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MS: is it one disease?


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)


(1.) Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000; 47: 707-717.

(2.) Gay FW, Drye TJ, Dick GWA, Esiri MM. The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis: identification and characterization of the primary demyelinating lesion. Brain 1997; 120: 1461-1483.

(3.) Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol 2004; 55: 458-468.

(4.) Barnett MH, Parratt JDE, Cho ES, Prineas JW. Immunoglobulins and complement in post mortem multiple sclerosis tissue. Ann Neurol 2009; 65: 32-46.

(5.) Breij EC, Brink BP, Veerhuis R, van den Berg C, Vloet R, Yan R et al. Homogeneity of active demyelinating lesions in established multiple sclerosis. Ann Neurol 2008; 63:16-25.

(6.) Confavreux C, Vukusic S, Adeleine P. Early clinical predictors of progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 2003; 126: 770-782.

(7.) Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain 2006; 129: 606-616.

(8.) Kremenchutzky M, Rice GP, Baskerville J, Wingerchuk DM, Ebers GC. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 2006; 129: 584-594.

(9.) Pittock SJ, Lucchinetti CF. The pathology if MS: new insights and potential clinical applications. Neurologist 2007; 13: 45-56.

(10.) Barnett MH, Parratt JDE, Pollard JD, Prineas JW. MS: is it one disease? Int MS J 2009; 16: 57-65.

(11.) Sinclair C, Kirk J, Herron B, Fitzgerald U, McQuaid S. Absence of aquaporin-4 expression in lesions of neuromyelitis optica but increased expression in multiple sclerosis lesions and normal-appearing white matter. Acta Neuropathol 2007; 113: 187-194.

(12.) Roemer SF, Parisi JE, Lennon VA, Benarroch EE, Lassmann H, Bruck W et al. Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 2007; 130: 1194-1205.

(13.) Misu T, Fujihara A, Kakita H, Konno H, Nakamura, Watanabe S et al. Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain 2007; 130: 1224-1234.

(14.) Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005; 202: 473-477.

(15.) Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006; 66: 1485-1489.

(16.) Wingerchuk DM, Hogancamp WF, O'Brien PC, Weinshenker BG. The clinical course of neuromyelitis optica (Devic's syndrome). Neurology 1999; 53: 1107-1114.

(17.) Keegan M, Konig F, McClelland R, Bruck W, Morales Y, Bitsch A et al. Relation between humoral pathological changes in multiple sclerosis and response to plasma exchange. Lancet 2005; 366: 579-582.

(18.) Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM et al. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer's disease. Neurology 1991; 41: 479-486.

(19.) Alafuzoff I, Arzberger T, Al-Sarraj S, Bodi I, Bogdanovic N, Braak H et al. Staging of pathology in Alzheimer's disease: a study of the BrainNet Europe Consortium. Brain Pathol 2008; 18: 484-496.

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


Received: 15 April 2009

Accepted: 22 April 2009
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2009 Gale, Cengage Learning. All rights reserved.

Article Details
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Author:Esiri, M.M.
Publication:The International MS Journal
Article Type:Report
Geographic Code:4EUUK
Date:Jul 1, 2009
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