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Aaron Miller, MD: Course, Prognosis Remain Challenges in MS Research

MacReady, Norra

doi: 10.1097/01.NT.0000284711.26436.ff
Best of the Field

The best papers published in multiple sclerosis (MS) within the last 12 months shed light on treatment, prognosis, cognitive impairment, and biomarkers to serve as surrogates for the course of the disease. In a telephone interview with Neurology Today, Aaron Miller, MD, professor of neurology and director of clinical affairs at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at the Mount Sinai Medical Center in New York, discussed the advances and what they mean for practice.

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Investigators have known that MS affects more than only white matter (WM) in the brain. In fact, a 2007 review by Istvan Pirko, MD, assistant professor of neurology at the University of Cincinnati in Ohio, and colleagues pointed out that gray matter (GM) involvement can be detected in the cerebral cortex and deep cerebral nuclei even in the earliest stages (Neurology 2007;68:634–642). Cortical lesions include neurons with demyelinated axons; this may influence virtually all aspects of neuronal function and viability and could have implications for disease progression.

WM pathology plays an important clinical role in MS, but some findings suggest that, at least in some cases, the earliest pathological events in MS occur in the GM. Histological studies suggest that inflammation is less prominent in lesions of GM than WM. GM involvement can be linked to clinical manifestations of MS, including seizures, cognitive dysfunction, physical disability, and fatigue. GM lesions are particularly extensive in progressive forms of MS, so they may correlate with irreversible disability.

Future research should focus on the mechanisms underlying GM damage and therapies that limit GM and WM damage, Dr. Miller said. These findings “may have implications for how we follow patients with early MS and provide insight into the process leading to cognitive impairment,” he added.

In another paper, Roberta Magliozzi and colleagues — at the Department of Cell Biology and Neuroscience of the Istituto Superiore di Sanità in Rome, Italy, and Department of Cellular and Molecular Neuroscience at the Imperial College Faculty of Medicine in London, UK — studied B-cells in postmortem brain tissue from 29 patients with secondary-progressive MS and seven with primary progressive MS (Brain 2007;130:1089–1104).They discovered B-cell follicles in the cerebral meninges of 12 patients with secondary progressive MS, but none in those with primary-progressive MS.

B-cell follicles were correlated with younger age at symptom-onset, more severe cortical pathology, and earlier irreversible disability and death. Indeed, follicle-positive women died some 20 years sooner than follicle-negative women with secondary progressive MS. “This study is the first to show an association between ectopic lymphoid tissue formation, clinical course, and extent of tissue destruction in the target organ of a chronic inflammatory CNS disease,” the authors wrote. Identifying the antigenic stimuli driving this process could shed light on the immune mechanisms responsible for the CNS injuries of MS.

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Another paper examined the role of infection in MS. Jorge Correale, MD, of the Raúl Carrea Institute for Neurological Research in Buenos Aires, Argentina — and co-investigators prospectively studied T-cell responses and assessed the risk of an MS relapse after a systemic infection in 60 patients with relapsing-remitting MS (Neurology 2006;67:652–659). There were 127 infections in 53 patients; 52 infections (41 percent) “were clearly associated with an exacerbation” of MS. The culprits were evenly divided among viruses and bacteria. Infection-related exacerbations produced more severe and sustained neurological deterioration than episodes not associated with infections. Systemic infections were also linked to increased MRI evidence of activity — from the number of gadolinium enhancing lesions observed — and greater activation of T cells on assays.

This research “extends previous observations by relating the phenomenon [that infection may cause MS relapses] to specific immunological changes,” Dr. Miller explained. “Unlike some earlier studies, these authors found a relationship with bacterial infection, specifically urinary tract infection.”

In another study from the same lab, Dr. Correale and colleagues hypothesized that parasitic infections may protect against allergies and autoimmune diseases by inducing T-cells to produce interleukins (IL) and transforming growth factors (TGF), among other protective agents (Ann Neurol 2007;61:97–108). They followed 12 patients with relapsing-remitting MS and eosinophilia attributed to intestinal parasitic infection, comparing them to 12 uninfected MS patients and 12 healthy controls.

Over the 4.6-year follow-up period, infected MS patients had significantly fewer relapses, minimal changes in disability scores, and lower MRI activity than uninfected MS patients. Infected patients also had higher levels of certain cytokines, such as IL-10 and TGF-beta, for example. The authors concluded that parasitic infection has a paradoxical salutary effect on MS patients through autoimmune downregulation.

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Ludwig Kappos, MD, of the Neurology-Neurosurgery Department at the University Hospital in Basel, Switzerland, and colleagues, reported that fingolimod showed promise in a year-long, double-blind, placebo-controlled proof-of-concept study (N Engl J Med 2006;355:1124–1140). Fingolimod binds to the sphingosine 1-phosphate receptor-1 on some circulating lymphocytes, reversibly trapping the cells in lymph nodes. This lowers the number of active T-cells circulating to the CNS, and decreases neuroinflammation and myelin damage in the brain and spinal cord.



For the first six months of the study, patients received fingolimod in a daily dose of 1.25 mg or 5.0 mg, or a placebo, and in month seven, they could choose to participate in an extension phase for another six months; 255 patients completed the first part of the study, and 227 completed the extension phase.

Patients who received the drug in either dose had significantly fewer gadolinium-enhanced MRI lesions than patients taking placebo, as well as significantly fewer relapses.

Lesions and relapses remained low during the extension phase, and decreased in patients who were initially in the placebo group. The investigators concluded that a single daily dose of oral fingolimod produces “significant and rapid improvement in MRI measures of inflammation and in relapse-related clinical end points in patients with relapsing multiple sclerosis.” However, side effects included elevated liver enzymes, reduced heart rate, and respiratory problems, and the authors cautioned that the drug must be tested in larger, longer-term trials before it is ready for general clinical use.

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Investigators are searching for a marker that could provide information about prognosis, but several papers demonstrate the difficulty of that quest. Jens Kuhle, MD, and colleagues in the Department of Neurology at University Hospital in Basel, Switzerland, could not reproduce a widely heralded report of the predictive value given by serum levels of antimyelin antibodies in patients who had experienced a clinically isolated syndrome suggestive of MS (N Engl J Med 2007;356:371–378).

In the Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) trial — a double-blind, placebo-controlled, multicenter trial sponsored by Schering — investigators assessed the ability of interferon beta 1-b to prevent patients who had a clinically isolated syndrome from progressing to full-blown MS.

Investigators analyzed serum from 462 patients for two kinds of antibodies to myelin, anti-myelin oligodendrocyte glycoprotein (anti-MOG) and anti-myelin basic protein (anti-MBP). During a two-year follow-up period, 150 patients (32 percent) were diagnosed with clinically definite MS and 331 (72 percent) with MS according to the McDonald criteria, but there was no relationship between serum antibody positivity and the risk of an MS diagnosis.

The authors state that these findings provide definitive evidence against using anti-MOG or anti-MBP as indicators of a patient's prognosis. “This negative paper confirms the findings of other single-center studies that failed to support the earlier observations, but it is important because of the critical nature of our search for biomarkers in MS,” Dr. Miller said.

He offered three other papers that underscore the difficulty of predictions for MS. Ana-Luiza Sayao, MD, and colleagues at the University of British Columbia in Vancouver, Canada, recounted a 10-year follow-up of 200 patients initially diagnosed with “benign” MS, defined as having an Expanded Disability Status Scale (EDSS) score less than or equal to 3 at 10 years — indicating moderate disability — after diagnosis (Neurology 2007;68:496–500). EDSS scores at 20 years was the primary outcome.

The bottom line: “neither an EDSS score <3 nor an EDSS score <2 [indicating mild disability] adequately represented ‘benign MS’ because an appreciable proportion [21.3 percent] of patients progressed in disease severity,” the authors wrote. “Appropriate and reliable criteria to identify which patients with MS remain with mild disability over the long term have yet to be determined.” This paper “emphasizes the unpredictability of MS by demonstrating that even those with ‘benign’ MS for 10 years still have a substantial risk for developing significant neurological disability,” Dr. Miller warned. “It behooves neurologists to be cautious about painting overly optimistic pictures for patients with MS, while maintaining a hopeful attitude. The fact that the disease is unpredictable must be emphasized when discussing the importance of treatment for patients with MS.”

The second paper supports that point. In a rigorous literature review, Annette Langer-Gould, MD, an instructor in the Department of Neurology and Neurosciences at Stanford University, and colleagues, found that factors traditionally deemed prognostic by many clinicians, such as female sex, optic neuritis, and sensory symptoms, actually have little if any relationship to prognosis. Sphincter symptoms at onset and incomplete recovery from the first attack were consistent predictors of a poor prognosis (Arch Neurol 2006;63:1686–1691).

The third study yielded more definite findings. Barcelona investigators Mar Tintoré, MD, of the Universitat Autònoma de Barcelona, and colleagues followed 175 patients who had brain MRI within three months of a first clinically isolated syndrome, with follow-up examinations at 12 months and five years (Neurology 2006;67:968–972).

In a median seven-year follow-up of 156 patients, investigators reported that baseline MRI could determine the risk of converting to clinically definite MS, and correlated with the severity of disability at five years.

“All patients with clinically isolated syndromes should be followed vigilantly for clinical or MRI changes that indicate conversion to definite MS,” Dr. Miller pointed out. “This study, as well as others on MRI in clinically isolated syndromes, may help physicians enable patients to better understand the risk of conversion to MS and to decide whether to begin treatment with disease-modifying therapy at this early stage.”

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Dr. Aaron Miller noted that several promising trials of monoclonal antibody therapies were described at the AAN annual meeting this year, including “impressive data” from a placebo-controlled phase 2 trial of rituximab and a phase 2–3 trial of alemtuzumab, in which alemtuzumab showed a significantly greater reduction in relapse rate and MRI lesions, compared to subcutaneous interferon beta-1a. (See Neurology Today's “Preliminary Studies are Encouraging for Rituximab in MS,” May 1; “Alemtuzumab Improves Disability in MS Patients and Prevents Relapse but Platelet Counts Should Be Monitored,” May 15.)

Clinicians are excited about these agents because they seem to be more effective than other available therapies for MS, Dr. Miller said, and because they can be taken less often, sparing patients frequent self-injections.

However, Dr. Miller warned that questions remain about safety, especially with alemtuzumab, which was associated with six cases of idiopathic thrombocytopenic purpura in the phase 2–3 trial. A third monoclonal antibody, natalizumab, has already been approved for relapsing MS in patients who do not respond well to other disease-modifying treatments.

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• Pirko I, Lucchinetti CF, Bakshi, et al. Gray matter involvement in multiple sclerosis. Neurology 2007;68:634–642.
    • Magliozzi R, Howell O, Aloisi F, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associated with early onset of disease and severe cortical pathology. Brain 2007;130:1089–1104.
      • Correale J, Fiol M, Gilmore W. The risk of relapses in multiple sclerosis during systemic infections. Neurology 2006;67:652–659.
        • Correale J, Farez M. Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol 2007;61:97–108.
          • Kappos L, Antel J, Radue EW, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006;355:1124–1140.
            • Kuhle J, Pohl C, Sandbrink R, et al. Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 2007;356:371–378.
              • Sayao A-L, Devonshire V, Tremlett H, et al. Longitudinal follow-up of “benign” multiple sclerosis at 20 years. Neurology 2007;68:496–500.
                • Langer-Gould A, Popat RA, Nelson LM, et al. Clinical and demographic predictors of long-term disability in relapsing-remitting multiple sclerosis. Arch Neurol 2006;63:1686–1691.
                  • Tintoré M, Rovira A, Montalban X, et al. Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 2006;67:968–972.
                    ©2007 American Academy of Neurology