As severe tissue destruction occurs the central nervous system may respond to this by shrinkage and reorganisation, changes that are only visible to us at the edges of a
structure; widening of the sulci and ventricles in the brain and shrinkage of the
circumference of the spinal cord. The measurement of the rate of shrinkage may therefore
directly reflect the progression of the pathological process responsible for disease progression. The nature of the process underlying atrophy is uncertain but recent
pathological and MR studies demonstrating axonal loss both in lesions and NAWM (Ferguson 1997, Fu 1998, Trapp 1998) make this the most likely candidate, although
demyelination alone has been shown to result in a reduction of axonal diameter (Prineas and Connell 1978) and could contribute to atrophy.
Spinal cord atrophy. The first quantitative study of spinal cord atrophy employed a T2 weighted gradient echo sequence and evaluated 5mm axial slices taken at four vertebral
levels; C5, T2, T7 and T i l (Kidd 1993). The cords were manually traced around and atrophy was considered to be present when the measured area was two standard
deviations below that of the mean for healthy controls. The mean cord areas of the patients were significantly smaller than that of the controls at each of the four levels.
Those patients with atrophy were found to have significantly higher levels of disability
as measured by the EDSS than those without. A further study measuring cross sectional
area at C5 showed a significant difference between patients with benign and SP MS (Filippi 1996c).
Subsequent studies concentrated on measuring serial cord cross sectional area at C5. In
a study comparing PP and SP MS, both groups showed a decrease in mean cord area over
one year, but there was no difference between the two groups and no significant
correlation with disease progression (Kidd 1996). The intra-rater reliability of the measurement technique was 2%, but the scan-rescan variability was in the order of 6%
and changes detected were within the 95% confidence limits for measurement variation.
A similar study of RR MS patients over one year using the same technique also failed to
demonstrate a significant change in cord area but the mean intra-rater variability was high at 4.8% (intra-rater limits of agreement -11.6 to 12.9%) (Thorpe 1996a).
All of these studies depended on two dimensional imaging with a T2 weighted gradient echo sequence and a manual outlining technique for cross sectional area measurement.
The poor reproducibility of this technique made the detection of small change, an essential prerequisite for serial studies, impossible.
More recently a new technique has been developed which addresses these difficulties
(Losseff 1996b). By using a volume acquired IR FSPGR acquisition the contrast between the grey cord and nulled black CSF is markedly improved. The cord area is calculated
from axial reformats obtained from a T l weighted IR FSPGR sequence at the level of C2/3 (see figure 3.1). This level was chosen as there is little variability in cross sectional
area over this segment and the CSF pool is capacious thus optimising cord/CSF contrast.
The boundary between cord and CSF is defined on each of the five axial reformats by using a threshold technique where the threshold is the mean signal intensity of cord and
CSF, thus reducing the partial volume effect (Losseff 1996b). The cord cross sectional area is calculated for each of the reformats and a mean value obtained. Using this
methodology measurements can be obtained in a very short time (<10 minutes) with
excellent intra, inter-observer and scan-rescan reproducibility (<1%) (Losseff 1996b).
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Kijiure 3.1 : Axial reformat o f an IR FSPGR sequence for eord atrophy assessment.
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In a cross sectional study 30 controls and 60 patients (15 in each subgroup of RR, PP, SP and benign MS patients) were studied (Losseff 1996b). The cord cross sectional areas of
the benign, PP and SP groups were significantly smaller than the controls, while the RR
group had no significant atrophy. Cord cross sectional area correlated strongly with the
EDSS (r= -0.7, p< 0.001) and with disease duration (r= -0.52, p< 0.001).
Despite the excellent reproducibility, including scan-rescan, when this technique was
applied serially there were problems. During the study period there was a major hardware
upgrade, which resulted in minor changes in the pulse sequence and spatial signal
intensity uniformity. As a consequence all of the control subjects exhibited an artefactual increase in their measured cord areas (Losseff 1996d). Chapter four deals with the
problems of serial cord atrophy measurements and assesses its use as a surrogate marker for disease progression and as an outcome measure for clinical trials in MS.
Cerebral atrophy. The measurement of cerebral atrophy is more complicated than cord atrophy as it involves both the extraction of the brain from the skull and the delineation of the lower border of the brain. An early study looked at a measure of partial brain
volume which assessed serial change in four contiguous 5mm slices with the most caudal
at the level of the velum interpositum cerebri (Losseff 1996a). These slices represent the ROI and were chosen as they cover most of the lateral ventricles, which along with the
cortical surface are the areas most likely to exhibit atrophic changes. The velum
interpositum cerebri is thought to be a stable landmark despite ongoing atrophy allowing repositioning for serial assessment. The brain is extracted from the skull using a
computer algorithm (DS Yoo, UCL, London, UK) and the ROI volume calculated by
multiplying the sum of the ROI areas by the slice thickness (see figure 3.2). Like the measurement of spinal cord atrophy this is extremely reproducible. In this study a
Kij»ure 3.2: Brain atrophy assessment; before (top) and after (bottom) skull extraction.
decrease in cerebral volume beyond the 95% confidence limits was seen in 16 of the 29
patients in a time period of 18 months. The rate of atrophy was significantly higher in
those with a definite change in disability compared to those without. Interestingly there
was no relationship between the rate of atrophy and the change in TLV or volume of
gadolinium enhancement, again highlighting the disparity between markers of inflammatory disease activity (new lesions, gadolinium enhancement) and disease
progression (Losseff 1996c).
This measurement technique is used in the studies in chapters five and six, but utilises six 3mm slices, again with the most caudal at the level of the velum interpositum cerebri.