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J. Zajicek
DOI: http://dx.doi.org/10.1093/brain/awf265 2784-2785 First published online: 1 December 2002


Edited by M. Filippi and G. Comi

2001. Italy: Springer Verlag

Price £59.50. pp. 128. ISBN 8847001676

The existence of a substantial minority of patients with multiple sclerosis who exhibit an insidious accumulation of disability from the onset of their disease has been recognized since Charcot. Although so‐called primary progressive multiple sclerosis (PPMS) may confer a worse prognosis in terms of time to particular disability levels than other forms of the disease, it has often been neglected in terms of general scientific research, and clinical trials in particular. Any all‐encompassing hypothesis meant to explain the pathogenesis of multiple sclerosis, must take account of this fascinating group of patients, yet aspects of PPMS are too often considered inconvenient to theories and individuals, who prefer to focus on the more common clinical phenotypes.

In this post‐β‐interferon era, although we are beginning to be able offer some treatments to our patients, we still have no convincing way of preventing the long‐term accumulation of progressive impairment. Opportunities therefore exist in studying patients with PPMS which may illuminate our greater understanding of those mechanisms underlying the progressive phase of the disease.

It was therefore with great interest that I read the present slim volume, which is the result of an international workshop held in Milan in 2001, which was part of a larger conference concerned with MRI techniques in multiple sclerosis. It was perhaps inevitable that this book therefore focuses on MRI, so that approximately half of the 128 pages deal with MRI aspects of the condition. Some aspects of PPMS are therefore dealt with in very few pages, with natural history, pathology, immunology and neurophysiology each taking up barely five pages of text. There is virtually no discussion of the important genetic and familial aspects of this condition; concordance rates between clinical phenotypes assist in supporting the view that PPMS is really a subdivision of the broader group of multiple sclerosis phenotypes rather than a separate disease.

One of the most interesting, and probably most important contributions to multiple sclerosis research in recent years has been the pathological subdivision of multiple sclerosis tissue into four distinct subtypes by Lassman, Luchinetti, Bruck and co‐workers. These sub‐types are described by Bruck in his contribution to the book. It is noteworthy that the three cases of PPMS included in the pathological analysis were all found to have pattern IV, with primary oligodendrocyte degeneration rather than features of autoimmunity. Conversely, no cases of RRMS were found to have this pattern of histopathology. If these findings are consistent across a wider variety of cases, then we may indeed be dealing with a greater diversity of pathogenesis than hitherto expected. Recent genome screens demonstrating ‘hotspots’ of susceptibility loci may help to disentangle this conundrum further. It is tempting to speculate that certain individuals, who inherit a particular set of susceptibility loci, which may include defective oligodendrocyte genes, are more susceptible to oligodendrocyte death, rather than specific autoimmune reactions. It is a little disappointing that this volume did not include a greater exploration of these issues.

Wolinsky and colleagues, in their chapter describing the PROMISe trial using glatiramer acetate to treat PPMS patients, discuss some of the day‐to‐day difficulties associated with making a diagnosis of PPMS. By necessity, this diagnosis relies heavily on the presence of intrathecal oligoclonal bands, which are not present in the serum. Adoption of the newly suggested McDonald criteria for diagnosing multiple sclerosis would exclude 20% of the patients on the PROMISe trial because of the reliance on CSF findings. It is debatable whether it is more useful to rely on oligoclonal bands or one or more members of a central patient eligibility review committee to ensure the diagnosis of PPMS is as correct as possible. The authors conclude that longitudinal analysis of patients entered into studies such as the PROMISe trial should provide critical evidence on which to base whether the international recommendations need revision for the diagnosis of PPMS. Clearly this is a fundamental issue when trying to disentangle pathogenesis and clinical trials.

The bulk of this book is concerned with MRI, and differences between PPMS and other forms of the disease. Clearly this is the strength of the present volume and there are separate chapters on conventional MRI, magnetization transfer and diffusion tensor MRI, proton magnetic resonance spectroscopy, and functional MRI. Conventionally, PPMS may show abnormalities in the cord where none are detectable in the brain, and indeed a consistent finding in PPMS cranial MRI is a lower T2 lesion load with less T1 hypointensity. Although techniques such as triple dose gadolinium administration demonstrate increased lesions in RR and SPMS, the same is not the case for PPMS. These chapters provide useful reference material for differences between PPMS and other forms of multiple sclerosis.

Newer magnetic resonance techniques such as magnetization transfer and diffusion tensor MRI consistently demonstrate that normal appearing white and grey matter is damaged in patients with PPMS. An extensive review of magnetic resonance spectroscopy in PPMS by Caramanos et al. concludes that there are no specific differences in standard spectroscopic analysis between PPMS and RRMS or SPMS. Newer techniques have not, therefore, helped in explaining why conventional cranial lesion load is less, although disability may be similar or worse in PPMS than other forms of the disease.

In a sense, dwelling on these newer techniques, which have so far failed to illuminate the major questions associated with PPMS, makes the reader wish even more that some of the initial chapters could have been expanded. The major questions with regard to PPMS remain. Why is this phenotype in the minority of multiple sclerosis cases? Is PPMS really just a different phenotype, or is there truly different pathogenesis? Why does it manifest at a later age, with different population characteristics? Why are the MRI characteristics different to other phenotypes? Until we can begin to address some of these issues in more detail, effective therapies for this group of patients will remain elusive.

This book is a useful addition to the multiple sclerosis section of the neurological bookshelf, but in future I would expect thicker volumes to emerge, which dissect the issues in more detail.