EVOLVING CONCEPTS IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS AND THEIR THERAPEUTIC IMPLICATIONS

EVOLVING CONCEPTS IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS AND THEIR THERAPEUTIC IMPLICATIONS Richard A. Rudick, M.D. Cleveland, Ohio INTRODUCTION In recent years, concepts of MS pathogenesis have evolved rapidly. Still considered an immune-initiated inflammatory disease, there has been increasing awareness of several features of the disease. This lecture will review some of these newer aspects, including the following: 1) There is increasing recognition the disease is largely subclinical in its early stages; in many patients, the pathologic process is continuously active despite few symptoms.. 2) Axonal and neuronal pathology is common, present early during the course of MS, and may have a complex pathogenesis. 3) Patients enter the secondary progressive MS (SPMS) stage at a relatively late stage of the pathologic process, probably because the extent of axonal pathology exceeds a threshold. These increasingly well-recognized aspects of multiple sclerosis will be reviewed, and the therapeutic implications will be highlighted. RELAPSING REMITTING MS AS A CONTINUOUSLY ACTIVE DISEASE Traditionally, patients with RR-MS have been. viewed as having a relatively benign form of the disease, probably because of minimal disability between relapses. Ill many instances, patients have been reassured and observed without treatment. Multiple lines of evidence have converged to indicate that the pathologic process is active in RR-MS patients, however, and data demonstrates that irreversible tissue injury can accumulate without clinical symptoms during RR-MS. These data suggest that the pathological process occurring during the RR-MS disease stage leads eventually to SP-MS in most patients TABLEl DATA SUGGESTS AN ACTIVE DISEASE PROCESS DURING RR-MS Gadolinium Enhancement Shows Disease Activity Gadolinium enhancing lesions occur iii approximately 50% ofrr-ms patients on random MRI scans; these lesions occur with about 10 times the frequency of clinical rela ses. Newer Imaging Techniques Demonstrate Widespread Abnormalities Magnetic resonance spectroscopy (MRS), magnetization transfer imaging (MTI), and high field strength magnetic resonance imaging show diffuse abnormalities in the nomial appearing white matter (NA WM). Pathology Data Demonstrates Transected Axons.Ax.ons are transected in large numbers in active MS lesions. Axonal transection corresponds to sites of active tissue inflammation, regardless of the disease duration. Magnetic Resonance Spectrocsopy Shows Neuronal Pathology Neuronal marker NAA is decreased in MS lesions and in normal appearing white matter during the relapsing remitting phase of the disease. Magnetic Resonance Imaging Shows Progressive Tissue Loss Early in the disease, increasing brain atrophy can be measured in a 1 year period. 199

GADOLINIUM ENHANCEMENT SHOWS DISEASE ACTIVITY Approximately 50-70% of RR-MS patients have one or more gadolinium enhancing lesions on a random cranial MRI scan 1 ' 2 Each new gadolinium enhancing brain lesion resolves after 4-6 weeks, leaving a residual T2 lesion, so that the volume of T2 brain lesions increases by about 10% per year in RR-MS patient groups. Clinical correlation studies have found that most gadolinium enhancing brain lesions in RR-MS patients are asymptomatic 3, and patients have been observed to have frequent new gadolinium enhancing lesions with no clinical symptoms whatsoever. This has led to the concept that there is an active pathologic process as measured by MRI in RR-MS, but that individual new lesions result in symptoms only when the lesion happens to affect an articulate part of the central nervous system; such as optic nerve or spinal cord. Various lines of evidence suggest that subclinical MRI disease activity, as reflected by gadolinium enhancement reflects brain inflammation. MRI pathology correlation studies have documented acute inflammation at the sites of gadolinium enhancement in MS tissue 4, and the presence of gadolinium enhancing lesions correlates with CSF pleocytosis 5 Relapsing re~itting MS patients with increased CSF cell counts were found to be significantly more likely to exhibit clinical and MRI disease activity during orie and two years of prospective follow up 5 These data are consistent with the interpretation that gadolinium enhancing lesions are a marker for active brain inflammation, and as such a marker for subsequent MRI and clinical disease activity. In support of this, gadolinium enhancing lesions on a random cranial MRI scan are strongly associated with gadolinium enhancing lesions on subsequent MRI scans, and with an increased volume of T2 lesions over the following one. and two years 6 The nuinber of gadolinium enhancing lesions on 6 monthly MRI scans was found to predict the relapse rate during a 12 month period 7 The relationship to progressive disability is unclear, becuse long term follow-up studies are lacking. NEWER IMAGING TECHNIQUES DEMONSTRATE WIDESPREAD ABNORMALITIES Magnetization transfer imaging (MTI) is an easily applied MRI technique that provides information on the structure of CNS tissue. Proton molecules associated with myelin are relatively non-mobile. As tissue water molecules become more mobile, magnetization transfer decreases. Therefore, this technique has been developed as a method to monitor myelin loss. MTI has demonstrated abnormalities not only in lesions, but also in normal appearing white matter in sites distant from 8 10 T2 lesions - Similarly, magnetic resonance spectroscopy (MRS), has shown abnormalities in the NA WM 11 Emerging data using high field MRI has shown much more' extensive abnormality in MS brain than is evident using conventional i~aging at 1.5 Tesla (R. Grossman, personal communication). These data suggest that the pathologic process in MS occurs much earlier, and is more widespread than is evident using conventional imaging. MAGNETIC RESONANCE SPECTROSCOPY SHOWS NEURONAL DYSFUNCTION In vivo magnetic resonance spectroscopy (MRS) studies demonstrated reduced levels of n-acetyl aspartate (NAA), a neuronal marker, in brain lesions, and in NA WM from RR-MS patients, suggesting that axonal pathology is a consistent and early feature of the MS disease process 12-23 In one study, reduced NAA was observed in cerebral cortex adjacent to subcortical white matter lesions in 8 children with MS 21 The average age of the children in that report was 15, and the average disease duration was 3.5 years. Recently, studies from a number of groups have shown reduced NAA in normal appearing white matter. Interestingly, NAA falls most steeply in normal appearing white matter during the RR-MS disease stage. The studies suggest that inflammation or related pathologic mechanisms result in axonal pathology during RR-MS, setting the stage for the secondary progressive stage of the disease. PATHOLOGY DATA DEMONSTRATES AXONAL PATHOLOGY Pathology studies have directly demonstrated that CNS axons are irreversibly damaged by the inflammatory process in active MS lesions. Trapp and colleagues used confocal microscopy to demonstrate large numbers of transected axons topographically related to inflammation in active brain lesions from 12 patients with MS 24, confirming the findings from a separate histologic study of ~yloid precursor protein in MS brain lesions 25 The data demonstrates that the inflammatory process destroys both myelin and axons, leaving foci of irreversibly damaged tissue. The. cumulative effect of this process over the years might account for irreversible neurologic disability in the secondary progressive stage of the disease. 200

In addition to the acute effects of the inflammatory process, results from animal models provides another potential cause of axonal injury in MS patients. In two separate systems, genetically altered myelin proteins resulted in chronic axonal pathology. Animal devoid of myelin associated glycoprotein (MAG) 26, or proteolipid protein (PLP) 27, created with gene knock-out technology, were found to have an acquired neurodegenerative disease. In both instances, the animals were found to develop and function normally. However, as the animals aged, they developed progressive neurologic deficits and Wallerian degeneration. This suggests that myelin provides a trophic function for CNS axons, and that axonal pathology develops as a consequence of myelin disruption. Conceivably, axonal pathology in MS can develop as a late secondary consequence of demyelination in CNS ofms patients. MAGNETIC RESONANCE IMAGING SHOWS PROGRESSIVE BRAIN TISSUE LOSS Simon and colleagues measured the diameter of the ill ventricle, diameter of the lateral ventricle, area of the corpus callosum in the midsagittal plane, and the brain width in serial MRI scans from placebo patients participating in the IFNB-la (Avonex) clinical trial. After one year, and two years there were significant increases in ventricular diameter, and corresponding decreases in corpus callosum area and brain width 27 a. This was one of the first studies to indicate loss of brain. tissue early in the course of MS. Gadolinium enhancing lesions at the baseline scan were the strongest predictor of progressive illrd ventricle enlargement in these patients, suggesting progressive brain tissue loss in patients with active disease as reflected by gadolinium enhancement. A normalized measure of whole brain atrophy, termed the brain parenchymal fraction (BPF), was also applied to patients in the IFNB-la (Avonex) clinical trial 28 The BPF is derived from the cranial MR. image set, by dividing the volume of brain parenchymal tissue by the total volume within the brain surface contour. It represents the proportion of volume within the brain surface that is tissue rather than CSF. As brain tissue is destroyed as a result of the pathologic process, CSF spaces are secondarily increased, and BPF decreases. Placebo patients in the Avonex clinical trial were found to have BPF over 5 standard deviations below the mean of the healthy control group. BPF decreased significantly during each year of observation. Over 70% of the placebo patients had significant decreases in BPF during the two-year observation. Importantly, decreasing BPF occurred in many patients without clinical relapses, and in many patients without worsening EDSS scores, implying the presence of a subclinical pathologic process resulting in brain tissue loss. WHAT CAUSES SECONDARY PROGRESSIVE MS? In aggregate, the above findings support the hypothesis that MS is active in many patients from early iri the disease, but that clinical symptoms only loosely reflect its severity. Why do patients with RR-MS function reasonably well and appear stable between relapses? This may occur because compensatory mechanisms are adequate to maintain neurologic function during RR-MS. Why do patients with secondary progressive MS develop continued neurologic decline years after the disease onset? This may occur because the extent of irreversible tissue injury has progressed beyond a threshold, where compensatory mechanisms are inadequate to maintain neurologic function. The onset of progressive deterioration is typically delayed for 15 or more years after the onset of relapsing remitting disease. Intermittent clinical relapses during the RR-MS disease stage indicate the presence of the underlying disease process but don't accurately reflect its severity. This may be one of the reasons why the relapse frequency does not accurately predict the long term prognosis. Once a critical threshold is exceeded, irreversible neurologic disability ensues. Beyond that point, any further disease progression results in progressive disability progression. This model implies that SP-MS represents a relatively late stage of the pathology, and that restorative therapy may be unrealistic at this stage of disease. It also implies the need for proactive monitoring and therapy during the relapsing remitting stage of MS. WHEN SHOULD THERAPY BE INITIATED, AND WHAT IS THE OPTIMAL DURATION OF THERAPY? There is a growing consensus that disease modifying therapy should be initiated early in the course of MS, before irreversible disability has occurred. The rationale for early therapy includes: 1) concerns that the immunologic process leading to tissue injury becomes more complex as time passes, and may be more difficult to control with immunosuppressive therapy 29.3 ; 2) Increasing awareness that the inflammatory process is active in many RR-MS patients during periods of clinical remission 1 ' 3 ; and 3) Concern that the inflammatory process results in 201

irreversible axonal injury 24 ' 31, which accumulates over time during the relapsing remitting stage of MS. These considerations imply that disease modifying therapy should be started when MS is definitively diagnosed, because the patient is at risk for subsequent disability progression. Identifying patients at higher risk of progressive MS for early therapy is an alternative to treating all patients at-the time of diagnosis. Unfortunately, clinical features are only weak predictors of subsequent disease severity, and their value for assigning prognosis to individual patients is limited. Disease severity measured by cranial MRI scan at the time of first symptoms has been shown to predict :rviri and clinical disease progression. This implies that patients with minimal disease by :rviri scan could be evaluated with a follow-up MRI scan to determine the need for disease. modifying therapy. Identifying prognostic factors early in the course of MS is an important goal of future MS research. The optimal duration of therapy has not been determined. For patients doing well, therapy should be continued, since a study of IFNa showed increased disease activity when therapy was discontinued after 6 months 32 studies are needed in which patients are randomly assigned to continue or stop therapy, and then carefully followed under double-masked conditions. WHAT IS THE EVIDENCE THAT EARLY THERAPY REDUCES THE DESTRUCTIVE PATHOLOGY? Recent evidence suggests that IFNB-la inhibited progression of Tl hole volume in the A vonex study 33 and that IFNB-1 b inhibited progression of Tl hole volume in the Betaferon SP-MS study (F. Barkhof, personnal communication). As Tl holes have been correlated with axonal loss in :rviri pathology correlation studies 34, this suggests that the well-documented anti-inflammatory effect of IFNB would inhibit the destructive pathologic process. This possibility was directly supported by the finding that IFNB-la (Avonex) reduced the rate of whole brain atrophy in the second treatment year by 55% 28 It is reasonable to hypothesize that this beneficial effect on whole brain atrophy would translate into meaningful clinical benefits. The duration of the effect, however, and the effect of other IFNB products or glatiramer acetate on whole brain atrophy is currently unknown. Two studies are ongoing that could provide empirical evidence for early treatment. Two forms of IFNB-la (Rebif and Avonex) have been tested in separate studies for efficacy in patients with clinically isolated syndromes. In both studies, patients with clinically isolated syndromes were eligible for the studies if there were clinically silent T2 lesions. Avonex was shown to decrease the probability of converting to clinically definite MS by 50%, and markedly reduced MRI disease progression 35 Rebif, in the dose tested, was also effective, but the results were considerably more modest. In aggregate, the studies suggest that early therapy with IFNB can inhibit destructive brain pathology. HOW SHOULD PATIENTS ON MONOTHERAPY BE FOLLOWED? The poor relationship between clinical relapses and the severity of brain inflammation implies that more accurate and sensitive markers of the pathologic process in RR-MS will be required to follow patients. Periodic cranial MRI scans may be useful in estimating MS disease activity and progression in some patients, to determine the need for disease modifying therapy in patients with clinically benign disease, and to follow the response to disease modifying therapy. Studies are needed to define precisely the methods and frequency for using MRI to monitor patients on disease monitoring therapy. The number of gadolinium enhancing lesions, tl).e number of new T2 lesions, and normalized measures of whole brain atrophy show promise. Methods are urgently needed to incorporate. standardized image acquisition and image analysis in the clinical setting. WHAT ARE THE LONG-TERM BENEFITS AND RISKS OF CURRENT MS DRUGS, AND DO THE LONG-TERM BENEFITS JUSTIFY THE COST OF THE DRUGS? Long-term benefits of the current drugs can only be surmised from existing stu.dies, because clinical trials run 2-5 years while MS unfolds over decades. Therefore, clinical trials provide information on only a limited part of the overall disease. Lengthy placebo-controlled studies are impractical, because patients who are deteriorating withdraw from the study leaving it less informative with time. Open-label studies do not provide definitive evidence about efficacy, since patients who are doing well elect to remain on drug while patients who are deteriorating stop therapy to try something else. This results in observer bias favoring long-term efficacy, a problem called informative censoring. Despite their limitations, the studies suggest that available disease therapies are likely to have a beneficial effect on long term disability. However, long-term cost-benefit analyses are needed. 202

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