The last decade has been an era of
unprecedented progress in our understanding of
multiple sclerosis (MS). MS is now considered a
destructive process of the central nervous system,
initiated by inflammatory demyelination but
including prominent axonal pathology. This new
knowledge has been acquired from new imaging
techniques and traditional histopathologic study.
New mechanisms of myelin destruction have been
uncovered, and hypothetical new therapies for MS
include neuroprotectants. Serial
gadolinium-enhanced magnetic resonance imaging
(MRI) scans reveal MS as a continuously active
process. Brain and spinal cord atrophy, defined by MRI, correlate closely with clinical state. MR imaging techniques therefore are considered the standard tools for monitoring disease activity and severity. These efforts have produced improved therapy for patients with MS. Two classes of agents, interferon beta and glatiramer acetate, have been approved by the US Food and Drug Administration for use. A major challenge for clinicians is to provide early diagnosis and determine appropriate treatment. New neuroprotective and anti-inflammatory drugs are on the horizon.
In the last 10 years, a fundamental paradigm shift has taken place in the way we view multiple sclerosis (MS). MS is now viewed as a continuous process. Although conceptually, MS remains a condition of inflammatory myelin destruction, the role of axonal transection is now recognized. This new knowledge has been acquired primarily through the direct study of MS patients and tissues, through the application of contemporary immunohistochemistry and microscopy and the use of magnetic resonance imaging (MRI), now the standard for monitoring disease activity, severity, and response to therapy. In this review, I will discuss new findings in pathogenesis, monitoring, and treatment of MS.
We now recognize MS as continuously active from the onset in most patients. Serial gadolinium-enhanced MRI has shown that many new lesions may occur in some patients every month, even without disease activity. It has been known for more than 100 years that autopsied MS brains show many more demyelinating lesions than can be accounted for by clinical attacks in life. (see Sidebar, "Multiple Sclerosis: A Brief History.") From MRI studies, we now recognize that these lesions accumulate continuously, from early in the disease process. Mechanisms of myelin injury—the hallmark of MS—have been studied for many years. More recently, the important role of axonal pathology in the development of disability in patients with MS has been revealed. Genetic susceptibility to MS is also considerably clearer.
In the 90s—the Decade of the Brain—epidemiologic descriptions of genetic susceptibility were available. With the Genome Project providing tools, the genetic susceptibility to MS has come into focus. And the likelihood that there is a single gene of major effect—MS as a disease of direct Mendelian inheritance—has been largely excluded. Genomic screening techniques with advanced statistical approaches have led to the identification of genetic loci associated with increased susceptibility to MS. Based on results of this work, MS depends either on independent or interactive epistatic influences of several genes, each with a small individual effect.
The human lymphocyte antigen (HLA) association, which is the most robust and reproducible association, accounts for a significant proportion of genetic susceptibility. Importantly, concordant results have emerged from analysis of sporadic MS and from studies of MS in multiply affected families (favored as a study population because of increased statistical power). Candidate loci and candidate genes are being further investigated. The important work of defining genetic contributors to disease type and severity has begun. Thus, our understanding of genetic susceptibility is being continuously refined.
T-cell autoimmunity to myelin, which had been hypothetical throughout the history of MS research, has now been demonstrated in MS patients. It is also clear that macrophages within the target tissue are major effectors of myelin destruction. It now seems likely that myelin protein-specific antibodies in some cases help to target macrophages to myelin (Nature Med. 1999;5:170). In some lesions and some individuals, myelin is destroyed because of primary oligodendrocyte pathology, essentially in the absence of significant inflammation (Semin Neurol. 1998;18:337). In these cases, zones of oligodendrocyte death in lesions are confined to periplaque white matter, indicating that myelin is absent from these lesions because the oligodendrocytes have died. Thus, there is distinct heterogeneity in the pathogenesis of MS.
Axonal pathology plays an important role in the development of irreversible and progressive disability in MS patients. This axonal pathology is closely related to inflammation. Immunocytochemical experiments on MS lesions of varying ages by Ferguson et al. showed the expression of amyloid precursor protein in damaged axons within the acute MS lesions and in the active borders of less acute lesions (Brain. 1997;120:393). Trapp and colleagues (N Engl J Med. 1998;338:278) showed, using dual immunofluorescence confocal microscopy, that the axons became physiologically impaired even as myelin was being "peeled away." Spectroscopic studies have identified highly dynamic changes in axonal N-acetylaspartate (NAA; a marker of axonal and neuronal integrity) within and near acute MS lesions. Abnormal levels of NAA have also been seen in normal-appearing white matter around MS lesions and within the corpus callosum.
Thus, loss of myelin and oligodendrocytes, along with axonal injury, provide a pathologic substrate for irreversible disability in patients with MS. This new knowledge has been revealed by techniques including immunohistochemistry, advanced microscopic techniques, and MRI.
In summary, axonal pathology is common in patients with early mild disease and occurs in most lesions. Pathologic studies have shown identical axonal damage in lesions that were of extremely recent origin—as little as weeks—and in cases of secondary progressive MS of as long as 30 years’ duration. This supports the hypothesis that MS, in addition to being continuously active in most patients most of the time, is a destructive process in most patients most of the time. It indicates a likely pathologic substrate for irreversibility and highlights the potential need for early and continuous neuroprotective treatment in most patients. It implies that formal neuroprotective strategies should be considered in MS.
Although we still do not know why axonal transection occurs, it is considered likely to result from loss of protection or trophic support of myelin, or both. This hypothesis leads to the corollary concept that remyelination is a major neuroprotective event in itself, as chronically demyelinated axons may not be viable. Studies of ways to protect axons in the context of inflammatory demyelination must now be conducted.
MRI has set a standard for determining how well treatment is working, as well as determining disease activity, disease burden, and disease type. It is a radical change in our thinking that MRI can be used in this way. Thompson and colleagues (BMJ. 1990;300:631) reported that MRI had revealed much about the disease process and was valuable in diagnosis, but that it was not helpful in predicting disability in an individual patient. By 1998, brain MRI was being used to predict long-term disability in MS and to determine the type and extent of disability. What changed was a series of extremely dedicated and persistent clinical-radiographic correlative efforts on the part of several groups. The most evident outcome of this work was the demonstration that individuals presenting with clinically isolated syndromes could be stratified accurately with regard to prognosis (see, for example, Brain. 1998;121:495). Thus, our view of what MR can do has changed radically.
Disease burden—the cumulative impact of disease—has been difficult to quantify. MRI analysis of the brain shows many abnormalities in patients with MS. It has not been clear which measurement most accurately reflects the total burden of disease: T2-weighted bright spots, T1-weighted "black holes," or magnetization transfer ratio (MTR) all have advocates. It has now become clear that no single MR parameter will provide all the answers.
Rudick, Fisher, and colleagues recently reported a method of quantitating brain atrophy in MS by simple postprocessing of conventional FLAIR images, potentially providing a convenient way to summarize the destructive process in MS (Neurology. 1999;53:1698). As MS damages and destroys myelin, axons, oligodendrocytes, and neurons, one outcome of the disease process is brain atrophy. The new measure of brain atrophy relies on calculation from segmented images of a brain parenchymal fraction (BPF), defined as the ratio of brain parenchymal volume to the total volume within the brain surface contour. Rudick, Fisher, and colleagues showed that in the normal population, BPF is a very narrowly distributed function—approximately 87.5% of the head is occupied by brain, regardless of age or gender. In a well-characterized cohort of patients with early relapsing remitting MS (70 placebo cases in a clinical trial; mean age = 36 years; mean duration of disease = five years; mean Expanded Disability Status Scale score = 2.5), the BPF was 83%, and this fraction was also narrowly distributed. Thus, patients with early, mild MS already had significant atrophy (P < .001 compared with healthy age-matched controls). Further, during two years of follow-up during the clinical trial, these patients lost a mean of 0.5% of BPF/year, much more than is observed in serial studies of healthy individuals.
MS is an heterogeneous disease. Demyelination can occur independent of perivenous inflammatory changes, supporting the presence of more than one pathophysiologic process leading to demyelination in MS. Narayana and colleagues (Ann Neurol. 1998;43:56) performed serial MR spectroscopic imaging for up to two years in patients with early mild MS and correlated their findings with quantitative lesion volumes. In these longitudinal studies, metabolic changes were observed on MR spectroscopic imaging in some subjects before the appearance of lesions on MRI scanning. Regional changes in metabolite levels were dynamic and reversible in some patients. Transient changes in N-acetylaspartate (NAA) levels were sometimes found in acute plaques and indicated that a reduced NAA level does not necessarily imply axon loss, but may signal the reversible altered physiology of demyelinated axons. They observed an inverse correlation between the average NAA within the spectroscopic volume and the total lesion volume. Strong lipid peaks in the absence of gadolinium enhancement and MRI defined lesions were seen in four of the 25 patients, implying demyelination without attendant inflammation. This provocative study therefore reinforced the concept of heterogeneity of pathologic alterations in the brains of MS patients.
MS is a Treatable Disease
It has been demonstrated that treatment modifies the natural history of MS in the short term. However, the biggest task that lies ahead is to extend short-term benefits to a long-term reduction in disability. McFarland and coworkers (Ann Neurol. 1995;37:611; Neurology. 1997;48:1446) showed that initiation of interferon beta therapy results in abolition of enhancing activity almost immediately, and in a robust and lasting way. Preliminary studies with glatiramer acetate, originally known as copolymer-1, show that it may also show comparable benefit in MRI indices of disease activity in relapsing-remitting MS. The impact of these short-term benefits on long-term disability remains the ‘$64,000 question.’
The availability of new treatments imposes challenges upon clinicians: We must diagnose MS early and with stringent accuracy, to take full advantage of MS-specific drugs. As a group of ‘treating physicians’ we are also faced with the challenge of determining when therapy should be started. If, as posited earlier, MS is, from the day of onset, a destructive process that continues even during asymptomatic periods, clinical progression should ultimately be determined by the magnitude of tissue injury. According to this concept, MS at the tissue level is monophasic and continuous, and patients enter the phase of secondary progressive MS when a threshold of tissue destruction has been exceeded. Closely monitoring patients’ rate, extent (by BPF, for example), and location of central nervous system atrophy could help to address the accuracy of this hypothesis and validate brain atrophy as a relevant measure of cumulative disease impact. In patients who have obvious, fulminant MS, disability occurs very quickly and BPF declines rapidly. However, for the great majority of patients, secondary progressive disease begins 10 to 20 years after the onset of MS. This phase of disease poses our greatest challenge and remains highly resistant to treatment.
That’s the bad news; the good news is that BPF decline appears to respond moderately to contemporary treatment. Rudick and coworkers (Neurology. 1999;53:1698) recently analyzed data from a trial of interferon-beta treatment for relapsing-remitting MS. They detected no differences between placebo and interferon-beta-treated patients during the first year, in regard to BPF decline. However, there was a 55% reduction in progression of atrophy (as measured by changes in the BPF) during the second year of active treatment compared with placebo. Such results are encouraging and suggest that early treatment may modify the risk of subsequent disability.
Other treatments in development include small-molecule antagonists of leukocyte trafficking, blockers of T lymphocyte co-stimulatory signaling, and innovative approaches such as T-cell and DNA vaccines. Given the pace of improved knowledge, innovative uses of sophisticated imaging techniques, and new therapies in the 10 years that comprised the Decade of the Brain, one may be encouraged that the next 10 years may be similarly productive.
The 90s—the Decade of the Brain—has been a period of paradigm shift in our understanding of MS. In addition to the steady progress of understanding myelin breakdown, the role of axonal pathology has been elucidated. The disease is now viewed as a continuous process from the onset. Monitoring tools—specifically, the use of MRI techniques—have shown tissue changes and have illuminated pathologic events. The systematic study of large numbers of active cases has been, and will continue to be, instrumental in improving our understanding of the immunologic and pathophysiologic mechanisms in MS. We have entered a challenging and exciting era in which MS, for the first time, is a treatable disease. The task that remains before us is to determine the optimal way to use these treatments and develop the next generation of therapies.
|Multiple Sclerosis: A Brief History
|Identification Of The Disease
| Early 1800s
||Tarnswell is the first to observe and describe the onset of MS symptoms.
||Cruveilher describe the anatomic lesions responsible for MS.
||MS is diagnosed for the first time and the clinicopathologic definition first stated by Jean-Martin Charcot still holds today.
||Discovery of myelin by Louis Ranvier. Other researchers later identify a specific category of myelin-producing cells (oligodendrocytes) and determine the importance of myelin in the conduction of nerve impulses.
|Understanding The Disease Process
||James Dawson identifies initial lesions indicating lymphocyte, macrophage, and plasma cell infiltration into the brain, leading to early demyelination.
||First discovery of anomalies in the cerebrospinal fluid of MS sufferers. First observations that MS does not occur in a uniform pattern worldwide and the incidence is higher in the Northern hemisphere.
||Thomas Rivers describes an animal model of a disease resembling MS and suggests an autoimmune basis for the disease, with myelin in the central nervous system being the target of the immune response. An animal model is also developed by Pasteur.
||Elvin Kabat underlines the significance of these cerebrospinal fluid anomalies within the immune system.
||The first comprehensive neuropsychological study of a small number of MS patients is carried out. The researchers Ross and Reitan find that patients have severe difficulties performing tasks that involve motor speed, strength and coordination, exhibit intermediate difficulties in abstracting and concept formation, but have preserved verbal ability.
||John Kurtze develops the first widely used scale enabling categorization of the different stages of MS; a later version of the scale, the Expanded Disability Status Scale (EDSS), is still used today.
The first controlled trial of MS is published in Neurology in 1969 by Tourtellote.
|Trying To Find The Cause
||Recognition of the characteristics of latent slow virus infection in animals and humans prompts researchers to consider anew the possibility of an infectious origin for the disease.
||Many studies examining different aspects of immunologic responses of MS patients are initiated Some link the condition to HLA associations, some suggest that astrocytes might have a role in the pathogenesis and symptomatology of MS.
||The first pictures of the brain of an MS patient are obtained by magnetic resonance imaging (MRI), providing the opportunity to visualize MS lesions within the central nervous system. MRI will revolutionize the diagnosis, management, and monitoring of MS.
|Further Knowledge And New Therapies For MS
||Trials with linoleic acid, linolenic acid and methylprednisolone are attempted. The first studies using interferon alpha and beta to treat MS are conducted.
||Axonal pathology, known to be present in MS lesions since the 1880s, is quantitated and shown to be irreversible. MRS studies demonstrate the pervasive nature of axonal and neuronal disruption in MS brains. The relationship between axonal pathology and progression of disability is proposed and intensive studies begin.
Interferon-beta-1b (1993) and –beta-1a (1996) are approved in the United States, and then in the European Community for use in relapsing-remitting MS.
Glatiramer acetate, a synthetic copolymer of four amino acids, is approved in the United States for use in relapsing remitting MS.
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