A Report on the Latest Research in Multiple Sclerosis Diagnosis and Treatment
This report was reviewed for medical and scientific accuracy by Andrew Goodman, MD , Department of Neurology, University of Rochester Medical Center, New York.
EDITORIAL: THE TENTH MEETING OF THE EUROPEAN NEUROLOGICAL SOCIETY MULTIPLE SCLEROSIS SESSIONS
Lawrence Jacobs, MD, Professor of Neurology at Buffalo School of Medicine and Biomedical Sciences, State University of New York, Head of the Department of Neurology at Buffalo General Hospital, New York
The major theme of the Multiple Sclerosis sessions at the 2000 European Neurological Society Meeting was the importance of early diagnosis and treatment of MS patients.
Two recently completed prospective studies found beneficial effects of interferon beta-1a (IFNЯ-1a) treatment with patients who experienced symptoms of a first demyelinating attack and also had "clinically silent" MS brain lesions revealed by MRI examination. Such patients are known to be at high-risk for a second clinical attack and the diagnosis of definite MS within one to four years. They are also at risk for repeated bouts of "clinically silent" inflammation, demyelination, axonopathy, and even brain atrophy before the second clinical attack occurs. Active treatment significantly reduced the occurrence of the second attack (relapse) and MRI evidence of brain disease compared to placebo in both studies, but the magnitude of the effect was greater in the CHAMPS (clinical p = 0.0023, MRI p < 0.0001) than the ETOMS study (clinical p = 0.047). The reasons for the difference in magnitude of the benefits in the two studies (CHAMPS-383 patients; ETOMS-308 patients) are not yet clear and will require analysis of the final published manuscripts.
Both studies, however, provide important rationale for early treatment of such patients even before they have the diagnosis of clinically definite MS by conventional criteria. This concept was fortified by Dr. Barkhof's presentation of MRI sensitivity for detecting "clinically silent" lesions disseminated in space and time by the time of the first clinical symptom. Such patients already have definite MS by MRI and clinical criteria and should be considered for early treatment without waiting for the second bout. Based upon a prospective six-year study of 289 optic neuritis patients in Sweden, Dr. Soderstrom suggests that it may be possible to devise an algorithm of clinical, MRI, CSF, and phenotype characteristics to select patients with first attacks of clinically isolated syndromes who already have MS for early therapy. Dr. Coyle reviewed the pathophysiologic and economic rationale for such early treatment of MS patients.
Investigators from Lille, France found no difference in the effect of Avonex® (interferon beta-1a, Biogen, Inc.) treatment on the accumulation of physical disability after 18 months in 188 patients with mild (EDSS = 3.5) or moderate disability (EDSS = 3.5) at baseline. Research from Lyon, France found a relative dissociation between relapses and progressive accumulation of disability over time among 1,844 consecutive patients seen at the same center during the past 43 years. This careful retrospective study confirms the impressions of many clinicians in their day-to-day care of MS patients. The "gold-standard" of treatment outcome-physical disability-may be quite independent from the occurrence of relapses.
The SPECTRIMS Study Group, reporting on 618 patients, found that patients with relapsing secondary progressive MS were younger, had shorter disease durations, more active disease, and responded better to IFNЯ-1a than patients with non-relapsing secondary progressive disease. This report supported the idea of early treatment in patients who already have the diagnosis of clinically definite MS. A group of investigators from Germany are conducting a prospective study comparing the first year of treatment in 498 patients who received one of the following immunomodulatory agents: Betaseron®, Avonex®, Rebif®1, Copaxone®, or immunoglobulins. The study results, which should be available in April 2000, may provide important information about the comparative benefits and side effects of early therapy in this relatively large group of patients.
Other important observations on MRI in MS were reported. Investigators from Queens Square, UK compared the increasingly popular fFLAIR technique with the more standard spin echo technique for identifying the T2 lesion load. While fFLAIR identified more T2 lesions than spin echo, the T2 lesion load was reliably derived from both techniques and both correlated equally with clinical physical disability. In another study from the UK, Hickman et al. found that approximately 35 percent of T2 hyperintense lesions of the posterior fossa were also hypointense on T1 weighted pulsing in patients with cerebellar ataxia due to MS. The EDSS score correlated significantly with the T1 hypointense lesions, but not the T2 hyperintense lesions. Thus, the T1 hypointense lesions appeared to play a significant role in these patients' physical disability.
Other studies, beginning to assess the effects of IFNЯ-1a therapy on gene expression by DNA arrays, found significant changes in several cytokines, adhesion molecules, and immunological factors produced by injections of IFNЯ-1a. This technology should be useful in further elucidating the mechanisms of IFNЯ-1a actions and monitoring treatment trials in the future.
In another study, mitoxantrone treatment was found to lower most lymphocyte subsets, but to have no effect on immunoglobulin or TNF-alpha levels in the blood.
Dr. Hohlfeld presented a stimulating review of the differing mechanisms of action of IFNЯ and glatiramer acetate (copolymer-1), the two approved therapies for MS, and a logical rationale for management of side effects of the two agents.
AVONEX® (INTERFERON BETA-1a) TREATMENT IN MULTIPLE SCLEROSIS: COMPARISON BETWEEN PATIENTS WITH MILD AND MODERATE DISABILITY
P. Vermersch, J. de Seze, T. Stojkovic, P. Hautecoeur, Hospital Roger Salengro, Lille, France
Trials have revealed that Avonex® (interferon beta-1a, Biogen, Inc.) reduces the annual relapse rate and slows down the progress of relapsing-remitting multiple sclerosis (RRMS). Currently, interferon beta-1a is used to treat patients with RRMS who have an EDSS between zero and 5.5.
In a recent study, Vermersch et al. evaluated the short-term clinical response of patients treated with Avonex®. A comparison was made between patients with mild disability, EDSS = 3.5, and patients with moderate disability, EDSS = 3.5.
One hundred and eighty-eight patients with RRMS participated in the study. One hundred and twenty-four patients had a baseline EDSS = 3.5, and 64 had a baseline EDSS = 3.5. The primary outcome measure was the number of patients in each group with a sustained increase in disability as measured by deterioration in the EDSS. A sustained increase in disability was one that persisted for at least six months during the 18-month follow-up period. The investigators also compared the number of relapses and the number of treatment dropouts.
For the group = 3.5 and the group = 3.5, the relapse rates were 1.29 and 1.24 respectively. For patients with an EDSS = 3.5, the percentage with a sustained increase in EDSS of at least 0.5 was 22.5, and for a sustained increase in EDSS of at least 1.0, the percentage was 16.9. The respective percentages were 29 and 23.4 for patients with an EDSS = 3.5. After 18 months of follow-up, the investigators concluded there was no difference in clinical response between the groups with mild disability and moderate disability.
EVIDENCE OF EARLY DISEASE ACTIVITY: MRI
Dr. Frederik Barkhof, Associate Professor of Radiology, Department of Radiology Academic Hospital, Vrije University, and Director of the Image Analysis Centre, Amsterdam, The Netherlands
Dr. Barkhof stated, "MRI is the most important paraclinical test in the diagnosis of MS." Its unusual sensitivity is such that it can detect clinically silent lesions. By the time many patients present to a clinician, they may have nine or more clinically silent lesions. The MRI reveals a similar pattern of lesion development at the time of, before, and during the early relapsing-remitting phase of clinically definite MS (CDMS). These similar patterns of lesion development suggest that approaches to treatment should be similar.
The white matter lesions shown by MRI are not pathognomonic for MS. Similar lesions can be seen in many other disorders and in aging asymptomatic subjects also. Knowledge of the morphology and topography of these lesions is being used in an attempt to increase the specificity of MRI lesions. Morphologic and topographic features include the following: ovoid shape and a periventricular, callosal, or subtentorial location. The subcortical U-fibers are often involved in MS; juxtacortical lesions are one of the most specific findings in MS and help to differentiate it from hypoxic-ischemic disease.
In spite of the attempts to increase the specificity of MRI lesions, the most statistically robust clinical use of the MRI is to exclude the presence of multiple sclerosis. A normal MR scan has a negative predictive value (NPV) of 95 percent; in contrast, an abnormal scan has a positive predictive value (PPV) of 54 percent.
Spinal cord imaging is performed on patients who have a "cord presentation." Recently, the specificity of spinal cord lesions has been demonstrated. Spinal cord lesions do not occur with aging and the lesions seen in spinal cord compression are different than those seen in MS. Even a single focal spinal cord lesion is more predictive of MS than brain lesions alone.
The MRI can also demonstrate multiple sclerosis to be disseminated in time. At baseline, the scan can demonstrate both gadolinium-enhanced (active) lesions and non-enhanced (old, inactive) lesions. On subsequent scans, the same strategies can demonstrate new lesions as well as old lesions. Finding enhanced lesions at baseline or new lesions on follow-up is an indication that the patient will develop CDMS in the future. In the past, treatment was withheld until the patient reported a second symptom or developed an additional finding. It is now believed that patients with active lesions at baseline or new lesions during follow-up should be considered for early treatment.
FIRST CLINICAL EVENTS-OPTIC NEURITIS
Dr. Mats Soderstrom, Associate Professor and Lecturer in Ophthalmology at the Karolinska Institute and Consultant in Ophthalmology at the Huddinge University Hospital, Stockholm, Sweden
New, effective therapies for multiple sclerosis have mandated the identification of patients at high risk of developing MS after an initial demyelinating episode. The first demyelinating episode may take the form of a clinically isolated syndrome (CIS) involving the brainstem and cerebellum, the spinal cord, or the optic nerves. Although optic neuritis is often related to multiple sclerosis, it is a heterogeneous disorder with more than one etiology. In various studies, the incidence of MS following optic neuritis has been found to range from 11.5 percent to 85 percent. The more modern prospective, follow-up studies show the incidence to exceed 50 percent.
To evaluate the clinical and paraclinical characteristics of acute optic neuritis (ON) presenting as an isolated symptom, a prospective, population-based study was started in Stockholm, Sweden in 1990. This study lasted six years and 289 patients with possible ON were referred. A careful examination revealed 150 of these patients to have acute, monosymptomatic optic neuritis. MRI imaging of the brain and immunological analyses of the spinal fluid were performed. The MRI disclosed at least three high signal lesions in 55 percent of the patients diagnosed with acute, monosymptomatic ON, and the immunological analyses disclosed oligoclonal bands in 72 percent of the patients.
Multivariate analysis was performed on the data and it was found that patients could be divided into two groups. The first group included patients with the onset of ON in the spring, oligoclonal bands in the cerebrospinal fluid (CSF), MRI lesions, and the Dw2 phenotype. Patients in this first group had a probability of 0.93 for the development of MS. The second included patients with the onset of ON from April to December, no oligoclonal bands in the CSF, normal MRI, and a negative Dw2 phenotype. The probability of developing MS for this second group of patients was only 0.02.
MRI abnormalities had value in predicting the progression from CIS to CDMS in several other studies. In aggregate, the studies show that optic neuritis is a heterogeneous condition. The studies also reveal that the majority of patients with optic neuritis have MS and that pertinent studies can identify these patients. Dr. Soderstrom believes that a similar situation exists for other clinically isolated syndromes that are suggestive of MS. It should be possible to devise an algorithm to select patients with CIS for therapy. Diagnosing MS very early will benefit the patient by enabling the deployment of new, effective, disease-modifying therapies. Dr. Soderstrom believes it is probably of equal importance "that MRI and CSF examinations can identify monosymptomatic patients with a very low risk of future MS."
RATIONALE FOR THE EARLY DIAGNOSIS AND TREATMENT OF MS
Patricia Coyle, MD, Professor of Neurology and Director of the Stony Brook Multiple Sclerosis Comprehensive Care Center at the School of Medicine, State University of New York, New York City
Excluding traumatic diseases, MS is the major acquired central nervous system (CNS) disease of young adults. Dr. Coyle emphasized in her presentation that therapy for multiple sclerosis should be started early and continued indefinitely.
Most patients will progress from RRMS to secondary progressive MS. Studies of natural history reveal that approximately 90 percent of untreated patients will develop severe disability within 25 years. Dr. Coyle stated, "In the minority of patients who truly have benign MS (no more than ten percent), it is a retrospective diagnosis. There is no way to assure that a given patient will maintain a benign course."
Pathologic studies reveal axonal damage and CNS atrophy to be early and ongoing disease features and to correlate with disability. Axonal damage reflects inflammation of the CNS and leads to atrophy. Axonal damage underlies the permanent neurologic deficit that inexorably progresses.
Most of the disease activity and CNS damage are clinically silent. Newer diagnostic techniques, such as MRI, show brain lesions to be five- to ten-fold as common as clinical relapses. Normal appearing white matter (NAWM) discloses major abnormalities when sensitive neuroimaging techniques (especially MRI) are used.
Multiple clinical trials confirm the benefits of early treatment. Both the CHAMPS and ETOMS studies document the benefits of early treatment in decreasing inflammation, the number and severity of clinical relapses, disability, and MRI disease measures. The Costar database (study) in Vancouver, British Columbia follows 63 patients who are being treated for MS for periods as long as 11 years. This study not only supports the benefits of treatment, but also shows treatment to be well tolerated.
Current understanding of organ-specific disease supports proactive treatment approaches. Proactive treatment decreases hospitalization and preserves functional capacity (i.e., the ability to work). Medical economic analyses suggest disease-modifying therapy can reduce costs. Current estimates are that MS results in a ten billion dollar annual cost to society. In contrast, the cost with proactive treatment is estimated at 3.5 billion dollars.
In summary, a compelling argument can be made for the early diagnosis, evaluation, and treatment of multiple sclerosis.
THE MECHANISMS OF ACTION AND MANAGEMENT OF SIDE EFFECTS OF ESTABLISHED MS THERAPIES
Professor Reinhard Hohlfeld, MD, Professor of Neurology and the Neurosciences and Director of the Institute for Clinical Neuroimmunology, Ludwig-Maximilians University, Munich, Germany
The currently approved therapies for the treatment of multiple sclerosis, interferon beta (IFNЯ) and glatiramer acetate (GA), differ markedly in their mechanism of action and profile of side effects.
Interferon beta is a cytokine with a broad spectrum of immunomodulatory effects. Some of its more important effects include the following:
• Antiviral effect (postulated) • Antiproliferative effect • Inhibition of immune cell activation • Inhibition of immune cell migration • Regulatory effects on cytokine network
Dr. Hohlfeld discussed in greater detail the actions of IFNЯ as a cytokine. Type I interferon augments nonspecific suppressor T-cell function, blocks the expression by certain cell types of the class II major histocompatibility complex (MHC), stops the secretion of interferon-gamma in some systems, and induces in vivo transcription of the interleukin-10 gene. IFNЯ inhibits the activation of T-cells by CD3 monoclonal antibody.
Interferon beta has several adverse effects: skin necrosis (IFNЯ-1b), flu-like symptoms, and inflammation and abscess formation at the injection site. These side effects usually disappear with continued treatment and seldom necessitate discontinuation of treatment.
Skin necrosis is attributed to interferon beta-1b acting like a cytokine at the site of injection. Flu-like symptoms are managed by non-steroidal anti-inflammatory drugs (NSAIDS), steroids, and decreasing the dose. Inflammation sometimes occurs at the site of injection, for which one percent hydrocortisone ointment is usually an adequate treatment. Finally, abscess formation at the site of injection is treated surgically or with antibiotics.
Several rare side effects include worsening of psoriasis, leaky capillary syndrome, and anaphylactic shock. The leaky capillary syndrome was reported in one patient with a defect in the complement system. Anaphylactic shock has not actually been reported; nevertheless, this is always a possibility in patients treated with a foreign protein.
In comparison, glatiramer acetate is thought to act via production of specific T-suppressor cells, which cross-react with myelin basic protein, thereby mediating "bystander suppression."
Dr. Hohlfeld also discussed several adverse reactions to glatiramer acetate that, with the exception of injection site reactions, seldom cause discontinuation of the drug. Reactions at the site of injection include pain, inflammation, and erythema. The recommended therapeutic agents for injection site reactions are hydrocortisone and antihistamines. If the reaction at the site of injection persists, treatment with glatiramer acetate may need to be discontinued.
Other side effects are "immediate post-injection reaction," transient chest pain, and localized lipoatrophy. The "immediate post-injection reaction" consists of flushing, chest pain, palpitations, dyspnea, urticaria, and throat constriction. Localized lipoatrophy may occur with prolonged treatment. Because of this long-term side effect, it is recommended that the site of injection be varied.
TUMOR-LIKE DEMYELINATING LESIONS IN MULTIPLE SCLEROSIS IN CHILDHOOD: A CLINICAL AND PARACLINICAL FOLLOW-UP STUDY OF TWO CHILDREN
K. Paderova, University Hospital Motol, Prague, Czechoslovakia
The study of the occurrence of multiple sclerosis before the age of ten years was the focal point for a new study including two children with large demyelinating lesions in the brain. Originally thought to be brain tumors, a wide spectrum of diagnostic modalities, including MRI, was used to reach the correct diagnosis.
The first patient is an eight year-old boy who has probable MS. He had a one-half year history of visual impairment and diplopia. An MRI with gadolinium (Gd) enhancement disclosed T2W hyperintense lesions in the parietal and occipital regions bilaterally. Because a brain tumor was suspected, a stereotactic biopsy was obtained. Microscopic examination of the biopsy showed a perivascular infiltrate composed of lymphocytes. MR spectroscopy revealed a low concentration of N-acetylaspartate and increased lactate and inositol. Cytology of the CSF was normal, and no oligoclonal bands were found. Visual-evoked potentials were prolonged. The diagnosis of adrenoleukodystrophy was excluded.
This patient's condition improved after steroid treatment. During a follow-up period of three years, he has experienced one exacerbation of his visual impairment. MRI showed a favorable response to steroid treatment, and this response continues.
The second patient is an 11 year-old girl with clinically definite MS (CDMS). She first presented with an acute disseminated encephalomyelopathy, which spontaneously resolved.
One and a half years later she developed an acute right hemiplegia. MRI showed a large demyelinating lesion in the left hemisphere. Three oligoclonal bands were present in the CSF. Evoked potentials were normal. After steroid treatment for ten days, she improved. She has had no relapses during a two and a half year follow-up. Although these patients had large lesions on MRI, therapy with methyl prednisolone stabilized their condition, thereby, leading to an improved quality of life.
EFFECTS OF INTERFERON BETA-1a ON GENE EXPRESSION BY USING DNA ARRAYS
B. Weinstock-Gutman, M. Ramanathan, L. Nguyen, L. Jacobs, State University of New York at Buffalo
The objective of these investigations was to identify gene expression changes brought about by therapy with interferon beta-1a (Avonex®, Biogen, Inc.) in patients with multiple sclerosis. DNA array technology was used to elucidate specific patterns of gene expression changes.
Recombinant interferon beta-1a has a significant effect on the course of multiple sclerosis; however, its exact mechanisms of action are incompletely understood. DNA array technology complements genetics and genotyping studies, and it can be used to visualize, quantitate, and interpret exhaustive patterns of gene expression. In this study, DNA arrays were employed to examine short-term effects of interferon beta-1a on patterns of gene expression in monocyte-depleted peripheral blood mononuclear cells (PBMC) from patients with MS.
All patients included in this study had relapsing-remitting MS (RRMS) and were deemed appropriate for interferon beta-1a therapy. Before and twenty-four hours after the first I.M. injection (30 ug) of interferon beta-1a, total RNA was obtained from monocyte-depleted PBMC from the MS patients. The mRNA obtained was reverse-transcribed to radiolabelled cDNA, and this cDNA was used to probe a DNA array. A paired t-test was used to determine the effects of interferon beta-1a therapy (percent mean change).
Fourteen patients (ten females and four males) took part in this study. Their mean age was 42.2 years with a standard deviation of 9.23 years. Treatment with interferon significantly increased the expression of the IL-10 receptor, transforming growth factor beta, and colony stimulating factor 3 receptor. In contrast, treatment significantly decreased the expression of tumor necrosis factor 2, lymphotoxin alpha, and lymphotoxin-beta-receptor precursor. Treatment resulted in marked up-regulation of certain adhesion molecules: integrin beta 3 (CD-61), integrin alpha 4b (CD49D), integrin alpha M (CD 11b), CD 1 DC, integrin beta 1 (CD 29), laminin receptor, and integrin beta 2 (CD 18). There was also significant up-regulation of mRNA's for beta-2-microglobulin precursor, immunoglobulin gamma 3 (Gm marker), while T cell surface glycoprotein CD5 precursor, proliferating cell nucleolar antigen p120, and CD81 antigen mRNA, were down-regulated.
The investigators concluded that injections of interferon beta-1a produced significant changes in the expression of several cytokines, adhesion molecules, and immunological factors. In the future, DNA arrays may prove useful to monitor the effects of IFNЯ on gene expression, thereby facilitating an understanding of the mechanisms of action and the nature of the differences seen in clinical response to this therapy.
COMPARISON OF THE EFFICACY OF TWO THERAPIES FOR THE FLU-LIKE SYMPTOMS INDUCED BY AVONEX® (INTERFERON BETA-1a)
C. Belin, V. Sallerin, Avicenne Hospital, Biogen, Bobigny, Nanterre Cedex, France
Avonex® (interferon beta-1a, Biogen, Inc.) is a medication known for its efficacy in reducing the frequency of relapses in multiple sclerosis patients and the progression of demonstrated neurological disability. Flu-like symptoms (FLS) are the most common adverse events experienced by patients receiving Avonex® treatments. FLS occur two to six hours after the injection, subside over one to two days, and tend to lessen as treatment progresses. These symptoms are important in that some of them, e.g., fever, can lead to a temporary aggravation of the symptoms of MS and can ultimately cause some patients to discontinue treatment with Avonex®. The objective of this trial was to compare the efficacy and safety of paracetamol (acetaminophen), ibuprofen (Motrin®, McNeil Consumer), and pentoxifylline (Pentoxil®, Upsher Smith) in alleviating the FLS associated with Avonex®.
This trial was a multicenter, open, randomized, comparative study with two parallel arms. It compared the efficacy and safety of ibuprofen (400 mg P.O. t.i.d.) and paracetamol (1000 mg P.O. t.i.d.) for the treatment of the flu-like symptoms associated with Avonex® treatment in relapsing MS patients. Initially it was planned to include a third arm (pentoxifylline); however, this was cancelled due to a delay in recruitment.
At the time of screening, initially patients were given one injection of 30 ug of Avonex® and then paracetamol (3000 mg P.O. t.i.d.) for two days. Patients assessed their flu-like symptoms (fever, chills, discomfort, sweats, and myalgia) and an FLS score (zero to eight) was obtained. An FLS score of two or less corresponded to mild symptoms. Almost one-half of the patients had these low FLS scores, and they were not randomly assigned to one of the parallel arms. Patients having FLS scores greater than two were given Avonex® injections for three weeks and were randomly placed in one of the two treatment groups. After this screening process, 125 patients were placed in the paracetamol group and 121 in the ibuprofen group.
This study showed no statistical difference in the efficacy of these two medications. An aggregate, or total, FLS score was obtained by adding up the FLS scores after the second, third, and fourth injections. The total FLS score was 8.68 for the paracetamol group and 8.41 in the ibuprofen group. The investigators measured global (patient) satisfaction with the treatments for FLS, inconvenience on daily activities associated with the treatments, and safety. There was no significant difference between the values obtained for each of the medications. Patient global discomfort in both arms of the study was nil to mild in 64.1 percent of the patients, and mean global satisfaction was greater than 60 percent for both therapies.
This study confirmed the efficacy of simple adjunct therapies in the management of the flu-like symptoms associated with injections of Avonex®.
COMPARISON OF IMMUNOMODULATORY TREATMENT OF RELAPSING-REMITTING MULTIPLE SCLEROSIS-A PROSPECTIVE OPEN STUDY IN 498 MS PATIENTS TREATED WITH INTERFERON BETA (IFNЯ)-1b, IFNЯ-1a I.M., IFNЯ-1a S.C., GLATIRAMER ACETATE, OR IMMUNOGLOBULINS
M. Firzlaff, M. Schroder, M. Schmid, J. Haas, Tembit Software GmbH, Jewish Hospital, Berlin Charite Teaching Hospital, Denmark
In Germany, Betaseron® (interferon beta-1b, Berlex, also known as Betaferon® in Europe), Avonex® (interferon beta-1a, Biogen, Inc.), Rebif® (interferon beta-1a, Serono Group), Copaxone® (glatiramer acetate, Teva Marion Partners), and immunoglobulins are used to treat relapsing-remitting multiple sclerosis. This is a prospective study comparing the first year of treatment for 498 patients with relapsing-remitting multiple sclerosis (RRMS) using these five medications. All patients had an EDSS less than or equal to 3.5.
Baseline data including the EDSS, exacerbation rate, duration of illness (D), and pretreatment progression were obtained. One hundred and fifty-seven patients were treated with Betaseron®, 142 with Avonex®, 90 with Rebif®, 123 with Copaxone®, and 103 with immunoglobulins. Patients were seen every three months to assess EDSS, exacerbation rate, and side effects.
The investigators determined the pretreatment progression rate to be 0.37 for Betaseron®, 0.33 for Avonex®, 0.40 for Rebif®, 0.29 for Copaxone®, and 0.24 for immunoglobulins. Further evaluations will be made upon completion of the twelve-month observation period (April, 2000). The evaluations will concern exacerbation rate, time until first exacerbation, number of patients without exacerbations, number of stabilized patients, progression, reasons for discontinuation, and, in cases of discontinuation, efficacy of continuous treatment.
It is hoped this prospective study will provide information about the comparative benefits of the different immunomodulatory treatments. With the exception of pretreatment progression rate, the five arms of this study are comparable in terms of baseline data. The investigators will perform a matched pair analysis, and the data will be compared to the published study data.
EFFECTS OF MITOXANTRONE ON MULTIPLE SCLEROSIS PATIENTS' LYMPHOCYTE SUBPOPULATIONS, IMMUNOGLOBULIN, AND TNF ALPHA PRODUCTION
J.G. Gbadamosi, C.H. Heesen, C.B. Buhmann, A.M. Moench, W.T. Tessmer, F.H. Haag, University Clinic Department of Neurology, University Clinic Department of Immunology, Hamburg, Denmark
The purpose of this study is to elucidate which lymphocyte subsets or secreted effector substances are affected by mitoxantrone when used for treating rapidly progressive multiple sclerosis patients and how long these effects last.
The study included 12 patients-five primary chronic progressive, four secondary chronic progressive, and three relapsing-progressive, with a total of 34 cycles of mitoxantrone for a maximum follow-up period of 16 months. The mean EDSS was 6.0. Mitoxantrone was given in three to four month intervals at a dose of 12 mg/m2. Serum samples were obtained before each treatment interval and at one and two weeks following the infusions. The first analysis covered the summarized data of all treatment cycles, and it compared the pretreatment data with the post-treatment data. A preliminary long-term analysis covered effects over consecutive treatment cycles.
The authors found in the short term that mitoxantrone lowered most subpopulations, excluding activated and naive T-lymphocytes. There was no quantitative effect on the levels of secreted immunoglobulins or TNF alpha. For this therapy, whole blood stimulated TNF alpha did not appear to be a particularly suitable marker for response to this therapy. It is hoped further studies will elucidate adequacy of lymphocyte subpopulations and their effector molecules in monitoring the effects of mitoxantrone. The authors stated, ". . . an extension of this study will concentrate on other cytokine parameters and correlations with the clinical outcome."
DISSOCIATION BETWEEN RELAPSES AND DISABILITY PROGRESSION IN MULTIPLE SCLEROSIS
S. Vukusic, T. Moreau, P. Adeleine, C. Confavreux, Hospital Neurologique, Lyon, France
The relationship of relapses to the accumulation of residual disability in multiple sclerosis was assessed in a recent study.
The authors analyzed the records of 1,844 consecutive patients seen in the same center since 1957. The following data was obtained: date of onset of multiple sclerosis, inaugural course, whether recurring-remitting or progressive, dates of relapses, date of entry into residual Kurtzke Disability Status Scale scores, and the occurrence of a primary progressive or secondary progressive course. This study also included survival analyses of the time to entry into DSS4 (limited walking without aid), DSS6 (walking with unilateral aid), and DSS7 (wheelchair-bound) scores.
Cases with a recurring-remitting onset had longer median time intervals from onset of MS to entry into DSS4, DSS6, and DSS7 than did cases with a progressive onset. Regardless of the inaugural course, transitions from one level of disability to another were similar. In comparison to cases without superimposed relapses, patients with primary progressive MS (PPMS) and secondary progressive MS (SPMS) did not have delayed transitions from one level of disability to the next.
The authors concluded, "There is a relative dissociation between relapses and progressive accumulation of disability in multiple sclerosis."
DIFFERENT PROGNOSIS AND RESPONSE TO REBIF® (INTERFERON BETA-1a) THERAPY IN "RELAPSING" AND "NON-RELAPSING" SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS
J. Palace, The SPECTRIMS Study Group, Radcliffe Infirmary, Oxford, United Kingdom
The SPECTRIMS group previously studied two doses of interferon beta-1a in secondary progressive MS (SPMS) and found treatment provided significant benefits in terms of relapse rate, MRI activity, and MRI burden of disease (BOD). However, only a trend was noted in terms of disability progression.
The goal of this study was to determine if relapses within two years preceding entry into the study influenced the response to treatment with Rebif®.
In the SPECTRIMS study, 618 patients were randomly assigned to one of three arms-22 ug of Rebif®, 44 ug of Rebif® t.i.w., or placebo t.i.w. Dr. Palace stated, "The primary endpoint was slowing in the progress of disability." Clinicians evaluated the patients on a quarterly basis and MRI scans were obtained at regular intervals.
The author reported, ". . . patients with relapsing SPMS have more active disease prior to and during the study, are younger with shorter disease duration than the non-relapsing group, and have a better response to therapy with IFNЯ-1a." Patients with more advanced SPMS and greater disability did not respond as well as those with less disability.
This study adds weight to the conception that MS should be treated early, during the relapsing phase of the disease, in order to provide patients with the maximum benefit.
T2 LESION LOAD IN MULTIPLE SCLEROSIS USING STANDARD 2D-FSE and 3D-fFLAIR: RELATIONSHIP TO DISABILITY
O. Ciccarelli, P.A. Brex, K.A. Miszkiel, A.J. Thompson, D.H. Miller, NMR Research Unit, UCL, London, United Kingdom
A larger T2 lesion load (T2LL) is detected utilizing imaging with three-dimensional fast-fluid attenuated inversion recovery (3D-fFLAIR) than with a standard fast spin echo (FSE) sequence.
This study compared the lesion loads obtained with these two methodologies and determined if 3D-fFLAIR yielded a T2 lesion load that correlated better with disability. The study group was comprised of 33 patients with multiple sclerosis who had been followed prospectively since their presentation with a clinically isolated syndrome. Since their initial presentation, the patients were followed with both FSE and 3D-fFLAIR. A clinician examined the patients to determine their disease course and extent of disability, which was measured on the EDSS.
Three of the patients had clinically probable MS and 30 had clinically definite MS (24 relapsing-remitting and six secondary progressive). The mean age of the patients was 46 years and the median disease duration was 13.5 years. Median EDSS score was two. The median T2LL was 21 percent higher using 3D-fFLAIR compared to using FSE, and there was good correlation between the T2LL obtained using each sequence. As well, the T2LL from each sequence correlated well with the EDSS.
The authors concluded the following, "Although 3D-fFLAIR did detect a significantly [higher] T2LL than the FSE sequence, the T2LL derived using each sequence very strongly correlated with each other and both correlated equally with disability. The robust correlation between T2LL and EDSS most likely reflects the prospective nature of the cohort studied which ensured homogeneity with regard to disease duration."
INFRATENTORIAL HYPOINTENSE LESION VOLUME ON T1-WEIGHTED MAGNETIC RESONANCE IMAGING CORRELATES WITH DISABILITY IN PATIENTS WITH CHRONIC CEREBELLAR ATAXIA DUE TO MULTIPLE SCLEROSIS
S.J. Hickman, C.M.H. Behan, N.C. Silver, I.F. Moseley, N.J. Scolding, D.A.S. Compston, D.H. Miller, Institute of Neurology, Cambridge Centre for Brain Repair, The National Hospital, Frenchay Hospital, London, Cambridge, Bristol, United Kingdom
In Multiple Sclerosis, areas of tissue disruption and axonal loss are thought to appear as hypointense lesions on T1-weighted magnetic resonance imaging (T1HL). Previous investigators reported infratentorial T1HL to be rare in patients with MS. The data presented here revealed that, in patients selected to have cerebellar ataxia, infratentorial T1HL are not as infrequent as previously thought and the volume of the T1HL correlates well with the degree of disability.
This study included nine patients with chronic cerebellar ataxia on the basis of MS. The investigators determined each patient's degree of disability, and the degree of disability was entered on an EDSS. "The patients' brains were then imaged with an axial-oblique T2-weighted fast spin echo sequence, and a post-gadolinium axial-oblique T1-weighted conventional spin echo sequence." A blinded observer calculated the number and total volume of infratentorial high signal lesions on T2-weighted images (T2HSL) and T1HL.
These sequences disclosed 96 infratentorial T2HS. Of these, 34 (35.4 percent) appeared hypointense with respect to the surrounding white matter on the T1-weighted images. "The expanded EDSS score correlated with the number per patient of . . . and the volume per patient of infratentorial T1HL." The expanded EDSS score did not correlate with the T2HSL.
In contrast to earlier reports, this study showed that T1HL are common in MS patients selected to have chronic cerebellar ataxia. T1HL lesions appear to play a significant role in these patients' disability.
1. Rebif® is not approved by the US Food and Drug Administration for use in the United States.
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