Of all the proposed MR measures of the neurodegenera-tive component of MS, measurement of tissue loss (atrophy)

is the most attractive and robust and to date is the most widely used in studies of MS natural history and treatment trials (Table 1). Axons make the largest bulk contribution to white matter volume (45%), followed by myelin (25%) and other tissue elements—glial and vascular tissues and water (Miller et al., 2002). Neuronal cell bodies and axons contribute the bulk of gray matter volume although there is also myelin in gray matter, albeit to a lesser extent than white matter. It follows that atrophy of white or gray matter in MS is likely to predominantly reflect axonal and neuronal loss. In a study of the spinal cord of five MS cases, in which atrophy and axonal loss were studied (Bjartmar et al., 2000), there was axonal loss within spinal cord lesions of between 45% to

85% and atrophy was more marked in the cervical than the lumbar area and affected gray and white matter equally.

Axonal loss is not the sole cause of atrophy and loss of myelin per se will contribute. Variation in glial bulk, inflammation, and tissue water content will also affect global or regional volume measures in MS: acute inflammation will increase volume, whereas a decrease in tissue water and inflammation due to treatment, dehydration, or other factors will decrease volume. Gliosis might increase volume by adding tissue bulk or decrease volume through retraction. It is likely that the use of atrophy to measure progressive neurodegeneration in MS will be made less sensitive because of the volumetric fluctuations due to inflammation. It should

Table 1 Clinical Studies of Atrophy in MS

Atrophy detected



Clinically isolated syndromes

Dalton 2002



Ventricular volume

Significant increase in those developing MS or with T2 lesions

Brex 2001



C2 area

Atrophy at presentation in those with brain lesions but no change over 1 year

Hickman 2002



Optic nerve area

Atrophy increases over months to years after an attack of optic neuritis

Dalton 2004




Progressive gray matter atrophy over 3 years in those developing MS

Filippi 2004




30% reduction in atrophy over two years in BIFN versus placebo-treated patients



Losseff 1996b



Central cerebral volume

Strong correlation with disability but not with lesions over 18 months

Rudick 1999




Slowing of atrophy during year 2 of BIFN therapy

Rovaris 2001



Central cerebral volume

No effect of glatiramer acetate over 9 months

Jones 2001




No effect of BIFN on atrophy

Zidavinov 2001



Brain volume

Absence of atrophy over 5 years in patients treated with regular IV steroids

Chard 2002a




Gray and white matter atrophy in early RR MS

Fisher 2002




Atrophy over two years relates to disability 8 years later

Gasperini 2002



Regional brain volumes

Enhancing lesions over 6 months corrrelated with atrophy in next 2 yrs

de Stefano 2003



Cortex volume

Cortical atrophy in RRMS and PPMS of short disease duration

Chard 2004




Progressive gray matter atrophy over 18 months in early RRMS

Frank 2004



Brain volume

Decreased rate of atrophy in second and third year after starting beta interferon

Secondary progressive MS

Losseff 1996a



C2 area

Atrophy correlated with disability

Coles 1999



Central cerebral volume

Progressive atrophy associated with increasing disability

Molyneux 2000



Central cerebral volume

No effect of BIFN on atrophy

Ge 2000



Parenchymal brain volume

Correlated with disability in SP but not RRMS

Filippi 2000

([email protected])


Whole brain volume

No effect of cladribine on atrophy

Wolinsky 2000



Normalized CSF volume

Higher CSF volume in more disabled patients

Kalkers 2001




Atrophy correlates better with disability than lesion load

Lin 2003



Upper cervical cord area

Progressive cord atrophy over 4 years

Primary progressive MS

Stevenson 2000



Central cerebral slices

Progressive atrophy over 1 year

Kalkers 2002



C2 area

Riluzole may slow cord atrophy

Ingle 2003



Brain andcord measures

Progressive cerebral and cord atrophy over 5 years

Glossary of terms for Table 1 +: atrophy detected (): number of patients studied WBR: whole brain ratio RR: relapsing-remitting

BPF: brain parenchymal fraction BVF: brain volume fraction CSF: cerebrospinal fluid volume SP: secondary progressive

C2 area: cross-sectional area of cervical cord at C2 level PBVC: percentage brain volume change

BIFN: beta interferon GMF: gray matter fraction WMF: white matter fraction PP: primary progressive IV: intravenous

»includes RR & SPMS; +Includes RR & PPMS; ^includes RR, SP, & PPMS; @includes SP & PPMS.

also be borne in mind that anti-inflammatory therapies (e.g., high-dose corticosteroids or beta interferon) may reduce brain volume without there having been axonal loss. If such an effect is anticipated, it would seem wise to wait for a period of time after receiving such therapy—for the antiinflammatory volume reduction effect to occur—before using ongoing atrophy as a presumed measure of axonal loss. Three months is a sufficient interval after a course of intravenous steroids, as this therapy has only a short-term effect on brain volume (Rao et al., 2002).

The optimal technique for detecting atrophy should be reproducible, sensitive to change, accurate, and practical to implement, although small errors of accuracy are probably insignificant, as long as they are constant between subjects and over time. The two distinct methodological aspects involved in measuring tissue volumes are data acquisition and data analysis.

Data Acquisition

The ability to reduce partial volume errors with high resolution scans means that 3-D acquisitions are attractive, although 2-D sequences have also been used successfully to derive volume measures in the CNS. For whole-brain atrophy measurements segmentation of the brain is necessary, and suppression of CSF helps to generate a sharp distinction in signal between cerebral and extra-cerebral matter. The most widely used 3-D sequence is a Tl-weighted gradient echo, with or without added CSF suppression, the latter provided by an inversion recovery pre-pulse, allowing 1 x 1 x 1mm resolution. Specific study of white or gray matter requires good contrast between white matter, gray matter, CSF, and lesions and may be aided by multiple-contrast acquisitions e.g. T1, T2 and proton-density.

Data Analysis Methods

Manual outlining or linear measurements provide the simplest approach to measuring changes in volume. An experienced observer is required, who is familiar with normal neuroanatomy and pathology. Manual segmentation is useful in small structures or regions, e.g., third ventricle, where significant atrophy is reported in MS (Simon et al., 1999). Disadvantages of manual segmentation include operator bias, long analysis time and poor reproducibility when compared with automated techniques.

Semiautomated methods improve speed and reproducibil-ity. Regional segmentation algorithms—e.g., seed growing, contouring—outline lesions, spinal cord, optic nerves and ventricles. Measurement reproducibility improves from ~3-5% for manual outlining to ~1-3% for semi-automated approaches for measuring spinal cord and ventricles.

A considerable number of automated methods exist for segmentation (and thus volume measurement) of the whole brain. Both single contrast and multi-spectral data have been utilized for whole-brain segmentation. Usually the difference in signal intensity between brain parenchyma and CSF

on a single contrast acquisition is enough to drive the segmentation process. Segmentation of gray and white matter may also be accomplished with either single-contrast or multi-spectral data, although additional sophistication is required to separate the two tissue types. Methods include Statistical Parametric Mapping-based segmentation and the fuzzy C-means algorithm. Masking of MS lesions is necessary to avoid their misclassification.

As atrophy is the measurement of change in volume, measurements of absolute volumes at separate time points are not necessarily needed; information may be obtained by looking for differences between serial scans (Smith et al., 2001). Nonlinear registration of such scans produces deformation fields that yield information concerning regional and global atrophy. Rigid body registration can be used to track the displacement of the surface of the brain during atrophy. Using the inner table of the skull as a standard of reference, Freeborough and Fox (1997) have developed a method to quantify atrophy with high sensitivity in many neurological diseases. Changes in the whole brain or in the ventricles can be investigated.

Comparisons between groups of patients are confounded by the presence of substantial inter-subject variations in head size that can mask differences attributable to atrophy. Normalizing the brain volume to head size reduces these variations. Relative volumes also remove variability in volume data due to scanner instability. A number of normalization methods have emerged: the scalp, total intracranial capacity determined by the sum of the volumes of gray matter, white matter, and CSF, or the sum of the brain and ventricular and sulcal CSF, have all been used to create volumes for normalization.

Tissue Volume Changes Produced by Individual Inflammatory/Demyelinating Lesions

The amount of atrophy that is produced by individual inflammatory/demyelinating lesions can best be investigated by studying the optic nerve of patients who have an attack of optic neuritis. Quantitation of optic nerve size is made difficult by its small size, liability to motion during imaging, and close proximity to CSF in the optic nerve sheath and also to orbital fat. Suppression of signal from orbital fat is required in order to avoid a chemical shift artifact at the interface between nerve and fat. This is achieved either by using a short tau inversion recovery sequence (STIR) or a fat suppressed sequence. Additional water suppression can be added to the latter by using a fluid attenuated inversion recovery sequence (FLAIR). The latter provides the most reliable assessment of the cross-sectional area of the nerve itself, being unhindered by signal from CSF in the sheath. A short TE fat suppressed fast FLAIR sequence (sTEfFLAIR) combined with semiautomated contouring on coronal images has proved sufficiently reproducible to detect and quantify the extent of optic nerve atrophy following a single episode of optic neuritis (Hickman et al., 2001a). Atrophy of about 10% to 15% has also been observed in the optic nerve following such an attack, and evidence has emerged to suggest that atrophy may continue to develop for several months or even years after the episode (Hickman et al., 2002).

A systematic investigation of the effect of unilateral optic neuritis lesions on the size of the nerve from the acute to the chronic stage has been undertaken with up to 7 MRI scans obtained using the sTEfFLAIR sequence over one year (Hickman et al., 2004). The first study was obtained within 4 weeks of onset of visual symptoms, at which time 27 of 28 acutely symptomatic lesions displayed gadolinium enhancement, indicating the presence of acute inflammation. At this stage, compared with the clinically unaffected companion optic nerve and with nerves of healthy control subjects, the cross-sectional area of the symptomatic nerve was increased by a mean of 20%. Subsequent studies showed a gradual resolution of swelling over several months and by one year there was a mean decrease in optic nerve area of 12% compared to healthy nerves. Almost all cases had a good recovery to normal or near normal visual acuity.

These observations of individual lesions have implications for interpretation of studies of atrophy in the brain, which reflect the global effects of the disease including both old and new lesions (as well as normal-appearing tissues). The observation of swelling in the acute inflammatory lesion and atrophy in the more chronic postinflammatory lesion suggest that the concurrent presence of lesions of differing ages—as is often seen in the brain of patients with relapsing forms of MS—may introduce noise when using the measure of progressive brain atrophy as a surrogate marker of axonal loss.

There is probably considerable potential to use optic neuritis as a model for the mechanisms of development of atrophy following single inflammatory demyelinating lesions. By obtaining, in parallel, visual evoked potentials (to monitor nerve conduction), detailed clinical measures of function and other MR techniques that investigate intrinsic aspects of the pathology (e.g., gadolinium enhancement to study inflammation; magnetization transfer imaging to study myelina-tion), it should be possible to develop a picture of pathophysiological events as atrophy develops. It is also now possible to obtain a more direct assessment of axonal damage following optic neuritis by investigating the retinal nerve fiber layer thickness using noninvasive measures such as ocular coherence tomography (Parisi et al., 1999); combining this technique with MR imaging of the optic nerve should help to understand the relationship between the MR measures and axonal damage.

A further implication of the demonstration of atrophy from single inflammatory/demyelinating lesions is that disease modifying therapies for preventing acute inflammation have the potential to decrease the extent of tissue damage and axonal loss in MS and that optic neuritis is a good model for evaluating new treatments which are given during the acute inflammatory episode with the aim of preventing or reducing subsequent tissue loss. Using STIR imaging, it has been reported that high dose intravenous methylpred-nisolone failed to prevent optic nerve atrophy 6 months after an attack of optic neuritis (Hickman et al., 2003), a finding consistent with the evidence that long-term clinical outcome for vision is not affected (Beck and Cleary, 1993). Novel therapies for preventing axonal loss and permanent disability associated with acute MS inflammatory lesions and relapses are therefore required. In future trials of such agents, inclusion of patients with optic neuritis and the use of combined clinical, electrophysiological, and quantitative MRI measures including optic nerve size would be useful in assessing the response to treatment.

Clinically Isolated Syndromes (CIS)

Fifty to 70% of patients presenting with a CIS (i.e., a single relapse of the sort seen in MS) affecting the optic nerve, brain stem, or spinal cord already have disseminated cerebral white matter lesions typical of MS and most such individuals will develop clinically definite MS with follow-up (Brex et al., 2002, Beck et al., 2003). A cohort of 55 CIS patients has been followed over a one year period to investigate ventricular enlargement (Dalton et al., 2002). Significant enlargement was seen in the 18 patients who developed clinical MS (i.e., experienced a second clinical relapse) and in the 40 patients with abnormal brain MRI at presentation (Fig. 1). There was no change in ventricular volume in the 15 patients with normal imaging. Significant but generally modest correlations were observed between ventricular enlargement and lesion load measures. Thus, brain atrophy occurs at the earliest clinical stage of MS and appears to be partly independent of lesions.

More recently, Dalton et al. (2004a) have investigated the location of progressive atrophy in the first 3 years following presentation with a CIS. Of 58 patients who were studied, 31 had developed multiple sclerosis according to the new McDonald criteria (McDonald et al., 2001). Statistical Parametric Mapping was used to segment gray matter from white matter on the baseline and 3-year follow-up scans after the lesions had been segmented and masked using a semi-automated local contour method. The subjects who developed MS displayed significant progressive gray matter atrophy (mean decrease in the gray matter fraction [normalized to intracranial volume] was -.3.3%, p = 0.001). In contrast the white matter fraction did not decrease and actually showed a marginal increase (+1.1%, p = 0.023). There was also a smaller decrease in the gray matter fraction in those subjects who did not develop MS during the 3 years (Fig. 2).

While the study by Dalton (2004a) suggests that neuro-axonal loss is occurring in gray matter in the earliest clinical stages of MS, the lack of atrophy in white matter does not exclude the possibility that there is also axonal loss occurring in this tissue. It is possible that other bulk tissue changes compensate for axonal loss, e.g., gliosis and inflammation. Inflammatory white matter lesions are often observed in early relapsing MS and may temporarily increase tissue bulk. The NAWM may also be affected by such processes. A recent

Baseline ventricular volume = 5.6cm3 One year ventricular volume = 12.8cm3

Baseline ventricular volume = 5.6cm3 One year ventricular volume = 12.8cm3

Figure I Ventricular enlargement over 1 year in a patient who presented with isolated optic neuritis and who had three further relapses during the 1-year follow-up period, leading to a diagnosis of clinically definite MS. (From Dalton et al. (2002), J. Neurol. Neurosurg. Psychiatry 73, 141-147.)

CIS Normal MRI Brain

McDonald MS

CIS and MRI Lesions Diagnosis at three years

CIS Normal MRI Brain

McDonald MS

CIS and MRI Lesions Diagnosis at three years

Figure 2 Changes in gray matter fraction seen at 3-year follow-up evaluation in patients with a clinically isolated syndrome. Box plot showing the medians, interquartile ranges (box), highest and lowest values, excluding outliers (whiskers), outliers (circles), and extreme value (asterisk) for gray matter fraction percentage change in patients with CIS, with and without MRI lesions, and patients with MS. (From Dalton et al. (2004), Brain 117,49-58.)

study using proton MR spectroscopy has observed an increase in myoinositol in the NAWM of patients within 6 months of presenting with a CIS (Fernando et al., 2004). This metabolite is produced by astroglia and potentially by other cell types involved in inflammation, e.g., microglia, and the increase was most evident in those subjects who already had MS according to the McDonald criteria at the time spec-troscopy was performed. In comparison to white matter lesions, gray matter lesions in MS show less inflammation (Peterson et al., 2001; Bo et al., 2003). Gray matter atrophy may therefore be a more sensitive measure of neuroaxonal loss in early relapse onset MS where the effect of inflammation on white matter volume may be more prominent.

One of the recurring limitations of studies that explore the relationship between inflammatory lesions and axonal loss is that they have a relatively short duration of follow-up. This shortcoming has been partly addressed in a recent study that investigated the extent of brain atrophy in 28 subjects who had developed MS 14 years after presenting with a CIS (Chard et al., 2003). Because the patients had undergone T2-weighted brain imaging at presentation and subsequently every 5 years, it was possible to investigate—over the 14 years—the extent to which T2-lesion load changes were related to subsequent atrophy. In this context, T2-lesion load was considered as an approximate surrogate marker for prior inflammation since almost all T2 lesions undergo an initial phase of gadolinium enhancement in relapse-onset MS. The main finding was a moderate correlation between T2-lesion load increase during the first 5 years and atrophy at year 14 (Spearman correlation = -0.53). This suggests that early inflammation has a modest link with much later neurodegeneration, although the mechanism for such a link is uncertain. The relatively low magnitude of the correlation emphasizes that factors unrelated to visible MRI lesions probably play an even larger role on the development of atrophy.

Relapsing Remitting MS

Recent studies have shown that both white matter and gray matter brain atrophy are evident in established relapsing remitting MS even within 3 to 5 years of symptom onset (Chard et al., 2002a; de Stefano et al., 2003). A serial study over 18 months of 13 patients compared with 9 healthy controls showed that at baseline there was significant white matter but not gray matter atrophy, but over the follow-up period, there was a significant loss of tissue in the gray matter but not white matter (Chard et al., 2004). This suggests that the temporal dynamics of atrophy in the two tissue types are different, possibly that white matter atrophy is present earlier but increases more slowly than gray matter atrophy.

Whereas brain atrophy is clearly present and increasing from clinical onset, the situation is less clear in the spinal cord. Using a 3-dimensional Tl-weighted sequence to measure cross-sectional area of the upper cervical cord, Losseff and colleagues (1996a) found no evidence for atrophy in 15 patients with relapsing remitting MS compared with healthy controls (Fig. 3). On the other hand, Brex et al. (2001a) observed a small but significant degree of atrophy in CIS patients who also had T2 lesions on brain MRI. However, there was no change in cord size over one year of follow-up. In this study, there was a slightly higher proportion of females in the patients versus controls and the scans in patients (but not controls) were obtained after administration of contrast; whether these factors have influenced the result is uncertain.

Figure 3 Upper cervical spinal cord atrophy and its relationship to disability in multiple sclerosis: (a) Normal cord size in a patient without disability; (b) Marked cord atrophy in a patient with severe disability; (c) Correlation between cord area and EDSS (r = 0.7). (From Losseff et al. (1996a), Brain 199, 701-708.)

Figure 3 Upper cervical spinal cord atrophy and its relationship to disability in multiple sclerosis: (a) Normal cord size in a patient without disability; (b) Marked cord atrophy in a patient with severe disability; (c) Correlation between cord area and EDSS (r = 0.7). (From Losseff et al. (1996a), Brain 199, 701-708.)

With the evidence for brain atrophy in relapsing remitting disease, measures of brain volume have not surprisingly been applied in several clinical trials at this stage of disease. Using a whole brain ratio (WBR) method, brain atrophy was assessed over two years in a placebo-controlled trial of beta interferon in relapsing remitting MS (Jones et al., 2001). Atrophy measures were available in 519 patients, 172 of whom were on placebo. Significant brain atrophy was seen in the total cohort over two years: the mean WBR decreased by 1.4%. The baseline WBR was weakly correlated with T2-lesion load. No difference in the rate of atrophy was seen between treatment arms.

Cerebral atrophy has been evaluated from 52 relapsing remitting patients for 6 months prior to and 24 months following beta interferon treatment and correlated with other MRI lesion and clinical parameters (Gasperini et al., 2002). During the two years of treatment there was a significant reduction of brain volume (mean -2.2%) that was correlated weakly with the mean number of enhancing lesions on monthly scans during the 6 months pre-treatment. During the two years of treatment, 26 patients exhibited significant atrophy and 26 did not; in the former group, 13 experienced an increase in disability whereas in the latter group only 3 became more disabled. This confirms other studies in showing a link between increasing atrophy and disability (Losseff et al., 1996b; Coles et al., 1999).

In a 2-year placebo controlled trial of beta interferon in relapsing remitting MS, atrophy was measured from yearly scans using the brain parenchymal fraction (BPF). The mean BPF decrease was similar in both arms in year 1, but was smaller in the beta interferon arm in year 2 (Rudick et al., 1999). The changes in BPF during this 2-year period showed little or no correlation with lesion measures. Prolonged 8-year follow-up of some of the placebo cohorts from this trial assessed the longer term relationship between earlier BPF change and later disability (Fisher et al., 2002). Comparison of patient quartiles based on change in BPF over the first two years revealed a greater likelihood of developing severe disability (EDSS of 6 or more at follow-up) in those with the most atrophy during the initial two years.

A recent uncontrolled study of 30 patients with relapsing remitting MS treated with beta interferon reported a -1.35% decrease in brain volume during the first year, but a much smaller reduction of -0.165%/year for the next two years (Frank et al., 2004). The authors proposed that the year one decrease in brain volume was accentuated by a treatment associated decrease in inflammation, and that the much lower rate of atrophy subsequently indicated a positive therapeutic effect.

A 5-year follow-up study has reported comparisons of outcome for patients treated with regular 3 monthly high dose methylprednisolone compared with a group who received steroids only as required for relapses (Zidavinov et al., 2001). The group on regular steroid treatment had a slowing in the rate of cerebral atrophy, in spite of an increase in T2 lesion volume. This surprising result has not been replicated, and is not sufficient to endorse such a treatment approach, especially bearing in mind the morbidity that could be anticipated from it.

A 9-month, placebo-controlled trial of glatiramer acetate in 239 relapsing remitting MS revealed a mean 0.7%-0.8% reduction in central cerebral volume with no significant differences between the patient groups (Rovaris et al., 2001). The study showed a weak association between enhancing lesion numbers and atrophy. Bearing in mind the evidence suggesting that an effect of beta interferon on atrophy in relapsing remitting MS might be delayed for up to a year (Rudick et al., 1999; Frank et al., 2004), the study may have been too short to definitively evaluate the treatment effect on this outcome.

Progressive Forms of MS

Atrophy is seen in both the brain and spinal cord in secondary and primary progressive MS. The most marked atrophy occurs in secondary progressive disease and correlates with disability (Losseff et al., 1996a, 1996b; Lycklana et al., 1998; Wolinsky et al., 2000; Kalkers et al., 2001; Ge et al., 2000; Lin et al., 2003) but weakly if at all with lesion load and activity (Figs. 3 and 4). In primary progressive MS, significant atrophy of brain and cord over one year was evident in a large cohort of primary progressive patients drawn from six European centers (Stevenson et al., 2000). Change in cerebral volume over one year correlated only weakly with change in T1 and T2 brain load. More recently, progressive cerebral and cervical cord atrophy have been observed over 5 years of follow-up in a cohort of 41 primary progressive MS patients (Ingle et al., 2003). The rates of atrophy appeared to be relatively constant within individual patients but varied between subjects.

A study of 16 patients with primary progressive MS evaluated riluzole, a neuroprotective glutamate antagonist, using change in cervical cord area as a putative measure of progressive axonal loss (Kalkers et al., 2002). During one year pre-treatment, there was a 2% reduction in mean cord area whereas during one year on treatment the cord area was stable (mean decrease of 0.2% only), but the difference was not significant. This preliminary study indicates the potential of using tissue volume measures in larger cohorts to study the efficacy of neuroprotective agents.

Therapeutic trials have evaluated the effect of three immunomodulatory agents in secondary progressive MS— beta interferon (Molyneux et al., 2000), Campath-1H (Coles et al., 1999), and cladribine (Filippi et al., 2000). In spite of all three therapies suppressing inflammatory MRI lesions, there was no evidence for a significant slowing in the rate of ongoing cerebral atrophy. In the beta interferon trial there was ~1% loss of central cerebral volume per year in the treated and placebo arms (Molyneux et al., 2000).

Time Course Issues for Measuring Atrophy

While it is clear that significant tissue loss can be detected in MS within as little as 12 months, little work has been done to determine the optimal sample sizes and length of study required to demonstrate significant slowing of

Figure 4 Patient with secondary progressive MS and increasing disability and cerebral atrophy over 18 months in spite of a paucity of inflammation (the volume of gadolinium-enhancing lesions was only 0.4 ml). (From Losseff et al. (1996b), Brain 199, 2009-2019.)

progressive atrophy as a result of therapeutic intervention. This is a priority area for further research, which should include a consideration of the stage of disease (e.g. relapsing remitting, secondary progressive), the type of acquisition and image analysis method, the region of CNS being studied (e.g. whole brain, regional brain, spinal cord etc), the frequency of scanning, and other potential confounding factors (e.g. atrophy due to anti-inflammatory therapy).

Summary of Atrophy as a Surrogate Marker in MS

For several reasons, atrophy has emerged as a preferred method for monitoring the neurodegenerative process in MS: (i) robust methods for detecting tissue loss are available; (ii) it is progressive from onset and increases with increasing disability; (iii) it correlates only modestly with inflammatory lesions, thus providing additional information in therapeutic monitoring and natural history studies; (iv) whereas a number of existing therapies have shown good suppression of inflammatory lesions, an effect on progressive atrophy has been less evident. A recent review discusses in-depth methodological and clinical aspects of atrophy in MS (Miller et al., 2002).

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