Multi-array spinal cord imaging in multiple sclerosis and

healthy controls

INTRODUCTION

As touched on in chapter 1, spinal imaging is of great importance in our understanding of MS. The spinal cord is the site of many of the disabling lesions of MS, in particular those affecting the motor tracts and the pathways subserving bowel and bladder function. One feasible explanation of the poor correlation between lesion load and clinical disability is that most studies have been limited to brain MRI. As discussed in chapter 3, imaging the whole spinal cord using conventional surface coils is extremely time consuming and using volume coils produces images of low SNR. There has therefore been only limited success in demonstrating small intrinsic spinal cord lesions such as those seen in MS (Maravilla

et a l, 1985; Masaryk et a l, 1986; Miller et a l, 1987b; Honig and Sheremata, 1989; Turano et a l, 1991). The work described in this chapter is an evaluation of a prototype multi-array coil (see chapter 3) in patients with MS as well as in healthy controls. Roemer

et a l (1990) comprehensively demonstrated the superiority of the multi-array coil in spinal cord imaging, so it was not felt that a further direct comparison with conventional surface coils in the detection of MS plaques was necessary or worthwhile (figure 6.1a,b). Neither was a formal comparison of SE and FSB carried out in the spinal cord, having previously established that the two sequences were very comparable in detecting MS lesions in the brain (chapter 4). Other workers (Sze et a l, 1992) using a conventional surface coil have found FSE to be as accurate as SE in a variety of intradural pathologies. Furthermore, to obtain whole spine SE images approaching the quality of those acquired by FSE was prohibitively time consuming; 256x256 resolution sagittal SE images of the cervical cord

took approximately 17 minutes to acquire, compared to under 3 minutes for FSE (figure 6.1b,c) and 512x512 images of the whole cord over 30 minutes. It was possible to halve the acquisition time of the SE (and FSE) images by acquiring a rectangular field of view (ie a 256x512 matrix, see chapter 2), with phase encoding being in the antero-posterior (A/P) direction, frequency encoding supero-inferior (S/I). However, spinal images acquired with either SE or FSE were marred by motion artefacts caused by breathing, blood flow and CSF pulsation, with the artefacts being distributed across the image in the phase encoding direction. Thus with A/P phase encoding, they were superimposed on the spinal cord whereas with S/I phase encoding they were mainly parallel to it. The use of cardiac gating (Enzmann and Rubin, 1987), in which the timing of each excitation is triggered by an ECG monitor, produced a modest reduction in cardiac and CSF motion artefact, but with a further time penalty. It appeared in addition that FSE was intrinsically less sensitive to motion artefact than SE, probably as a result of the rapid dephasing and rephasing of spins by the multi-echo train.

Preliminary assessment was made of sagittal 7^*-weighted gradient echo (GE) imaging of the cord. As has been found by others (Enzmann and Rubin, 1988b), in addition to being marred by motion and magnetic susceptibility artefacts, lesion contrast within the cord proved to be poor (figure 6.Id). However, as reported in previous studies (Enzmann and Rubin, 1988 (a,b); Kulkami et al, 1988; Katz, Quencer and Hinks, 1989), axial GE images can be useful for confirming the presence of lesions seen on sagittal images (figure 6.2). GE images were also useful in the axial plane for the assessment of cord atrophy (see below) where cord/CSF rather than lesion/cord contrast was important.

Figure 6.1. Sagittal images of the cervical cord in a patient with clinically definite MS.

(a) FSE obtained using the multi-array coil (FSE2000/51, 2 excitations, taking 4 minutes 16 seconds to cover a 48 cm FOV). A lesion (arrowed) can clearly be seen at C3.

(b) FSE obtained with a conventional posterior neck coil (FSE2000/51, 2 excitations, 2 minutes 8 seconds, 24 cm FOV). The lesion can still be seen, but the SNR is lower than in (a)

(c) SE with posterior neck coil (SE2000/8O’ 2 excitations, 17 minutes 4 seconds, 24 cm FOV). The contrast is similar (but not identical) to FSE.

(d) GE with posterior neck coil (GE300/15, flip = 15°, 6 excitations, 7 minutes 40 seconds, 24 cm FOV). The lesion is scarcely visible.

Figure 6.2. Four adjacent axial GE images (GE400/15, flip = 15°, 4 excitations) through the cervical cord. A lesion can be seen posteriorly on the middle two slices.

An evaluation of the multi-array coils and sagittal FSE was therefore made in patients with MS as well as in healthy adults. The aims were to establish the sensitivity and specificity of white matter lesions within the cord; to compare the abnormalities found in both patients and controls with those found in the brain; to assess the relationship between cord lesion load and disability in MS; and to establish whether there were significant differences between subgroups of patients with a different clinical course. An additional aim was to establish, from axial GE images, the normal range of spinal cord cross-sectional area and see whether it varied in patients.

METHODS

Controls

Forty-five healthy volunteers (23 male and 22 female), aged 18-72 (mean 42.9) years were scanned. They were recruited from hospital staff and friends of patients attending the unit. Relatives of MS patients were excluded. All completed a general health questionnaire seeking evidence of previous neurological illness, hypertension, cerebrovascular or cardiovascular disease, or diabetes.

Patients

Eighty patients with definite MS (Poser et a l, 1983) were recruited. They comprised twenty in each of four clinical subgroups:

1. Relapsing-remitting, in which there was a history of relapses and remissions with no progressive deterioration between relapses, but excluding benign patients.

2. Benign, in which the course had remained relapsing and remitting for at least ten years from first symptom without the development of significant disability (Expanded disability status scale (EDSS) of Kurtzke (1983) <3.5)

3. Primary progressive, in which there was progressive disability from outset without superimposed relapses.

4. Secondary progressive, in which following an initial relapsing-remitting course there had been progressive deterioration for at least 6 months, with or without additional relapses.

All patients, but not controls, underwent a full neurological assessment and were graded according to the Functional Systems and EDSS of Kurtzke (1983). All subjects gave their written informed consent.

MRI

Sagittal T2-weighted FSE images of the spinal cord were obtained in all (FSE2500/51 and FSE2500/102, 3 mm contiguous interleaved slices, 512 x 512 matrix with S/I phase encoding, echo train length 16,48 cm FOV, two excitations, image time 5.5 minutes). Images were corrected for signal non-uniformity using the algorithm described in chapter 3. In 37 of the 45 controls and in all MS patients proton density weighted, axial GE images (TR=300 ms, TE=15 ms, flip angle=15°) were also acquired, with simultaneous collection of a single slice at each of four vertebral levels (C5, T2, T7 and T11). All patients and 34 controls had either 7^-weighted SE or FSE axial imaging of the brain with 5 mm thick slices and a 2.5

mm interslice gap. Typical parameters were SE2ooo/32,8o or FSE3200/19.95"

Image analysis

The sagittal FSE images were reviewed without reference to the clinical history by one neuroradiologist (Dr BE Kendall) with patients and controls intermingled. Areas of high signal within the cord were noted only if present on both moderately and heavily T2-

weighted images. Their position within the cord was also recorded as anterior, posterior, central or full thickness and their size scored according to their maximum longitudinal extent (1 = <5 mm, 2 = 5-10 mm, 3 = >10 mm). The presence of any disc protmsion and/or bony spondylosis was noted, and graded as mild (thecal indentation not reaching the cord), moderate (thecal indentation reaching but not compressing the cord) or severe (cord compression). The presence of any artefacts across the cord was noted.

The axial GE images were transferred to Sun workstations and cross-sectional areas measured manually by two independent observers (Dr D Kidd and myself) using image

analysis software, Dispimage (Plummer, 1992). Once again images from patients with MS and controls were intermingled and the observers were blind to the clinical history. Cord atrophy was defined as a cross-sectional area more than two standard deviations below the mean of the control group.

Brain images were reviewed by a second neuroradiologist (Dr IF Moseley), once again blind to the clinical details. Lesions were documented in 16 anatomical sites and graded according to their maximum diameter (1 = <5 mm, 2 = 5-10 mm, 3 = >10 mm), with an additional point being added for confluent lesions. This permitted a semi-quantitative measure of lesion load to be made.

RESULTS

The clinical and MRI characteristics of the patients and controls are summarised in table 6.1.

There were no significant differences in age or disease duration amongst the four MS subgroups. As would be expected the benign group had a lower median EDSS than the two progressive groups (Kruskal-Wallis, 2-tailed, p<0.01).

One hundred and thirty nine lesions were found in 59 patients (74%), 8 6 of which were in the cervical cord and 53 in the thoracic cord. Cervical lesions were significantly more common than thoracic ones (p=0.007, Mann-Whitney U). Six lesions were classified as

anterior (4%), 100 central (72%), 25 posterior (18%) and eight full thickness (6%). Full thickness lesions were found only in patients with progressive disease, but there were no

other significant group differences. No correlation was found between either cord (r = -0.06, Spearman's rank correlation) or brain (r = 0.15) lesion load and EDSS, with any of the functional system scores or with disease duration. Neither was there a significant correlation between brain and spinal cord lesion load (r=0.23).

Controls RR B PP SP Age (years) 42.9 ±13.5 33.4 ± 7 .2 48.5 ± 7 .2 46.2 ± 5.2 43.4 ± 8.0 Disease duration (years) - 4.5 ± 8.0 17.0 ± 4 .0 9.0 ± 3 .4 12.5 ± 3 .5 EDSS - 4.0 ± 2.0 2.8 ± 0.6 5.6 ± 2.3 6.0 ± 1.8

Cord lesion load - 3.5 ±3.1 3.5 ± 3 .9 3.1 ± 2 .5 4.7 ±4.1

C5 area (mm^) 106 ± 9 9 7 ± 16 100 ± 11 99 ± 11 97 ± 1 7

T2 area (mm^) 68 ± 8 61 ± 8 61 ± 9 61 ± 10 63 ± 1 1

T7 area (mm^) 56 ± 7 51 ± 8 53 ± 7 53 ± 8 51 ± 8

T11 area (mm^) 7 2 ± 12 68 ± 1 2 70 ± 8 65 ± 1 1 65 ± 1 2

Table 6.1. Clinical and MRI characteristics of controls and MS patients. Figures are given as mean ± standard deviation.

Signal change within the cord, thought to be compatible with an intrinsic lesion, was only seen in one control (2%): this was a small lesion at C6/7 in an 18 year-old female which was clearly visible on the image with TE^j of 51 ms but only faintly seen on the TE^f 102 ms image. Signal within the cord appeared normal in all 17 subjects over the age of 50 years.

On the images with TE^f of 102 ms, the CSF appeared very bright giving a good myélographie effect. This was useful for the detection of degenerative changes in the

vertebral column. Some degree of spondylosis or disc protrusion was significantly commoner in controls than patients being found in 29/45 (64%) and 34/80 (43%) respectively (%^ with Yates' correction 4.70, p<0.05). This probably relates to the high prevalence of spondylosis in the older controls as within the controls there was a significant positive correlation between the age and the frequency of spondylosis (p<0.005, Spearman's rank correlation). Spondylosis was present in 2/8 (25%) of those under 30 years old, 6/12 (50%) aged 30-39, 6 /8 (75%) aged 40-49, 11/13 (85%) aged 50-59 and 4/4 (100%) aged >60 years. Taking the patients and controls together, spondylosis was graded as mild in 24/125 (19%), moderate in 30 (24%) and in nine (7%) severe: one man, a healthy control aged 54 years, had a large disc protrusion at T9/10, markedly displacing and compressing the cord (figure 6.3) and yet was entirely asymptomatic and had no abnormal physical signs. The mid to lower cervical region was the commonest overall site of degenerative disease, with a second smaller peak in the mid-thoracic region (figure 6.4). This pattern mirrored the distribution of MS lesions; however degenerative changes were found at the exact level of only 11% of lesions. The axial GE images provided good contrast between cord (low signal) and CSF (high signal), probably due mainly to differences in proton density. In many instances they also permitted differentiation between grey and white matter within the cord (figure 6.5), but not individual white matter tracts. Inter- and intra-observer "limits of agreement" (Bland and Altman, 1986) were from -17.6 mm^ to +8.1 mm^ (-24.3% to +11.5%) and from -13.7 mm^ to +9.0 mm^ (-20.2% to +13.2%) respectively. The mean inter- and intra-observer differences were 6.1 mm^ (8.3%) and 4.4 mm^ (6.5%) respectively.

Figure 6.3. 72-weighted sagittal FSE image of the spinal cord (FSB25oo,io2) showing disc protrusion at T9/10.

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Figure 6.4. Percentage of patients and controls with degenerative vertebral changes by disc level. The distribution of lesions is also shown.

The mean cord area was significantly smaller in the patients than the controls at each level, especially at C5 (p=0.0006, Mann-Whitney U test). Cord atrophy was present in 32 patients (40%) and was equally prevalent in all four subgroups. Eighteen patients had atrophy at one level only (C5 in 15), five at two, eight at three and one at all four. Disability was greater in those patients with atrophy than without (p=0.006, Mann-Whitney U). Intrinsic lesions were significantly more common in patients with a normal sized cord (42/48) than those with atrophy (17/32) (%^ with Yates' correction = 10.01, p<0.01). By the criteria used atrophy was only present in one control at one level (T7).

Figure 6.5. Axial gradient echo image through C5 level showing good grey/white differentiation.

Brain MRI

In nine (26%) of the 34 controls who underwent brain MRI one or more areas of high signal were seen within the cerebral white matter. Two of 18 (11%) subjects <50 years old and seven of 16 (44%) >50 years old had lesions. Brain MRI was normal in only two patients, both of whom had multiple spinal cord lesions and primary progressive disease. The problem of “brain MRI normal” MS is considered further in chapter 8.

DISCUSSION

Multi-array coils represent a major advance in spinal cord MRI. The coils we used cover a field of view of 48 cm in a single acquisition and allow complete coverage of the spinal cord from the cranio-cervical junction to approximately Ll/2 level without having to resort to a two-stage procedure; to examine the conus and lumbosacral nerve roots in addition would require a separate examination but this could be carried out without having to move the patient, simply by selecting the lower four coils of the six-coil set.

As discussed in chapters 3 and 4, the FSE sequence permits the generation of images with

T2 contrast that is similar though not identical to conventional SE (Mulkem et a l, 1990;

Melki et a l, 1991) and has the advantages over SE of being much faster and, despite the lack of linear flow compensation on the sequence used, having lower sensitivity to CSF pulsation artefacts. Thus, for the detection of small intrinsic cord lesions with an increased

T2 (e.g an area of inflammatory demyelination), FSE appears to be the sequence of choice.

Using this technique, lesions were demonstrated in three quarters of MS patients, whereas in controls abnormalities were rare: in only one subject was a small area of high signal found within the cord. None of 17 subjects aged more than 50 years had intrinsic cord lesions, whereas 44% of those examined had white matter lesions in the brain. White matter brain lesions occur in 40-100% of healthy subjects over 50 years old (Brant- Zawadzki et a l, 1985; George et a l, 1986; Gerard and Weisberg, 1986; Fazekas et a l,

1988a,b; Fazekas 1989; Hunt et a l, 1989) and in the great majority are probably due to small vessel disease (Kirkpatrick and Hayman, 1987; Braffman et a l, 1988). Although there are criteria to help distinguish white matter lesions due to MS from those due to vascular disease (Robertson et al, 1985; Cutler et al, 1986; Fazekas et a l, 1988b; Paty et a l, 1988), they are not always reliable, and are least so in the elderly (Offenbacher et a l,

1993). This study suggests that the presence of cord lesions will be particularly useful in confirming the diagnosis of MS in this age group. It should however be emphasised that, although white matter lesions in the spinal cord appear quite specific for MS when compared to healthy controls, they can also be found in a variety of other conditions including systemic lupus erythematosus (Miller et a l, 1992), sarcoidosis (Miller et a l,

acute disseminated encephalomyelitis (Caldemeyer et a l, 1994) and subacute combined degeneration of the cord (Timms et a l, 1993).

MRI abnormalities were most frequently found in the cervical cord, in keeping with previous pathological studies (Fog, 1950; Oppenheimer, 1978). There was, however, a notable lack of any correlation between lesion load and disability as measured by the Kurtzke EDSS or functional system scores. This is perhaps surprising, as the EDSS depends very heavily on locomotion, a function subserved to a great extent by the spinal cord. There are several possible reasons for this. First, previous studies in the brain have shown that clinical activity correlates better with changes in MRI over time (Willoughby

et a l, 1989; Thompson et a l, 1992; Morrissey et a l, 1993b). Therefore a clearer picture might be obtained by a longitudinal study rather than a cross-sectional study such as this. This issue is addressed further in chapter 9.

Secondly, the method used to quantify lesion load took into account the length of lesions rather than their cross-sectional extent and as axial T2-weighted images were not obtained it was not possible to identify in which fibre tracts the lesions were located. It is quite possible, for instance, that a small lesion occupying the whole axial extent of one lateral corticospinal tract would be more disabling than, say, a long lesion taking up only a part of the dorsal columns. On this point it is worth noting that lesions appearing to occupy the full thickness of the cord occurred solely in progressive patients. Further studies incorporating axial imaging are therefore needed. Current FSE technology does not permit consistently high quality axial images to be obtained, mainly due to low SNR and flow artefacts. It is to be hoped that further developments, in particular three-dimensional

Fourier transform FSE images (Sze et a l, 1992), will resolve this problem.

Thirdly, it is quite possible that in some cases with extensive involvement of the cord, the abnormalities were so diffuse as to be not identified as discrete lesions. Support for this notion comes from the seemingly paradoxical observation that lesions were found less frequently in those patients in whom there was cord atrophy demonstrated; in these patients it is also possible that increased CSF partial volume effects, due to the small size of the cord, made lesion identification more difficult. A recent report, using a more proton density-weighted sequence described diffuse cord hyperintensity in progressive MS patients with cord atrophy (Lycklama à Nijeholt et a l, 1997). The extent of such hyperintensity correlates with motor and sensory signs and with the extent of bladder and bowel involvement (Lycklama à Nijeholt et a l, 1998).

Finally, as previously discussed in chapter 1, the appearances on MRI lack pathological specificity. Some chronic MS lesions exhibit marked axonal loss, whereas others have preservation of axons, with marked surrounding gliosis (Barnes et a l, 1991). One might surmise that the former would be much more disabling, especially if strategically placed within the spinal cord, than the latter. It was notable that there was a modest correlation between cord atrophy and disability as it seems likely that atrophy is the long term sequela of axonal loss.

The quantitative measurements of cord cross-sectional area obtained from the axial GE images are similar to those of a detailed pathological study of four spinal cords (Donaldson and Davis, 1903) which reported mean cross-sectional areas of 95.6, 59.5, 51.0 and 55.9

mm^ at the spinal cord segments (C5/6, T3, T8 and T12/L1) corresponding to the vertebral levels (C5, T2, T7 and T il) measured in the current study. The post-mortem measurements