MS: is it one disease?
Abstract: Understanding the molecular pathology of multiple sclerosis (MS) is crucial to interpretation of magnetic resonance imaging appearances in the disease and to developing new therapies. The pathology of MS has always been recognized to be heterogeneous, with the basis of this heterogeneity being hitherto largely attributed to differences in the age of lesions. However, one influential group of researchers put forward the suggestion in 2000 that there are four pathological subtypes of MS that are distinct between cases but consistent within cases. Two more recent attempts to replicate this finding have been unsuccessful, as reviewed by Barnett et al. (this issue, pages 57-65). This inability to confirm pathological disease subtypes within the MS disease spectrum is in contrast to recent work on neuromyelitis optica--until recently regarded as part of the MS spectrum--in which evidence from a variety of sources has led to the rapid, widespread acceptance that this condition is indeed distinct from MS. It is important to resolve the outstanding controversies in MS immunopathology and one way to do this might be to conduct a consensus study, a method that has proved valuable in bringing better consistency to the reporting of Alzheimer's disease pathology.

KEY WORDS:

IMMUNOPATHOLOGY OF MULTIPLE SCLEROSIS; HETEROGENEITY OF MULTIPLE SCLEROSIS LESIONS; NEUROMYELITIS OPTICA
Article Type: Report
Subject: Multiple sclerosis (Development and progression)
Multiple sclerosis (Diagnosis)
Multiple sclerosis (Causes of)
Pathology, Molecular (Research)
Author: Esiri, M.M.
Pub Date: 07/01/2009
Publication: Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 PAREXEL MMS Europe Ltd. ISSN: 1352-8963
Issue: Date: July, 2009 Source Volume: 16 Source Issue: 2
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: United Kingdom Geographic Code: 4EUUK United Kingdom
Accession Number: 217847858
Full Text: Introduction

The neuropathology of multiple sclerosis (MS) has become controversial over the last 10-15 years. This matters, because the molecular events contributing to the earliest cellular changes leading to the familiar MS plaque provide an essential key to understanding the pathogenesis of the disease and to devising more effective therapy. Clinicians and imagers have become bewildered and it is easy to see why.

The controversy surrounds findings of those attempting to delve into a molecular understanding of the origins of the plaque and its fate once formed. Magnetic resonance imagaing (MRI) scans have provided a wealth of information in living subjects about the appearance of plaques as the clinical disease arises and progresses, but the interpretation of scan appearances requires understanding of the underlying pathology. As the decades have passed (fortunately) fewer and fewer MS sufferers succumb to the disease at an acute or active phase. Inevitably, therefore, pathologists depend on mining information mainly from archival material, much of which contains no more than scarce footprints pointing to the events that triggered off the disease many years earlier. Because early lesions (and there can be debate about how to define these) are increasingly scarce in autopsy material, resort has been made in some studies to examining biopsy material. This runs the risk of being unrepresentative (since typical cases are never biopsied), and, furthermore, biopsies are likely to sample lesions incompletely and inadequately. Nevertheless, on the basis of such material, supplemented by scarce early lesion autopsy material, important claims have been made that lesions, that have long been recognized to have heterogeneous appearances, derive such heterogeneity from fundamental differences between cases, not from differing ages of lesions within cases, as had been previously concluded. (1) In 1997, Gay et al. published a paper (2) suggesting that there are five distinct clusters of MS lesions based on their immunohistochemical and pathological profiles, but these clusters were contributed to by lesions from different cases, supporting the views of Barnett et al. (3,4) and Breij et al. (5) that they represent different stages in the evolution of lesions. The very different implication of heterogeneity between cases is that MS may represent multiple diseases, each with its own pathology, developmental trajectory, risk factors, outcomes and, potentially, responses to therapies.

Although clinical presentations of MS may differ widely, recent studies of the natural history of the disease have presented a more uniform picture of the disease as it unfolds. (6-8) Likewise, the most distinctive genetic risk factor for the disease, HLA-DR2 (DRB1*1501, DQB1*0602) genotype, is common to all clinical varieties of the disease. There are no clear geographical differences in the prevalence of different clinical types of the disease with the important exception (discussed below) of opticospinal MS, seen particularly in Asian countries. Nor have the separate disease categories, distinguished on a pathological basis by Lucchinetti et al., (1,9) been found to have differing clinical features or genotypes. These findings should caution against embracing the multiple disease hypothesis without strong evidence in its favour. Evidence both for and against the hypothesis therefore requires careful scrutiny. Some such scrutiny is provided by Barnett et al. in their review in this issue (see pages 57- 65). (10)

Before considering this evidence about MS in general, it is worth paying attention to the evidence that has accrued recently about Devic's disease or neuromyelitis optica (NMO). For many decades this condition was considered to be a relatively rare variant of MS. Many cases of optico-spinal MS, which occurs in Japan and other Asian countries (where it is less rare than is NMO in Western countries), were thought likely to be identical. Recent research has created a convincing distinction of NMO from MS, based not only on: 1) differing pathology that is widely acknowledged to be so by independent investigators, (11-13) but also: 2) on the presence of a circulating antibody to aquaporin 4 (14) that is not present in MS; moreover, 3) imaging appearances are also distinctive in NMO, with lengthy lesions in the upper spinal cord and in the optic nerves, but with lesions in the brain absent or restricted to regions around the third and fourth ventricles; (15) 4) cerebrospinal fluid findings are different from MS, with generally more pleocytosis, but absent oligoclonal bands of immunoglobulin (16) and 5) the natural history of the disease is different from MS (the outcome is worse and there are associations with other autoimmune diseases).16

Turning now to MS in general, the main case for different types of disease rests solely on the claim of differing immunopathology. It is true that it is also claimed that one disease type (Pattern 2) responds favourably to plasma exchange while the other (Pattern 3) cases do not. (17) However, this claim rests on few examples and awaits independent confirmation. Moreover, the differing pathology supporting the view that there are differing diseases within MS has been challenged by two independent groups. (3-5) Whilst able to find similarly heterogeneous immunopathological features in early MS lesions, they do not find them distinctive in different individuals; instead they find them spread within, and shared, among individuals.

How do we account for these differing views? As:

1) Material to study is scarce; 2) distinctions rest in part on subtle immunostaining differences (relatively selective loss of one myelin antigen, myelin-associated glycoprotein [MAG] over another, such as myelin oligodendrocyte protein or proteolipid protein; MAG immunostaining was not employed by one dissenting group, (3) though it was by the other (5)); 3) other distinctions rest on complement and immunoglobulin staining patterns that are not straightforward to interpret in formalin-fixed, paraffin-embedded sections of the type used in these studies; they are also recognized to be largely non-specific when a wide variety of conditions is studied; (4) 4) likewise, a further distinction between types of cases depends on recognizing apoptosis of oligodendrocytes, a feature that is not easy to recognize and may, anyway, have other confounding causes such as terminal hypoxia or autolysis; 5) the nature of the material available to the different investigators differed; only Lucchinetti's group has studied biopsies in any numbers while the Breij et al. (5) material was from older subjects with longer duration of disease than the Barnett or Lucchinetti material. These are important ways in which the studies differ. Nevertheless, I doubt if they are sufficient to explain the different conclusions reached.

A start to reconciling the perplexing differences that remain in this important field might be made by assembling a panel of observers and circulating material contributed by each of them with the request that they score independently, and without knowledge of the origin of the tissue, the features that are purported to distinguish disease types. The results may help a consensus to emerge. Such an effort has been made successfully in the Alzheimer pathology field by CERAD and BrainNet Europe leading to better consistency of reports in this field. (18,19)

While we need to be receptive to new observations, and the multiple disease model of MS has had the virtue of generating further experimentation and discussion, application of Ockham's razor would exhort us to opt for a simpler, single disease model for MS until there is better evidence requiring us to abandon this hypothesis.

Conflicts of Interest

The author has no conflicts of interest to declare, other than being a co-author of the paper by Gay et al. (2)

References

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MM Esiri

Departments of Clinical Neuropathology and Neurology, University of Oxford, Oxford Radcliffe NHS Trust, UK

Address for Correspondence

Margaret M Esiri, Neuropathology Department, Level 1, West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK

Phone: +44 (0) 1865 234403

Fax: +44 (0) 1865 231157

E-mail: margaret.esiri@clneuro.ox.ac.uk

Received: 15 April 2009

Accepted: 22 April 2009
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