Speakers' Abstracts that contain the words "Multiple Sclerosis"

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Multiple Sclerosis: Immunological Effects of Statins In Vitro - A New Therapeutical Approach?

Tuesday, April 16, 2002
Oliver Neuhaus, Siegrid Strasser-Fuchs, Franz Fazekas, Hans-Peter Hartung, Juan J. Archelos Graz, Austria; Düsseldorf, Germany

Objective:

In order to evaluate the potential role of statins as immunomodulators in multiple sclerosis (MS), we studied their immunological effects in vitro in comparison to the established effects of interferon (IFN)-b1b.

Background:

Statins are widely used lipid-lowering agents. Recent in vitro data suggest that statins might also be potent immunomodulatory agents. In addition, lovastatin attenuates disease severity in a rat model of experimental allergic encephalomyelitis.

Design/Methods:

Peripheral blood lymphocytes (PBL) obtained from untreated or IFN-b-treated patients with relapsing-remitting MS or from healthy donors (HD) were stimulated in the presence or absence of lovastatin, simvastatin, mevastatin, IFN-b1b or statins plus IFN-b1b. We analyzed proliferative activity, cytokine production by ELISA and intracellular immunofluorescence, and surface expression of activation markers, adhesion molecules and chemokine receptors.

Results:

Irrespective of the source of the PBL (untreated vs. treated MS vs. HD), all three statins inhibited proliferation of unspecifically stimulated PBL in a dose-dependent manner, simvastatin being most potent, followed by lovastatin and mevastatin. IFN-b1b showed a similar effect, statins and IFN-b1b together added their inhibitory potentials. Statins reduced activation surface markers, increased production of IL-4, and downregulated chemokine receptors both on B and T cells.

Conclusions:

We conclude that statins are effective immunomodulators in vitro equipotent to IFN-b1b that should undergo clinical studies in MS as a putative future treatment option.

Longitudinal Cytokine Responses to Myelin Peptides in Multiple Sclerosis (MS): Persistence and Spreading of Immune Responses

Tuesday, April 16, 2002
Clara M. Pelfrey, Ioana R. Moldovan, Sarah E. Born, Anne C. Cotleur, Matthew Karafa, Jar-Chi Lee, Elizabeth Fisher, Richard A. Rudick Cleveland, OH; Cleveland, OH

Objective:

To examine longitudinal cytokine responses to myelin antigens in MS patients and healthy controls in order to understand the role of persistence and spreading of immune responses in disease progression.

Background:

Myelin-specific immune responses can be found in both MS patients and healthy controls. Consequently, the relevance of these immune responses to MS disease progression is not clear. Unresolved issues include: Which features of the immune response to myelin relate specifically to MS disease maintenance/progression over time; Which myelin responses persist from one timepoint to another; Which myelin responses spread to new epitopes; Whether HLA type plays a role in maintaining responses over time.

Design/Methods:

We performed a 1-year longitudinal study measuring cytokine responses every 3 months in 20 relapsing-remitting MS patients and 27 age/gender matched controls. Using the ELISPOT assay, we determined ex-vivo Interferon-g (IFN-g) and IL-10 production by peripheral blood mononuclear cells in response to 9-mer overlapping peptides. By using peptides that span the entire PLP and MBP molecules, we obtained at each time-point the number and location of epitopes that induced memory T cell responses, the magnitude of the response, whether there was preferential induction of responses to PLP or to MBP, and whether these were associated with the HLA type of the responder.

Results:

At 3 months, 88% of MS patients responded to myelin peptides compared to 53% of controls, which was similar to the baseline proportions. After 3 months, cytokine responses to PLP persisted in 63% of MS patients and new PLP epitopes appeared in 13% of patients. In contrast, MBP responses persisted in only 25% of patients and new MBP responses appeared in 50% of MS patients. In controls, very few responses persisted between timepoints and new responses were equally distributed between MBP and PLP. Among DRB1*1501+ and *0401+ subjects, 4/8 MS patients showed persistence of responses between timepoints, whereas HLA-matched controls showed no persistent responses.

Conclusions:

These data suggest that persistent cytokine responses to the same myelin epitopes over time distinguish MS patients' responses from controls. The data also support the hypothesis that PLP responses occur early, followed by spreading of the immune response to MBP. This finding is relevant to strategies for antigen-specific therapies in MS.

Supported By:

Supported by National Multiple Sclerosis Society grant #RG3005-A-2 and NIH grant #NS 38667-02.

Cytokine Responses to Myelin Peptides Correlate with Clinical Parameters in Multiple Sclerosis

Tuesday, April 16, 2002
Ioana R. Moldovan, Sarah E. Born, Anne C. Cotleur, Matthew T. Karafa, Jar-Chi Lee, Elizabeth Fisher, Richard A. Rudick, Clara M. Pelfrey Cleveland, OH

Objective:

To perform a cross-sectional study involving determinant mapping of interferon (IFN)-g and interleukin (IL)-10 cytokine responses to proteolipid protein (PLP) and myelin basic protein (MBP) in relapsing-remitting multiple sclerosis (MS) patients and matched controls. To identify correlations between cytokine responses and clinical or MRI measures of disease progression.

Background:

There is increasing evidence that T cell responses to myelin-derived antigens play a significant role in the etiology of MS. Putative myelin antigens, like PLP and MBP,can trigger cytokine secretion in autoimmune T lymphocytes from MS patients, but also from healthy blood donors. There is evidence for in vivo activation and clonal expansion of myelin-reactive T cells in MS patients. In the activated state, T cells produce Th1/proinflammatory cytokines, like IFNg, which have been linked to exacerbations of the disease. Th2/antiinflammatory cytokines have a less clear-cut effect in the disease. The relationship between immune responses to myelin antigens and clinical measures of disease progression is poorly understood.

Design/Methods:

By using the ELISPOT assay, we determined ex-vivo IFN-g and IL-10 production by peripheral blood mononuclear cells in response to 9-mer overlapping peptides derived from PLP and MBP in 20 relapsing-remitting MS patients with early disease (disease duration 2.88±1.91 years) and 27 age- and gender-matched controls. Both MS patients and controls were HLA-typed. Our analysis was focused on identifying the number and location of epitopes that induced memory T cell responses, on the magnitude of the response, and on possible skewing of the response to Th1 vs. Th2 cytokines. We examined correlations between cytokine expression and brain parenchymal fraction (BPF), a highly reproducible MRI measure of whole brain brain atrophy.

Results:

80% of MS patients responded to myelin peptides compared to 56% of controls. High IFNg and IL-10 responders were more frequent in the MS patient group. Isolated PLP responses with no MBP response occured in over 1/3 of study subjects. Isolated MBP responses in the absence of PLP responses were very rare. A large majority of responses were directed towards PLP. Within an individual MS patient, PLP responses showed pronounced skewing towards either IFNg or IL-10, whereas MBP responses were mixed. Higher IFNg responses to PLP correlated with more brain atrophy in MS patients (p=0.02). Higher IL-10 responses to PLP correlated with less brain atrophy in the patients (p=0.36).

Conclusions:

The data suggest that PLP responses may play a significant role in initiation/maintenance of early disease. Relationship of the nature of the PLP response to brain atrophy suggests that IFNg responses promote brain tissue injury, while IL-10 responses appear protective. This suggests that inflammatory cytokine responses to myelin antigens have clinical relevance in MS patients.

Supported By:

The National Multiple Sclerosis Society Grant # RG3005-A-2,and NIH grant # NS38667-02.

The Association between Oligoclonal IgG Bands and Corpus Callosal Lesions in Japanese Multiple Sclerosis Patients

Tuesday, April 16, 2002
Ichiro Nakashima, Kazuo Fujihara, Tatsuro Misu, Hidemitsu Miyazawa, Juichi Fujimori, Shigeru Sato, Sadao Takase, Yasuto Itoyama Sendai, Miyagi, Japan

Objective:

To determine whether the presence of cerebrospinal fluid (CSF) oligoclonal IgG bands (OB) is related to corpus callosal lesions in Japanese multiple sclerosis (MS) patients.

Background:

OB is currently a diagnostic laboratory marker supporting the diagnosis of MS, and over 90% of MS patients are positive for OB in Western countries. In contrast, the frequencies of OB in Japanese MS patients have been much lower (35 - 46%) compared with those in Caucasian patients. It is known that the so-called optic-spinal form of MS, which is characterized by selective involvement of the optic nerves and spinal cord and is relatively common in Orientals including Japanese, is rarely positive for OB. These findings suggest that OB may be associated with the presence of brain lesions in MS patients. Since the corpus callosum is frequently involved in Caucasian MS patients, we investigated the association of OB and the callosal lesions in Japanese MS patients.

Design/Methods:

OB was tested in 33 Japanese MS patients (clinically definite MS (30), laboratory-supported definite MS (2), probable MS (1)) by isoelectric focusing methodology using Phast System™. Magnetic resonance imaging (MRI) was performed on a commercially available 1.5-T system. Sagittal 2-mm fast fluid-attenuated inversion-recovery (FLAIR) imaging was added to the routine MR studies of the brain. The images were reviewed for the presence of callosal lesions and subcallosal striations, which appear as notches on the undersurface of the corpus callosum on sagittal views and are considered as a relatively specific indicator for MS.

Results:

Among the 33 patients, 19 (57.6%) patients were OB-positive. Sex ratio, onset age, disease duration, and annual relapsing rate did not differ between OB-positive MS and OB-negative MS. Callosal lesions were seen in 17 (51.5%) out of 33 patients. All of the patients with callosal lesions had other discrete lesions adjacent to the body or temporal horn of the lateral ventricles and subcallosal striations were observed in all except one OB-negative patient. Among 19 OB-positive MS patients, 15 (79.0%) had callosal lesions on MRI. The other 4 OB-positive patients, however, had subcallosal striations. Among 14 OB-negative MS, only 2 (14.3%) had callosal lesions, 4 patients had subcallosal striations without callosal lesions, and 8 had neither callosal lesions nor subcallosal striations. Using Fisher's exact test, the relation between OB and the presence of callosal lesions was highly significant (p<0.001). The IgG index of the patients with callosal lesions (1.025±0.652) was significantly higher than that of the patients without callosal lesions (0.562±0.165) (p<0.001).

Conclusions:

The present study showed a strong association between OB and callosal lesions on sagittal brain fast FLAIR MRI in Japanese MS. The lower frequency of cerebral or callosal lesions in Japanese MS may be related to the low frequency of OB.

Study of the APOE and SCA2 Loci in Multiple Sclerosis Patients of Portuguese Origin

Tuesday, April 16, 2002
Mónica Santos, Maria do Carmo Costa, Maria Edite Rio, Maria José Sá, Marta C. Monteiro, Angela Valença, Alfredo Sá, José Dinis, José Figueiredo, Luís Bigotte de Almeida, António Valongueiro, Isabel Coelho, Anabela Ferro, Jorge Pinto-Basto, Maria Teresa Matamá, Jorge Sequeiros, Patrícia Maciel Porto, Portugal; Lisbon, Portugal; Leiria, Portugal; Viana, Portugal; Braga, Portugal; Almada, Portugal

Objective:

To study the influence of APOE and SCA2 loci in the susceptibility to multiple sclerosis in Portuguese patients.

Background:

Multiple sclerosis (MS) is a disorder of the central nervous system with a highly variable clinical presentation, which affects around 1:500 European young adults. It is a major demyelinating disease that follows a progressive or relapsing-remitting course, having a predilection for the spinal cord, cerebellum and optic nerves. Genetic factors are thought to play a role in susceptibility to MS.
The APOE gene is involved in myelin homeostasis and in several studies decreased CSF apoE levels in patients with MS have been reported, as well as the association of the e4 allele with other neurodegenerative disorders
The SCA2locus, containing a (CAG)n tract, is known to influence the survival of spinocerebellar neurons. Previous studies proposed that the 22 CAG allele of this gene segregated preferentially with MS.

Design/Methods:

Subjects: a sample of 194 patients of Portuguese origin with definite MS diagnosis according to the criteria of Poser et al and 194 healthy controls (HC), matched by sex, age and region of origin. The parents of 92 of these patients were also studied.
Methods: Genomic DNA from all subjects was isolated from peripheral blood using standard protocols. APOE genotyping was performed by PCR-RFLP, in a 8% non-denaturing polyacrilamide gel, using the restriction enzyme HhaI. Typing of the CAG repeat in the SCA2 locus was carried out by hybridization of PCR products, separated in a 6% denaturing polyacrylamide gel, with a (CAG)15 32P-labelled oligonucleotide probe.
Statistical analysis: The genotype frequencies for the APOE gene and the allele frequencies for the SCA2 gene were compared between cases and controls using the Chi-square test. This test was also used to compare genotype frequencies, at these loci, of cases with primary progressive versus other forms of the disease, and of each of these patient subgroups with matched controls. Disequilibrium of transmission was tested for both loci using the TDT-STDT program 1.1 in 92 trios.

Results:

There were no significant differences between cases and controls for both APOE genotype and SCA2 allele frequencies. The comparison of frequencies for APOE and SCA2 between cases with primary progressive versus other forms of the disease, and of each of these patient subgroups with matched controls, did not show significant differences. We also did not found any transmission disequilibrium for any allele of both loci.

Conclusions:

Our study on Portuguese MS patients does not confirm the previously reported influence of the e4 allele of APOE gene on the susceptibility to this disease. Additionally, in our population, the 22 CAG SCA2 allele does not seem to segregate preferentially with MS.

Supported By:

SERONO Portugal

Activated T Lymphocytes Exert Potent Cytotoxic Effect on Human Neurons

Tuesday, April 16, 2002
Fabrizio Giuliani, V. Wee Yong Calgary, AB, Canada

Objective:

To determine whether activated human T cells can kill human neurons and to elucidate the mechanisms of this toxicity.

Background:

MS is considered a T cell-mediated autoimmune disease of the CNS. MS lesions are characterized by the infiltration of inflammatory cells, demyelination, axonal loss and neuronal degeneration. It has been reported by others that CD8+ T cells can induce the apoptosis of rodent neurons via an MHC-I mediated mechanism; MHC-I expression on neurons was induced by pre-treating them with IFNg and tetrodotoxin. Given that neurons have not been found to express MHC-I in vivo, the current study seeks to investigate whether human neurons are also susceptible to T cell cytotoxicity and whether this can occur through a bystander mechanism without the involvement of MHC.

Design/Methods:

We used a co-culture system of human fetal neurons and T cells from allogeneic PBMC or syngeneic splenocytes. T cells were activated with an anti-CD3 antibody (OKT3) for 72h and then incubated with neurons. Following a pre-determined period of co-culture, neurons were stained with mouse anti-MAP-2 antibody conjugated to Cy3. The number of surviving MAP-2 positive neurons was counted using an automatic counting software (ImagePro). In some experiments, neutralizing antibodies to defined antigens were introduced to the co-culture system to modify the killing. Finally, enriched neuronal cultures, in the absence of T cells, were treated with a variety of inflammatory cytokines.

Results:

When activated T lymphocytes were added to neuronal cultures, they aggregated around neuronal elements and death to neurons occurred promptly. By 3h of co-culture, the number of MAP-2 positive neurons was reduced by over 60% when compared to controls (p<0.001). Neuronal toxicity required the activation of T cells since unactivated T lymphocytes did not produce any death to neurons over a 72h period analysed. Allogenic or syngeneic activated T cells were equally deleterious to neurons. The mechanism of T cell mediated neuronal toxicity required cell-cell contact, and was not reproduced by T cell conditioned media. In correspondence, purified TNF-a, IFN-g and IL-1b, alone or in combination, did not affect neuronal survival. Finally, neutralising antibodies to FasL attenuated the toxicity of activated T cells (% of surviving cells in OKT3-treated control alone=17±9; % of surviving cells in 10mg/mL FasL antibody-treated group=62±11.8;p<0.001) , suggesting the involvment of these molecules in T cell-mediated neuronal death.

Conclusions:

These data demonstrate that activated human T cells can kill human neurons in vitro without the apparent involvment of MHC-I. Toxicity was not a result of a graft-versus-host response as demonstrated using the syngeneic co-culture. We suggest that when T cells are appropriately activated, they can traffic into the CNS to induce neuronal death.

Supported By:

Canadian Institute for Health Research.

Regulation and Functional Effects of Monocyte Migration across Human Brain-Derived Endothelial Cells

Tuesday, April 16, 2002
Rosanne Seguin, Katarzyna Biernacki, Alexandre Prat, Jack P. Antel Montreal, QC, Canada

Objective:

We evaluated the molecular mechanisms that regulate passage of ex vivo peripheral blood derived monocytes across an in vitro human brain-derived endothelial cell (HBEC) barrier and the functional consequences of HBEC-monocyte interactions on the properties of both the HBECs and the monocytes.

Background:

Early lesions in the multiple sclerosis (MS) disease process are characterized by focal accumulations of perivascular lymphocytes and macrophages and enhanced permeability of the blood-brain barrier (BBB).

Design/Methods:

We developed an in vitro model of the initial immune cell migration process across the BBB using Boyden chambers coated with a monolayer of HBECs derived from surgically resected adult temporal lobe tissue. Monocytes and T cells were isolated from peripheral blood of healthy donors.

Results:

Monocytes migrate across HBECs in the absence of inflammatory conditions, at rates exceeding those of T cells. Monocyte migration could be inhibited by the addition of blocking antibodies to intercellular adhesion molecule-1 (40% inhibition) and monocyte chemoattractant protein-1 (30 % inhibition). Treatment with tissue inhibitor of metalloproteinase also reduced monocyte migration by over 25%. Following monocyte migration, there was a significant increase (30%) in permeability to soluble molecules (bovine serum albumin) across the HBECs as compared to resting HBECs or HBECs examined following T cell migration. Initial monocyte migration resulted in a subsequent enhanced rate of T cell migration across HBECs. These effects were observed in absence of detectable TNF production by the monocytes. The migration process did not induce the up-regulation of either co-stimulatory molecules or chemokine receptors on the monocytes.

Conclusions:

Monocyte migration across an initially intact human brain endothelium is an active process which renders the endothelium more permeable to soluble molecules and more susceptible to subsequent transmigration by inflammatory cells.

Supported By:

Multiple Sclerosis Society of Canada

Binding Antibodies to Interferon Beta during Treatment of MS Are Biologically and Clinically Relevant

Tuesday, April 16, 2002
Ebrima Gibbs, Gavin MacDonnell, Florian Deisenheimer, Joel Oger Vancouver, BC, Canada; Innsbruck , Austria

Objective:

To examine the incidence, the effect on bioavailability and the effect on clinical effectiveness of Binding Antibodies in MS patients treated with Interferon Beta 1b for 2 years.

Background:

There has been suggestive evidence that neutralizing antibodies reduce the effectiveness of injected Beta interferon 1b in relapsing MS.

Design/Methods:

One hundred relapsing MS patients started on medication in a post-marketing study were followed immunologically by binding antibody assay (sandwich ELISA) and clinically by repeated examinations. Monthly BAB titers were obtained and some samples were also assayed for Neutralizing antibodies (NABs) and for MxA content of lymphocytes.

Results:

Sixty seven out of 100 treated patients developed BABs. Most BABs appeared during the first 6 months of treatment. Maximum was reached at 5 months (78.7% +/- 4.3) (percentage of maximal normalized level +/- SEM). Therafter the titers fell to an average of 32.5% +/- 4.8 at 24 months. Out of 16 randomly chosen patients, 9 were positive for BAB. and 5 of these 9 devlopped NABs. None of the 7 BAB- developped NABs. BAB positives destined to become NAB+ had higher BAB peak titers than those BAB+ who did not become NAB+. Lymphocyte MxA protein was measured; it increased following IFNbeta-1b administration but fell following the appearance of BABs. Finally patients were adjudicated to 2 groups according to their clinical course. Success was considered when no relapse and no increase in EDSS was observed over 2 years; all the others were considered as failures. Clinical information was available for 92 patients. There was 43 "successes" and 49 "failures". Interestingly BABs segregated with failure: 20/33 successes occured in BAB negative and 36/59 failures were BAB positive (X2=4.19, p<.05).

Conclusions:

We conclude that BABs are not only a predictor of future NAB positivity but are also, by themselves, associated with reduced bioavailibility and reduced clinical effectiveness of Interferon beta-1b. As they are clearly much simpler to measure, they could be used clinically on a large scale.

Supported By:

This study was supported by a grant from Berlex Canada and Shering AG.

Clinical Evaluation of Oral Fampridine-SR (Sustained-Release 4-Aminopyridine) in Patients with Chronic Motor-Incomplete Spinal Cord Injury

Tuesday, April 16, 2002
Daniel Lammertse, Virgina Graziani, Mitchell A. Katz, Andrew R. Blight, SCI-F201 Study Group Englewood, CO; Philadelphia, PA; Hawthorne, NY

Objective:

Assess the safety and efficacy of multiple oral doses of fampridine-SR, a sustained-release formulation of fampridine (4-aminopyridine), in patients with chronic motor-incomplete spinal cord injury (SCI).

Background:

Fampridine-SR is a potassium channel blocking agent being investigated for its efficacy to improve neurologic function in patients with chronic SCI and multiple sclerosis.

Design/Methods:

In this double-blind, parallel-group study, a total of 91 patients in 11 centers were randomized to receive fampridine-SR 25 mg bid, fampridine-SR 40 mg bid, or placebo for 8 weeks (2-week dose escalation, 4-week fixed dose, 2-week down-titration). Safety was evaluated from adverse event reports and standard clinical assessments. Efficacy assessments included measures of spasticity (Ashworth scale), bowel and bladder function, male sexual function, Clinical Global Impression, and Subject Global Impression (SGI). Statistical significance was established at P<.025 to adjust for multiple comparisons.

Results:

In total, 78% of patients completed the study. Proportionally, more patients dropped out from the 40 mg bid group. The most frequently reported adverse events for all treatment groups (30%) were hypertonia, generalized spasm, insomnia, dizziness, asthenia, pain, constipation, and headache. One patient in the 40-mg group with a history of traumatic brain injury experienced a seizure; study medication was stopped and no further seizures occurred. Two outcome measures were statistically significant in favor of fampridine-SR 25 mg bid: SGI (P = .02) and number of days with bowel movements (P = .02). Several other outcome measures favored fampridine-SR 25 mg bid (spasticity, number of bladder accidents per day, and male sexual function), but did not reach statistical significance.

Conclusions:

Fampridine-SR 25 mg bid was well tolerated and showed statistically significant improvement on SGI and in bowel function. Further testing of fampridine-SR (25 mg bid) in larger clinical trials is ongoing.

Results of the Extension of a Trial to Assess the Longer Term Safety of Combining Interferon Beta-1a and Glatiramer Acetate

Tuesday, April 16, 2002
Fred Lublin, Monika Baier, Gary Cutter, Chris Bever, Robert Elfont, Omar Khan, Robert Lisak, Henry McFarland, Pan Narayana, John Noseworthy, Hillel Panitch, Stephen Reingold, Michele Weber, John Whitaker, Jerry Wolinsky, Khurram Bashir, Kenneth Johnson New York, NY; Denver, CO; Birmingham, Al; Baltimore, MD; Jenkintown, PA; Detroit, MI; Bethesda, MD; Houston, TX; Rochester, MN; Burlington, VT

Objective:

To determine whether weekly intramuscular treatment with interferon B-1a when used in combination with daily subcutaneous injections of glatiramer acetate is safe in relapsing-remitting (RR) multiple sclerosis (MS) as determined by the frequency of gadolinium-enhancing lesions on MRI scans.

Background:

The commonest employed agents for relapsing MS are interferon beta and glatiramer acetate. We have reported the initial six month safety data of combining these agents and now report the results of extending the study to 12 months.

Design/Methods:

Thirty-three subjects aged 18 to 50 with RR MS, with an MRI consistent with MS, and EDSS between 0 and 5.5, inclusive who have been taking interferon B-1a (IFN) injections for 6 or more months were entered into the study. After a run-in period of 3 months on IFN monotherapy, 31 subjects received additional treatment of glatiramer acetate. Of those, 26 completed 6 months of combination therapy and 16 completed 12 months of combination therapy. At each monthly follow-up visit an MRI scan was done through month 6, then again at months 9 & 12. The EDSS and the Multiple Sclerosis Functional Composite (MSFC) were assessed at the screening visit, month -2, at the start of combination therapy, and every 3 months thereafter.

Results:

The results reject the null hypothesis, that the addition of glatiramer acetate would block the effect of IFN, demonstrated by increasing the average number of gadolinium enhanced MRI lesions by 1 (p<0.001). There is suggestion of increased effectiveness of combination therapy since 8 of the 11 patients (73%) with any gadolinium lesions at baseline showed a decline in lesion number and volume at 6 months. Of the 16 patients completing 12 month follow-up only 2 had lesions present during the final 6 months. In both cases there was a decrease from the previous 6 months in lesion number and volume. A downward trend in Gad lesion numbers and volumes over time was found. Also, a statistically significant improvement in the MSFC over time on combination therapy was evident during the first 6 months. Over 12 months the timed walk showed a statistically significant improvement. There were no exacerbations seen during the final 6 months. No clinical or laboratory safety issues occurred.

Conclusions:

The above results indicate that there is no evidence for increased risk in terms of new lesion load from this combination therapy. Number and volume of gadolinium enhanced lesions showed a decline from baseline to 6 months, as well as from 6 months to 12 months, suggestive of increased effectiveness. Combination of IFN and glatiramer acetate is safe and deserves study in a larger, pivotal trial.

Supported By:

Biogen, Inc, and TevaNeuroscience

The Independent Comparison of Interferon (INCOMIN) Trial: Final Long-Term Results

Tuesday, April 16, 2002
Luca Durelli, Elisabetta Verdun, Pierangelo Barbero, Elisabetta Versino, Angelo Ghezzi, Enrico Montanari, Mauro Zaffaroni, the INCOMIN Trial Study Group Torino, Italy; Gallarate, Italy; Fidenza, Italy; Italy

Objective:

To compare clinical and MRI efficacy of two interferon (IFN) beta formulations in MS.

Background:

Controlled trials have demonstrated efficacy of once-a-week IFN beta-1a or of on-alternate-day IFN beta-1b compared to placebo. Patient's compliance and efficacy may be affected by different formulations or doses, and a direct clinical-MRI comparison of the two IFN betas is needed.

Design/Methods:

Prospective 2-year follow-up of 188 consecutive relapsing-remitting MS patients recruited by 15 MS centers. Patients randomised by independent statisticians blind of patients clinical characteristics to receive IFN beta-1a, 30 mcg intramuscularly once a week, or IFN-beta-1b, 8 million international units subcutaneoulsy on alternate days. Clinical evaluation conducted on an open-label basis, MRI scans analysed blind of the treatment used. Study conducted independently of the pharmaceutical industry. Primary outcome measures: proportion of patients free of relapses, or free of new T2 lesion. Secondary outcomes: relapse rate, corticosteroid-treated relapse rate, proportions of patients with sustained EDSS score progression of 1.0 point or more and of patients free of gadolinium-enhancing lesions, percent changes of T2 disease burden. Data were evaluated according to the intention-to-treat analysis.

Results:

The proportion of patients free of relapses was 51% in the IFN beta-1b group versus 36% in the beta-1a group (p=0.036), a 42% increased probability that patients on IFN beta-1b remained free of relapses compared to those on IFNbeta-1a. Mean annualised relapse rate was lower in IFN beta-1b (0.47) than in IFN beta-1a group (0.73) (p<0.03). Sustained EDSS progression was significantly lesser in patients on IFN beta-1b, with 14% of patients worsening compared with 30% of those on IFN beta-1a: a relative risk reduction of 56% in favour of IFN beta-1b (p=0.005). Of the patients receiving IFN beta-1b, over 24 months 55% were free of new T2 lesions at MRI compared with only 26% of those on IFN beta-1a(P=0.0003). T2 disease burden decreased by 2.8% in IFN beta-1b group, and increased by 11.7% in IFN beta-1a group (p<0.0001). The relative difference between the two treatments increased with time and was particularly pronounced during the second year of follow-up. Side effects occurrence was similar in the two treatment arms, except for a greater proportion of injection site reactions in the IFN beta-1b arm (p<0.001). Treatment was discontinued due to lack of a clinical response by 10 patients on IFN beta-1a and by only 3 of those on IFN beta-1b.

Conclusions:

Blind MRI evaluation confirmed the unblind clinical results indicating that IFN beta-1b reduced clinical and MRI signs of disease activity and progression more effectively than IFN beta-1a. The increasing relative difference between the two treatments during the second year of follow-up underlines the importance of conducting long-term studies, the only ones which, in the context of a chronic disease, may provide clinically relevant results.

Supported By:

Italian Ministry of Health and Italian MS Society.

Beta Interferon Use among Multiple Sclerosis Patients in a Managed Care Setting: Demographics, Cost of Care, Utilization, Health Status, and Quality of Life

Tuesday, April 16, 2002
Stanton B. Elias, Jennifer Elston-Lafata, Lonni R. Schultz, Jackie Reuther, Christina H. Moon Detroit, MI

Objective:

To describe differences in demographics, cost, utilization, health status (HS), and quality of life (QoL) by treatment with beta Interferon (IFN beta) among patients with multiple sclerosis (MS).

Background:

IFN beta was introduced for use in MS patients in 1993. Since that time, there has been controversy concerning the high cost of treatment and whether it is justified by a favorable impact upon overall medical care cost, utilization of health-related resources, HS, and QoL among MS patients. Several studies have followed QoL during early (6-12 months) treatment, or modeled or estimated costs that are incurred or avoided after long term use. The association of IFN beta on cost, HS, and QoL as typically used in an MS population has not been measured.

Design/Methods:

HMO patients with MS receiving care from a multispecialty practice in 1997 were identified (n=229). Automated data sources, medical records and telephone surveys were used to compile information on patient sociodemographic, clinical characteristics, HS (SF-36), QoL (Farmer), satisfaction with care, medical care use, and costs. Generalized Estimating Equations (GEE) approaches were used to test for differences in sociodemographic and comorbidity characteristics by treatment status, and assess differences in cost, HS, QoL, and satisfaction by IFN beta treatment, controlling for patient sociodemographic and comorbidity characteristics.

Results:

During the year, 27.1% of patients were treated with IFN beta. Treated patients were significantly younger (40 vs 47 years), had shorter disease duration (6.6 vs 9.7 years), and more likely to have psychiatric disorders requiring treatment (32 vs 16%). No significant differences were found for male gender (18 vs 29%), Caucasian race (69 vs 72%), full time employment (56 vs 45%) or Charlson Comorbidity scores (.16 vs .22). Median total ($10,251 vs $1,791), pharmacy ($8,606 vs $99) and non-pharmacy ($1,969 vs $1,272) medical care costs were higher for IFN beta treated patients. Although no significant differences were found in office visit frequency (12.1 vs 9.4), MS visit frequency (3.4 vs. 2.3), or ED (26 vs 19%) or hospital (15 vs 8%) use by IFN beta treatment, the trend was always towards higher utilization among IFN beta treated patients.
Only the health perception domain of the SF-36 varied significantly between treated and untreated patients (45.2 vs 51.0), and only the affect domain of the Farmer instrument indicated treated patients exhibited reduced QoL (34.9 vs 37.7). No differences in satisfaction with medical care were found.

Conclusions:

Treatment with IFN beta was an added cost for medical care for MS patients and did not reduce utilization of other medical services. Treatment with IFN beta was not associated with improvement in self-reported HS, QoL or satisfaction scores. Results reported here reflect concurrent associations with IFN beta use. Whether there are potential long term benefits that might accrue from delaying disability are yet unknown.

Supported By:

National Multiple Sclerosis Society

Evidence of Dose Response: Effects of Two Interferon Beta-1a Products on Relapse-Related Parameters in Multiple Sclerosis

Tuesday, April 16, 2002
Mohammad K. Sharief, EVIDENCE Study Group London, United Kingdom

Objective:

To compare the effects of two interferon (IFN) beta-1a products on relapse-related parameters in patients with relapsing-remitting multiple sclerosis (RRMS).

Background:

Two IFN beta-1a products are available for the treatment of RRMS: Rebif® (Serono) and Avonex® (Biogen). The EVIDENCE study was designed to permit a direct comparison of these products. Key data from this prospective, randomised, assessor-blinded study have been presented elsewhere. This presentation describes in more detail results relating to relapses.

Design/Methods:

677 patients with RRMS were randomised to receive Rebif®, 44 mcg three times weekly (tiw), or Avonex®, 30 mcg once weekly (qw), for 24 weeks. To ensure that all relapses were detected, patients were contacted every 2 weeks throughout the study and were required to inform their physicians within 48 hours of the onset of each suspected relapse. The severity of each relapse was assessed and the functional systems affected were noted. In addition, the numbers of hospitalisations and steroid courses needed because of relapses were recorded. All assessing neurologists were blinded to treatment.

Results:

The proportion of patients remaining relapse-free throughout the 24 weeks of the study was 74.9% with Rebif® and 63.3% with Avonex® (p=0.001), and the mean number of relapses per patient was 0.29 with Rebif® and 0.40 with Avonex® (p=0.022). The mean time that elapsed before the first 20% of patients had their first relapse was 118 days with Rebif® and 89 days with Avonex® (p=0.001), and the hazard ratio for relapsing with Rebif® as opposed to Avonex® was 0.63 (p<0.001). The impact of Rebif® on relapses was greater than that of Avonex® for all relapse severity categories. Patients receiving Rebif® and Avonex® were similar with respect to the proportion of relapses affecting each functional system. Only one relapse (Avonex® patient) led to hospitalisation for a reason other than facilitation of steroid administration. The mean number of steroid courses needed per patient was 0.094 with Rebif® and 0.177 with Avonex® (p=0.004).

Conclusions:

In this large, multicentre, randomised, assessor-blinded trial, Rebif®, 44 mcg tiw, had a significantly greater impact than Avonex®, 30 mcg qw, on several relapse-related outcomes, and was not associated with any new or dose-limiting safety concerns. The superiority of Rebif® was not due simply to suppression of mild relapses, but applied across all severity categories. These findings support the hypothesis that dosing schedule has a major impact on the efficacy of IFN beta-1a, and indicate that higher and more frequent doses of IFN beta-1a are beneficial in RRMS.

Supported By:

Serono International SA.

Gray Matter T2 Hypointensity in Multiple Sclerosis: A 2-year Longitudinal Clinical-MRI Study of 79 Patients

Tuesday, April 16, 2002
Rohit Bakshi, Srinivas R. Puli, Christopher W. Tjoa, Robert A. Bermel, Elizabeth Fisher, Richard A. Rudick, Andrew J. Fabiano, Bianca Weinstock-Guttman, Frederick E. Munschauer, Jack H. Simon Buffalo, NY; Cleveland, OH; Denver, CO

Objective:

Study the longitudinal progression of T2 hypointensity and its prognostic value in predicting neurologic disability and brain atrophy over 2 years in multiple sclerosis (MS).

Background:

Gray matter MRI T2 hypointensity (purported iron deposition) has been described in MS and has been related to physical disability, disease course, MRI lesion load, and atrophy in cross-sectional studies. But, no longitudinal studies have tested the progression of T2 hypointensity and its ability to predict the development of disability and brain atrophy.

Design/Methods:

We analyzed 79 placebo patients who completed a 2-year phase III treatment trial of relapsing-remitting MS. Patients had a mean+/-SD age 35+/-6 years and physical disability (EDSS) score 2.4 +/- 0.9 (range 1.0-3.5) at baseline. Brain MRI was obtained at baseline, year 1, and year 2 using conventional spin echo axial T1-/T2-weighted images. T2 hypointensity was determined quantitatively in the thalamus, caudate, globus pallidus, putamen, red nucleus, and dentate nucleus at the Buffalo Neuroimaging Analysis Center. Reliability (coefficients of variation) of the T2 hypointensity data was intraobserver mean 1%, range 0.7% to 1.4% and interobserver mean 0.8%, range 0.6% to 1.7%. Whole brain atrophy (brain parenchymal fraction-BPF) and total T2 hyperintense, gadolinium enhancing, and T1 black hole lesion volumes were determined quantitatively in Cleveland and Colorado. Regression modeling compared the strength of MRI variables to predict dependent variables. Paired Difference tests assessed the 2-year change of T2 hypointensity.

Results:

Baseline T2 hypointensity in several gray matter regions was associated with higher baseline T1 and T2 lesion loads and lower BPF (p=.0001 to .04). Stepwise regression selected low BPF, and T2 hypointensity in the red nucleus and globus pallidus as predictive of baseline EDSS (R-square=.17, p=.007). A regression model containing dentate, caudate, putamen, and thalamus T2 hypointensity predicted prestudy exacerbation rate (R-square=.17, p=.009). Stepwise regression selected baseline thalamus, red nucleus, dentate, and globus pallidus T2 hypointensity as predictive of the 2-year reduction of BPF (R-square=.29, p<.001). Total T1, T2, and enhancing lesions were not selected by any of the regression models as predictive of dependent variables. None of the baseline MRI variables predicted 2-year progression of disability. T2 hypointensity worsened during the 2-year period in the caudate (p=.06) and putamen (p=.45), but the changes were not significant.

Conclusions:

This study provides additional evidence that gray matter T2 hypointensity in MS patients is related to atrophy, lesion load and clinical disease severity. This T2 hypointensity may have prognostic value in predicting the 2-year progression of brain atrophy, suggesting a relationship between iron deposition and subsequent tissue loss.

Supported By:

National Institutes of Health (NIH-NINDS) 1 K23 NS02210-01 (R. Bakshi), American Academy of Neurology Student Interest in Neurology Summer Scholarship (R. Bermel), and Alpha Omega Alpha Student Research Fellowship (R. Bermel).

A Follow-Up Study with Diffusion, Magnetization Transfer and Spectroscopic Imaging of Corpus Callosum in Clinically Isolated Syndromes suggestive of Multiple Sclerosis

Tuesday, April 16, 2002
Jean-Philippe Ranjeva, Jean Pelletier, Sylviane Confort-Gouny, Yann Le Fur, Danielle Ibarrola, Patrick Viout, André Ali Cherif, Patrick J. Cozzone Marseille, France

Objective:

to characterize on follow-up MRI and MRS procedures, the corpus callosum(CC) of patients who underwent clinically isolated syndromes suggestive of multiple sclerosis (CISSMS) from structural and metabolic point of view.

Background:

Morphological callosal impairment is a frequent finding that can be detected in patients with relapsing-remitting MS (RRMS) early in the disease. Neuronal involvement and axonal loss have been demonstrated in early RRMS by Diffusion, Magnetization Transfer and Spectroscopic Imaging .

Design/Methods:

Twenty patients with CISSMS were compared to 22 age and sex matched controls. All subjects were explored on a 1.5T Vision Plus MR imager (Siemens, Erlangen, Germany). The MRI protocol included a sagittal T1-w acquisition, a T2-w sequence in the axial plane followed by two sagittal MT-w flash sequence to calculate the MTR map, and single shot diffusion weighted EPI sequence (b=0, 250 500, 1000 s/mm2) sensitized sequentially in the three directions to compute the mean diffusivity map. Metabolic exploration was performed in the medial sagittal plane with a 2D-SE acquisition weighted CSI sequence. Four ROI in the corpus callosum were drawn on the medialsagittal slice of each modality and referred as the genum, the central anterior part of CC, the central posterior part of CC and the splenium.

Results:

Baseline data have shown a significant decrease in MTR and a significant increase in MD in the CIS group (p<0.1). In the splenium and the central anterior part, a significant decrease of NAA/Cho ratio was also observed (p<.01). A significant increase in MD and a significant decrease in MTR was observed in the CIS group between baseline and month 6. At this stage (M6) NAA/Cho and Cho/Cr ratios came back to values similar to control group while a tendancy of decrease in NAA/Cr was observed (p=0.07).

Conclusions:

These data suggest that the early myelin breakdown observed at the very early stage of MS tend to evolved within the next 6 months to an axonal injury. The results will be confirmed at the 1 year time point.

Supported By:

Association de la Recherche sur la Sclerose en Plaques (ARSEP) et la Fondation Jean et Odette Duranton de Magny (Fondation de France)

Diagnostic MRI Criteria: Prediction of Conversion to CDMS

Tuesday, April 16, 2002
Frederik Barkhof, Massimo Filippi, Giancarlo Comi, the ETOMS Study Group Amsterdam, Netherlands; Milan, Italy

Objective:

To prospectively test the predictive value of MRI criteria as developed by Barkhof et al. [Brain 1997;120:2057] in patients with a first episode consistent with demyelinating disease for progression to clinically definite MS (CDMS) in the ETOMS (Early Treatment of MS) study.

Background:

Several diagnostic MRI criteria have been proposed for the diagnosis of MS. In the recently adopted diagnostic criteria for MS by McDonald et al. [Ann Neurol 2001;50:127], the modified Barkhof criteria have been incorporated. Neither the modification of the criteria, or the proposed cut-off of 3 positive criteria, have yet been tested in a large sample prospectively.

Design/Methods:

ETOMS was a randomized, double-blind, placebo-controlled study of 308 patients equally distributed to 22mcg interferon beta-1a (IFN, Rebif) once weekly and placebo. Baseline MRI scans were assessed for the presence of gadolinium-enhancement (with or without substitution by 9 or more T2 lesions when no gadolinium lesions present), a juxtacortical lesion, an infratentorial lesion, or at least 3 periventricular lesions. The predictive value of the individual criteria and the cumulative number of positive criteria for conversion to CDMS was assessed by Chi-square analysis, and possible treatment interaction by calculation of odds ratios using logistic regression.

Results:

Conversion to CDMS occurred in 43% of patients with gadolinium-enhancement vs. 34% without (p=0.085); similar comparisons were 44% vs. 31% for infratentorial (p=0.031), 40% vs. 35% for juxtacortical (p=0.497), and 41% vs. 17% for more than 3 peri-ventricular lesions (p=0.025). When the lack of a gadolinium lesion was substituted by the presence of 9 or more T2 lesions, the predictive value increased (41% vs. 11%, p=0.008). No significant treatment interaction was noted for any of the parameters. For the cumulative number of modified Barkhof criteria, a nearly linear increase was seen from 25% for 1 abnormal criterion to 47% with 4 abnormal criteria; the most effective cut-off was for 3 or less vs. 4 criteria (p=0.003); for the cumulative number of Barkhof criteria, again no significant treatment interaction was noted.

Conclusions:

This study confirms the validity of the modified Barkhof criteria for conversion to CDMS in a prospective study, and indicates that the efficacy of treatment with Rebif occurs independent of baseline MRI findings.

Supported By:

Serono

Diffusion-Weighted MRI Evidence of Gray Matter Damage in Multiple Sclerosis

Tuesday, April 16, 2002
Andrew J. Fabiano, Robert A. Bermel, Christopher W. Tjoa, Bianca Weinstock-Guttman, Frederick E. Munschauer, Joan M. Feichter, Colleen E. Miller, Eileen Gallagher, Rohit Bakshi Buffalo, NY

Objective:

To assess whether subcortical gray matter damage can be detected by diffusion-weighted MRI in patients with multiple sclerosis (MS) and to compare gray matter diffusion coefficients with clinical findings.

Background:

Injury to the deep gray matter in MS has been suggested from recent studies using PET scanning and by the detection of T2 shortening (proposed iron deposition). This gray matter damage supports a global disease process and may contribute to neurologic dysfunction in patients with MS. Diffusion-weighted MRI (DWI) can noninvasively detect changes in water Brownian motion, offering a novel method to assess tissue damage in a variety of neurologic diseases with a higher sensitivity than conventional MRI. DWI has revealed areas of microscopic disease in the normal appearing white matter (increased diffusion) in patients with MS, but has not been applied to the study of gray matter damage in MS.

Design/Methods:

DWI was performed in 64 patients with clinically definite MS on a General Electric Signa 4x/Lx 1.5-T magnet (Milwaukee,WI) using a single-shot spin-echo echoplanar technique with a TR/TE/NSA 9999/106/1, 5-mm nongapped (contiguous) slices, matrix size 96x128, FOV of 36x27 cm and scan time of 40 seconds, generating 28 axial slices through the brain. Four images per slice location were produced, with a diffusion-weighing b-factor of 0, and 1000 s/mm2 applied in three orthogonal directions. Mean apparent diffusion coeffecient (ADC) maps were reconstructed at the Buffalo Neuroimaging Analysis Center using customized software (Java Image, Xinapse Systems, Leicester, England). The diffusivity was computed separately in the x, y, and z directions, and the results averaged to form the mean ADC. ADC values were obtained from the globus pallidus, putamen, caudate, and thalamus using a standardized region of interest template. Fifty-two patients had relapsing-remitting (RR) and 11 had secondary progressive (SP) MS. Physical disability was assessed using the Expanded Disability Status Scale (EDSS) and ranged from 0 to 8.0 (mean ± SD: 2.8 ± 2.2); patient age ranged from 22 to 59 years (41.4 ± 8.0). Group differences were assessed using t-tests. Correlations were tested using Pearson's or Spearman Rank coefficients.

Results:

ADC was higher in the caudate in SP (0.870x10-3mm2/s ± 0.135x10-3) vs. RR patients (0.764x10-3mm2/s ± 0.083x10-3) (p=.028). ADC in the caudate was positively associated with greater physical disability (higher EDSS score) (rho=.404, p=.001). Age or gender was not related to gray matter ADC in any of the regions.

Conclusions:

Increased water diffusion in the deep gray matter may be associated with clinical markers of disease severity in patients with MS. DWI is potentially useful as a surrogate marker of gray matter tissue damage in MS.

Supported By:

Supported by National Institutes of Health (NIH-NINDS) 1 K23 NS02210-01 (R. Bakshi), American Academy of Neurology Student Interest in Neurology Summer Scholarship (R. Bermel), and Alpha Omega Alpha Student Research Fellowship (R. Bermel).

Evolution of Diffuse and Focal Magnetization Transfer Abnormalities in Multiple Sclerosis

Tuesday, April 16, 2002
Cornelia Laule, Irene M. Vavasour, Kenneth P. Whittall, Joel Oger, Donald W. Paty, David K. B. Li, Alex L. MacKay, Douglas L. Arnold Vancouver, BC, Canada; Montreal, QC, Canada

Objective:

To determine the evolution of magnetization transfer in NAWM of patients with MS

Background:

A range of pathologies is seen in multiple sclerosis (MS), including inflammation, demyelination and axonal loss, which cannot be differentiated on conventional magnetic resonance (MR) images. Magnetization transfer (MT) is a MR technique that investigates the exchange between motionally restricted and mobile protons, allowing for the indirect measurement of tissue structure. In normal healthy white matter, strong interactions between mobile water protons and the restricted protons associated with non-aqueous tissue result in a high magnetization transfer ratio (MTR). Tissue destructive processes, such as demyelination, cause a decrease in MTR.

Design/Methods:

Nine patients with clinically definite MS were enrolled in the study. Patients were scanned 5 times over one year at months 0, 2, 4, 6 and 12. Age and gender matched controls were scanned once. MR examinations for each visit included a conventional dual echo scan, post-contrast gadolinium T1 weighted images and 3D gradient echo experiment with and without a 2000Hz off-resonance MT pulse. Proton density images were registered with MT images with and without the MT pulse, IMT and InoMT, respectively. MTR was defined as MTR=((InoMT-IMT)/InoMT)*100%. Regions of interest were drawn around 10 bilateral normal appearing white matter (NAWM) and normal white matter (NWM) areas in all subjects and in lesions in MS patients. The MTR of NAWM was investigated as a function of disease duration. For new lesions, MTR was examined before and after lesion appearance on conventional MRI.

Results:

The mean NAWM MTR was found to correlate strongly (R=0.93) with the length of time since the patient's first clinical presentation and was well characterized by a linear decrease of -0.16%/year (p<0.0001). The time zero intercept of the NAWM MTR regression was 30.6±0.2%, which was not different from the average MTR of NWM from age and gender matched controls (30.4±0.2%). An additional gradual decrease in NAWM MTR was observed 6 to 12 months before the appearance of a new lesion on conventional MRI, while a more precipitous decrease in MTR was seen 2 to 6 months before the lesion appeared. Those lesions that exhibited pre-lesion MTR decreases showed less MTR recovery than lesions which had no pre-lesion MTR decrease.

Conclusions:

NAWM in MS undergoes a slow progressive decrease in MTR that starts at disease onset and accelerates rapidly in focal areas just prior to lesion appearance on conventional MR images.

Supported By:

MS Society of Canada

A Functional MRI Study of Patients with Clinically Definite Multiple Sclerosis and Atypical Conventional MRI

Tuesday, April 16, 2002
Massimo Filippi, Maria A. Rocca, Maria Codella, Andrea Falini, Mauro Zaffaroni, Angelo Ghezzi, Lucia Moiola, Giuseppe Scotti, Giancarlo Comi Milan, Italy, Italy; Milan, Italy; Gallarate, Italy

Objective:

We used functional magnetic resonance imaging (fMRI) to evaluate the brain pattern of cortical activations during the performance of a simple motor task in patients with clinically definite multiple sclerosis (CDMS) and atypical conventional MRI of the brain.

Background:

FMRI changes have been demonstrated in MS patients with different clinical phenotypes. To which degree these changes are correlated with the extent of microstructural tissue damage has not been clarified yet.

Design/Methods:

We studied 12 right-handed patients with CDMS (10 women and two men; mean age=38.0 years, mean disease duration=7.2 years, median expanded disability status scale score=1.5, range=0.0-6.0). Patients were included if they had normal or near-normal brain MRI scans (defined as three or fewer T2 lesions). None of them had clinical evidence of right hand function impairment at the time of fMRI acquisition or lesions located along the motor pathways on T2-weighted images. Twelve sex- and age-matched right-handed healthy volunteers served as controls. In each subject, we acquired: 1) fMRI during the performance of repetitive flexion-extension of the last four fingers of the right hand; 2) dual-echo turbo spin echo and 3) pulsed-gradient spin-echo (PGSE) echo-planar imaging. Mean diffusivity (MD) histograms of the normal appearing brain tissue (NABT) were produced. FMRI data were analyzed using a random effect analysis (SPM99).

Results:

Although CDMS patients had a very low mean T2-weighted lesion load (0.4 ml), they had a lower NABT MD histogram peak height when compared to healthy subjects (p=0.004). Compared to healthy volunteers, CDMS patients also showed a more significant activation of the contralateral secondary somato-motor cortex (SII). On the contrary, they had significantly reduced activation of the ipsilateral primary somatomotor cortex (SMC), and contralateral inferior frontal gyrus.

Conclusions:

This study suggests that microstructural white matter damage in MS is associated with cortical functional reorganization.

Brain Atrophy in Patients with Clinically Isolated Syndrome

Tuesday, April 16, 2002
Andrea Paolillo, Patrizia Pantano, Francesca Caramia, Maria Cristina Piattella, Silvia Di Legge, Walter Nucciarelli, Isabella Pestalozza, Carlo Pozzilli Rome, Italy

Objective:

To seek MRI parameters predictors of brain atrophy in patients with clinically isolated syndrome (CIS).

Background:

The assessment of brain volume changes provides an objective marker of the progression of Multiple Sclerosis (MS) and appears intriguing in CIS patients. In this population, the relationship between brain atrophy, inflammation and the irreversible axonal damage is debated.

Design/Methods:

Monthly Gd-enhanced MRI scans over a period of 6 months were obtained in 39 consecutive CIS patients with an abnormal MRI scan at baseline. Further MRI scans were performed at 12 and 18 months. Patients who developed a 2nd clinical episode were withdrawn from the study to be treated with disease modifying therapies. For each scan, we obtained measurements of lesion load for Gd-enhancing lesions (Gd-LL), T2 hyperintense lesions (T2-LL) and T1-black holes (T1-LL). Brain volume changes were assessed using the SIENA method. This program estimates percentage brain volume change (PBCV) between two input images, taken of the same subject, at different points in time.

Results:

Twelve of 39 CIS patients showed a 2nd relapse and therefore did not complete the MRI follow-up; 27 patients were followed from baseline to 18 months. They had a median increase of 13% in the T2-LL and of 15% in the T1-LL. There was a decrease of 1.15% in PBCV. The mean monthly Gd-LL (6 months) was significantly associated with PBCV over the study period (r = -0.59, p = 0.001). Exploratory subgroup analyses showed that patients with at least one Gd-enhancing lesion during the first 6 months, (i.e. active patients) (n=16), developed greater brain atrophy (-1,44% vs - 0,67%, p = 0.01) than patients without Gd-enhancing lesions (inactive patients) (n=11).

Conclusions:

The data suggest a robust relationship between the development of brain atrophy and inflammation in patients with CIS. Monthly Gd-enhanced MRI scans over a period of 6 months after the first clinical episode suggestive of MS may help to characterize patients who will develop brain atrophy in short term.

Whole Brain N-Acetylaspartate Concentrations Are Reduced in Patients at Presentation with Clinically Isolated Syndromes Suggestive of MS

Tuesday, April 16, 2002
Massimo Filippi, Marco Bozzali, Anna Gambini, Marco Rovaris, Andrea Falini, Angelo Ghezzi, Vittorio Martinelli, Giuseppe Scotti, Oded Gonen, Robert I. Grossman, Giancarlo Comi Milan, Italy; Gallarate, Italy; New York, NY

Objective:

To quantify the presence and extent of axonal loss/dysfunction in patients at presentation with clinically isolated syndromes (CIS) at risk for subsequent conversion to definite multiple sclerosis (MS), by measuring whole brain N-acetylaspartate (WBNAA) concentration.

Background:

It has been suggested that permanent tissue damage can occur early in the course of MS and have a predictive value for the subsequent disease evolution. WBNAA, which can be considered a global measure of irreversible neuronal loss, was found to be lower in relapsing-remitting MS patients than in normal controls.

Design/Methods:

Eighteen patients with CIS and 10 sex- and age-matched healthy controls were studied. All patients had had a CIS suggestive of demyelination within the three months preceding magnetic resonance (MR) acquisition. During a single session, the following brain MR sequences were acquired in all study subjects: a) 1H-MR spectroscopy (MRS) pulse sequence, based on a four-step cycle of non-selective 180° inversion pulses, to obtain WBNAA spectra; b) dual-echo turbo spin-echo; c) pre- and post-contrast T1-weighted conventional spin-echo. Whole brain volume, T2 and T1 lesion volume (LV) were calculated using a semi-automated segmentation technique. Absolute WBNAA amounts (in mmoles - mM) were calculated using a phantom replacement method and were then corrected for individual subjects' brain volumes.

Results:

In CIS patients, median T2 and T1 LV were 1.7 ml and 0.3 ml, respectively. The average brain volume was significantly lower in CIS patients than in healthy controls (mean values: 1165.4 ml vs 1276.5 ml, p=0.01). The average WBNAA concentration (corrected for brain volume) was also significantly lower in patients than in controls (mean values: 11.1 mM vs 14.3 mM, p=0.002).

Conclusions:

These findings suggest that axonal loss/dysfunction occurs at a very early stage in patients at presentation with CIS suggestive of MS. The magnitude of the reduction of WBNAA concentrations in these patients might be a strong predicting factor of subsequent clinical evolution.

The Evidence of Interferon Dose-Response: European-North American Comparative Efficacy (EVIDENCE) Study: 48 Week Data

Tuesday, April 16, 2002
Hillel Panitch, Patricia Coyle, Gordon Francis, Douglas Goodin, Paul O'Connor, Brian Weinshenker, the EVIDENCE Study Group Burlington, VT; Stony Brook, NY; Norwell, MA; San Francisco, CA; Toronto, ON, Canada; Rochester, MN

Objective:

To assess whether differences in efficacy based on dose of interferon (IFN) and treatment regimen persist to 48 weeks in patients with relapsing-remitting multiple sclerosis (RRMS).

Background:

Although IFN-b therapy is effective in RRMS, debate persists regarding the importance of dose and frequency of administration. At the 24-week primary endpoint, the EVIDENCE study demonstrated significant improvement on relapse and MRI outcome measures for high dose IFNb-1a (44 mcg subcutaneously three times weekly, sc tiw) compared to low dose (30 mcg intramuscularly weekly, im qw). We now present data up to 48 weeks of treatment.

Design/Methods:

This was a prospective, assessor-blinded, comparative study of 677 RRMS patients randomized to treatment with either IFNb-1a 44 mcg sc tiw (Rebif) or IFNb-1a 30 mcg im qw (Avonex). After a screening MRI study, patients had MRI scans every 4 weeks for 24 weeks with and without Gadolinium, plus an additional non-enhanced scan at week 48. Clinical assessments were performed every 12 weeks, and as needed for documentation of relapses. The primary endpoint was the proportion of relapse-free patients. The principal secondary outcome measure was MRI active lesion count (combined unique lesions for 24 weeks based on monthly scans, and T2 active lesion count for 48 weeks based on 6-monthly scans). All analyses were performed according to intention to treat.

Results:

Of the 677 patients enrolled, 339 were randomized to Rebif and 338 to Avonex. All but a single patient received at least one dose of drug. Adherence to study at 48 weeks was 96% for both groups, while adherence to therapy was 91% for both groups. The most common causes for stopping therapy were adverse events (15 Rebif, 8 Avonex) and patient decision (9 Rebif, 15 Avonex). Three patients (all on Avonex) were lost to follow-up. Data on proportion of relapse-free patients, time to first relapse, relapse rate, relapse severity, T2 lesion activity (active T2 lesions, proportion of active scans and proportion of patients free of T2 lesion activity), as well as safety, will be presented.

Conclusions:

This is the first randomized, examiner-blinded comparative study examining the efficacy of two disease modifying drugs in MS. Patient adherence to the study and investigator adherence to the protocol were excellent. IFNb-1a 44mcg administered sc tiw was shown at 24 weeks to provide significant clinical and MRI benefit compared to 30mcg weekly therapy. The 48-week data provide information about the longer-term durability of these beneficial effects.

Supported By:

Serono International SA

Clinical Application of Autologous Stem Cell Transplantation in Severe Multiple Sclerosis Treated with High-Dose Immunosuppressive Thyerapy

Tuesday, April 16, 2002
George H. Kraft, James D. Bowen, Jimmy Y. Cui, Richard A. Nash Seattle, WA

Objective:

To evaluate the possible therapeutic roles of high dose immunosuppressive therapy (HDIT) and rescued with autologous stem cell transplantation (SCT)in the management of severe, non-responsive multiple sclerosis (MS)patients.

Background:

At the present time, there are four FDA approved disease-modifying agents available in the United States. However, none of these completely stops disease progression. All of them produce varying degrees of slowing of the disease process. Our hypothesis was that by ablating the immunoactive cells in an MS patient, and replacing them with non-conditioned naive cells, the disease process could be stopped.

Design/Methods:

we enrolled 26 patients with severe MS including primary progressive-MS (n=7), secondary progressive-MS (n=18), and relapsing remitting-MS (n=1). Their median age was 41 (range 27-60) years. The median EDSS at HDIT was 7.0 (5.0-8.0). Eligibility requirements included an EDSS from 5.0-8.0 and deterioration of one or more points over the previous year. 21 patients had failed previous therapy with interferon-beta, and 15 had failed multiple therapies including copaxone, prednisone and methotrexate. The median follow-up was 12 (3-36) months.

Results:

With a minimum follow-up of 6 months (n=22;1912 months), the majority of patients remain neurologically stable with unchanged EDSS. 6 patients had improvement on EDSS, 5 have had an increase in EDSS. No change was greater than 1.0 EDSS point. Only 2 patients had enhancing lesions on brain MRI at 1 year after SCT. One of these two had a flare of MS associated with the administration of granulocyte-colony stimulating factor (G-CSF). No patient has received further treatment with interferon-beta or copaxone after SCT. Complication included 12 patients of the first 18 patients had an engraftment syndrome involving T38, rash and fatigue. The subsequent 8 patients who received prednisone did not develop this syndrome. One patient had a flare during G-CSF for mobilization, but no more patients experienced MS flare after adding prednisone during the mobilization. One patient developed Guillain-Barre syndrome and pneumonia 17 months after SCT. Another patient had a sustained fever of unknown origin early after transplant and had an associated increase in baseline EDSS of 1.0. The only patient who received rabbit anti-thymocytic globulin (ATG) due to a positive skin test to horse ATG developed CMV disease and EBV- associated post-transplant lymphoproliferative disorder and expired at day 53.

Conclusions:

In conclusion, we believe that HDIT/SCT may become an effective treatment to control severe, progressive and refractory MS. The procedure appears to be effective to date. This and additional studies should be continued to fully assess long term efficacy in these heterogeneous high-risk patients.

Validation of the McDonald Criteria in Patients with Clinically Isolated Syndromes Suggestive of Multiple Sclerosis

Tuesday, April 16, 2002
Catherine M. Dalton, Peter A. Brex, Katherine A. Miszkiel, Gordon T. Plant, Alan J. Thompson, David H. Miller London, United Kingdom

Objective:

The objective of this study was to validate the new McDonald criteria at three months in patients with Clinically Isolated Syndromes (CIS) suggestive of MS who were followed for three years.

Background:

Traditionally MS has been diagnosed on the basis of clinical evidence of dissemination in time and space. New diagnostic criteria of the international panel of McDonald and colleagues incorporate MRI evidence of dissemination in time and space and allow a diagnosis of MS in patients with CIS.

Design/Methods:

Adult patients aged 16-50 years with CIS were recruited and imaged within three months of the onset of symptoms (mean 5 weeks) and again after three months, one year (79 patients) and three years (46 patients). A diagnosis of clinically definite MS was based on the traditional Poser criteria and a diagnosis of MS incorporating MRI findings was made using the McDonald criteria. Using the Poser criteria as the gold standard, the McDonald criteria were evaluated in terms of sensitivity, specificity, positive and negative predictive values.

Results:

38/79 (48%) of patients had a diagnosis of MS at one year using the McDonald criteria compared with 16/79 (20%) who had clinically definite MS. Using baseline and three month scans the McDonald MRI criteria alone have a sensitivity of 59%, specificity of 92%, positive predictive value of 83% and negative predictive value of 76% for the development of clinically definite MS. Specificity is higher than an abnormal baseline MRI brain (30%) or the traditional Barkhof criteria (78%).

Conclusions:

The McDonald criteria more than double the number of patients with a diagnosis of MS at one year. In making a diagnosis of a lifelong condition specificity is more important than sensitivity, therefore the McDonald criteria are valid.

Supported By:

The NMR Unit is supported by Multiple Sclerosis Society of Great Britain and Northern Ireland. CM Dalton was sponsored by elan. Schering AG supported PA Brex.

The Impact of Revised McDonald's Criteria in Predicting Multiple Sclerosis

Tuesday, April 16, 2002
Silvia Di Legge, Maria C. Piattella, Patrizia Pantano, Isabella F. Pestalozza, Valter Nucciarelli, Luigi Bozzao, Gian L. Lenzi, Carlo Pozzilli Rome, Italy

Objective:

To test reliability of the revised McDonald's criteria of Multiple Sclerosis (MS) in a cohort of patients with Clinically Isolated Syndrome (CIS) followed by serial Gd-enhanced MRI.

Background:

To facilitate the diagnosis of MS the revised criteria integrate MRI in the diagnostic scheme. Lesions in the brain detected by MRI can provide evidence of dissemination of lesions in both space (DIS) by Barkhof criteria and dissemination in time (DIT) by the appearance of at least a new Gd-enhanced lesion and/or new T2 lesion in serial MRI.

Design/Methods:

A series of consecutive CIS patients showing at least 3 typical white matter lesions on their brain MRI were followed-up for the first six consecutive months after enrollement with monthly Gd-enhanced brain MRI. Brain MRI were then performed at 12, 18, 24 and 36 months from the inclusion in patients who did not develop a second clinical episode during the study. In patients who developed a second clinical episode the study ended at the time of the relapse. For the present study we analyzed scans performed at baseline, 3, 6 and 12 months of those patients who were observed for at least 18 months.

Results:

We examined 53 patients, 35F and 18M, with a mean age of 30.5 yrs, time since clinical onset of 4.2 months and baseline EDSS of 1.3. During the observation period 19/53 (36%) of patients developed a second clinical episode and 45/53 (85%) developed MS by the McDonald's criteria.
Baseline MRI showed DIS in 89% (47/53) of patients. Out of them, DIT was observed in 28/53 (53%) at 3-month scan, in 40/50 (80%) at 6-month scan and in 31/40 (77.5%) at 12-month scan. At three-month MRI scan, sensitivity of the new McDonald's criteria was 89% (17/19) [95% confidence interval (CI) 75-100%], while specificity was 68% (23/34) [95% CI 52-84%]. Positive predictive value (PPV) and negative predictive value (NPV) were 61% (17/28) and 92% (23/25), respectively.

Conclusions:

These preliminary results obtained in CIS patients show a high sensitivity of the diagnostic McDonald's criteria at three-month MRI scan, while the specificity is low. It is likely that the specificity of the new McDonald's criteria will increase with a longer follow-up. Furthermore, the high NPV at three-month MRI scan suggests that McDonald's criteria can early detect patients who will remain disease-free.

MRI Criteria for Multiple Sclerosis: Evaluation in a Paediatric Cohort

Tuesday, April 16, 2002
Cecil D. Hahn, Manohar M. Shroff, Susan I. Blaser, Brenda L. Banwell Toronto, ON, Canada

Objective:

To investigate whether existing MRI criteria used in the evaluation of multiple sclerosis (MS) in adults are applicable to the paediatric MS population.

Background:

MRI criteria for the evaluation of MS in adults have been proposed and validated by several authors. (Paty et al., Fazekas et al., Barkhof et al.) The validity of these MRI criteria in the paediatric MS population has not been determined.

Design/Methods:

This study was an analysis of children with clinically definite MS (CDMS) by Poser's criteria who are followed in a multidisciplinary paediatric multiple sclerosis clinic at The Hospital for Sick Children. Clinical records were reviewed to identify the dates and clinical features of their first attack and subsequent MS-defining attack. MRI studies performed at the time of each attack were graded according to the criteria of Paty, Fazekas and Barkhof.

Results:

Twenty children with CDMS were identified and 3 were excluded because applicable MRI studies were unavailable for review. Of the remaining 17 children, 13 had MRI studies performed at both attacks, 2 had MRI studies performed only at the first attack, and 2 had MRI studies performed only at the MS-defining attack. 9 children were female. The mean age at diagnosis of CDMS was 11 years (range 6-18 years). The median interval between the first attack and the MS-defining attack was 6 months (range 2-29 months). At the time of the first attack, the criteria of Paty, Fazekas and Barkhof were met by 11 (73%), 10 (67%) and 7 (47%) children, respectively, and 4 children (27%) met none of the criteria. At the time of the MS-defining attack, the criteria of Paty, Fazekas and Barkhof were met by 11 (73%), 12 (80%) and 9 (60%) children, respectively and 3 children (20%) met none of the criteria.

Conclusions:

Recently, McDonald et al. have proposed revised diagnostic criteria for MS which employ the MRI criteria of Barkhof. In the present study of children with CDMS, we have found that less than half met the Barkhof criteria at time of their first attack and only 60% met the Barkhof criteria at the time of their MS-defining attack. The children were more likely to meet the Paty and Fazekas criteria, but still not as likely as has been reported in adults. (Offenbacher et al., Tintore et al.) We conclude that the typical MRI features of adult MS are less common in paediatric MS. The accurate and timely diagnosis of MS in children would be supported by the development of MRI criteria that are validated in the paediatric MS population.

Natalizumab Treatment for Relapsing MS: Further Results of a Randomized, Double-Blind, Placebo-Controlled Trial

Tuesday, April 16, 2002
Catherine Dalton, Paul O'Connor, George Rice, Omar Khan, J. Theodore Phillips, Gareth Barker, David MacManus, Katherine Miszkiel, David Miller, the International Natalizumab (Antegren™) MS Trial Group London, United Kingdom; Toronto, Canada; London, ON, Canada; Detroit, MI; Dallas, TX

Objective:

To assess the effect of monthly IV administrations of natalizumab (3.0 or 6.0 mg/kg) vs placebo over a 6 month treatment period and for an additional 6 months following discontinuation of study treatment on brain lesion activity in patients with relapsing MS.

Background:

The cell adhesion molecule alpha4beta1 integrin, also known as VLA-4, is thought to play an important role in the trafficking of mononuclear cells into sites of inflammation. Through its interaction with vascular cell adhesion molecule-1 (VCAM-1), alpha4beta1 mediates migration of autoreactive lymphocytes into the brain leading to the inflammatory lesions of multiple sclerosis. Recently it has been demonstrated that monthly treatments with natalizumab, an alpha4-integrin antagonist in the class of selective adhesion molecule inhibitors (SAMIs), reduced the occurrence of new gadolinium enhancing MRI lesions and clinical relapses in patients with multiple sclerosis over the six month treatment period (Multiple Sclerosis 2001 (Abstract;7:S16.). The present report describes additional analyses performed during the six months of treatment and follow up.

Design/Methods:

213 patients with relapsing MS were randomized to receive either natalizumab at 3 or 6 mg/kg or placebo IV every 4 weeks for 6 months and were followed for an additional 6 months for safety. Inclusion criteria included relapsing disease with 2 relapses within the last 2 years, an EDSS of 2.0 to 6.5 and no concomitant disease modifying treatment. T1 gadolinium-enhanced and T2-weighted imaging were performed pretreatment, every 4 weeks during the 6 month treatment period and quarterly during the 6 month post-treatment safety follow-up.

Results:

At the six month time point, natalizumab treatment resulted in a statistically significant reduction in the number of new and enlarging T2 lesions, the number of new T1 hypointense lesions and the number of active scans, i.e. containing new enhancing lesions. During the six month follow-up period there were no significant differences in numbers of enhancing brain lesions or relapses between treatment groups. Natalizumab treatment appeared to be well tolerated.

Conclusions:

During the six month treatment period, natalizumab suppressed new T1 gadolinium-enhanced, T2-weighted and T1 hypointense brain lesions as well as clinical relapses. Post treatment MRI and clinical activity resumed to a level similar to placebo. In view of these promising findings, Phase III trials are underway to evaluate the longer term effect on relapses and disability.

Supported By:

Elan Pharmaceuticals Inc. and Biogen Inc.

Safety and Efficacy of Combination Therapy with Interferon Beta-1b and Mitoxantrone in Worsening Multiple Sclerosis Using Monthly Gadolinium Enhanced MRI

Tuesday, April 16, 2002
Douglas R. Jeffery, Neraj B. Chepuri, Jason Rosenburg Winston-Salem, NC

Objective:

To examine the safety and efficacy of combined therapy with Mitoxantrone (MITX)and Interferon Beta-1b (IFNb-1b)in patients with worsening multiple sclerosis (MS) and a subotimal therapeutic response to IFN-b-1b alone.

Background:

Despite the demonstrated efficacy of immunotherapeutic agents in the treatment of MS, many patients show a suboptimal response with continued progression of disability and frequent relapse. Mitoxantrone decreases relapse rates, decreases the progression of disability, decreases the accumulation of new T2 and new gadolinium enhancing lesions in both relapsing-remitting (RR)and secondary progressive (SP)MS. The purpose of this trial was to examine the safety and efficacy of combined therapy with IFNb-1b and MITX in patients with worsening MS not controlled on IFNb-1b alone.

Design/Methods:

Ten patients with RR or SP MS were enrolled in the trial. All patients had to be on IFNbb-1b for at least six months, have at least one new enhancing lesion on a screening MRI, one relapse in the six months prior to study enrty, and be neutralizing antibody negative. All patients were required to have normal cardiac function prior to study entry. Monthly MRI scans using triple dose contrast with 30 min delay between contrast administration and scanning were carried out for three months to obtain baseline numbers of new enhancing lesions (NEL). At the end of the baseline phase, MITX was administered at 12 mg/m2 (month 1), and 5 mg/m2 at month 2 and 3. Dosing was then continued at 5 mg/m2 every third month. Monthly MRI scanning was continued for the duration of the study. The primary outcome measure was the number of NELs. Secondary outcome measures included relapse rates, EDSS, and change in T2 and T1 lesion volume.

Results:

The addition of MITX to therapy with IFN was well tolerated and there no serious adverse events. Mean white blood cell counts decreased to 2,800 at day 14 but returned to normal levels by day 21. Five upper respiratory tract infections occurred in three patients and one patient had a urinary tract infection. No adverse cardiac events were noted. The mean number of NELs per month in the baseline phase was 2.93±2.46. Mean NELs decreased to 1.09±1.5 following the addition of MITX. Median NEL number decreased 81% following the addition of MITX. New enhancing lesion numbers were suppressed to a greater extent with longer duration of exposure to MITX. At the time of the last scan (month 6)only two patients had new enhancing lesions. Relapse rates decreased 74% following the addition of MITX.

Conclusions:

The combination of therapy with IFNb-1b and MITX was well tolerated and there were no serious adverse events. Both clinical and MRI measures of disease activity responded well to the combination. Relapse rates decreased by 74% and by the time of the last scan only two patients had NELs and volumes were very small. While these results are preliminary, they suggest that patients with aggressive forms of MS failing immunotherapy may benefit from the combined use of IFNb-1b and MITX.

Supported By:

This study was supported by grants from Berlex Laboratories and Immunex.

Neuropsychological Features of Pediatric Multiple Sclerosis

Tuesday, April 16, 2002
Brenda L. Banwell, Peter E. Anderson Toronto, ON, Canada

Objective:

To provide a comprehensive assessment of the cognitive profile and academic achievement of a cohort of pediatric MS patients and to compare these results to age-matched normative data.

Background:

Although Multiple Sclerosis (MS) is a disease that primarily affects adults, approximately 2-5% of all MS patients will be diagnosed prior to their 18th birthday. Cognitive deficits are common in adults with MS, and adversely influence patient employment and quality of life. The impact of MS on the developing brain, both on cognition and academic achievement is essentially unknown.

Design/Methods:

Ten children, aged 9-16 years with clinically definite MS as defined by the criteria of Poser et al, were studied. All patients were examined by a pediatric neurologist on the morning of testing to ensure that none were experiencing an MS-related relapse, and all patients were at least 30 days from last corticosteroid exposure. A detailed neuropsychological battery was administered in two 4 hours sessions. Patient, parent and teacher evaluation forms were also completed.

Results:

The mean age at the time of study was 13.2 years (9-16 years), 5 patients were male. Mean time since diagnosis 2.7 years, mean time from first attack was 3.65 years. Relative to normative data, the MS patients performed significantly poorer on some indices from a measure of psychometric intelligence (FSIQ; VIQ, PIQ, VCI) visual motor integration, visual learning and memory, story recall, receptive language, and spelling. Examination of the impact of time since diagnosis (< 2 years, n=4; 2 years, n=6) revealed that participants with a longer time since diagnosis showed even greater deficits on some measures of psychometric intelligence (FSIQ; PIQ; POI), visual perception/construction, visual motor integration, visual memory, and applied mathematical knowledge. These latter findings are consistent with those reported in the adult literature, with a clear deficit in visual-spatial processing in the face of relatively preserved verbal functioning. Overall, however, a wider range of deficits was found in pediatric MS patients than has been documented in studies of MS in adults. Parents and teachers were aware of the child's neurocognitive weaknesses, as well as their socioemotional status and the effect of these variables on scholastic performance.

Conclusions:

Cognitive deficits are common in pediatric MS, are more widespread than in adult MS patients, are more severe in patients with longer duration of disease, and are of sufficient magnitude to influence academic performance.

Supported By:

This study was supported by a pilot project grant from the Canadian Multiple Sclerosis Society.

Safety Profile of Mitoxantrone in a Cohort of 802 Multiple Sclerosis Patients

Tuesday, April 16, 2002
Gilles Edan, Bruno Brochet, David Brassat, Michel Clanet, Pierre Clavelou, Christian Confavreux, Marc Debouverie, Olivier Heinzleff, Christine Lebrun, Catherine Lubetzki, Jean Pelletier, Michel Madigand, Lucien Rumbach, Emmanuelle Leray Rennes, France; Bordeaux, France; Toulouse, France; Clermont-Ferrand, France; Lyon, France; Nancy, France; Paris-Tenon, France; Nice, France; Paris-Salpétrière, France; Marseille, France; St Brieuc, France; Besancon, France

Objective:

To determine the incidence of drug-related adverse events in a cohort of MS patients treated with mitoxantrone.

Background:

MITOX, originally developed as an antineoplastic drug, has been recently approved by the FDA for the treatment of MS. The experience of 12 French MS centers with mitoxantrone from 1992 to 2001 allowed us to evaluate the safety profile of this agent

Design/Methods:

Since 1992, 802 MS patients (302 Relapsing Remitting MS, 351 Secondary Progressive MS, 143 Primary Progressive MS) were treated with MITOX in a consortium of French MS Centers. The median age at MITOX onset for treatment was 39 years; median MS duration before MITOX onset was 8.3 years; median follow-up duration after MITOX onset treatment was 2 years with a follow-up duration more than 2 years for 367 patients. MITOX was administered either monthly for 6 courses in 87% , or every 3 months in 13% of the cohort. The median and the mean cumulative dose of MITOX was 70 mg/m2. 656 consecutive patients completed echocardiograms at 0, 6, 24 or 60 months. Patients underwent clinical and hematological evaluation before every MITOX course and every 6 months after MITOX withdrawal. At baseline, LVEF in all patients was greater than 50%. Treatment was discontinued if LVEF fell below 50%.

Results:

There was no evidence of clinical heart failure in any patient. Twelve patients (1.8%), experienced assymptomatic reduction of LVEF to < 50%. In 3 of these 12 patients, assymptomatic LVEF <50% persisted for follow-up ranging from 4.5-7.0 years. Other adverse events included: 1 case of acute myelogenous leukemia detected 22 months after initiating Mitox, 6 patients with infection associated with ANC < 500, and 10 % of women at risk to lose menses experienced amenorrhea persisting more than 6 months. and up to the last control . There were 11 deaths, none related to therapy. . Most current data for this cohort will be provided at AAN presentation.

Conclusions:

Mitoxantrone was generally well tolerated as administered to this cohort. Continued pharmacovigilence is warranted to ascertain the long term risk of t AL and cardiac toxicity in this population.

Ultra High Field Strength MR Imaging of White Matter at 8 Tesla in Multiple Sclerosis

Tuesday, April 16, 2002
Kottil W. Rammohan, Alayar Kangarlu, Eric Bourekas, Donald Chakeres Columbus, OH

Objective:

To characterize the spectrum of white matter abnormalities that occur in patients with relapsing and progressive multiple sclerosis, and to examine the hypothesis that high-resolution imaging of the white matter in patients with MS at 8 Tesla is superior to conventional imaging at 1.5 Tesla.

Background:

It has been impossible to directly define abnormalities in the normal appearing white matter (NAWM) in patients with progressive MS using conventional imaging at 1.5 Tesla. It is clear that NAWM in patients with progressive MS is not normal. Point-of-interest or whole brain N-acetyl aspartate (NAA), magnetization transfer imaging, magnetization transfer ratios and whole brain apparent diffusion coefficients have all identified abnormalities the NAWM in patients with progressive MS. The potential for high field MR in better defining demyelinating abnormalities remains to be elucidated.

Design/Methods:

Six patients with definite multiple sclerosis (2 relapsing-remitting MS (RRMS),2 primary progressive (PPMS), and 2 secondary progressive (SPMS)) were imaged after informed consent under an IRB. All patients underwent imaging at 1.5 and 8 Tesla using gradient echo and RARE sequences.

Results:

MR images at 8 Tesla were more inhomogeneous compared to the 1.5 Tesla images. The more homogeneous regions on the 8 Tesla images demonstrated better definition, since image matrices of up to 1024 x 1024 were used compared to matrices of 256 X 256 at 1.5 Tesla. This permitted magnifications of lesions 16 times greater than conventional imaging and definition of white matter abnormalities not previously possible. In spite of this greater resolution, preliminary imaging at 8 Tesla did not improve detection of disease burden in patients with PPMS as compared to imaging at 1.5 Tesla. By contrast, imaging of patients with RR and SPMS identified significantly higher disease burden in their white matter at 8 Tesla as compared to 1.5 Tesla. Numerous well defined areas of plaque formation were evident at 8 Tesla in the NAWM in patients with RR and SP MS. Because of the near microscopic (200 micron) definition, a consistent relationship between plaques and vessels was routinely demonstrated, with plaques noted centered around the veins (Dawson's fingers).

Conclusions:

High field MR imaging at 8 Tesla did not improve the detection of lesions in brains of patients with PPMS. On the other hand, patients with RR and SPMS demonstrated improved resolution, permitting better definition of abnormalities in the NAWM. Characterization of such abnormalities will undoubtedly facilitate improved classification of MS patients for evaluation of natural history studies, as well as clinical therapeutic trials. Our preliminary studies at 8 Tesla have established a role for imaging at high field in improving characterization of lesions in patients with MS. Characterization of these white matter abnormalities not previously possible will permit better definition of the NAWM and help to define the progressive nature of the disease in some patients.

MRI Results of the European Interferon Beta-1a Dose-Comparison Study

Wednesday, April 17, 2002
Ernst-Wilhelm Radue, Ludwig Kappos, Nancy Simonian, Mariska Kooijmans, Michel Clanet, Peter Slasor, Richard A. Rudick, the European Interferon Beta-1a Dose-Comparison Study Group Basel, Switzerland; Cambridge, MA; Toulouse, France; Cleveland, OH

Objective:

To report magnetic resonance imaging (MRI) results from the European Interferon Beta-1a (IFNb-1a, AVONEX®) Dose-Comparison Study.

Background:

IFNb-1a 30 mcg IM once weekly slows physical and cognitive disability progression, reduces relapses, reduces conversion to clinically definite MS, and decreases active lesions on MRI. Studies of IFNb at different doses have suggested a ceiling effect. But, until now, studies designed solely to evaluate the efficacy between two doses have not been performed.

Design/Methods:

This was a multinational, randomized, double-blind, parallel-group, dose-comparison study conducted at 38 sites in 10 European countries. Patients with relapsing MS were randomized to receive IFNb-1a 30 mcg (n=402) or 60 mcg (n=400) IM once weekly for 3 years. The first 386 patients enrolled at 28 MRI sites received scans at baseline, months 12, 24, and 36 (annual MRI cohort); 138 of these patients also received scans at Months -4, -3, 4, 5, 6, 10, 11, and 12 (frequent MRI subgroup). MRI endpoints included: number and volume of gadolinium-enhanced (Gd+) lesions for both the annual MRI cohort and the frequent MRI subgroup; and T2-hyperintense lesion accrual, T1 (hypointense) lesion accrual, and brain parenchymal fraction (BPF) for the annual MRI cohort only.

Results:

At baseline, there were no significant differences between groups on any of the MRI parameters. At follow-up, in both doses of IFNb-1a, substantial reductions from baseline in all MRI measures at all time points were found. There were no statistically significant differences nor trends observed between IFNb-1a 30 mcg and 60 mcg with regard to change in T2 lesion volume, change in T1 lesion volume, change in BPF, number and volume of Gd+ lesions, and number of new or enlarging T2 lesions compared with baseline.

Conclusions:

MRI findings corroborate clinical results, which showed no added benefit of IFNb-1a 60 mcg compared with the current commercially available dose of 30 mcg IM once weekly.

Supported By:

Biogen, Inc.

Differences in Brain Atrophy between Early Relapsing Remitting Multiple Sclerosis Patients with Different APOE Genotypes

Wednesday, April 17, 2002
Maria Pia Amato, Maria Letizia Bartolozzi, Benedetta Nacmias, Valentina Zipoli, Marzia Mortilla, Elena Cellini, Silvia Bagnoli, Leonello Guidi, Paolo Lambruschini, Sandro Sorbi, Antonio Federico, Nicola De Stefano Florence, Italy; Empoli, Italy; Siena, Italy

Objective:

To evaluate axonal and tissue damage in relapsing remitting (RR) multiple sclerosis (MS) patients in the early stages of the disease and with different apoliprotein E (APOE) genotypes.

Background:

Recent clinical and imaging studies have raised the still debated hypothesis that MS patients who carry the APOE e4 allele (e3/e4 or e4/e4) may have a more severe disease course with respect to those without the APOE e4 allele (e3/e3). This seems to be related to more extensive tissue destruction and less efficient neuronal maintenance and repair in APOE e4 carriers.

Design/Methods:

We determined the APOE genotype in 27 consecutive RR MS patients with a short disease duration (median = 1 year) and mild disability (median Expanded Disability Status Scale [EDSS] = 1.5. Each MS patient underwent combined proton MR imaging (MRI) and MR spectroscopic imaging (MRSI) examinations in order to obtain measures of cerebral volumes and central brain levels of N-acetylaspartate (NAA, a reliable measure of axonal integrity), respectively. Measures of the MS patient group were compared to those of 18 demographically matched normal controls (NC) using the nonparametric Kruskal-Wallis test of variance. Differences between different patient subgroups and NC were assessed using analysis of variance (ANOVA) followed by pairwise post-hoc comparison using Tukey's HSD procedure to account for multiple comparisons.

Results:

We identified 20 patients with the APOE e3/e3 genotype and 7 patients with the e4 allele. The two patient groups showed no significant differences in age, age at disease onset, EDSS and disease duration (p 0.5) for all measures. Both patient groups showed similar significant (p<0.01) decreases in central brain NAA levels (normalized to creatine [Cr]) with respect to NC (NAA/Cr in e3/e3 MS patients = 2.8 ±0.22, NAA/Cr in e4 MS patients = 2.7 ±0.10, NAA/Cr in NC = 3.1 ±0.20). However, automated measurements of normalized brain volumes (NBV) showed significant decreases (p<0.001) in MS patients carrying the e4 allele with respect to both NC and MS patients without the e4 allele (NBV in e3/e3 MS patients = 1605 ± 39 cc, NBV in e4 MS patients = 1523 ± 038 cc, NBV in NC = 1600 ± 39 cc).

Conclusions:

Preliminary data of this ongoing study could not confirm the hypothesis of more severe disease course in MS patients with APOE e4 genotype. Also, decreases in NAA/Cr, suggesting a relevant axonal damage despite the early disease stage, were similar in the two patient groups. However, significant brain volume loss was found only in early RR MS patients with the APOE e4 genotype. This suggests that the e4 allele can influence more severe tissue destruction in MS patients and that this influence can be seen from early disease stages.

Consensus Guidelines for Standardized MRI Scanning in Multiple Sclerosis

Wednesday, April 17, 2002
P. K. Coyle, CSMC MRI Consensus Committee Stony Brook, NY

Objective:

To develop consensus guidelines for standardized neuroimaging diagnostic protocols, and indications for follow up magnetic resonance imaging (MRI), in multiple sclerosis (MS).

Background:

MRI is usually done as part of the diagnostic workup for MS, and random scans are often obtained to follow patients on treatment. There are no guidelines for such use. Standardized MRI protocols would help maximize the value of individual scans, allow systematic data collection for clinical and comparison studies, and act to guide / standardize MS neurologic practice.

Design/Methods:

An expert consensus meeting on "MRI Protocols for the Diagnosis and Follow Up of MS", sponsored by the Consortium of MS Centers (CMSC) was convened November 3 - 4, 2001, in Vancouver. Participants included MS neurologists and neuroradiologists from the United States, Canada, Europe, and New Zealand, with representation from the American Academy of Neurology, American Society of Neuroradiology, and Radiological Society of North America. A literature review identified important articles for consideration.

Results:

Preliminary results of the consensus meeting propose ten MRI guidelines. The guidelines endorse a standardized MRI protocol to image brain and spinal cord, with specified required and optional features. Images would be obtained on a 1 Tesla or higher machine, using a slice thickness of 3mm ( 1.5mm for 3D sequences), without gaps. Scan orientation would be on the subcallosal line using 3 planes, and using a localizer if available.
Routine follow up MRI is not recommended, although clinical indications for follow up imaging are provided (unexpected worsening, reassessment of disease burden to initiate therapy, suspicion of a second diagnosis). The guidelines provide a prototype radiology report using standardized and consistent common language, describing such features as lesion number, location, size, shape, and character. They recommend that a copy of the MRI be retained permanently.

Conclusions:

These preliminary consensus guidelines are available for review on the CMSC website (MSCARE.ORG). They need to be disseminated widely for discussion and comment, in order to establish standardized practice patterns in MS worldwide.

Supported By:

Sponsored by the Consortium of MS Centers

Functional MRI and Neural Activation Patterns Associated with Recognition Memory Performance in Multiple Sclerosis

Wednesday, April 17, 2002
Lorri J. Lobeck, Julie A. Bobholz, Sally Durgerian, Judy Zaferos, David Miller, Julia Rao, Catherine L. Elsinger, Eric F. Maas, Steve M. Rao Milwaukee, WI

Objective:

This study was done to assess changes in patterns of activation on functional magnetic resonance imaging and their relationship to encoding or retrieval deficits in patients with mutliple sclerosis and abnormal memory function.

Background:

Forty-five to sixty percent of patients with multiple sclerosis will experience cognitive deficits during the course of their illness. The extent of disease burdun or white matter lesions present on conventional T2 weighted MRI scans correlates with the severity of cognitive deficits. Memory functions, including new learning are frequently compromised in cognitively impaired patients. Whether this is due to encoding or retrieval difficulties is not known.

Design/Methods:

15 patients with multiple sclerosis and 8 demographically matched control subjects underwent fMRI and FLAIR imaging. To test encoding memory, subjects made a sematic decision (abstract versus concrete) regarding 60 nouns, presented every 4.5 seconds. Thirty minutes later subjects were tested for recognition memory by testing 60 targets and 60 foils.

Results:

Recognition accuracy was similar for the two groups. However, when investigating the relationship between lesion load and the patterns of neural activation, activation in the bilateral dorsolateral prefrontal cortex and lateral cerebellum was more common in patients with higher lesion load. Lower lesion load was associated with increased activation in the left hipppocampal gyrus.

Conclusions:

Even when recognition memory is normal, the neural systems involved in encoding appear to shift from long-term (left hippocampus) to working memory (bilateral dorsolateral prefrontal cortex and lateral cerebellum) strategies as lesion burden increases in multiple sclerosis.

Supported By:

Biogen
Fourteen Cambridge Center
Cambridge, Massachusetts 02142

T2 Relaxation Measurements of In-Vivo Water Content and Myelin Water Content in Normal Appearing White Matter and Lesions in Multiple Sclerosis

Wednesday, April 17, 2002
Cornelia Laule, Irene M. Vavasour, Joel Oger, Donald W. Paty, David K. B. Li, Alex L. MacKay Vancouver, BC, Canada

Objective:

To measure in-vivo water content and myelin water content of white matter, grey matter and lesions in patients with multiple sclerosis (MS) and controls

Background:

Measurements of the T2 decay curve can provide estimates of total and myelin water content in vivo, which may help in understanding the pathological progression of MS. This study reports total water content and myelin water content in normal white matter (NWM) of controls, normal appearing white and gray matter (NAWM, NAGM) and lesions of MS patients.

Design/Methods:

Thirty-three MS patients (24 RR, 8 SP, 1 PP, mean disease duration = 9yrs) and 15 controls underwent MR examinations. T2 relaxation data were acquired using a 32 echo CPMG experiment. All controls and 18 of the 33 MS patients were scanned in the transverse plane through the genu and splenium of the corpus callosum. Five white matter structures (genu and splenium of the corpus callosum, internal capsule, minor forceps, major forceps) and 6 grey matter structures (cingulate gyrus, insular cortex, cortical grey, thalamus, putamen, caudate) were outlined in these subjects. The remaining 15 MS patients were scanned in various other transverse planes. A total of 185 lesions were outlined in the MS patients. Total water content was estimated from the ratio of signal in the chosen region of interest to that in an internal grey matter standard (putamen or cortical grey). Myelin water content was defined as the fraction of signal with T2 below 50 ms divided by the total signal in the T2 distribution.

Results:

The NAWM total water content was, on average, 1.8% greater than that of NWM, with significant differences occurring in the posterior internal capsules, genu and splenium of the corpus callosum, minor forceps and major forceps (p<0.002). On average, MS lesions had 7.7% higher water content than NAWM (p<0.0001). The average myelin water content was 15% lower in NAWM than NWM, with the largest differences being in the major forceps (p=0.005), minor forceps (p=0.03), genu (p=0.05) and splenium (p=0.02). The myelin water content of MS lesions averaged 50% that of NAWM.

Conclusions:

Normal appearing white matter in MS has a higher water content and lower myelin water content than controls. The cause of the total water content increase in NAWM could be due to either diffuse edema or inflammation. As our understanding of T2 improves, we may be able to distinguish these two pathologies from the shape of the T2 distribution. A simple model of white matter suggests that a 1.8% increase in total water content by edema is not sufficient to account for the observed 15% decrease in myelin water. Therefore, we believe that the white matter of NAWM has diffuse demyelination.

Supported By:

MS Society of Canada

Application of the New McDonald's Diagnostic Criteria in a Cohort of Patients with Clinically Isolated Syndromes

Wednesday, April 17, 2002
Mar Tintore, Alex Rovira, Jordi Rio, Carlos Nos, Elisenda Grivé, Jaume Sastre-Garriga, Imma Pericot, Esther Sánchez, Manuel Comabella, Xavier Montalban Barcelona, Spain

Objective:

To apply the new McDonald's diagnostic criteria in a cohort of patients with clinically isolated syndromes (CIS).

Background:

An international Panel on MS Diagnosis has recently presented revised diagnostic criteria for MS.

Design/Methods:

139 patients with CIS were longitudinally studied (58 optic neuritis, 34 brainstem syndromes, 39 spinal cord syndromes and 8 polyregional syndromes). Brain MRI was performed after the first demyelinating event and repeated after 12 months of follow-up. Criteria proposed by Barkhof et al were applied in the basal MRI. The number of new T2 weighted lesions was also studied in the first year MRI. Poser's and McDonald's diagnostic criteria were applied after a one year follow-up cut point.

Results:

During the first 12 months of follow-up, 15 patients (11%) had developed CDMS. Barkhof's criteria (3 out of 4) showed 71% sensitivity, 69% specificity and 70% accuracy in predicting conversion to CDMS, whereas on adding the alternative condition of at least 2 lesions plus oligoclonal bands, we obtained 87% sensitivity, 56% specificity and 65% accuracy. Seventy-seven patients (55%) fulfilled criteria for dissemination in space according to McDonald's criteria. Sixty-two patients (45%) fulfilled MR criteria for dissemination in time. Fifty-one patients (37%), 10 of whom had previously had one second clinical attack, fulfilled both radiological conditions of dissemination in time and space. Consequently annual MRI anticipated MS diagnosis in 41 patients (29%). At one year follow-up, 40% of the patients (11% because of a second event and 29% according to MR criteria for dissemination in time and space) would be diagnosed as MS according to McDonald's criteria compared 11% with Poser's criteria.

Conclusions:

The alternative condition for dissemination in space (at least 2 lesions plus OB) should be used with caution as the high specificity of Barkhof's criteria may be clearly compromised. McDonald's criteria anticipate the diagnosis of MS in 29% of the patients after one year of follow-up.

Depression in MS: The Relationship to Interferon Therapy

Wednesday, April 17, 2002
Luanne M. Metz, Gordon Francis, Yves Grumser Calgary, AB, Canada; Norwell, MA; Geneva, Switzerland

Objective:

To determine depression and suicide rates in a pooled series of cohorts of MS patients treated with interferon (IFN) beta-1a.

Background:

Depression is common in MS and, with suicide, was linked to IFN therapy based on data in the pivotal IFN beta-1b (Betaseron©) study. Subsequent studies have not confirmed a similar relationship even when objective measures (depression rating scales) were used to evaluate the relationship. Data is presented from a large pooled data set of all MS studies of IFN conducted by Serono.

Design/Methods:

Any event labeled depression by the physician was included. Safety data for 4469 patients (total trial patients [TP]), treated for 6 months to 6 years, was available for analysis. Both randomized controlled trials (RCTP) and uncontrolled studies were included. Only data on serious adverse events (SAE), AE dropouts, and deaths were available from the latter. Both RRMS (n = 3450) and SPMS (n = 1019) patients were included. Patients received either placebo or active drug (3995 Rebif©, 337 Avonex© and 824 placebo patients). Doses ranged from 22mcg weekly (qw) to 44mcg thrice weekly (tiw).

Results:

In RCTP depression was reported within 6 months by 7.6% of placebo patients (n = 824) vs. 4.6% of 22mcg qw (n = 435), 13.4% of 30mcg qw (Avonex) (n = 337), 8.2% of 44mcg qw (n = 98), 9.0% of 22mcg tiw (n = 398), and 11.7% of 44mcg tiw patients (n =727). By 24 months, 26.5% of placebo (n = 392), 24.1% of 22mcg tiw (n=398), and 27.6% of 44 mcg tiw (n = 388) patients had a depressive event (p = 0.75, Fisher's exact test, 44mcg vs. placebo). The proportion of dropouts in RCTP (n =1995) due to depression was 1.35% for IFN and 0.12% for placebo (p = 0.001, Fisher's exact test). For TP the rate was 0.88/100 pt-yr for IFN patients and 0.06/100 pt-yr for placebo patients (p=0.007). Depression was cited as the reason for 32% (27/84) of all IFN RCTP AE dropouts, and 8% (1/12) of placebo AE dropouts (p=0.17), and was twice as common in SPMS as RRMS. Over 2-years suicide attempts were equal in RCTP treatment groups. The rate of suicide in TP was 0.12/100 pt-yr for placebo and 0.08/100 pt-yr for IFN (p=0.62, Poisson regression). There were two suicides in RRMS (one each, placebo and 22 mcg tiw) and six in SPMS (one placebo, one 22mcg qw, two 22mcg tiw and two 44mcg tiw).

Conclusions:

At 6 months, depression varied by IFN dose group. After 2 years of treatment, depression was more frequent overall, but was not significantly different between IFN and placebo. Dropouts due to depression were significantly more common in IFN beta-1a (Rebif©) than placebo treated groups, and were also more common in SPMS than RRMS. The suicide rate was lower on active therapy than placebo. No association between the risk of depression or suicide and interferon therapy was seen but depression is still one of the more common causes to stop therapy. Early identification and treatment of depression may increase adherence to therapy.

Supported By:

Serono.

The Predictive Value of Gadolinum Enhancement for Clinical Status over a 5-10 Year Period

Wednesday, April 17, 2002
Lael A. Stone, Elizabeth Fisher, Gary R. Cutter, Roger Stone, Jennifer McCartin, Joan Ohayon, Nancy D. Richert, Joseph A. Frank, Henry F. McFarland Cleveland, OH; Denver, CO; Bethesda, MD

Objective:

To investigate the predictive value of gadolinium enhancement (GdE) for clinical status in multiple sclerosis (MS) over a 5-10 year period.

Background:

In patients with a clinically isolated demyelinating syndrome, a relationship between amount of T2 weighted MRI abnormality at onset and clinical status over a 5-10 year period has been shown. Although GdE is helpful for diagnostic MRI in MS, little is known about the prognostic value of GdE. This study reports the clinical findings of a cohort of MS patients assessed with 3 consecutive monthly Gd-enhanced MRI scans at baseline and followed up some 6-12 years later.

Design/Methods:

113 MS patients evaluated at the Neuroimmunology Branch (NIB)of the NIH between 1989 and 1994 with three clinical visits and three consecutive monthly Gd-enhanced MRI scans were identified for inclusion in this study: Out of 90 patients contacted, 79 have been evaluated by follow-up clinical examinations and MRI scans. The mean interval between baseline and follow-up was 8.3 years (sd=1.6 range 6-12 years).

Results:

Mean EDSS at entry in this initial group of 79 patients reexamined to date was 3.1 (sd=2.0 range 0.3 to 8.4) and at follow-up was 4.3 (sd= 2.4 range 1 to 9). The majority of the initial group were relapsing remitting MS by clinical course (RRMS-65.3%). Preliminary analyses suggest a relationship between higher levels of GdE at baseline and poorer patient status at follow-up as measured by various measures including the MSFC and its components, in some but not all clinical sub-types of MS. Duration of disease may be an additive factor to GdE as well for prognosis.

Conclusions:

GdE may require additional information on clincial subtype and duration of disease to be useful for prognosis in MS.

Supported By:

National Multiple Sclerosis Society, National Institute of Neurological Disorders and Stroke, and Laboratory for Diagnostic Radiology Research, NIH

Ganglioside Reactive Antibodies in Multifocal Inflammatory Sensory and Motor Neuropathy (MISAM)

Wednesday, April 17, 2002
Armin Alaedini, Howard W. Sander, Norman Latov New York, NY

Objective:

To determine whether anti-ganglioside antibodies are present in patients with acquired multifocal sensory and motor neuropathy.

Background:

Autoimmune mechanisms are suspected in some of the acquired multifocal neuropathies, including multifocal motor neuropathy (MMN), and multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). IgM antibodies to gangliosides have been reported in MMN, but not in multifocal sensory and motor neuropathy.

Design/Methods:

Sera from 218 patients with a variety of chronic neuropathies, and from 76 control subjects (20 with multiple sclerosis, 10 with amyotrophic lateral sclerosis, and 46 healthy individuals) were tested for anti-ganglioside antibodies by a newly developed ganglioside agglutination assay, using polystyrene microparticles coated with a total ganglioside extract from bovine brain. Sera found to be positive by the agglutination assay were also tested by ELISA for IgM and IgG antibodies to GM1, GM2, GD1a, GD1b, GQ1b, and GT1b gangliosides.

Results:

Ten of 20 sera (50%) from patients with multifocal sensory and motor neuropathy were found to be positive for anti-ganglioside antibodies. Electrodiagnostic studies revealed neuropathic dysfunction, affecting legs more than the arms. Focal or multifocal abnormalities were present in 9/10 patients. In 2/10 there were features of demyelination. Sural nerve biopsies in 2 revealed changes consistent with an axonal neuropathy. By ELISA, 5 of the patients had mildly elevated titers of IgG antibodies to one or more gangliosides including GM1, GM2, GD1b, GD1a, and GT1b. None of the control sera were reactive by the agglutination assay or ELISA. Five of 6 patients treated with intravenous gammaglobulins (IVIg), etanercept, or plasmapheresis plus etanercept, showed clinical improvement.

Conclusions:

The presence of anti-ganglioside antibodies in acquired multifocal sensory and motor neuropathy indicates a possible immune mechanism consistent with the observed clinical response to immunomodulating agents. The term multifocal inflammatory sensory and motor neuropathy (MISAM) may be appropriate, given that both axonal and demyelinating features are present. The presence of IgG antibodies suggests a T-cell mediated response. In some of the patients, antibody activity was demonstrated by the agglutination assay, but not by ELISA, possibly due to higher sensitivity of the assay, or because the antibodies are directed at minor or as yet unidentified ganglioside antigens.

Age-Related Disability in Multiple Sclerosis

Wednesday, April 17, 2002
Maria M. Trojano, Maria M. Liguori, Giovanni Bosco G. B. Zimatore, Roberto R. Bugarini, Carlo C. Avolio, Damiano D. Paolicelli, Maria Giovanna M. G. Marrosu, Paolo P. Livrea Bari, Italy; Roma, Italy; Cagliari, Italy

Objective:

The relationship between age and rate of disability progression in a large hospital-based cohort of definite multiple sclerosis (MS) patients was evaluated.

Background:

The clinical course of MS shows evidence of pathological processes and neurological symptoms that are age related.Recent experimental and clinical studies also have demonstrated that pathological and clinical manifestations of autoimmune demyelination are age-dependent.

Design/Methods:

The study population included 1,463 definite MS patients from Apulia (n = 1,039) and Sardinia (n = 424) regions of Italy who were followed for a total period of observation corresponding to 11387.8 person years. At enrollment,clinical and demographic details (age, age at onset, disease duration and EDSS score) were established.Each patient was followed every 6 to 12 months. EDSS was assessed at each visit. Mean EDSS scores for MS patients were calculated according to current age and disease duration within each current age category.The Kruskal-Wallis one-way analysis of variance was used to analyze differences in EDSS scores based on age and disease duration. Association between current age and time to irreversible EDSS scores of 4.0 or 6.0, was assessed using an extended Kaplan-Meier method, with age as a categorical time-varying covariate. For Kaplan-Meier analyses, patients were distributed into three groups based on current age (20 to 35 years, 36 to 50 years, and 51 to 65 years.Polytomus logistic regression analyses were performed to determine the existence of multiplicative effects of covariates.

Results:

EDSS scores significantly increased with current age and disease duration (p = 0.007). A total of 435 patients reached an EDSS score of 4.0 and 180 patients reached an EDSS score of 6.0 by 15 years. Median times to reach EDSS scores of 4.0 and 6.0 were significantly longer among patients 20 to 35 years of age compared with patients 36 to 50 and 51 to 65 years of age (p < 0.0001). Polytomus logistic regression showed significant associations between mean EDSS scores and age at disease onset, current age, and their interaction (p < 0.001). Current age had a larger effect (59% of variability in the model) on disease severity than did age at disease onset. A positive correlation was observed between current age and EDSS score, independent of age at disease onset (bcurrent age = 0.1325), whereas a negative correlation was observed between age at disease onset and EDSS score, independent of current age bage at onset = -0.174). These two estimated effects indicated a positive correlation between disease duration and EDSS score. Furthermore, a multiplicative effect on EDSS score was observed for age at disease onset and current age combined (bage at onset x current age = 0.0013), indicating a significantly faster rate disease progression in older patients.

Conclusions:

Results of the current study demonstrate the impact of age on rate of disability progression in MS, and suggest that an age-adjusted progression index may be a more relevant criterion for defining differences between MS groups.

Induction Treatment with the Monthly Combination Mitoxantrone-Methylprednisolone for 6 Months Followed by a Maintenance Therapy in Worsening Relapsing-Remitting MS: The Clinical Benefits Last at Least 4 Years

Wednesday, April 17, 2002
Emmanuelle Le Page, Marc Coustans, Gregory Taurin, Jacques Chaperon, Gilles Edan Rennes, France

Objective:

To assess the concept of induction therapy by mitoxantrone before initiating other long term disease modifying therapies for worsening relapsing-remitting MS patients

Background:

Mitoxantrone (MITO), administered every 3 months up to the maximum cumulative dose of 140 mg/m2 has recently been approved by the Food and Drug Administration for the treatment of MS.MITO 20 mg is most frequently administered as monthly infusionsx6 months ("induction therapy") to treat MS in France

Design/Methods:

Since 1992, 100 RRMS patients followed in our MS Clinic were treated monthly for 6 months with mitoxantrone IV 20 mg combined with methylprednisolone IV 1g. After mitoxantrone induction , 25 patients received mitoxantrone every 3 months, 53 patients received an other long term modifying therapy (Azathiaprine 19, Interferon beta 21, Methotrexate 9, Glatiramer acetate 4 ) or had no maintenance therapy up to the next relapse ( 22 patients). The median duration of MS before starting mitoxantrone was 3.7 years. Within the 12 months before treatment , the annual relapse rate was 2.8, the mean worsening of EDSS was 2.2. and gado-enhanced lesions were detected in 77 out of 95 patients. The median duration after starting mitoxantrone was 3.8 years (1-8 years). Clinical , MRI and safety data were yearly collected in EDMUS.

Results:

After the induction treatment , the activity of the disease dropped dramatically: The mean number of relapses was 0.3; 0.4 and 0.4 at year 1, 2 and 3 ( 88,3 and 84,5% reduction compared with the annual relapse rate before treatment. p<0,0001). The percentage of relapse free patients were respectively 78%, 63%, 48% and 42.5% at year 1, 2, 3 and 4 . Compared with EDSS at Mitox onset , EDSS was improved of 1 point or more in 58%, 50%, 50% and 40,5% at year 1, 2, 3 and 4 (p<0001). Only 7 out of 80 patients had a Gd+ lesions on the MRI performed after the induction treatment (90% reduction compared with MRI before treatment. P< 0.0001). 15 patients moved to a secondary progressive MS.

Conclusions:

The clinical benefit and the reduction of MRI activity provides support for the notion that MITO as administered in this study may be used effectively as an induction treatment before initiating other long term disease modifying therapies for worsening relapsing-remitting MS patients

Detection of White Matter Pathology in Multiple Sclerosis Using q-Space Analyzed Diffusion Weighted MR Imaging and Spectroscopic Imaging

Wednesday, April 17, 2002
Yaniv Assaf, Joab Chapman, Dafna Ben-Bashat, Yoram Segev, Talma Hendler, Moshe Graif, Amos D. Korczyn, Yoram Cohen Tel Aviv, Israel

Objective:

The objective of this study were to explore the diagnostic capacity of the q-space method in MS and to correlate it to spectroscopic imaging.

Background:

Magnetic resonance imaging (MRI) is the major imaging method for diagnosis and evaluation multiple sclerosis (MS). However, a discrepancy exists between the disease load detected by MRI and the clinical severity of the disease. Indeed, magnetic resonance spectroscopy studies of normal appearing white matter (NAWM) of MS patients have shown that it is abnormal. Previously, we showed that diffusion-weighted imaging (DWI) at high b value provides additional information that seems to be more specific to axonal water and hence increase the ability to detect pathologies in the white matter. One way to analyze the signal decay at high b values is by using q-space analysis. The q-space analysis gives the displacement distribution profile of water molecules in the tissue from which the displacement and probability for zero displacement can be extracted.

Design/Methods:

Here we present q-space MR images (acquired with b values of up to 14,000 s/mm2) on MS (n=6) and control (n=6) human brains. These images were acquired on 1.5T GE Signa MRI scanner using diffusion-EPI pulse-sequence with the following parameters: TR/TE/D/d=1500/167/71/65ms, slice thickness of 4.5mm and Gmax of 2.2 gauss/cm. The q-space images were correlated with NAA/Cr levels derived from 2D spectroscopic imaging (SI) done with the following parameters: TR/TE=1600/135ms,matrix size 16x16, voxel dimensions: 12x11x11mm.

Results:

The q-space images provided a pronounced differentiation between NAWM in controls and MS patients as compared to other MRI techniques (T1, T2 and diffusion tensor images). Mean displacements of 3.4±0.6, 4.9±0.8 and 8.1±2.3 mm were extracted from regions of interests (ROIs) in control patients, NAWM and MS lesions in MS patients, respectively. For the same ROIs, probability for zero displacement of 8.2±0.5, 6.5±0.5 and 5.0±0.8 were extracted. The q-space parameters show overall good correlation with the EDSS of the whole group (r=0.66).
The q-space indeces corrlated well with NAA/Cr values as derived from SI (r=0.61). Using the SI data we performed ROI analysis on two groups of NAWM - one that has normal metabolite distribution (NAA/Cr level higher than 1.8) and one that has abnormal metabolite distribution (NAA/Cr<1.80). The q-space intensities of these ROIs were significantly different (p<0.001) indicating that areas that appear abnormal in the SI are also abnormal in the q-space images.

Conclusions:

q-Space imaging provides a contrast that is based on the probability for displacement of water molecules. These images were shown to be highly sensitive to the integrity of the myelin in white matter. Indeed intensity of the q-space images correlated with NAA/Cr value suggesting that these king of images can provide that same infromation as SI but with much better spatial resolution.

Hospitalization for Neurological Disorders in the United States

Wednesday, April 17, 2002
John K. Lynch, Ann Scher, Karin B. Nelson Bethesda, MD

Objective:

To provide national estimates on the hospitalization of the most common neurological disorders in the United States.

Background:

Neurological disorders are a major cause of morbidity and mortality in the United States. The National Hospital Discharge Survey (NHDS) is a periodic nationwide sample survey of approximately 500 short-stay hospitals in the United States. The NHDS provides information on selected patient hospitalizations including data on patient demographics, diagnostic codes, procedures, length of stay and discharge status. The number of inpatient records sampled between 1990-1999 ranged from 235,000 to 300,000 each year.

Design/Methods:

NHDS data were analyzed for the period 1990-1999 for individuals 17 years of age with a neurological disorder(according to ICD-9 code). The rate of each neurological disorder was calculated as the estimated number of hospital discharges for each disorder among the mid-year resident population in the United States each year and was calculated according to gender and race.

Results:

For the period 1990-99, the most common neurological disorders resulting in hospitalization were (in decreasing order): cerebrovascular diseases, he