Abstract
Article abstract The aim of this study was to determine whether atrophy could be detected at the earliest clinical stages of MS. Patients were selected from a 1-year follow-up MRI study of clinically isolated syndromes. Nine patients who developed MS were compared with eight matched patients who had no further symptoms. Significant ventricular enlargement occurred in the group that developed MS but not in the other group. Our findings show that atrophy, albeit mild, can be detected early in the course of MS.
Using pathologic and imaging studies, whole brain and regional CNS tissue loss has been shown to occur in MS in excess of that expected with age.1-3 In vivo measurements of brain and spinal cord atrophy and ventricular enlargement have recently become possible with improved MRI sequences and image analysis techniques. These have demonstrated that atrophy occurs at a greater rate in MS patients than in healthy age- and sex-matched controls.3-5
The rate of atrophy in some CNS regions has been found to correlate with disability,2,6 implying that the pathologic processes responsible for atrophy may be of functional importance. Early cerebral atrophy has also been suggested to be an indicator of a poor prognosis.1 Whereas demyelination itself may result in tissue loss, it is probable that axonal loss is the most significant component of atrophy. A recent study has demonstrated that axonal damage can occur in early, acute MS lesions.7
In this study, we aimed to determine whether atrophy could be detected in patients following their first symptomatic demyelinating event, which in the majority of cases is the earliest clinical stage of MS. Change in ventricular volume over 1 year was used as a marker of atrophy. Ventricular volume could be measured accurately and reproducibly on the images available and is a sensitive marker of tissue loss in MS, where pathology often occurs in tissue around the ventricles.
Methods.
Patients.
All patients were taking part in a prospective, longitudinal multisequence MRI study of clinically isolated syndromes (CIS) suggestive of MS. A CIS was defined by the occurrence of a presumed inflammatory demyelinating event of acute onset in any part of the CNS in an individual without a history suggestive of earlier demyelinating episodes. Patients were imaged within 3 months of the onset of the isolated syndrome (baseline) and again after 1 year. In all patients, appropriate investigations were carried out as necessary to exclude alternative diagnosis. Local medical ethics committees approved the study and informed consent was obtained from the patients before entry.
After 1 year of follow-up, two age- and sex-matched groups of patients were retrospectively selected from the total cohort of patients. The first group consisted of nine patients who had a further relapse, separated in time (greater than 3 months) and space from the initial symptoms (four optic neuritis, one optic tract lesion, two brainstem, and two spinal cord syndromes), leading to a diagnosis of clinically definite MS. All these patients had one or more areas of high signal suggestive of disseminated disease on their baseline T2-weighted brain images. A second matched group of eight patients from the cohort (three optic neuritis, three brainstem, and two spinal cord syndromes) had either normal imaging or only the symptomatic lesion visible at baseline and no further symptoms at follow-up.
Image acquisition.
All imaging was performed on a 1.5-T Signa (General Electric, Milwaukee, WI) imager. At baseline and 1 year, all patients had a proton density (PD) and T2-weighted fast spin-echo (FSE) (repetition time [TR] 3200 msec, effective echo time [TE] 15/95 msec) and a T1-weighted spin-echo (TR 600 msec, TE 14 msec) study. For both sequences, 3-mm–thick contiguous slices were acquired with a field of view (FOV) of 24 cm, matrix 2562, and one excitation. Before imaging, an IV bolus of 0.1 mmol/kg of gadolinium-DTPA was administered.
Image analysis.
The T1-weighted images were analyzed using an interactive image analysis package (MIDAS).8 Measurements were performed retrospectively in a randomized and blinded fashion by the same individual. Whole brain regions were obtained using semiautomated iterative morphologic techniques originally developed for three-dimensional volumetric scans. Mean signal intensity over these brain regions was calculated. Ventricular regions were outlined using a thresholding technique with the ventricular–brain boundary set at 60% of whole brain signal intensity. The ventricular region consisted of the lateral ventricles including the temporal horns but excluding the third and fourth ventricles. High signal structures within the ventricles on the enhanced images—e.g., blood vessels—were excluded. Ventricular volumes were automatically calculated from the outlined regions by multiplying total area outlined by slice thickness and used to determine the change over the year.
Reproducibility.
Five randomly chosen individuals had ventricular volumes measured twice by a single operator blind to subject details. The mean coefficient of variation (SD divided by mean) for intrarater reproducibility of the ventricular volumes was 0.13% (range 0.02 to 0.23).
Statistics.
Comparisons between ventricular volumes measured in the groups of patients were performed using a Mann-Whitney test. Measurement of change within groups was calculated using Wilcoxon signed-rank test.
Results.
There were no significant differences in sex, age, or presenting symptom between the groups. At baseline, the early MS patients had a median of 25 high-signal lesions on T2-weighted imaging (range 2 to 71) and eight enhancing lesions (range 0 to 10). In the matched group of CIS patients, only a symptomatic lesion was seen in one patient who had a brainstem presentation.
After 1 year of follow-up, the patients who developed MS had a median of five new T2 lesions (range 0 to 28) and one new enhancing lesion (range 0 to 10). None of the patients in the matched group had developed either new T2 or enhancing lesions. Ventricular enlargement had occurred at a significantly greater rate in the patients developing MS than in those without further symptoms (table). Using the matched group as “controls” to determine the expected rate of atrophy in this population, 95% confidence limits were calculated. Five of the nine (56%) patients who developed MS had an increase in ventricular volume in excess of this, whereas none of the matched group showed such an increase.
Patient data
Discussion.
Our study detected a significant, albeit small, increase in ventricular size in a small group of patients in the earliest clinical stage of MS. Such a change was not seen in a matched group of patients differing in that they had no evidence of disseminated disease on their baseline T2-weighted images and had no further symptoms during the follow-up period. This latter group is known to have a much lower risk of developing MS (<5%) compared with patients with evidence of disseminated disease at presentation (>80%).9 The findings indicate that atrophy is not an end-stage event in MS but reflects ongoing pathology and can be detected in patients very early in the disease using highly reproducible techniques.
Whereas axonal loss may occur early in MS lesions7 and is expected to cause atrophy, other factors also need to be considered as causes of ventricular enlargement. Proton MR spectroscopy of the normal-appearing white matter from CIS patients has not shown reduced concentrations of N-acetyl–derived metabolites, which are neuronal markers, suggesting that the widespread axonal damage that is found in established relapsing-remitting MS has not occurred.10 Demyelination itself has been shown to result in a reduction of axonal diameter and remyelinated fibers are thinner than unaffected axons. Reactive gliosis is likely to have occurred in the MS group, which might cause contraction of the tissue with a resulting increase in the size of the ventricles. Drugs, illness, pregnancy, poor diet, and alcohol abuse can also cause cerebral atrophy. None of these are applicable to this cohort with the exception of one patient who received steroids and started interferon beta between the two scans. Analysis excluding this one case still revealed a significantly greater rate of atrophy in the early MS group.
Future studies are required, optimizing acquisition and image analysis; registration of precontrast three-dimensional T1-weighted images may permit more accurate measures of cerebral atrophy. Larger patient groups with longer prospective follow-up need to be studied to determine if a relationship exists between atrophy, which is thought to predominantly represent axonal loss, and other markers of disease in MS, and to determine if the rate of atrophy predicts future clinical course.
Footnotes
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P.A.B. and J.I.O. were sponsored by Schering AG. N.C.F. holds an MRC Clinical Scientist Fellowship. The NMR Unit is supported by a generous grant from the MS Society of Great Britain and Northern Ireland.
- Received October 26, 1999.
- Accepted January 12, 2000.
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