At AAN's biggest meeting: MS holds its own.

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The 1991 Annual Meeting of the American Academy of Neurology, held in April, showed the largest attendance to date. More than 5,000 neurologists, neuro-scientists, nursing specialists and exhibitors thronged the meeting rooms and hallways of the Boston convention site.

Presentations at the academy dealt with epilepsy, spinal cord injuries, autism, Parkinson's disease, stroke, migraine, amytrophic lateral sclerosis, and a score of other neurological disorders. Among the wealth of presentations, multiple sclerosis more than held its own. No less than 75 courses, lectures and posters focused on the etiology, diagnosis and management of the disease. As with many meetings of this sort, much of the work reported presented stepwise increments in our knowledge about MS. Controversies were raised (and not completely resolved), new data were presented, and other data were confirmed.

A small sampling of the MS presentations is encapsulated below.

CLINICAL TRIALS OF MS THERAPIES

Mitoxantrone, a possible candidate; Cytoxan controversy continues Mitoxantrone, an immunosuppressive drug that has proved effective in a number of cancer trials was tested for safety in a small, uncontrolled trial of chronic progressive MS. After a year of study, where efficacy was not examined, adverse reactions proved mild and readily managed and patients did not appear to worsen any more rapidly than prior to the study. In the view of the principal investigator, Dr. John Noseworthy of Mayo Clinic in Rochester, Minn., mitoxantrone may be a candidate for a controlled clinical trial to assess its value as well as its continuing safety in progressive MS; trials of this agent are also under way in Europe.

The conference provided a special forum for the discussion of the use of cyclophosphamide Cytoxan) in treating progressive MS. Dr. Howard Weiner of Brigham and Women's Hospital in Boston presented data showing that booster shots of intravenous Cytoxan, given every two months over two years after the initial Cytoxan treatment, allowed a subgroup of patients to become more stable than those who received no boosters. Dr. George Ebers from the University of Western Ontario reported that people who were treated with Cytoxan for as long as 22 weeks did not do statistically better when monitored for up to three years than people who were not treated. (His study did not address the issue of booster shots.)

While the issue was not resolved, both groups agreed that (1) a single initial dose of Cytoxan gives no prolonged benefit; (2) the toxicities of the agent preclude its widespread use; and (3) future therapeutic trials should focus on drugs that are more specific in terms of immune function and have less potential toxicities.

COGNITIVE DYSFUNCTION

Knowledge expands

Cognitive dysfunction occurs in about 40%-50% of all patients with MS. Society grantee Stephen Rao and colleagues at the Medical College of Wisconsin conducted a three-year study of 59 MS patients and 60 healthy people to see whether cognitive disorders increased during that time period. By the end of three years the MS patients had become more physically disabled, but their cognitive functions had not deteriorated to an appreciable extent. Dr. Rao will look for an explanation for this phenomenon in further studies using magnetic resonance imaging (MRI) to correlate changes in brain lesions with cognitive test data.

Emotional problems are often associated with MS. Scientists from Viale University in Rome found no particular correlation between depression and level of cognitive dysfunction or appearance of lesions on MRI scans. They did, however, link depression with level of physical disability, and they concluded that depression in mild MS could be a result of emotional reactions to physical impairment rather than a direct result of lesions caused by the disease. However, in a different study, emotional problems were linked to disease severity in MRI lesions. Clinicians at Jefferson Medical College in Philadelphia examined mood state in 40 patients and found 20% euphoric, 30% depressed, 17.5% mixed euphoric and depressed, and 32.5% free of emotional problems. The mixed-mood state occurred most often in patients with most severe disease, largest number of MRI lesions, and most significant cognitive deficits.

FATIGUE

Investigation into management grows

A series of five separate presentations dealt with issues of sleep disruption and fatigue in MS. Groups from the Medical College of Wisconsin, the Oregon Health Sciences University, and Georgetown University reported that bladder problems, periodic leg movements, spasticity and depression often contribute to disruption of sleep patterns and that this in turn can contribute to the often overwhelming fatigue typical of MS. Agents used to treat bladder dysfunction, spasticity and depression were proposed to help alleviate, indirectly, some of the MS fatigue.

In related work, a group from the New York University Medical Center in New York reported that the drug selegiline (also called L-deprenyl, a drug used in Parkinson's disease to help increase amounts of the brain chemical dopamine) helped to lessen fatigue in uncontrolled studies of MS patients. Still untested is the drug's benefit compared with that of other widely used anti-fatigue agents, and its possible side effects in MS. Finally, investigators at the University of California at Irvine have examined parts of the central nervous system to see which are most affected by fatigue. No changes in perception of sensory information or in muscle response were observed; however, "central processing" of information (the transfer of sensory input to a "motor" response) does appear to be affected in fatigued MS patients. These findings may lead to a better understanding of the fatigue state in multiple sclerosis.

EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS RESEARCH (EAE)

Its role remains important EAE has some similarities to MS and often serves as a model for the human disease. Many new treatment approaches come from studies of mice, rats and guinea pigs in which this MS-like disease has been induced. In one study, Israeli scientists found bone marrow transplants from healthy mouse donors so successful in combating EAE that, in their view, the technique deserves to be considered for use in human demyelinating autoimmune conditions. At Hadassah University Hospital, EAE-primed mice treated with total body irradiation and bone marrow transplants were clear of EAE signs for up to three months. In another group, bone marrow transplants given two days after EAE began led to complete recovery in 75% of the animals. On the other hand, all untreated control mice developed severe paralysis characteristic of the disease. However, the feasibility, practicality and safety of such an approach in MS is questionable and has not been tested. Tumor necrosis factor (TNF) is a cytokine (a type of soluble protein) produced by cells of the immune system that is known to induce demyelination at the same time that it regulates immune-cell traffic into the brain.

Theorizing that blocking TNF might be a way of keeping harmful immune cells out of the brain, a team from Albert Einstein College of Medicine injected antibodies against TNF into mice already primed to develop EAE. In three separate experiments, no animals treated with anti-TNF developed EAE or showed any central nervous system changes. Control animals, conversely, developed EAE. Drs. Krzysztof Selmaj, Anne Cross and Cedric Raine, all Society grantees, believe this anti-cytokine therapy could open up new avenues for MS treatment. Transforming growth factor beta I is a different cytokine with demonstrated immunosuppressive effects on T cells. Dr. Leonard Johns and Society grantee Subramaniam Sriram of the University of Vermont, with Dr. Kathleen Flanders at the National Institutes of Health, administered the growth factor to mice that were later inoculated to develop EAE. The result was a reduced incidence of disease and less inflammation and demyelination in the animals' brains and spinal cords. Lab studies on control animals that had recovered naturally from EAE showed that the same transforming growth factor was present in their brain lesions. The scientists believe that this cytokine may both protect animals from EAE and help them recover from it, possibly paving the way for its use in the treatment of human autoimmune disorders. Dr. Howard Weiner and researchers at Brigham and Women's Hospital in Boston produced a striking suppression of EAE in mice by feeding them myelin basic protein. Such "oral tolerance" to myelin is a potentially safe and easy-to-use therapy for MS. Initial human studies with whole myelin are under way now.

T-CELL IMMUNOLOGY Limited T-tymphocyte response raises possibilities and controversies

The conference included several presentations on what is currently known about specific immune abnormalities in MS. Publications over the past year have suggested the existence of a relatively limited number of identified T-lymphocyte immune cells in the brain tissue and blood of people with MS. These findings were very exciting, raising the possibility that, because of their limited number, it might be easier to target specific kinds of immune therapy against these identified T-lymphocytes. However, recent reports by research groups in the U.S., Canada and Europe, suggest that our optimism may have been premature. Additional studies of MS patients and healthy individuals have produced questions about just how restricted the immune response really is, especially among different patients with the disease. New technologies are bringing very rapid changes in this field, and the whole topic is controversial. Nonetheless, some groups are beginning to use the concept of limited Tlymphocyte responses in MS as a basis for developing new types of therapy. We will surely be hearing more about this work in the future.

Stephen Reingold, Ph.D.

Vice President Research and Medical Programs