SEATTLE—The Decade of the Brain saw major advancements in the understanding of the pathogenesis and treatment of multiple sclerosis (MS). At the 124th Annual Meeting of the American Neurological Association, Richard M. Ransohoff, MD, reviewed the mounting evidence that MS is a continuously active disease, even during clinically quiet periods. He further proposed that new monitoring techniques, such as measurement of brain atrophy, will become a routine part of MS management.

"We think of MS fundamentally differently from how we thought of it at the beginning of the previous decade," said Dr. Ransohoff. Advanced imaging techniques and traditional histopathology have helped to uncover new mechanisms of disease pathology. This has led to a paradigm shift that has an impact on our approaches to pathogenesis, monitoring, and treatment of MS, he continued. Dr. Ransohoff is from the Department of Neurosciences and Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation.

ACTIVE ALL THE TIME

Magnetic resonance studies have led to the discovery that MS is a continuously active process in most patients. "We have all known for years that there are many more lesions in an autopsied brain than can be accounted for by attacks that were observed during life. What was not known was when those lesions occurred," Dr. Ransohoff pointed out.

Serial gadolinium-enhanced magnetic resonance images have shown that many new lesions occur every month. "Because most resolve within a month, the new lesions and total lesions for most months are about the same," Dr. Ransohoff said. One patient, for example, had only two clinical attacks over a period of 18 months despite dozens of new lesions. "I still find it shocking that this disease is so active despite apparent clinical quiescence in patients who seem perfectly fine and barely troubled by their disease," Dr. Ransohoff commented.

MYELIN ATTACKED ON TWO FRONTS

Myelin injury, the hallmark of MS, has been the center of study for many years. Myelin pathology has been clearly linked with autoimmune processes. Myelin-specific antibodies have been identified, and recently, macrophages have been implicated as the major effectors of the T-cell mediated process. Myelin injury can also occur without significant inflammation. "In these lesions myelin is gone not because it has been removed by action of the immune system but because the oligodendrocytes have died," Dr. Ransohoff explained.

Axonal damage has also been found in all stages of MS and in most lesions. Immunostaining has revealed abnormal axons in the demyelinated segments and "large, bulb-like structures that are termini of transected axons." Spectroscopic studies, Dr. Ransohoff continued, have identified "extremely dynamic" changes in axonal N-acetyl aspartate (NAA) within acute MS lesions. Abnormal levels of NAA were also seen in normal-appearing white matter around MS lesions and within the corpus callosum.

Loss of myelin and oligodendrocytes, along with axonal injury, provide a pathologic substrate for irreversible disability in patients with MS. In light of these findings, there is a potential need for early and continuous neuroprotective treatment, Dr. Ransohoff said. "This suggests that MS, in addition to being continuously active, is a destructive process in most patients, most of the time."

MR FOR MS

The monitoring of disease activity, disease burden, and disease type in patients with MS has been improved in recent years by the availability of MR scanning techniques. "There has been a remarkable coherence between MR findings and classic pathology studies of MS," Dr. Ransohoff noted. The two major indices of disease activity are appearance of T-1 lesions that are first dark and then bright or enhanced and the occurrence of new or enlarging T-2 bright lesions. "These are now commonly accepted indications of active disease, both in clinical practice and in clinical trials," Dr. Ransohoff explained.

Whole-brain atrophy is also being measured using advanced post-processing of conventional FLARE images. This method calculates a brain parenchymal fraction from the volume of the parenchyma divided by the volume of the head, which normalizes for the head size. In healthy controls this is a narrowly distributed function; on average, 87.5% of the head is occupied by the brain regardless of sex or age in 20- to 50-year-olds, Dr. Ransohoff explained. One particular study of patients with relapsing-remitting MS over a mean of five years (mean age, 35 years) reported significantly reduced brain parenchymal fractions, averaging 83%. "These patients with mild MS already had significant atrophy. This is five standard deviations from the mean," Dr. Ransohoff pointed out. "Unlike healthy individuals, they were losing one-half percent of brain a year." Magnetic resonance imaging techniques are now considered "gold standard" tools for monitoring MS disease activity, severity, and response to therapy, according to Dr. Ransohoff. A task force of the National Multiple Sclerosis Society developed improved complementary methodology for clinical assessment during therapeutic trials, Dr. Ransohoff added.

EARLY TREATMENT?

Treatment has been successful in managing MS over the short term. However, it is unclear whether these short-term benefits can translate into long-term reduction in disability. An immediate question, said Dr. Ransohoff, is: "Can we prevent or delay onset of progressive MS?"

According to the continuous MS paradigm, the clinical progression of disability implies a threshold of tissue injury, as opposed to a switching process. "When a threshold of tissue destruction has been exceeded, the patient is in secondary progressive disease," Dr. Ransohoff explained. Closely monitoring patients' rate, extent, and location of central nervous system atrophy could help determine this threshold, he added.

Rudick, Fisher, and their colleagues recently completed a study that supports early treatment for relapsing-remitting MS. They found no differences between placebo and interferon-beta treated patients during the first year. However, there was a 55% reduction in progression of atrophy (as shown by changes in brain parenchymal fraction) in treated patients during the second year of treatment. "We consider this to be highly encouraging and to suggest that early treatment modifies the risk of later disabling disease," Dr. Ransohoff said.

Other treatments that are currently under development include small-molecule antagonists of leukocyte trafficking, blockers of T lymphoctye co-stimulatory signaling, and innovative approaches such as T-cell and DNA vaccines. "Given the current pace, we may hope that the next 10 years will be as productive as the Decade of the Brain," Dr. Ransohoff concluded.

—Janis Kelly
Contributing Writer

Suggested Reading

Trapp BD, Ransohoff R, Rudick R. Axonal pathology in multiple sclerosis: Relationship to neurologic disability. Curr Opin Neurol. 1999;12:295-302.

Rudick RA, Fisher E, Lee JC, et al. Use of the brain parenchymal fraction to measure whole brain atrophy in relapsing-remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology. 1999; 53:1698-704.

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