EL MATERIALES DE SOPORTE DE LOS VITRALES

This study demonstrates that it is possible to reproducibly measure and detect change in cord cross sectional area over a time period of 12 months in MS patients. It also confirms the previous findings of a strong correlation between a clinical measure of disability (the EDSS) and spinal cord atrophy. The study has been possible due to improvements in the

measurement technique. With the application of an IR FSPGR sequence and assessment at the C2/3 level, excellent cord/CSF contrast is obtained. This increase in contrast combined with a semi-automated contouring technique eliminates much of the measurement variability that occurred with the previous method (manual outlining of the

cord at the C5 level using a gradient echo sequence).

These findings are independent of vertebral degenerative disease, which was mild and comparable in both the control and patient group. The commonest site of spondylosis

was the C5/6 disc space, no subjects had abnormality at or above the C2/3 disc space where atrophy measures were obtained. The scoring system used was extremely sensitive

and scores of 1 or 2 were not felt to be of clinical significance. Six subjects had evidence

of mild cord compression at one or both of their examinations, two of these were controls

and four were patients (15% of controls and 14% of patients).

There was no significant change in cord area over one year in the control group. Cord

atrophy was present at baseline in the benign and PP groups, but was most marked in the SP MS group. Increasing atrophy over the 12 month period was only detectable in the RR

and PP patient groups.

In order to understand the mechanisms and clinical importance of atrophy it is relevant

to consider the pathophysiology of the development of disability, which results from two causes. Firstly from incomplete recovery following relapse and secondly, and most

importantly, as the result of insidious disease progression. The RR MS patient group who are very early in their disease process have normal sized cords, but have a high rate of

cord cross sectional area loss. These patients are experiencing relapses which are predominantly associated with conduction block secondary to demyelination although

some axonal loss can occur acutely (Ozawa 1994, Ferguson 1997). Demyelination per se

has been shown to result in a reduction of axonal diameter (Prineus and Connell 1978)

and combined with an element of acute axonal loss could well result in atrophy of a structure such as the spinal cord following a relapse.

The benign patients begin with a similar relapsing course resulting in associated cord

loss, however minimal change in function occurs. This may be due to predominant demyelination rather than axonal loss. Subsequently in their disease course, they

experience very few relapses and little further change in cord area.

The largest degree of cord atrophy over time was seen in the PP MS group, which is not

surprising if we consider their slowly progressing disability as a consequence not of

inflammatory demyelinating lesions but of progressive axonal loss. Certainly less inflammation is seen in this group as shown by pathological (Revesz 1994) and MRI

studies (Thompson 1991).

The SP patient group who had the smallest cords may have a combination of both demyelination and acute axonal loss secondary to relapses and subsequently progressive axonal loss underlying the later progressive phase. The small sample in this study is not

entirely representative of SP MS as all four patients were very disabled and perhaps consequently no further change in cord cross sectional area was detectable.

The suggestion that atrophy may have two mechanisms, one non disabling (demyelination), the other disabling (axonal loss) is supported by the almost identical atrophic cord areas seen in the disabled PP and non disabled benign MS cohorts. Another

factor that should be considered is the role of reactive gliosis; this in theory may partly

compensate for the loss of myelin by filling space but could also lead to contraction of the underlying tissue. Evidence of gliosis comes from histological (Allen and McKeown

1979) and MR spectroscopy studies (Rooney 1997). A reduced NAA/ creatine ratio has

been demonstrated in areas of NAWM, which appeared to be produced by a rise in the level of creatine and could be accounted for by an increase in gliosis. This study did not

find evidence of diffuse axonal loss (decreased NAA levels) although the patient group was not defined and may have comprised only of early RR MS cases (Rooney 1997).

These arguments are hypothetical and could be investigated further by combining the

assessment of atrophy with markers of demyelination (MT imaging) and axonal loss (MR

spectroscopy). The reported reduction of NAA in both lesions and NAWM in PP MS

(Davie 1997 and Leary 1998a) suggests that diffuse axonal loss is present in this subgroup. Further evidence for pathological change apart from new lesion formation in

this patient group comes from the presence of diffuse signal change on proton density

weighted conventional spin echo images of the spinal cord. The degree of this signal change has been shown to correlate with cord atrophy (Lycklama a Nijeholt 1997a). The

combination of MR studies with post mortem data will further enable us to correlate

changes in the size of the spinal cord with pathological changes (Lycklama a Nijeholt 1997b, Mottershead 1997).

The fact that significant changes in cord cross sectional area can be measured over only 12 months is important, both in increasing our understanding of the underlying

mechanisms of disability and in the potential use of serial cord atrophy measures as a surrogate measure of disease progression in the monitoring of therapeutic trials. The

findings in the PP MS group are of particular importance as this patient group do not show the rate of new lesion development and enhancement which is used to monitor

activity in RR or SP MS. The use of cord and brain atrophy to monitor disease progression in PP MS is explored in detail in chapters five and six.

This study does have limitations, the sample size is small, in particular there are few

patients in the SP and benign MS patient groups, and follow up is relatively short. Larger

and longer serial studies are needed to confirm the detected differences between disease subgroups and ideally should commence in the early stages of MS allowing evaluation of cord atrophy as a potential prognostic marker.