More MS news articles for Jan 2002

Evolving Concepts in the Pathogenesis of Multiple Sclerosis and Their Therapeutic Implications

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J Neuroophthalmol 2001 December;21(4):279-283
Richard A. Rudick, MD
From the Mellen Center for Multiple Sclerosis Treatment and Research Department of Neurology, Cleveland Clinic Foundation, Cleveland, Ohio.

JOURNAL OF NEURO-OPHTHALMOLOGY 2001;21:279-283

Recent evidence suggests that multiple sclerosis (MS) is a continuously active neuropathologic process, even during the subclinical relapsing/remitting phase of the disease. Patients commonly feel well and function without disability for many years, experiencing only occasional relapses and nondisabling symptoms. In time, many evolve into a pattern of continuously progressive neurologic disability termed secondary progressive MS (SP-MS). SP-MS is hypothesized to occur once disease severity has exceeded a threshold. Above that threshold, compensatory mechanisms are inadequate to maintain normal function, and further disease progression is accompanied by progressively worsening disability. Inflammation dominates the early stage of disease. Progressive axonal pathology may underlie clinical disease progression in later stages. These concepts have important implications related to the diagnosis, methods for patient follow-up, type and timing of disease therapy, and the testing of neuroprotective drugs in MS.

In recent years, concepts of multiple sclerosis (MS) pathogenesis have evolved rapidly. There is increasing recognition that, although the disease is largely subclinical in its early stages, the pathologic process is continuously active. Axonal and neuronal pathology may be accumulating during this period. Patients enter the secondary progressive MS (SP-MS) stage relatively late in the course of the disease, possibly because the extent of axonal pathology, has exceeded a threshold.

RELAPSING/REMITTING MS AS A CONTINUOUSLY ACTIVE DISEASE

Traditionally, patients with relapsing/remitting MS (RR-MS) have been viewed as having a relatively benign form of the disease, probably because of minimal disability between relapses. In 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 demonstrate that irreversible tissue injury can accumulate without clinical symptoms during this phase. The pathologic process leads eventually to SP-MS in most patients. During RR-MS, the following features are noted:

  1. Areas of signal enhancement on magnetic resonance imaging (MRI). Gadolinium-enhancing lesions occur in approximately 50% of patients with RR-MS on random MRI scans. These lesions occur with approximately 10 times the frequency of clinical relapses.
  2. Newer imaging techniques demonstrate accumulation of imaging abnormalities. Magnetic resonance spectroscopy (MRS), magnetization transfer imaging (MTI), and high field strength MRI show an increase in abnormalities in the white matter that appears normal on conventional MRI sequences.
  3. Pathology studies demonstrate transected axons in active MS lesions. Axonal transection corresponds to sites of active tissue inflammation, regardless of the disease duration.
  4. MRS shows neuronal pathology. Neuronal markers are decreased in MS lesions and in normal-appearing white matter during the relapsing remitting phase of the disease.
  5. MRI shows progressive tissue loss. Early in the disease, increasing brain atrophy can be measured.
Areas of signal enhancement on MRI

Approximately 50% to 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 to 6 weeks, leaving a residual T2 lesion, so that the volume of T2 brain lesions increases by approximately 10% per year in RR-MS patient groups. Clinical correlation studies have found that most gadolinium-enhancing brain lesions in patients with RR-MS 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 (CNS), such as the optic nerve or spinal cord.

Subclinical MRI disease activity, as reflected by gadolinium enhancement, suggests 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 cerebrospinal fluid (CSF) pleocytosis (5). Patients with RR-MS with increased CSF cell counts were found to be significantly more likely to exhibit clinical and MRI disease activity during 1 and 2 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 random cranial MRI scans are strongly associated with gadolinium-enhancing lesions on subsequent MRI scans, and with an increased volume of T2 lesions over the following years (6). The number 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, but long-term follow-up studies are lacking.

Newer imaging techniques demonstrate accumulation of imaging abnormalities

MTI is an easily applied MRI technique that provides information on the structure of CNS tissue. Proton molecules associated with myelin are relatively nonmobile. 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 in white matter that appears normal on conventional MRI (810). MRS has shown abnormalities (11). Emerging data using high field strength MRI have shown much more extensive abnormalities in MS brains than are evident using conventional imaging at 1.5 T (R. Grossman, personal communication).

Pathology studies demonstrate transected axons in active MS lesions

Pathology studies have directly demonstrated that CNS axons are irreversibly damaged by the inflammatory process in active MS lesions. Trapp et al. (12) used confocal microscopy to demonstrate large numbers of transected axons topographically related to inflammation in active brain lesions from 12 patients with MS, confirming the findings from a separate histologic study of amyloid precursor protein in MS brain lesions (13). The data demonstrate that the inflammatory process destroys axons as well as myelin. The cumulative effect of this process might account for irreversible neurologic disability in the secondary progressive stage of the disease.

Results of animal experiments provide another cause of axonal injury in patients with MS. Animals devoid of myelin-associated glycoprotein (14) or proteolipid protein (15) created with gene knock-out technology were found to develop and function normally at first. But 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.

MRS shows neuronal pathology

In vivo MRS studies have demonstrated reduced levels of N-acetyl aspartate (NAA), a neuronal marker, in brain lesions and in normal-appearing white matter in patients with RR-MS, suggesting that axonal pathology is a consistent and early feature of the MS disease process (1627). In one study, reduced NAA was observed in cerebral cortex adjacent to subcortical white matter lesions in eight children with MS (25). The average age of the children in that report was 15 years, 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.

MRI shows progressive tissue loss

Simon et al. (28) measured the diameter of the third and lateral ventricles, the area of the corpus callosum in the midsagittal plane, and the brain width in serial MRI scans in placebo-treated patients participating in the interferon beta (IFN-b)-1a (Avonex) clinical trial. After 1 and 2 years, there were significant increases in ventricular diameter and corresponding decreases in corpus callosum area and brain width. This was one of the first studies to indicate loss of brain tissue early in the course of MS. Enhancing lesions in the baseline scans were the strongest predictors of progressive third ventricular enlargement in these patients, suggesting that active inflammation promotes brain atrophy.

A normalized measure of whole brain atrophy, termed the brain parenchymal fraction (BPF), was also applied to patients in the IFN-b-1a (Avonex) clinical trial (29). The BPF is derived from the cranial MRI 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 by the pathologic process, CSF spaces are secondarily increased, and BPF decreases. Placebo-treated patients in the Avonex clinical trial were found to have BPFs more than 5 standard deviations below the mean of the healthy control group. BPF decreased significantly during each year of observation. More than 70% of the placebo-treated patients had significant decreases in BPF during the 2-year observation. Importantly, decreasing BPF occurred in many patients without clinical relapses, and in many patients without worsening Expanded Disability Status Scale scores, implying the presence of a subclinical pathologic process resulting in brain tissue loss (see below).

WHAT CAUSES SP-MS?

In aggregate, the above findings support the hypothesis that MS is active in many patients early in the disease course and that clinical symptoms do not fully reflect its severity. Why do patients with RR-MS function reasonably well and appear stable between relapses? This may be because compensatory mechanisms are adequate to maintain neurologic function during RR-MS. Why do patients with SP-MS develop continued neurologic decline years after the disease onset? Perhaps 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 RR-MS. Intermittent clinical relapses during the RR-MS disease stage indicate the presence of the underlying disease process but do not 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 RR-MS.

CLINICAL IMPLICATIONS OF MS AS A CONTINUOUSLY ACTIVE BRAIN DISEASE

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 three concerns: 1) that the immunologic process leading to tissue injury becomes more complex as time passes and may be more difficult to control with immunosuppressive therapy (30,31); 2) that the inflammatory process is active in many patients with RR-MS during periods of clinical remission (1,3); and 3) that the inflammatory process results in irreversible axonal injury (12,32), 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. Trials of IFN-b-1a beginning with the first MS symptom have shown significant therapeutic benefit and long-term follow-up of these patients may clarify the importance of treating at the time of the first symptom.

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 the first symptoms has been shown to predict MRI and clinical disease progression. This implies that patients with minimal disease by MRI 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 because a study of INF- showed increased disease activity when therapy was discontinued after 6 months (33). 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 IFN-b-1a inhibited progression of T1 hole volume in the Avonex study (34) and that IFN-b-1b inhibited progression of T1 hole volume in the Betaferon SP-MS study (F. Barkhof, personnal communication). Because T1 holes have been correlated with axonal loss in MRI pathology correlation studies (35), this suggests that the well-documented anti-inflammatory effect of IFN-b would inhibit the destructive pathologic process. This possibility was directly supported by the finding that IFN-b-1a (Avonex) reduced the rate of whole-brain atrophy in the second treatment year by 55% (29). 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 IFN-b products or glatiramer acetate on whole-brain atrophy is currently unknown.

Two ongoing studies could provide empirical evidence for early treatment. Two forms of IFN-b-1a (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 (36). Rebif, in the dose tested, was also effective, but the results were more modest. In aggregate, the studies suggest that early therapy with IFN-b can inhibit destructive brain pathology.

How should patients on monotherapy be followed up?

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-up 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, the 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 studies because clinical trials run 2 to 5 years whereas 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 because patients who are doing well elect to remain on the drug, whereas 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.

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Address correspondence and reprint requests to Richard A. Rudick, MD, Cleveland Clinic Foundation Mellen Center, Area U100, Cleveland, OH 44195, USA;
 

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