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On Multiple Sclerosis
Advances in Monitoring, Genetics, and Treatment

Important findings in the monitoring, genetics, and treatment of multiple sclerosis (MS) have been made in the past year, according to Gary Birnbaum, MD, director of the Multiple Sclerosis Treatment and Research Center at the Minneapolis Clinic of Neurology, Ltd.

In an interview with Neurology Today, Dr. Birnbaum described research progress and why he thinks it is important for clinicians.

FOLLOWING THE LESIONS

The power of MRI in predicting the clinical course of MS was demonstrated in a study by Leonara K Fisniku, MD, and colleagues at the Institute of Neurology of University College London in the UK. They have been following patients who initially had clinically isolated syndromes such as optic neuritis and spinal cord syndromes, between 1984 and 1987, and have already published follow-up studies at one, five, 10, and 14 years. These syndromes are frequently the first clinical signs of MS, although not all patients with MS develop them, and the degree of disability is highly variable in those who do, the authors explained in the March 2008 issue of Brain.

The investigators used MRI to assess the volume of white matter lesions on these patients at baseline and 10 and 14 years out. Of 107 people, 67 (63 percent) developed clinically definite MS: 60 of 73 (82 percent) with abnormal baseline MRIs, and seven of 34 (21 percent) whose baseline scans were normal. At all time points, lesion volume correlated with disability status and functional capacity. Lesion growth was significantly faster in patients with secondary progressive multiple sclerosis (SPMS), than those with the relapsing-remitting form (p<0.001).

The authors concluded that baseline MRI findings predict the development of clinically definite MS; disability at 20 years is correlated with the size and change of lesion volumes at earlier time points; lesion volume increases for at least 20 years in patients with relapsing-onset MS; and lesions grow three times faster in patients who develop the secondary progressive form of MS than those who have the relapsing-remitting form.

“These data provide strong evidence for the predictive power of MRI and for the value of monitoring MRI in patients with MS on active therapy as an additional measure of treatment efficacy,” Dr. Birnbaum said.

IN THE GENES

David A. Hafler, MD, Breakstone Professor of Neurology at Harvard Medical School, and colleagues from an international consortium of MS investigators, used DNA microtechnology to perform genomewide association scans on nearly 20,000 people and found variations in DNA sequences in those with MS compared to those of healthy control subjects.

Single-nucleotide polymorphisms (SNPs) within the interleukin-2 receptor alpha gene (IL2RA) were strongly associated with MS, along with a SNP in the interleukin-7 receptor alpha gene (IL7RA), and multiple SNPs in the HLA-DRA locus. The authors concluded that these alleles are heritable risk factors for MS, although they accounted for only 2 percent of the risk.

“Even though the genes they found contribute only marginally to disease susceptibility, these techniques may provide insights into the large number of genes that determine, not only susceptibility, but also disease course and response to treatment,” Dr. Birnbaum said. (For more on the original study, see Neurology Today's “New Risk Genes for MS Identified — What it Means for Future Research,” Sept. 4, 2007.)

FOLLICULAR FINDINGS

An April 2007 report in Brain detailing the postmortem analysis of ectopic meningeal B-cell follicles in brains from 29 patients with SPMS and seven with primary progressive MS (PPMS) has furthered understanding of MS pathogenesis, Dr. Birnbaum told Neurology Today.

Through detailed immunohistochemistry and morphometry, Roberta Magliozzi, MD, and colleagues, examined the location of the follicles to determine their association with clinical and neuropathological features. They detected no follicles in the meninges of the PPMS patients, but observed follicles in the meninges entering the cerebral sulci in 41.4 percent of cases with SPMS.

Patients with follicles had more numerous and severe grey matter lesions, compared to patients with no follicles. The follicles were always adjacent to subpial lesions, suggesting a causal relationship between them and cortical damage.

Perhaps most important, the median age of symptom-onset among follicle-positive (F+) SPMS patients was 23.5 years, compared to a median of 34 years in follicle-negative (F−) patients with SPMS (p=0.0019). The median ages at death also differed significantly: 42 years for F+ patients and 55 years for F− (p=0.0003).

These findings suggest that an aggressive inflammatory environment is hospitable to follicular development. Dr. Birnbaum explained that this paper “is important, not only because it demonstrates the extent and importance of grey matter involvement in the MS-associated disability, but also because it reveals a pathogenic process distinct from that seen in the white matter, one involving a major component of B cells.” He added that it is also the first to show an association between ectopic lymphoid tissue formation, clinical course, and extent of tissue destruction in the target organ in a chronic, inflammatory disease of the CNS.

B-cell follicles also may be associated with Epstein-Barr virus (EBV) infection, long a suspected culprit in the development of MS. In an analysis of postmortem tissue from 22 MS cases with various disease courses, Barbara Serafini, MD, and colleagues at the Italian National Institute of Health in Rome observed that the accumulation of infected B cells and plasma cells in the meninges and perivascular compartment of white matter lesions is a common feature of MS. What's more, the number of EBV-infected cells correlated with the degree of brain inflammation.

This finding appears to be unique to MS, the authors wrote in the Nov. 26, 2007 issue of the Journal of Experimental Medicine, as EBV infection of brain-infiltrating cells has not been observed in other inflammatory neurological disorders. They also reported that, in patients with secondary progressive MS, ectopic meningeal B cell follicles were significant sites of EBV persistence, supporting the notion of a direct link between EBV infection and B cell dysregulation in this disorder.

“This article demonstrates a potential role for EBV in the pathogenesis of MS, and also a potential role for the development of the B cell follicles demonstrated in the study by Magliozzi, et al.,” Dr. Birnbaum said.

REFERENCES

Fisniku LK, Brex PA, Miller DH, et al. Disability and T2 MRI lesions: A 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 2008;131(Pt 3):808–817.
The International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007;357:851–862.
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.
Serafini B, Rosicarelli B, Aloisi F, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exptl Med 2007;204(12):2899–2912.