Editorial

William Stuart, MD, Medical Director, MS Center of Atlanta, Georgia

The 1999 AAN Meeting in Toronto was a great success. Over 7,000 attendees (the largest ever) were able to learn about new concepts in Multiple Sclerosis (MS) pathogenesis that are changing our attitudes about the treatment of this disease. We entered the Decade of the Brain with MS being largely an untreatable disease. MRI techniques have and will continue to modify our understanding of how this disease progresses. We are finishing the Decade of the Brain having added new and effective therapies and new understandings of this disease process. The devastating outcome data of the past will almost certainly be improved in the future. This meeting of the AAN has added further to this new understanding.

The 1999 AAN meeting contributed several new and informative ideas regarding MS progression and clinical monitoring. The brain parenchymal fraction (BPF) data presented by Dr. Richard Rudick documented surprisingly statistically significant, nonvisible, brain atrophy that was reduced by treatment, in this case, by Avonex®. Consistent pathological changes of a progressive nature that are measurable with computerized MRI techniques and have p values of < 0.0001 are extremely uncommon in biological systems. This finding was in my opinion the highlight of the MS presentations. These findings will almost certainly be validated, establishing a new technique for monitoring therapeutic efficacy in both the clinical and research setting.

Dr. R. Philip Kinkel in another analysis of these patients was unable to demonstrate any significant correlation between other measures of MS progression (EDSS and relapse rates) and BPF. The mechanism by which Avonex® (Interferon beta 1a) can have a significant effect on all of these measures without internal correlation raises many questions about the pathophysiology of MS progression. Perhaps recently described new understanding of the pathological changes in the normal appearing white matter (NAWM) by immunohistochemistry and advanced MRI techniques (MRS, MTR) will be helpful. These observations, while not presented at the AAN, have shown that NAWM is a misnomer and that MS, rather than being a focal disease, is in all likelihood global in the CNS.

Another MRI report by Dr. Jack Simon, again from the Avonex® data, demonstrated therapeutic efficacy by Avonex®, reducing the severity of "black hole" formation. This MRI finding has been strongly correlated with functional impairment. These changes similar to the BPF are irreversible. Early skepticism about the usefulness of the MRI as a tool to monitor MS progression is surely waning.

Measures of disease progression until now cumbersome and inaccurate were expanded by two excellent reports from Dr. John Whitaker and Drs. Jeffrey Cohen and Jill Fischer. The measurement of myelin basic protein-like material (MBPLM) in the urine and its correlation with "black hole" formation on MRI may lead to a noninvasive surrogate marker of disease activity in MS. Drs. Cohen and Fischer reported the findings on the Multiple Sclerosis Function Composite (MSFC) tests, a measure combining three standardized and reproducible tests (timed 25-foot walk, the 9-hole pegboard test and the paced auditory serial addition test (PASAT).

This test will be very complementary to the traditional EDSS in clinical trials and may eventually have clinical application, as well.

Monitoring of MS progression in future clinical trials will likely consist of varying combinations of: MRI, BPF, "Black Hole" Volume, T1 Enhancing lesion, T2 lesion load, MTR ratios, Spectroscopy, EDSS, and MSFC.

NonInvasion Surrogate Markers (MBPLM)

The MS community was pleased and reassured by the statistically significant MRI outcome data in the Copaxone® study. While the result was moderate, the trial was only 9 months long, and the onset of benefit seemed to be delayed for 6 months. Longer follow-up of these patients might have demonstrated better results. This delay in improvement correlated with other outcome measures in the Copaxone® trial and may reflect on the mechanism of this drug's action. Consensus regarding when to treat MS continues to evolve. Dr. Anat Achiron presented data that describes the high probability of "probable" MS progressing to define MS. Dr. Lawrence Jacobs presented early data from the CHAMPS (early treatment of monophasic symptoms) trial. If continued pathogenetic mechanism of this disease further demonstrates a "therapeutic window" in MS that encourages early immunotherapy, then our longstanding subcategories of possible and probable MS may, at least in the clinical setting, be anachronistic.

A new well-designed and performed multicenter, double blind Phase III clinical trial from Europe of Mitoxantrone was reported by Dr. H. Peter Hartung. The results were significant for all outcome measures. Further study and discussion will be needed to this drug's place in an increasingly complicated algorithm for MS immunotherapy.

The MS Section of the AAN held its third meeting. Dr. Randall Shapiro succeeded the founding chair, Dr. Aaron Miller, this year. Dr. Andrew Goodman will be chair in 1999?Dr. Patricia Coyle was voted Chair-Elect. The Sections in the AAN are becoming increasingly important in representing their special interests to the major committees and the Board of the AAN. Membership is free and all interested in MS should consider joining.

As we exit the Decade of the Brain, those working in MS (research, clinical care, industry) should be pleased with their efforts. Three new and effective drugs are now available. Clinical trial results appear to be even better in the clinical setting. New drugs are in development and old drugs are being re- examined in multidrug trials.

Even neurologists had to be touched by the emotion of the moment at the Plenary Session on Tuesday when Dr. Dennis Choi presented the awards to four young high school adults for their work in basic neuroscience. One of the four, Miss Nina Langram, did her work in an MS-related subject with special interest to MS patients in the future: "Progenitor oligodendrocytes in MS Lesions of Different Ages: A Neuropathological and Immunocytochemical Study." The future is in good hands, and our MS patients should be reassured.

The Effect of Avonex® (Interferon Beta-1a) on Cerebral Atrophy in Relapsing Multiple Sclerosis

Richard Rudick, MD, Professor of Neurology, Director of the Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland, Ohio

The Multiple Sclerosis Collaborative Research Group has reported further data from their Phase III trial that corroborates the benefit of treatment with Interferon Beta-1a (Avonex®) on the destructive CNS pathologic process that underlies multiple sclerosis (MS).

At the annual meeting of the American Academy of Neurology, Richard Rudick, MD, Professor of Neurology at the Cleveland Clinic and Director of the Mellen Center for MS Treatment and Research, said Avonex® slowed the progression of cerebral atrophy over 2 years in patients with relapsing MS, as documented by MRI scans at baseline and years 1 and 2 of therapy.

The study included 140 MS patients, 70 patients receiving Avonex® and 70 receiving placebo. Atrophy was assessed by the brain parenchymal fraction (BPF), which is calculated by dividing the brain parenchymal volume by the total volume within the outer brain surface contour. Patients' BPF was already below healthy control levels at baseline, indicating that brain atrophy had already occurred by study entry.

By the end of year 2, placebo recipients had significantly reduced BPFs compared to their baseline levels. 0Patients treated with Avonex® demonstrated a similar degree of atrophy to placebo recipients at the end of year 1, but after 2 years of treatment their rate of cerebral atrophy was 55% less than placebo recipients (p = 0.03), reported Dr. Rudick.

BPF is a highly reproducible means of assessing atrophy. MS patients began the 2-year study with a baseline BPF of 0.83, about five standard deviation units below the healthy controls at 0.87. This means the MS patients had BPF's that were already significantly lower than the normal reference range, Dr. Rudick said. The difference between MS patients and controls at baseline was significant at (p< 0.00001).

The change (reduction) in the BPF by year 2 was 0.527 units for placebo recipients whereas Avonex®-treated patients worsened by only 0.236, a 55% difference (p = 0.028). After adjustments for baseline covariates, the favorable effect of Avonex® during the second year of treatment remained significant with an even greater p value (p < 0.01), Dr. Rudick said.

Avonex®-treated patients worsened during year 1 by 0.715% while placebo recipients worsened by a similar 0.746%. "These findings suggest that Avonex® reduced the rate of (brain) atrophy after the first year of the study," Dr. Rudick commented, proposing that it takes some time for disease activity to "play out" as atrophy.

"These are biological changes occurring in the population of placebo patients," he added. Seventy percent of the placebo recipients had progressive brain atrophy evidenced by worsening baseline levels.

Unfortunately, no strong predictors of brain atrophy emerged from the data. Baseline EDSS score and T1 lesion volume were significantly related to rate of atrophy, but together accounted for only 14% of the variance.

"Our conclusions are that relapsing-remitting MS patients have brain atrophy that increases yearly, that predictors of atrophy are largely undefined at this point, and that the relapse rate and EDSS are not sensitive measures of this. A lot of patients in the study were experiencing brain atrophy without clinical symptoms. Avonex® significantly reduces progressive atrophy," Dr. Rudick said.Even neurologists had to be touched by the emotion of the moment at the Plenary Session on Tuesday when Dr. Dennis Choi presented the awards to four young high school adults for their work in basic neuroscience.

One of the four, Miss Nina Langram, did her work in an MS-related subject with special interest toMS patients in the future: "Progenitor oligodendrocytes in MS Lesions of Different Ages: A Neuropathological and Immunocytochemical Study." The future is in good hands, and our MS patients should be reassured.

Brain Atrophy: Refining the Concept

The favorable effect of Avonex® during the second year of treatment remained significant with an even greater p value, (p < 0.01), Dr. Rudick said.

Avonex®-treated patients worsened during year 1 by 0.715% while placebo recipients worsened by a similar 0.746%. "These findings suggest that Avonex® reduced the rate of (brain) atrophy after the first year of the study," Dr. Rudick commented, proposing that it takes some time for disease activity to "play out" as atrophy.

"These are biological changes occurring in the population of placebo patients," he added. Seventy percent of the placebo recipients had progressive brain atrophy evidenced by worsening baseline levels.

Unfortunately, no strong predictors of brain atrophy emerged from the data. Baseline EDSS score and T1 lesion volume were significantly related to rate of atrophy, but together accounted for only 14% of the variance.

"Our conclusions are that relapsing-remitting MS patients have brain atrophy that increases yearly, that predictors of atrophy are largely undefined at this point, and that the relapse rate and EDSS are not sensitive measures of this. A lot of patients in the study were experiencing brain atrophy without clinical symptoms. Avonex® significantly reduces progressive atrophy," Dr. Rudick said.

Multiple Sclerosis--from Probable to Definite Diagnosis: A 7-Year Prospective Study

Anat Achiron, MD, Multiple Sclerosis Center, Department of Neurological Rehabilitation, Sheba Medical Center, Tel Hashomer, Israel.

The vast majority of patients with a diagnosis of probable MS and positive findings on brain MRI will progress to clinically definite MS within one year, according to Israeli researchers who presented their study at this meeting. Anat Achiron, MD, and colleagues from the Multiple Sclerosis Center, Department of Neurological Rehabilitation, Sheba Medical Center, Tel Hashomer, Israel, conducted a prospective study with up to seven years of follow-up to determine the frequency with which patients progressed from a probably to a clinically definite diagnosis and to more closely examine the characteristics of patients who progressed rapidly, within one year.

As background, they explained that a composite of symptoms?motor, sensory, coordination, visual, and cognitive impairments along with fatigue and urinary dysfunction?always raises the suspicion of MS in a young adult. The diagnostic algorithm still requires that definite MS be clinically diagnosed only upon the second neurological relapse. Between the first and second relapse patients are classified as suffering from probable MS. "This seemingly subtle phenomenological difference may, in fact, be a critical period within which the immunological processes underlying the disease are not at bay, awaiting our clinical confirmation," Dr. Achiron said.

"Therapeutic intervention immediately after onset of the autoimmune process may be of particular importancein patients with the first episode of a demyelinating syndrome at high risk for progressing to definite MS."

The study included 198 patients suffering from the first episode of neurological symptoms suggestive of MS. All had a brain MRI scan that demonstrated demyelinating lesions at onset. Demographic and clinical variables at presentation were analyzed to identify variables predictive of rapid progression to clinically definite disease.

Of the 198 patients, 193 had an additional relapse and were thus defined as clinically definite MS. Five patients remained with a clinically probable MS status. Of the relapsing patients, 112, or 58%, experienced the additional relapse within one year. Motor involvement at the onset of the probable illness was the only clinical parameter found to be associated with rapid progression to a definite diagnosis, Dr. Achiron reported in a poster session at the 51st Annual Meeting of the American Academy of Neurology.

Natural History and Effect of Interferon Beta-1a (Avonex®) on T1 Hypointense Lesions (T1 'Black Holes')

Jack H. Simon, MD, Ph.D., Professor of Neuroradiology, University of Colorado Health Sciences Center, Denver

Treatment with Interferon Beta-1a (Avonex®) appears to lessen the accumulation of destructive T1 hypointense lesions, or "black holes," according to data from the MS Collaborative Research Group Phase III trial.

Jack H. Simon, MD, Ph.D., reported on behalf of the group that Avonex® can impact the progression of the lesions thought to be most responsible for exerting damage within the brain.

"We knew that therapy interfered with the development of acute inflammatory lesions and reduced the incidence of new T2 hyperintense nonspecific lesions, but we didn't know if treatment would decrease the more destructive T1 hypointense lesions," he explained.

The study involved 160 relapsing MS patients with mild-to-moderate disability, randomized to Avonex® or placebo. Patients were evaluated by MRI at baseline and at year 2. All patients had lesions that were defined as sharply demarcated and nonenhancing.

"We think of these lesions as having a more specific, destructive pathology than T2 lesions, and a stronger correlation with disability," Dr. Simon added. The study found stronger on-trial correlations between clinical measures of disease and T1 hypointense lesions than between clinical measures and T2 hyperintense lesions. But no single MRI measure accounted for the bulk of the relationship between MRI findings and clinical disease.

T1 lesion volume significantly correlated with EDSS at baseline (p = 0.005) and after 2 years of observation (p = 0.0124). No 2-year correlation was found for T2 lesions and EDSS. Moderate-to-strong on-trial correlations (r = 0.40 to 0.71, p = 0.0001 to 0.0003) were seen between change in T1 lesion volume and new T2 lesions, change in T2 lesion volume, cumulative number of enhancing lesions, and atrophy around the third ventricle, Dr. Simon reported.

The impact of treatment on the T1 hypointense lesions of MS was evident in the comparison between treated and untreated patients. Over 2 years, placebo recipients demonstrated a significant increase (29%) in mean volume of T1 lesions (median 124 mmł) over baseline (p = 0.0004), but no significant increase occurred in Avonex®-treated patients (mean increase 11.8%, median 40 mmł). A comparison of the treatment groups showed a strong trend for reduction in T1 lesion accumulation in Avonex®-treated patients (p = 0.065). The most significant contributor to change in T1 lesion volume for placebo patients was the baseline number of gadolinium-enhancing lesions (p = 0.0001).

"'Active' patients with gadolinium-enhancing lesions at baseline seem to accumulate destructive T1 hypointense lesions more aggressively," Dr. Simon observed.

Correlation of Black Hole Volume on Cranial MRI and Urinary Myelin Basic Protein-Like Material in Advanced Multiple Sclerosis Patients

John N. Whitaker, MD, Professor and Chair, Department of Neurology, University of Alabama at Birmingham, Staff Neurologist, Birmingham Veterans Medical Center, Alabama

Urinary myelin basic protein-like material (MBPLM) may be a marker for the transition of relapsing remitting MS to secondary progressive MS and advancing disability, according to a report at the 51st Annual Meeting of the American Academy of Neurology.

John N. Whitaker, MD, of the University of Alabama at Birmingham, showed that in the more disabled MS patients, especially those in advanced secondary progressive disease, urine MBPLM levels significantly correlate with the volume of black holes on cranial MRI, an indictor of MS progression.

The finding of such a correlation adds to other evidence that urine MBPLM values might serve as a surrogate marker of progression of disability in MS, helping answer the critical need for a noninvasive and cost-effective test for monitoring disease activity, he noted.

It has previously been reported that a significant correlation exists between neurological disability and black hole lesion volume (BHLVOL) on cranial MRI, which are hypointense lesions on T-1 weighted spin-echo images. A correlation has also been reported between urine MBPLM, especially when corrected for creatinine concentration (MBPLM/Cr), and the transition towards secondary- progressing (SP) from relapsing-remitting (RR) MS, Dr. Whitaker explained.

The study paired 642 urine samples with cranial MRI images obtained from MS patients during the Phase III Linomide Drug Study. These included 86 RRMS, 259 SPMS without continued attacks, and 317 SPMS patients with continued attacks. The urine specimens were analyzed for MBPLM and MBPLM/Cr levels and the MRI images were analyzed for BHLVOL on post-gadolinium images. The data were analyzed for correlations between baseline neurological disability and BHLVOL with levels of urinary MBPLM, both directly and related to creatinine concentration, and for differences within these variables between the MS patient groups.

The study found the greatest correlations to be between urine MBPLM levels and BHLVOL in the most disabled patients, especially those with advanced SPMS. Weak but highly significant correlations were found between MBPLM and BHLVOL among all 662 MS patients (r = 0.114, p = 0.0032), among the 259 SPMS patients without attacks (r = 0.185, p = 0.0027), and among all 576 SPMS patients (r = 0.122, p = 0.0032), Dr. Whitaker reported.

No significant correlations were detected in any of the disease groups or subgroups whose EDSS was 5.0 or less (320 patients). In analyzing the disease subgroups whose EDSS was at least 5.5, moderate but highly significant correlations were found between MBPLM and BHLVOL in all 342 patients (r = 0.228, p = 0.0001), in 138 SPMS patients without continued attacks (r = 0.397, p = 0.0001), and in all 305 SPMS patients (r = 0.247, p = 0.0001). Correlations were not detected in RRMS (r = -0.32, p = 0.8524, n = 37) or in SPMS patients with continued attacks (r = 0.083, p = 0.2893, n = 167).

A significant correlation was noted between MBPLM/Cr and BHLVOL in the 138 SPMS patients without continued attacks in the higher EDSS group (r = 0.417, p = 0.0001) and in both EDSS groups combined (r = 0.238, p = 0.0001, n = 259). MBPLM/Cr was not significantly correlated with BHLVOL in any other groups, Dr. Whitaker said. The study also found black hole lesion volume to be significantly increased in patients with EDSS greater than or equal to 5.0, further strengthening the previously reported association between this MRI parameter and increased neurological disability, he noted.

"As a reflection of progression, failed remission, axonal loss or other process, these findings furnish additional evidence for the possible role of urinary myelin basic protein-like material as a marker for the transition of relapsing- remitting MS to secondary-progressive MS and advancing disability," Dr. Whitaker commented. "These findings remain consistent with our earlier speculation that urine myelin basic protein-like material reflects synthesized MBP with a block to its incorporation into CNS myelin."

The Challenge of Progressive MS

Mitoxantrone in Progressive Multiple Sclerosis: A Placebo-Controlled, Randomized, Observer-Blind Phase III Trial

H. Peter Hartung, MD, Professor of Neurology, University Clinic of Neurology, University of Graz, Austria

Mitoxantrone, a cytotoxic agent in the anthracenedione family, has demonstrated benefit in the treatment of patients with progressive MS, according to a report from the MIMS-Study Group (Mitoxantrone In Multiple Sclerosis) presented by H. Peter Hartung, Professor of Neurology at the University of Graz, Austria.

Mitoxantrone (MX), an antineoplastic agent, interacts with DNA and inhibits topoisomerase II. It is immunosuppressive by reducing the number of B cells, inhibiting T helper cell function, and augmenting T cell suppressor activity. MX is effective in experimental allergic encephalomyelitis and evidence of efficacy has been suggested in several Phase II clinical MS trials.

This Phase III trial included patients with active relapsing-progressive or secondary-progressive MS. For entry, patients had to have a worsening EDSS of one point or more during the preceding 18 months but no relapse or corticosteroid therapy within 8 weeks of study entry.

The 194 patients (188 evaluable) were randomized to receive MX 5 or 12 mg/m2 i.v. or placebo every 3 months for 2 years. They had a mean age of 41, disease duration of 10 years, an average of 1.3 relapses in the year before study entry, and deterioration in EDSS of 1.57 points in the past 18 months. Baseline EDSS values were 4.5, 4.6, and 4.7 in the 5 mg (MX5), 12 mg (MX12), and placebo groups, respectively. A neurological examination was done every 3 months by a blinded observer to determine EDSS and ambulation index.

All primary and secondary outcome measures were significantly affected by treatment with MX, Dr. Hartung reported. EDSS was decreased from baseline by 0.12 in the MX12 group and by 0.23 in the MX5 group, but was increased by 0.23 in the placebo group (p < 0.038). Ambulation index was increased by 0.8 with MX5, 0.4 with MX12, and 0.8 with placebo (p < 0.040).

Mean number of treated relapses were 0.4 for MX12, 0.7 for MX5, and 1.2 for placebo (p < 0.0002). There was also a statistically significant difference in the time to first treated relapse in patients receiving the highest dose. In both the placebo group and the MX5 group relapse occurred at about 7 months, but was delayed to over 20 months with 12 mg/m2 of MX (p < 0.0004).

EDSS deterioration occurred in 22% of placebo patients, 14% of MX5 patients, and 8% of MX12 patients. Percentage of patients without relapses in 2 years was 44% on placebo and 59% on MX5, rising to 72% with the higher MX12 dosage, the study found.

"The relapse rate was sustained into the third year, and there was evidence of the drug's effects a full year after treatment was stopped," Dr. Hartung added. A subgroup of patients evaluated by MRI again showed the drug's benefit in markedly reducing the number of Gd-enhancing lesions.

Although the drug is cytotoxic, there were few serious adverse events. Most were limited to nausea, alopecia, urinary tract infections, menstrual disorders, amenorrhea, transient leucopenia, and increased gamma-glutamyltransferase. While 28 patients developed some reduction in left ventricular ejection fraction, no patient showed clinical evidence of congestive heart failure and "the cardiologists have not been concerned," Dr. Hartung commented.

"Mitoxanthrone positively impacts on progressive MS, and the MRI results corroborate the clinical data," he concluded.

Relationship between Clinical Outcome Measures and Progressive Cerebral Atrophy in Relapsing Remitting Multiple Sclerosis

R. Philip Kinkel, MD, Director of Medical Programs, Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio, MS Collaborative Research Group

Routine clinical outcome measures that are used in both the trial and office settings are less than perfect. As more data emerges regarding the dynamic pathologic process within the brain, the need for more sophisticated methods of following MS patients is becoming clear.

R. Philip Kinkel, MD, Director of Medical Programs for the Mellen Center for MS Treatment and Research, presented findings on behalf of the MS Collaborative Research Group that emphasize the insensitivity of traditional clinical outcome measures such as relapse rate and EDSS. Newer measures, especially the brain parenchymal fraction (BPF) that can document progressive atrophy make it clear that traditional markers are not keeping pace with the changes in the brain.

The objective of Dr. Kinkel's research was to evaluate the relationship between traditional clinical outcome measures and progressive cerebral atrophy in patients with relapsing-remitting MS. Relapse rate and EDSS have been found to correlate only weakly with T2 lesion volume and with the number of gadolinium- positive lesions. Their ability to predict clinically significant disability in relapsing-remitting MS patients has been uncertain, as is their optimal use in clinical trials.

This study was intended to provide insight through an analysis of MRI scans from patients who participated in the Avonex® Phase III study clinical trial. Scans were reanalyzed to determine BPF, the proportion of the whole brain volume represented by brain parenchyma. Reductions in BPF are presumed to indicate progressive cerebral atrophy.

Results were obtained from 70 Avonex® and 70 placebo recipients who had baseline, year 1, and year 2 MRI scans. The patients had average disease duration of 6.5 years and average baseline EDSS of 2.4. The number of relapses and the magnitude of EDSS changes during the 2-year trial were compared with the rate of atrophy as measured by BPF changes over 2 years.

As background, Dr. Kinkel gave the following hypothetical BPF measures relative to disease status: 0.87 for healthy controls, 0.85 for a relapsing-remitting MS patient with disease duration of 2 years, and 0.71 for a secondary-progressive MS patient with disease duration of 19 years. A BPF change of 0.5% is considered significant.

In the total group of 140 patients, 67% of patients had evidence of progressive brain atrophy at 2 years, and 24% of patients had a change of at least 0.5% in BPF.

Progressive atrophy, as reflected by change in BPF, did not differ according to number of relapses, indicating that relapse rate is an insensitive measure of atrophy, Dr. Kinkel reported. BPF changes did not differ in patients with no relapses, one relapse, or two relapses during the 2-year interval, although BPF change was significantly greater (p<0.03) for patients with three or more relapses. In these patients, a BPF change of 1.5% was associated with three or more relapses, he reported. "Most of the relationship between BPF and number of relapses is in the outliers," he noted.

The relationship between unsustained EDSS changes and BPF changes was similarly vague. The percent change in BPF was not different in 25 patients who improved by 1.0 or more points, 73 who remained within 1.0 point of baseline, or 20 patients who worsened by 1.0-1.5 points.

The 26 patients who worsened by at least 2 EDSS points, however, had a higher rate of cerebral atrophy. This was indicated by a BPF change of -1.96%, compared with BPF changes observed in the 114 patients who did not worsen by 2 or more EDSS points (p < 0.01), Dr. Kinkel reported.

During the 2-year study the percent BPF change was significantly greater in 36 patients with sustained EDSS worsening of more than 1.0 point compared with 104 patients who did not have sustained EDSS changes (p < 0.01).

Overall, Dr. Kinkel concluded, atrophy was greater in patients with more than three relapses, more than 2 EDSS points worsening (sustained and unsustained) from baseline EDSS, and those with 6-month sustained EDSS worsening of more than 1 point.

"Progressive cerebral atrophy was also present in the large majority of patients who did not exhibit this degree of clinical activity or worsening. In those patients, EDSS and relapse outcomes were not related to progressive atrophy," he said. "We conclude that traditional clinical outcome measures are not sensitive to the underlying pathologic process in relapsing-remitting MS patients and more sensitive measures are needed for clinical trials and for monitoring patients during routine office visits."

The Effect of Glatiramer Acetate on Disease Activity as Measured by Cerebral MRI in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS): A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study Extended by Open-Label Treatment

Giancarlo Comi, MD, Professor of Neurology, University of Milan, Milan, Italy, for the Copaxone® MRI Study Group

In patients with relapsing remitting MS, glatiramer acetate (Copaxone®) reduced disease activity and accumulated burden of disease by MRI measures in a multicenter international trial. The study was reported on behalf of the Copaxone® MRI Study Group by Giancarlo Comi, MD, Professor of Neurology at the University of Milan, Italy.

The study included 239 patients from 29 centers in Europe and Canada who received daily subcutaneous injections of 20 mg glatiramer acetate. The first phase of the trial, on which the presentation was based, was a 9-month double- blind, placebo-controlled component; this was followed by a 9-month open-label phase in which all patients received the agent (data not available). All patients had one or more relapses in the prior 2 years and at least one gadolinium (Gd)-enhancing lesion on their screening MRI scans. Brain and MRI scans and clinical assessments were performed monthly during the double-blind phase.

The primary outcome measure was the total number of Gd-enhancing lesions on T1- weighted images. Secondary outcome measures included the proportion of patients with Gd-enhancing lesions on T1-weighted images; the total volume of Gd- enhancing lesions on T1-weighted images; total number of new Gd-enhancing lesions on T1-weighted images; total volume of lesions on T2-weighted images; number of new lesions detected on T2-weighted images; and total volume of hypointense lesions on unenhanced T1-weighted images.

Active treatment resulted in a 35% reduction in the adjusted mean of total number of Gd-enhancing T1 lesions, a statistically significant improvement in the primary endpoint, Dr. Comi reported.

"Glatiramer acetate reduces new lesion formation and slows the increase in lesion volume in relapsing-remitting MS," Dr. Comi concluded. "The decrease in MRI-measured disease activity parallels the reduction in clinical activity seen here and in previous trials."

Two double-blind, placebo-controlled trials have previously demonstrated that glatiramer acetate reduces relapse rate. Glatiramer acetate appears to act via production of specific T-suppressor cells, which cross-react with myelin basic protein and mediate "bystander suppression," he explained.

Almost all secondary outcome measures were favorably affected by treatment with the drug. These included a larger median change from baseline in the volume of Gd-enhancing lesions on T1-weighted images; a 35% reduction in the adjusted mean number of new Gd-enhancing lesions on T1-weighted images.

The drug also significantly reduced the clinical relapse rate. Patients treated with glatiramer acetate had 33% fewer relapses; placebo patients experienced a mean of 0.76 relapses compared to 0.51 for treated patients (p = 0.017), Dr. Comi reported.

The improvements that occurred with glatiramer acetate, however, were not evident until patients had completed several months of treatment. For example, differences in the cumulative number of new T2 lesions were not significant until month six.

"There was not the immediate change you see with beta-interferon," Dr. Comi commented. He attributed the delayed effect to the gradual reduction of anti- inflammatory cytokines, which peaks at six months.

"MRI measures of change are seen after three months and become significant after six months. MRI effects increase significantly with time, and there is a significant decrease in relapse rate in the third trimester of treatment," Dr. Comi elaborated.

Oligoclonal IgG Bands in Japanese Multiple Sclerosis Patients

Ichiro Nakashima, MD, Tohoku University School of Medicine, Department of Neurology, Aobaku Sendai, Japan

Japanese investigators attempted to correlate the presence of cerebrospinal fluid oligoclonal IgG bands, which are much lower in Japanese than in Western persons, with clinical features of MS. Ichiro Nakashima, MD, Tohoku University School of Medicine, Department of Neurology, Aobaku Sendai, Japan, reported their findings at the 51st Annual Meeting of the American Academy of Neurology, at a poster session.

The presence of CSF oligoclonal IgG supports the diagnosis of MS, as over 90% of MS patients are positive for this marker in Western countries. However, the frequency of oligoclonal bands is reportedly much lower in Japanese patients with MS by approximately 35-46%. It is known that the so-called optic-spinal form of MS, which is characterized by relatively severe and selective involvement of the optic nerves and spinal cord, is relatively common in Asians, including Japanese patients. Asian patients, including Japanese patients, may also demonstrate MS with clinical and MRI findings similar to those of Caucasian MS patients.

It remains unknown whether the low prevalence of oligoclonal bands in Japanese MS patients might be associated with the occurrence of the optic-spinal form of MS, versus the conventional form. The present study, therefore, examined the relative frequency of oligoclonal bands in the optic-spinal form.

Dr. Nakashima's study included 44 consecutive Japanese patients with clinically definite MS, classified into two subgroups based on neurological manifestations and MRI findings: (1) the Western type, or conventional form,in which various parts of the central nervous system are diffusely involved, or (2) the Asian type, or optic-spinal form, of MS, which is characterized by selective involvement of the optic nerves and spinal cord.

Oligoclonal banding was tested using a standard isoelectric focusing methodology. The IgG index, a crucial marker of abnormal intrathecal humoral immune responses, was also evaluated in these patients. Among the 44 patients, 35 had conventional MS and 9 had the optic-spinal form. The percentage of patients positive for oligoclonal bands was higher in the conventional patients (46%) than in the optic-spinal patients (11%), although this difference was not significant, Dr. Nakashima reported.

There appeared to be gender-based differences, however. Among the conventional MS patients, 15 of the 23 female patients (65%) were positive for oligoclonal bands, while only one out of the 12 male patients (8%) was positive (p < 0.005). In female MS patients, oligoclonal bands were significantly more likely to be seen in patients with conventional MS (65%) than in patients with optic-spinal MS (14%) (p < 0.05).

An abnormally high IgG index was observed in 53% of conventional MS patients and 14% of optic-spinal MS patients. Values of the IgG index were significantly higher for conventional MS (0.81 +/-0.34) than for optic-spinal MS (0.55 +/- 0.12) (p < 0.05). As expected, patients who demonstrated oligoclonal bands had significantly higher values of the IgG index (1.0 +/-0.35) than those who did not (0.60 +/-0.17) (p < 0.001). Most of the patients without oligoclonal bands had normal IgG indexes, less than 0.73. On the other hand, CSF cell counts and CSF total protein levels were not different between patients with or without the bands.

The authors concluded that among Japanese patients with MS, the optic-spinal form was more common in females than males. The frequency of oligoclonal bands was much lower in the optic-spinal form than in conventional MS in female MS patients. Few male patients demonstrated oligoclonal bands, regardless of their clinical expression. The IgG index correlated with the presence of oligoclonal bands.

"Racial and genetic background, as well as gender, may influence the occurrence of abnormal intrathecal humoral immune responses as well as the clinical form of MS," Dr. Nakashima suggested.

A Profile of Patients at High Risk for the Development of Clinically Definite MS (CDMS): The First Report of the CHAMPS Study

Lawrence D. Jacobs, MD, Professor of Neurology, University of Buffalo, New York

The extent and activity of MS pathology of the brain appear to be greatest in patients who present with brainstem-cerebellar syndromes, according to a report from the CHAMPS study (Controlled Trial of High-Risk Subjects in A Multiple Sclerosis Prevention Study).

Lawrence D. Jacobs, MD, principal investigator of the CHAMPS Study Group, presented baseline demographic and MRI data comparing patients with acute first episodes of optic nerve, brainstem-cerebellar, or spinal cord syndromes. The patients were part of the multicenter double-blind, placebo controlled 3-year CHAMPS study of 383 patients with acute monosymptomatic syndromes and positive brain MRIs consistent with MS. Patients who experience first episodes of monosymptomatic syndromes whose MRIs reveal "clinically silent" brain lesions are at high risk for developing clinically definite MS in the future. The CHAMPS interferon-beta-la trial will randomize such persons to treatment or placebo in order to determine whether intervention at this very early stage will prevent the progression to full-blown disease.

In the study of 383 patients, the acute event was optic neuritis in 50%, brainstem-cerebellar syndrome in 28%, and spinal cord syndrome in 22%. There were no differences in baseline demographics between the syndrome groups, including age (33 years average), sex (75% female), race (86% Caucasian), or incidence of MS in first-degree relatives (9%). Mean duration of symptoms was about 18 days for all groups.

Overall, the median brain T2 lesion load was 1,919 mmł. About half the patients had five or more T2 lesions and 27% had at least one gadolinium-enhancing lesion.

The brain T2 lesion load was significantly greater in patients with brainstem- cerebellar syndromes than those with optic neuritis (p = 0.0001) or spinal cord syndromes (p = 0.004). The lesion load was similar in optic neuritis and spinal cord syndromes. The presence of at least one enhancing lesion was more common in patients with brainstem-cerebellar syndromes than the other two syndromes (p = 0.0001), Dr. Jacobs reported in a poster session.

The T2 lesion load, by syndrome, was as follows: brainstem-cerebellar syndrome, 3,664 mmł; spinal cordsyndrome, 1,914 mmł; optic neuritis, 1,669 mmł. Enhancing scans were seen in 29% of all patients, including 43% of brainstem-cerebellar syndrome patients, 31% of spinal cord syndrome patients, and 21% of optic neuritis patients, with a significant difference (p = 0.0002) between brainstem- cerebellar and optic neuritis patients. Maximum enhancing lesion volume was also significantly increased by brainstem-cerebellar lesions as compared with optic neuritis lesions: 2,834 mmł to 413 mmł (p = 0.0001).

"The thing we saw is that some lesions are typical of brainstem-cerebellar syndromes, and some are typical of the other syndromes. There are many more lesions in the patients with brainstem syndrome. We don't know what this means yet," Dr. Jacobs commented.

"Several questions arise from these findings," he continued. "Will MS involvement of the brain be expressed clinically as greater or more rapid conversion to clinically definite MS in the brainstem-cerebellar group? Will MRI activity rates and conversion to 'MR-definite MS' segregate based on initial syndromes? The answers can only be determined at the end of the full 3-year follow-up."

The Multiple Sclerosis Functional Composite: Intra-and Inter-Rater Reliability and Its Use as an Outcome Measure

Jeffrey Cohen, MD, Director of Experimental Therapeutics, and Jill S. Fischer, Ph.D., Director of the Psychology Program, Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio

The Multiple Sclerosis Functional Composite (MSFC) is a multidimensional quantitative outcome measure that comprises tests of leg, arm, and cognitive function. These include the timed 25-foot walk, the 9-hole peg test, and the paced auditory serial addition test (PASAT). It was developed by the National MS Society Clinical Outcomes Assessment Task Force in response to the poor reliability and insensitivity to change of the available MS clinical rating scales.

Jill S. Fischer, MD, a Task Force member and co-author of two presentations on the MSFC at this meeting, noted, "Everybody acknowledges that the EDSS is not sufficiently sensitive in clinical trials. So the panel designed this functional composite based on an empirical analysis of existing data to be a novel approach to outcomes assessment. It is a way to systemically and quantitatively capture three independent important clinical dimensions of MS, not just walking. So it makes the assessment of MS broader," said Dr. Fischer, Ph.D., director of the Mellen Center for MS Treatment and Research Psychology Program.

Research was presented at the meeting by Jeffrey Cohen, MD, Director of Experimental Therapeutics at the Mellen Center for MS Treatment and Research at the Cleveland Clinic Foundation, Cleveland, OH, demonstrated the reliability and usefulness of the new composite measure, both in the clinical trial setting and potentially, in the clinician's office.

To test the reliability of the MSFC, two examining technicians with no previous experience with the composite were trained using standardized training materials. Ten patients with secondary-progressive MS and moderate disability underwent six testing sessions (two per day) within a 2-week period. The test proved to be very reliable, both for intra- and inter-rater measures. It was easily taught, and took about 15 minutes to administer, reported Dr. Cohen.

For a given patient, the first five sessions were performed by the same technician and the sixth was performed by the alternate technician; each technician was the primary examining technician for five patients. In addition, patients were reassessed by the same examining technicians after 6 months. The dependent variable, the MSFC score, was calculated as the mean of the Z-scores of the three components. The Z-score is a standardized score representing the number of standard deviations a given value is from a population mean, calculated in this case with reference to the Task Force pooled data set of secondary progressive MS patients in previous clinical trials and natural history studies.

Practice effects (manifested as improved performance and decreased variability) were evident initially for the MSFC and its components, but stabilized by the fourth session, Dr. Cohen reported at the meeting.

Intra-rater reliability was evaluated using the intra-class correlation coefficient for the MSFC for sessions four versus five, because practice effects were anticipated in earlier sessions. Inter-rater reliability was evaluated using the intra-class correlation coefficient for sessions five versus six. The study was powered to detect a major problem affecting reliability, defined as a correlation coefficient of 0.6 or less.

The correlation coefficient for sessions four versus five--which measured intrarater reliability?was 0.97. For sessions five versus six--the test for inter-rater reliability?the correlation coefficient was 0.95. Reliability remained excellent when patients were retested at 6 months (0.96). This study concluded that the composite would be a useful surrogate outcome measure in clinical trials, and that it can be designed to compensate for practice effects, Dr. Cohen said.

The MSFC was chosen as the primary outcome measure in the Phase III trial of interferon beta-1a (Avonex®) in secondary progressive MS (IMPACT) to determine if treatment slows the progression of disability.

The study is designed to detect a change in MSFC Z-scores (deviations from the population mean) between placebo and actively treated patients over 18 months of 0.523. This translates to a 6-second difference in the timed 25-foot walk, or a 4.6-second difference in the 9-hole peg test, or a difference of six correct on the PASAT, or a combination of smaller changes in these measures. A total of 436 patients were enrolled. their baseline values were almost identical to those in the Task Force database.

The three components of the composite did correlate with each other, but only modestly, which suggests they are measuring different aspects of neurological function. All three components correlated with the composite to roughly the same degree, which suggests they are all contributing to the composite score.

In the group, the worse the EDSS the worse the composite score, particularly at EDSS 6.5. There is some variability in the composite at each EDSS level, suggesting that it may be able to provide additional information. Once again, the reliability of the composite was excellent, with the correlation coefficient at the last baseline visit 0.93. Practice effects were seen as anticipated. On average, patients improved, especially in the first two sessions. The PASAT was the main contributor to this practice effect.

These results strongly support the feasibility of using the MSFC in a multicenter trial. They also confirm some of the assumptions made in designing the IMPACT trial including reliability of the measure, session-to-session change (which was modest), presence of practice effects, and strategies for compensating for practice effects, Dr. Cohen said.

Dr. Fisher added, "These findings confirm the assumptions we made going into the IMPACT study. Right now, the applicability of the MSFC is in the clinical trial setting, but once we confirm what constitutes a clinically significant change in an individual, it will be used in clinical practice to monitor the effects of therapy."