neurosurg Psychiatry 1987;50:125-
133 31. Larsson HBW, Frederiksen J, Kjaer L, et al. In-viw determination of T, and Tr in the brain of patients with severe but stable multiple sclerosis. Magn Reson Med 1988;7:43-55 32. Barnes D, Munro PiMG, Youl BD, et al. The longstanding MS lesion: a quantitative MRI and electron microscopic study. Brain (in press) 33. McDonald WI. Pathophysiology of multiple sclerosis. In McDonald WI, Silberberg DH, eds. Multiple sclerosis. London: Bunerworths, 1986:128-129 34. Hawkins CP, Munro PMG, Mackenzie K, et al. Duration and selectivity of blood-brain barrier breakdown in chronic relapsing experimental allergic encephalomyelitis studied using gadolinium-DTPA and protein markers. Brain 1990;113:365-378
