October 15, 2000
Rohit Bakshi, MD
[Medscape Neurology, 2000. © 2000 Medscape, Inc.]
The Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) celebrated its fifth anniversary at its annual meeting in Boston, Massachusetts. ACTRIMS provides a forum for basic scientists, clinical researchers, and clinicians to exchange information and network with colleagues to further the science and treatment of multiple sclerosis (MS) and related diseases. The lecture program is constructed each year to provide information on both basic research and clinical management issues. Hundreds of professionals came together for this year's meeting in Boston. Recent developments pertaining to the pathophysiology, neuroimaging findings, clinical manifestations, and immunomodulatory treatment of MS were presented at the meeting as highlighted in this summary. Written summaries based on these platform presentations will be published in an upcoming issue of the journal Multiple Sclerosis.
Keynote Address: The New Pathology of MS?
Dr. Hans Lassmann, Professor of Neuroimmunology at the University of Vienna, Austria, focused on the immunology and neuropathology of MS and outlined the basic concepts of the pathology of MS and then discussed newer hypotheses in this field.
Recent studies suggest heterogeneity in the patterns of inflammation, demyelination, oligodendrocyte damage, axonal injury, and remyelination in patients with MS. These findings raise the possibility that different mechanisms of tissue injury may be occurring across a spectrum of patients and thus different therapeutic approaches may be necessary.
Platform Presentations: Original Research Studies
The Role of Cannabis in Reducing Symptoms of MS
Evidence suggests that marijuana (cannabis) or related compounds may improve the symptoms of MS through their binding to cannabinoid receptors in the brain. One study by Consroe and colleagues found that at least one third of patients with MS reported improvement in spasticity, pain, limb spasms, tremor, mood, appetite, fatigue, double vision, sexual function, sphincter function, and memory after smoking cannabis. However, a separate study showed that marijuana may cause acute worsening of posture and balance in patients with spasticity due to MS.
Baker and colleagues, from London, United Kingdom, showed compelling evidence for the effectiveness and mechanisms of cannabinoids in a rat model of MS (experimental allergic encephalomyelitis). First, the investigators showed that excitation of brain cannabinoid receptors improved tremor and spasticity in diseased animals. Second, inhibition of these receptors worsened tremor and spasticity. Third, in areas of tissue damage, spastic animals had elevated levels of endogenous cannabinoid receptor ligands compared with nonspastic animals. Finally, increasing endogenous cannabinoid levels through the use of reuptake inhibitors improved spasticity without stimulating cannabinoid receptors.
This work provides further insight into the mechanisms of action of marijuana in reducing the symptoms of MS. These findings also suggest that the disease-ameliorating potential of the cannabinoid system may be separate from the mechanisms that cause adverse psychological effects. This should aid in the development of drugs targeted to the appropriate pathways that will benefit patients with MS while giving rise to only acceptable side effects.
Cognitive Impairment in MS
Approximately 50% of patients with MS experience cognitive impairment, and more may be affected if subtle deficits are included.[5-11] The typical pattern of cognitive impairment includes slowing of informational processing speed, reduction of new learning capacity, and impaired problem solving.[7-11] Cognitive function appears to play an important role in the quality of life (QOL) of patients with MS. Cognitive impairment in patients with MS is associated with unemployment and social isolation, regardless of the level of physical disability.[12,13] Thus, it is desirable to be able to rapidly and easily recognize cognitive dysfunction in the routine care of patients with MS.
Krupp and associates, from Stony Brook, New York, reported on their experience with the Rey Auditory Verbal Learning Test (RAVLT) to screen patients with MS for cognitive dysfunction. The RAVLT takes only 10 minutes to perform in the clinical setting. This team used a cutoff of a RAVLT score at least 0.5 standard deviations below published norms to identify cognitively impaired patients. Patients showed evidence of impaired functioning on comprehensive neuropsychological testing.
This study indicates that the RAVLT may be a useful bedside test to screen patients with MS for cognitive impairment. Such patients can then be referred for neuropsychological evaluations, cognitive and vocational therapies, and pharmacologic trials of agents that might improve cognition, such as cholinesterase inhibitors.
QOL in MS
Physical disability assessment using the Expanded Disability Status Scale (EDSS) is currently considered the most useful clinical measure of MS disease activity and is the primary clinical outcome measured by physicians. However, EDSS is strongly influenced by limb and gait dysfunction and may be insensitive to other important clinical effects of MS such as fatigue, depression, and sexual and cognitive dysfunction. There is a need for more sensitive clinical measures that assess the behavioral consequences of brain lesions in patients with MS. The QOL scales are comprehensive clinical measures that assess a variety of domains of health from a patient's perspective and reveal a host of impairments in patients with MS compared with healthy populations.[17-19] Miller and colleagues reported results of an interim analysis on the health-related QOL of patients enrolled in MSTRAC, an ongoing nationwide US registry of patients with relapsing MS. Patients completed the Multiple Sclerosis Quality of Life Inventory, which included general disease measures, such as the 36-Item Short-Form Health Survey, which is composed of subscales of Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. The questionnaire was completed by 2690 patients since 1998. Patients with MS had significant impairment in all 8 QOL subscales compared with the general US population or patients with hypertension or diabetes. This study shows that many domains of QOL are adversely affected in MS, highlighting the importance of assessing QOL in the evaluation and treatment of patients with MS.
Gray Matter Involvement in MS: Iron Deposits Detected by Magnetic Resonance Imaging?
Traditionally, MS is thought of as a white matter disease of inflammatory demyelination. However, recent data indicate that MS is a destructive process that includes axonal transection and brain atrophy. It is increasingly recognized that the gray matter is commonly involved, including hypometabolism and direct plaque formation.
A growing body of evidence also indicates that the cortical and subcortical gray matter may develop hypointensities on T2-weighted images (black T2 lesions) that most likely represent pathologic iron deposition. One previous study of 114 patients with MS showed that, in most patients, these hypointensities were present in the thalamus; they were also seen in the putamen, caudate, and rolandic cortex. The degree of hypointensity was related to clinical severity of disease as assessed by disease course, disease duration, and neurologic function (EDSS score).
Previous studies of gray matter black T2 lesions were limited by the use of visual analysis of magnetic resonance imaging (MRI) films, heightening the need for a quantitative study to confirm and extend these findings. I presented results of a quantitative study done by me and my colleagues at the State University of New York at Buffalo, of cortical and subcortical gray matter T2 signal using a computer-assisted approach.
In 60 patients with MS and 50 healthy controls, MRI signal intensities were obtained from T2-weighted images in various gray matter structures. Third ventricular width (a measure of central atrophy) and total hyperintense T2 parenchymal lesion volume were obtained from T2-weighted fluid attenuated inversion recovery (FLAIR) images. T2 intensity was lower in patients with MS than controls in gray matter structures throughout the brain, including the brain stem, basal ganglia, thalamus, and primary motor (rolandic) cortex.
Lower T2 intensity in the thalamus was associated with increasing disease duration, and hypointensity in substantia nigra, thalamus, and caudate was associated with secondary progressive clinical course. Lower T2 intensity in substantia nigra, thalamus, caudate, and globus pallidus was associated with increasing third ventricular width, and hypointensity in substantia nigra, thalamus, caudate, putamen, rolandic cortex, and globus pallidus was associated with increasing total hyperintense parenchymal lesion volume. Most importantly, stepwise regression indicated that T2 hypointensity in thalamus was the strongest predictor of secondary progression and T2 intensity in putamen and caudate predicted physical disability (EDSS score), but total hyperintense parenchymal lesion volume and third ventricular width did not predict either of these.
This study provides convincing evidence that patients with MS have widespread gray matter T2 hypointensity that is associated with physical disability, clinical course, central atrophy, and total hyperintense parenchymal lesion volume. Further study is warranted to determine the pathologic significance of the black T2 lesions, including the cellular localization of iron deposits that may be correlated with the MRI findings. It would also be of interest to determine if the black T2 lesions worsen over time in patients with MS who are accumulating disability.
Whether the black T2 lesions will be helpful in diagnosing MS and predicting long-term outcome is not known. If iron deposition plays a direct role in the pathogenesis of MS, then this would open a new avenue for the development of therapies.
Featured Speakers Sessions
Manipulating the Bone Marrow: Potential Benefit in MS?
Dr. Mark Freedman, from Ottawa, Ontario, discussed how the immune system contributes to the pathogenesis of MS. He first outlined the various targets for immunotherapy in MS: T cells, macrophages/microglia, natural killer cells, and B cells. Immunosuppressive therapies, such as total body irradiation, cyclophosphamide, and mitoxantrone, are limited by their toxic effects and inability to induce complete remission. Because autoimmune processes are thought to play an important role in the pathogenesis of MS and because the immune system arises from hematopoietic cells in the bone marrow, there is rationale for the use of stem cell therapy. He discussed the procedures involved in stem cell transplantation, including harvesting, immunoablation, and reconstitution.
Dr. Richard Burt, from Chicago, Illinois, gave an overview of the role of stem cell therapy in the treatment of experimental and human MS. Dr. Burt's group began the study of autologous hematopoietic stem cell transplantation (HSCT) in MS in 1993. Before performing this treatment, stem cells must be harvested from the patient's bone marrow or peripheral blood. The peripheral blood collection may be necessary to enrich the cells that are obtained from bone marrow. The infusion of the stem cells is preceded by high-dose chemotherapy and/or radiation therapy to maximally suppress the patient's immune cells.
Experimental MS in animals (experimental autoimmune encephalomyelitis) can be cured by HSCT if the treatment is started early in the disease process. Dr. Burt has used HSCT in 18 patients with secondary progressive MS and high disability. The treatment was not associated with mortality or significant morbidity. Results are preliminary at this time, but the findings suggest a significant reduction in MRI progression and a slight slowing of clinical progression. Dr. Burt cautioned that, although the results are encouraging, further study is necessary to fully evaluate the role of HSCT in MS.
Dr. Athanasios Fassas, from Thessalonika, Greece, discussed his group's experience with the use of HSCT in 24 patients with progressive forms of MS who had moderate to severe disability. Most of the patients remained clinically stable or improved after HSCT, whereas 5 continued to progress. However, most patients eventually developed relapse or progression months or years after initial improvement, indicating that HSCT had only a temporary benefit.
Dr. Fassas concluded that further studies are warranted to evaluate bone marrow transplantation strategies in patients with MS. The panel agreed that multicenter, randomized, double-blind, controlled trials will be necessary to fully appreciate the role of HSCT and that patients with less severe forms of MS should be considered for these studies.
Rohit Bakshi, MD, http://www.drbakshi.com/, is a staff neurologist and multiple sclerosis specialist at the State University of New York at Buffalo.