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Objective: We report analyses of a pooled database by the Multiple Sclerosis Outcome Assessments Consortium to evaluate 4 proposed components of a multidimensional test battery., Methods: Standardized data on 12,776 participants, comprising demographics, multiple sclerosis disease characteristics, Expanded Disability Status Scale (EDSS) score, performance measures, and Short Form-36 Physical Component Summary (SF-36 PCS), were pooled from control and treatment arms of 14 clinical trials. Analyses of Timed 25-Foot Walk (T25FW), 9-Hole Peg Test (9HPT), Low Contrast Letter Acuity (LCLA), and Symbol Digit Modalities Test (SDMT) included measurement properties; construct, convergent, and known group validity; and longitudinal performance of the measures individually and when combined into a multidimensional test battery relative to the EDSS and SF-36 to determine sensitivity and clinical meaningfulness., Results: The performance measures had excellent test-retest reliability and showed expected differences between subgroups based on disease duration and EDSS level. Progression rates in detecting time to 3-month confirmed worsening were lower for T25FW and 9HPT compared to EDSS, while progression rates for LCLA and SDMT were similar to EDSS. When the 4 measures were analyzed as a multidimensional measure rather than as individual measures, progression on any one performance measure was more sensitive than the EDSS. Worsening on the performance measures analyzed individually or as a multidimensional test battery was associated with clinically meaningful SF-36 PCS score worsening, supporting clinical meaningfulness of designated performance test score worsening., Conclusion: These results support the use of the 4 proposed performance measures, individually or combined into a multidimensional test battery as study outcome measures., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Although patients with multiple sclerosis (MS) are advised to stop interferon (IFN) beta-1a therapy before becoming pregnant, some patients become pregnant while on treatment., Methods: We examined individual patient data from eight clinical trials with IFNbeta-1a., Results: Of 3,361 women in the studies, 69 pregnancies were reported, of which 41 were patients receiving (or who had stopped receiving within 2 weeks prior to conception) IFNbeta-1a (in utero exposure group), 22 were patients who discontinued IFNbeta-1a treatment more than 2 weeks before conception (previous exposure group), and six were patients receiving placebo. The 41 in utero exposure pregnancies resulted in 20 healthy full-term infants, one healthy premature infant, nine induced abortions, eight spontaneous abortions, one fetal death, and one congenital anomaly (hydrocephalus). One patient was lost to follow-up. The 22 previous exposure pregnancies resulted in 20 full-term healthy infants, one healthy premature infant, and one birth-related congenital anomaly (Erb palsy)., Conclusions: The majority (21/31) of pregnancies that had the potential to go to full term produced healthy infants. The rate of spontaneous abortion was higher, but not significantly so, in the in utero exposure group compared to general population estimates. Until more exposure data become available, patients remain advised to stop IFNbeta therapy before becoming pregnant.

Background: Debate continues concerning the relevance of neutralizing antibody (NAb) development on the efficacy of interferon (IFN) therapy in patients with multiple sclerosis (MS). The PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study of subcutaneous IFNbeta-1a showed significant benefit on all efficacy outcomes with no significant impact from NAb development on relapses at 2 years. The 2-year extension permitted longer observation following NAb development., Methods: Exploratory post-hoc analyses of pharmacodynamic response and clinical and MRI outcomes were performed on data from 368 patients with relapsing MS treated with IFN from study start, based on NAb status., Results: Persistent NAbs, above 20 NU/mL, were present in 14% of the 44-microg three times weekly (TIW) and 24% of the 22-microg TIW group over 4 years. NAb development was associated with reduced pharmacodynamic marker induction at 1 year. Over the entire 4 years of study, relapse and disability measures were similar between NAb+ and NAb- patients. However, once NAbs developed, significant differences were noted between NAb+ and NAb- groups, particularly on MRI and relapse measures. The presence of binding antibodies alone did not affect outcome., Conclusion: Neutralizing antibody development in interferon-treated patients is correlated with reduced efficacy and is a potential cause for renewed disease activity.

Interferon (IFN) beta has been shown to be an effective therapy in pivotal studies of multiple sclerosis (MS), with differences in outcomes based on dose and/or frequency of administration. Glatiramer acetate (GA) has also shown to have an effect on relapses and magnetic resonance imaging measures, but not on disability. All products are associated with adverse events, and utilisation of a specific therapy needs to consider benefit in relation to risk. Evidence-based medicine provides a means of assessing benefit and risk in the context of the number of patients one needs to treat to obtain benefit (NNT) compared with the number needed to treat for an adverse outcome (NNH). Efficacy and safety data are presented from IFN beta-1a (Rebif) clinical trials, including relevant NNT and NNH values, to allow assessment of the overall benefit-to-risk ratio compared with placebo. Additional comparisons are made with published data for other IFN products and GA. The indirect comparative information reviewed demonstrates that IFN appears to have a better benefit- to-risk ratio than GA. Indirect comparisons suggest better efficacy of thrice weekly (tiw) IFN beta-1a compared with alternate-day IFN beta-1b, but no direct comparative data are available. Direct comparative data show that IFN beta-1a at a dose of 44 mcg tiw has a favourable benefit-to-risk ratio compared with both 22 mcg tiw and 30 mcg once weekly, suggesting that 44 mcg tiw currently has the best benefit- to-risk ratio for the treatment of relapsing MS.

Patients with multiple sclerosis (MS) can benefit from treatment with interferon beta-1b. However, the mechanisms of action of this drug are incompletely understood and effects of interferon beta-lb on axonal injury are not known. A measure of axonal injury can be obtained in vivo using magnetic resonance spectroscopy to quantify the resonance intensity of the neuronal marker, N-acetylaspartate (NAA). In a small pilot study, we performed combined magnetic resonance imaging and magnetic resonance spectroscopic imaging on 10 patients with relapsing-remitting MS before and 1 year after starting treatment with subcutaneous interferon beta-lb. Resonance intensities of NAA relative to creatine (Cr) were measured in a large, central brain volume. These measurements were compared with those made in a group of 6 untreated patients selected to have a similar range of scores on the Expanded Disability Status Scale and mean NAA/Cr at baseline. NAA/Cr in the treated group [2.74 (0.16), mean (SD)] showed an increase of 5.5% 12 months after the start of therapy [2.89 (0.24),p = 0.05], while NAA/Cr in the untreated group decreased, but not significantly [2.76 (0.1) at baseline, 2.65 (0.14) at 12 months,p > 0.1]. NAA/Cr had become significantly higher in the treated group at 12 months than in the untreated group (p = 0.03). Our data suggest that, in addition to losing axons, patients with chronic multiple sclerosis suffer from chronic, sublethal axonal injury that is at least partially reversible with interferon beta-lb therapy.

Objective: To assess axonal damage and its contribution to disability at different stages of multiple sclerosis (MS)., Background: Recent in vivo imaging and in situ pathologic studies have demonstrated that substantial axonal damage accompanies the inflammatory lesions of MS. However, the relation of axonal damage to the duration of MS and its contribution to disability at different stages of the disease remain poorly defined., Design: We performed proton magnetic resonance spectroscopic imaging in 88 patients with a wide range of clinical disability and disease duration to measure N-acetylaspartate (NAA, an index of axonal integrity) relative to creatine (Cr) in a large central brain volume that included mostly normal-appearing white matter on magnetic resonance imaging., Results: We observed that the NAA/Cr values were abnormally low in the early stages of MS, even before significant disability (measured using the Expanded Disability Status Scale [EDSS]) was evident clinically, and declined more rapidly with respect to EDSS at lower than at higher EDSS scores (P<.001). The correlation of NAA/Cr values with EDSS score was significantly (P<.03) stronger in patients with mild disability (EDSS score <5, Spearman rank order correlation = -0.54, P<.001) than in patients with more severe disability (EDSS score >/=5, Spearman rank order correlation = -0.1, P<.9). When similar analyses were performed in patients with MS grouped for duration of disease, the subgroup with early disease duration (<5 years) also showed central brain NAA/Cr resonance intensity ratios significantly lower than healthy controls (P<.001)., Conclusion: Cerebral axonal damage begins and contributes to disability from the earliest stages of the disease.

Background: The Canadian Burden of Illness Study Group reported that the quality of life (QoL) of multiple sclerosis (MS) patients falls drastically, early in the disease. With disability progression, the physical functioning scales of the Short Form 36 (SF-36) showed further decreases in QoL. The objective of this study is to describe the QoL of MS patients treated with interferon beta-1b (IFNB-1b) and to compare it to the QoL observed in a group of patients who had not been treated with IFNB-1b., Methods: Treated patients were prospectively recruited and were seen at their regular visit to the MS clinic. They self-completed the SF-36 questionnaire and their QoL was described and retrospectively compared to that of historical controls., Results: When IFNB-1b treated patients were compared to historical control patients with the same relapsing forms of MS, the treated patients with an Expanded Disability Status Scale (EDSS) score lower than 3.0 had a significantly better QoL. This was significant for four of the eight SF-36 domains: Physical Function (+22%, p = 0.0102), Role-Physical (+100%, p = 0.0022), General Health (+27%, p = 0.0070) and Social Function (+19%, p = 0.0287). The average QoL difference was 8% in the EDSS 3.0-6.0 group and 10% in the EDSS > 6 group., Conclusion: Patients with relapsing forms of MS treated with IFNB-1b have better QoL than patients who are not treated, especially those with an EDSS < 3.0.

To test for axonal damage or dysfunction in white matter tracts remote from acute demyelinating lesions, we used brain proton magnetic resonance spectroscopic imaging to measure changes in N-acetyl aspartate (NAA), an index of neuronal integrity, in the white matter of the normal-appearing hemisphere of three patients with large, solitary brain demyelinating lesions of the type seen early in multiple sclerosis. During the acute phase of their disease, all patients showed normal ratios of NAA to creatine (Cr) resonance intensity throughout the hemisphere contralateral to the lesion. However, on examination 1 month later, all of the patients showed abnormally low NAA/Cr resonance intensity ratios (reduction of NAA/Cr by 22-35%) in voxels of the contralateral hemisphere which were homologous to the demyelinating lesion. Other voxels in the normal-appearing hemisphere showed normal NAA relative resonance intensities. The decrease in NAA/Cr in voxels of the normal-appearing hemispheres resolved in all patients after 6 months, with a time course similar to that observed for NAA from voxels within the lesions. We conclude that effects of damage or dysfunction to axons traversing inflammatory lesions can be transmitted over long distances in the normal-appearing white matter. Such remote, secondary effects may be an expression of dysfunction of axons in projection pathways or of the reorganization of functional pathways seen in brains recovering from an acute injury.

Previous reports by our group and by others have shown that in vitro treatment of T cells derived from healthy, normal subjects with interferon beta-1b (IFN-beta1b) reduces metalloproteinase (metalloproteinase type 9 [MMP-9]) activity with a consequent reduction in lymphocyte migration. In this study, we used a Boyden chamber assay to assess the migratory capacity of T cells derived from multiple sclerosis patients who either did or did not receive IFN-beta1b. Lymphocytes derived from patients treated for less than 2 years with IFN-beta migrated at a low rate that was indistinguishable from that of cells isolated from healthy donors. However, longer term treatment with IFN (>3.5 years) was associated with a reversion of the migration to a high level that did not differ statistically from that of cells isolated from untreated multiple sclerosis patients. For both high-migratory groups, migration could be reduced to control levels after the exogenous addition of TIMP-1, a relatively specific inhibitor of the MMP-9, implicating this protease in the process of T-cell migration. Our findings suggest that one of the mechanisms by which IFN-beta exerts its action is by reducing MMP-9 activity and thus the entry of inflammatory cells into the nervous system and, as such, MMPs may constitute potential therapeutic targets in inflammatory diseases such as multiple sclerosis.

Background and Purpose: Conventional MR imaging of multiple sclerosis (MS) provides relatively poor pathologic specificity, which has led to the investigation of more sophisticated MR techniques. The purpose of this study was to combine magnetization transfer (MT) imaging and proton MR spectroscopic imaging (MRSI) to evaluate the specific pathologic features of myelination and neuronal integrity in patients with MS and to determine the relationship between these measures within plaques., Methods: We acquired conventional MR, MT, and proton MRSI data and evaluated clinical disability in 30 patients with MS, whose conditions were categorized as relapsing-remitting, primary progressive, or secondary progressive. The lesions were classified, using a semiautomated edge-following technique, on T2-weighted MR images, and an analysis of MT and proton MRSI data was conducted for lesion regions as well as for tissue that was categorized as normal., Results: The MT ratio (MTR) of normal-appearing white matter in the patients with MS was significantly lower than in the healthy participants, whereas gray matter values were unchanged. MS lesions showed a large reduction in MTR, with old lesions exhibiting a lower MTR than new lesions. The average lesion MTR and the MR spectroscopic imaging-measured relative concentration of N-acetylaspartate, a marker of neuronal integrity, was positively correlated in patients with relapsing-remitting MS. This relationship was strengthened in regions containing new lesions., Conclusion: The integrated use of MT and MR spectroscopic imaging provides a more complete description of the pathologic features of MS than does conventional MR imaging alone, and our data suggest that axonal damage occurs in step with new demyelination and is not a late feature of the disease.

It has been difficult to establish a strong correlation between total brain T2-weighted lesion volume on MRI and clinical disability in multiple sclerosis, in part because of the lack of pathological specificity of T2-weighted MRI signal changes. Proton magnetic resonance spectroscopy studies have shown that measurements of the resonance intensity of N-acetylaspartate (which is localized exclusively in neurons and neuronal processes in the mature brain) can provide a specific index of axonal damage or dysfunction. Here we report a 30-month longitudinal study of 29 patients with multiple sclerosis who had either a relapsing or a secondary progressive clinical course. Conventional brain MRI and single-voxel proton magnetic resonance spectroscopy examinations were obtained at intervals of 6-8 months with concurrent clinical evaluation. At the onset of the study, the brain N-acetylaspartate:creatine resonance intensity ratio was abnormally low for the whole group of patients (control mean = 2.93 +/- 0.2, patient mean = 2.56 +/- 0.4, P < 0.005). There were no significant differences between the relapsing and secondary progressive subgroups. Over the follow-up period, there was a trend towards a decrease (8%) in the brain N-acetylaspartate:creatine ratio for the 11 relapsing patients and a significant (P < 0.001) correlation between changes in the brain N-acetylaspartate:creatine ratio and expanded disability scale scores for the patients in this group. This correlation was even more evident for the patients who had clinically relevant relapses during the 30 months of follow-up (seven of 11 patients). Increases in T2-weighted lesion volumes (35% in 30 months for the group as a whole, P < 0.0001, without differences between the subgroups) did not correlate with disability either in the group of patients as a whole or in the different subgroups. We conclude that indices of axonal damage or loss such as brain N-acetylaspartate may provide a specific measure of pathological changes relevant to disability. Total T2-weighted lesion volumes, although more sensitive to changes with time than brain N-acetylaspartate, may be less relevant to understanding the progression of disability.

The current study was designed to determine the relative distribution of decreases of N-acetylasparate (NAA), a marker of axonal damage, between lesions and normal-appearing white matter of patients with established multiple sclerosis and to test for associations between changes in the ratio of NAA to creatine/phosphocreatine (NAA:Cr) in those compartments and changes in disability. Data were collected from a 30-month longitudinal study of 28 patients with either a relapsing course with partial remissons and no progression between attacks (relapsing/remitting) (11 patients) or a course of progressively increasing disability, following a period of relapsing/remitting disease (secondary progressive) (17 patients). Proton magnetic resonance spectroscopic imaging (MRSI) and conventional MRI examinations were performed at 6-8-month intervals with concurrent clinical assessments of disability. General linear models were used to test associations between MRSI, MRI, lesion volume and clinical data. Analysis confirmed that the NAA:Cr ratio is lower in lesions than in the normal-appearing white matter (-15.3% in relapsing/remitting multiple sclerosis and -8.8% in secondary progressive multiple sclerosis). The lower NAA:Cr ratio per unit lesion volume previously observed for secondary progressive relative to relapsing/remitting patients was found to result from a lower ratio (8.2%, P < 0.01) in the normal-appearing white matter rather than from any differences within lesions. The importance of changes in the normal-appearing white matter was emphasized further with the observation that the NAA:Cr ratio in the normal-appearing white matter accounted for most of the observed 15.6% (P < 0.001) decrease in the NAA:Cr ratio in the brains of relapsing/remitting patients over the period of study. The decrease in the NAA:Cr ratio in normal-appearing white matter correlated strongly (P < 0.001) with changes in disability in the relapsing/remitting subgroup. These results add to data suggesting that axonal damage or loss may be responsible for functional impairments in multiple sclerosis. The accumulation of secondary axonal damage in the normal-appearing white matter may be of particular significance for understanding chronic disability in this disease.

Recent magnetic resonance imaging (MRI) and magnetic resonance spectroscopic (MRS) techniques have focused the attention of the multiple sclerosis (MS) research community on reanalysis of classic pathological approaches that have suggested significant axonal injury in this demyelinating disease. There now is abundant evidence from animal work that substantial "innocent bystander" damage to axons can occur with central nervous system (CNS) inflammation. Given the close interactions between axons and glia, it is no surprise that glial damage leads to secondary axonal changes. MRI, MRS, and MRS imaging studies have emphasized that axonal loss or damage in MS can be both substantial and early. The dynamic observations that are allowed by these noninvasive measures of pathology have demonstrated direct correlations between these axonal changes and disability, making a compelling case for increased emphasis on finding treatments of MS that may limit damage to CNS axons or salvage injured axons.

Due to the modest benefit, inconvenience and high cost of currently available therapies for MS, it is appropriate to seek alternative treatments. Based on anecdotal evidence suggestive of benefit for i.v.IG in MS, we conducted an open-label, unblinded protocol of i.v.IG in nine MS patients. The patients were given induction doses of i.v.IG followed by monthly boosters for 1 year and had clinical, MRI and CSF analyses performed. Patients included were both progressive and relapsing. There was no clinical benefit nor apparent MRI benefit utilizing this protocol. During treatment the majority of patients continued to progress or have attacks and MRI demonstrated continued accumulation of T2-weighted lesions. CSF was unaffected by treatment.

In a 6-year longitudinal study of a patient with relapsing progressive multiple sclerosis (MS), we used proton magnetic resonance spectroscopy to assess N-acetylaspartate (NAA) from a large central brain volume to evaluate the relationship between this marker of neuronal integrity and clinical disability. During the follow-up period, there was one major relapse and its subsequent partial remission. Changes in the brain NAA to creatine ratio correlated strongly with clinical disability (Spearman rank coefficient = -0.73, p < 0.001). We interpret this as evidence that axonal dysfunction or loss contributes to functional impairment of patients with MS. Because the NAA signal in the large volume of interest originated predominantly from white matter that appeared normal on conventional MRI, these results also suggest that some degree of axonal dysfunction may be widespread in acute, severe relapses.

Background: Spasticity is a serious problem in multiple sclerosis (MS) and many patients do not achieve a satisfactory response to currently available oral antispasticity drugs. Tizanidine hydrochloride, an alpha 2-noradrenergic agonist, has been shown to have an antispasticity effect in single center trials of patients with MS., Objective: To compare plasma concentrations of tizanidine with objective measures of muscle tone in patients with MS with moderate to severe spasticity., Setting: Ten centers, all tertiary referral centers for the specialized treatment of patients with MS, in the United States and Canada., Design: A randomized, double-blind, placebo-controlled, dose-response study of tizanidine hydrochloride (8 or 16 mg)., Patients: One hundred forty-two patients with spastic MS who were not taking any interfering medication, such as an antispasticity drug or other alpha-noradrenergic agonist, entered the trial., Results: Tizanidine treatment reduced muscle tone significantly, as shown by improved Ashworth scores and increased knee swing amplitude recorded by the pendulum test, both of which correlated significantly with plasma concentration. Placebo had no significant effect on muscle tone. Dizziness, drowsiness, dry mouth, and fatigue were reported most often in the group treated with tizanidine at peak plasma concentration., Conclusions: Tizanidine reduces spasticity in MS, and both therapeutic effects and side effects are related to the plasma drug levels.

We performed magnetic resonance imaging and magnetic resonance spectroscopic imaging on 28 patients with multiple sclerosis stratified for disability and clinical course (relapsing with at least partial remissions or secondary progressive disease). Lesions were segmented on the conventional proton density and T2-weighted magnetic resonance images, and lesion distribution images were generated for, each patient. The conventional magnetic resonance and spectroscopic images were transformed into a standard brain-based stereotaxic coordinate space, allowing comparison of images from different patients on a voxel-by-voxel basis. The spatial distribution of lesions in the transformed magnetic resonance images did not differ significantly between the relapsing and the progressive disease groups. We then generated from the individual data sets, group lesion probability distribution images for the relapsing and the progressive disease groups. The spatial distribution of metabolites was characterized with respect to lesion distribution using the magnetic resonance spectroscopic images transformed into stereotaxic space and averaged. The neuronal marker N-acetylaspartate was diffusely lower in the multiple sclerosis patients than in normal control subjects. Comparison of the averaged metabolite and T2-weighted lesion probability images confirmed loss of N-acetylaspartate in regions of both high and low lesion probability. This suggests that diffuse axonal volume loss or dysfunction extends beyond the inflammatory lesions of multiple sclerosis, perhaps due to microscopic disease or wallerian degeneration along projection pathways of axons traversing the lesions.

Neuroimaging in multiple sclerosis is now dominated by MR imaging. This article will focus primarily on conventional MR imaging studies in multiple sclerosis, but will also discuss briefly some of the more recent advances related to MR imaging. Fast spin-echo imaging, fluid attenuated inversion recovery MR studies, three-dimensional volumetric studies, magnetization transfer, and magnetic resonance spectroscopy as it applies to multiple sclerosis are examined.

Decreases in brain N-acetylaspartate are associated with neuronal loss or dysfunction. We report a longitudinal study in which changes in the N-acetylaspartate to creatine resonance intensity ratio measured by brain proton magnetic resonance spectroscopy were used to follow the progression of brain pathology in 7 patients with multiple sclerosis over an 18-month period. Four of the patients had a history of recurrent relapses and 3 had a secondary progressive course. All had clinical and magnetic resonance imaging evidence of persistent neurological abnormalities. At 6-month intervals proton magnetic resonance spectra were obtained and the N-acetylaspartate-creatine ratio was determined for each patient. The volumes of hyperintense signal from lesions on conventional magnetic resonance images and the Kurtzke Expanded Disability Status Scale scores were determined concurrently. At the onset of the study, the N-acetylaspartate-creatine ratio was significantly (p < 0.05) lower in the central brain volumes from the patients than in 13 normal control subjects. At 12 and 18 months of follow-up, the ratio had decreased further in all patients (p < 0.05), consistent with progressive accumulation of neuronal damage. In contrast to magnetic resonance spectra data, changes in lesion volume on magnetic resonance images or disability status did not reach significance over this period. Subgroup analysis showed that changes (increases or decreases) in the N-acetylaspartate-creatine ratio between consecutive 6-month examinations correlated significantly (r = -0.74, p < 0.005) with changes in lesion volume on magnetic resonance images in patients with a history of relapses.(ABSTRACT TRUNCATED AT 250 WORDS)

Patient sharing of HLA-DQ allelic polymorphisms is a possible explanation for the association of multiple sclerosis (MS) with different HLA class II haplotypes in different populations. We used two-locus linkage analysis to investigate the relevance of three different polymorphisms to MS susceptibility in 79 French Canadian patients and 62 mixed ethnic white patients. In French Canadians, we found that an MS association with shared DQB1 sequences and a DQA1 codon for glutamine at residue 34 is secondary to an MS association with the common DR2 haplotype, DRB1*1501-DQA1*0102-DQB1*0602. In contrast, we found that an MS association in French Canadians with a DQB1 codon for leucine at residue 26 (DQ beta Leu26) is not secondary to an MS association with the DR2-bearing haplotype. Mixed ethnic whites showed a positive MS association with the DR2 haplotype but no MS association with any of these polymorphisms. We conclude that (1) the DR2 haplotype is predispositional for MS in both populations, (2) DQ beta Leu26 is an additional predispositional factor in French Canadians, and (3) none of the DQ polymorphisms fully explains the association of MS with HLA alleles in both patient groups.

We analyzed the association of HLA-DQA1 and -DQB1 alleles with multiple sclerosis (MS) in a collaborative study of 116 Sardinian and 75 French Canadian MS patients by the relative predispositional effect method. In French Canadians, MS was positively associated with DQA1*0102 and DQB1*0602, but there was no positive association of either allele with Sardinian MS, which, by contrast, was positively associated with DQB1*0302 and *0201 and with DQA1*0301, whereas none of these alleles was MS-associated in French Canadians. In comparison with French Canadian results, DQA1*0102 was protective against MS in Sardinians. We suggest that DQA1*0102 has no MS predispositional role in French Canadians, but is MS-associated because it is in linkage disequilibrium with true predispositional alleles present within the DQB1*0602-bearing haplotype. Whereas DQB1 alleles encoding leucine (Leu) at residue 26 showed a strong MS association in French Canadians (relative risk = 24.7), there was no correlation with DQ beta Leu26 in Sardinian MS. No other DQA1 or DQB1 codons showed a positive disease correlation in both groups. Together the data suggest that the two MS patient groups are immunogenetically distinct, and it may be impossible to formulate a unifying hypothesis that explains the different MS-class II associations in these and other ethnic groups.

Putative disease susceptibility and resistance HLA class II alleles were studied in 78 French Canadian multiple sclerosis (MS) patients and 79 controls by using sequence-specific oligonucleotide probes to analyze in vitro amplified DNA (PCR-SSOP) typing). In this relatively homogeneous ethnic group, MS was positively associated with DRB5*0101, DQB1*0602, and DQA1*0102 and negatively associated with DQB1*0301. The strongest disease association was with DQB1*0602. Complete DQB1 typing of these individuals, plus RFLP DQ beta typing of an additional five patients showed that 98% of patients compared with 73% of controls carry DQB1 alleles encoding leucine at residue 26. In contrast, 16% of patients compared with 38% of controls carry DQB1 alleles encoding tyrosine at the same residue, and 22% of patients versus 44% of controls carry DQB1 alleles encoding glycine at residue 26. The positive disease correlation was confirmed with SSO probes designed to hybridize to codons for amino acids 22-27 of DQB1*0602, 0603, 0604, 0302, 0303 or to codons for amino acids 25-31 of DQB1*0201; all of these alleles encode Leu 26. These findings suggest that DQ beta chain polymorphisms at a single residue contribute to the development of MS in the French Canadian population.

We used proton magnetic resonance (MR) spectroscopic imaging to determine the serial changes in MR signals from choline, creatine, lactate, and N-acetylaspartate in and around a large demyelinating lesion followed over a period of 8 months. Elevated lactate and choline signals were observed at the first examination 3 days after the onset of symptoms. Reduced N-acetylaspartate signals were observed a few days afterward. The abnormal metabolite signals varied in different regions of the lesion and extended beyond the borders of abnormal signal intensity seen on conventional MR imaging (MRI). On the last examination at 8 months when the lesion appeared much smaller on MRI, choline signals from the center of the lesion were still high, but were falling. Choline signals outside the lesion on MRI had returned to normal as had lactate signals everywhere. Importantly, there was no recovery of N-acetylaspartate signals in or adjacent to the lesion on MRI. This serial study demonstrates the potential of MR spectroscopic imaging for characterizing the chemical pathological evolution of demyelinating lesions in ways that conventional MRI cannot. We propose that abnormal signals from choline can indicate recent regional demyelination, while persistent abnormal signals from N-acetylaspartate can provide an index of irreversible damage in the nervous system.

HLA-DPB1 typing was performed using polymerase chain reaction DNA amplification and sequence-specific oligonucleotide probing (PCR-SSOP) which permitted identification of 17 distinct DPB alleles using 15 oligonucleotide probes. The accuracy of this approach was confirmed in an initial study of 26 human B-lymphoblastoid cell lines which demonstrated close agreement between PCR-SSOP and PLT assigned types. A cohort of 47 adult French Canadians was then studied to provide an estimate of DPB1 allelic frequencies in an ethnically homogeneous population. DPB1*0401 was the most frequent phenotype (61.5%) and only DPB1*0101, 0301 and 0402 were also present at frequencies greater than 10%. HLA-DPw4 has been reported to be associated with multiple sclerosis (MS) but our PCR-SSOP analysis of 52 French Canadian MS patients showed no association with either the DPB1*0401 or DPB1*0402 splits of DPw4 or with any other DPB1 allele.

HLA class II DRB1, DQB1 and DQA1 gene probes were used to study DNA from unrelated French Canadian multiple sclerosis (MS) patients and controls by restriction fragment length polymorphism (RFLP) analysis. An MS-associated and linked series of allele-specific RFLPs or allogenotypes was identified among this relatively homogeneous ethnic group; the allogenotypes include DRw15, DQw6 and a DQA1 allogenotype termed DQ alpha 1b. An additional allogenotype which cross-hybridizes with DQA1 and is termed DQA2 upper (DQA2U), was shown not only to be part of the MS-associated extended haplotype, but also to be independently associated with MS in DRw15-negative patients. Conversely a second DQA2 allogenotype, termed DQA2 lower (DQA2L) and a DQB1 allogenotype (DQw7) linked to DQA2L showed negative correlations with MS. It seems likely that the relationship of the HLA class II gene region to MS is complex and that MS susceptibility may reflect interaction between disease susceptibility and resistance genes.

Probes to the HLA class II genes DR beta, DQ beta, and DQ alpha were used to study DNA from unrelated Caucasian multiple sclerosis (MS) patients by sequential restriction fragment length polymorphism (RFLP) analysis in Taq 1 restriction enzyme digests. Comparison of 104 patients and 108 controls, who were not matched for DR type, has identified for the first time a linked series of allele-specific RFLPs or allogenotypes which form an extended haplotype that is preferentially associated with MS. These allogenotypes include DRw15 or DR2(15); DQ beta lb, which corresponds at the DNA level to the DQwl(DQw6) serotype; a DQA1 allogenotype termed DQ alpha lb; and a 2.2 kb DX (DQA2) allogenotype termed DX alpha U (DQA2U). The role of HLA class II genes in susceptibility to MS was found to be complex. First, 23 of 104 MS patients showed DR-DQ linkages which were not observed in our control population. We suggest these anomalous associations may be important in the pathogenesis of MS. Second, homozygosity of a 2.0 kb DX (DQA2) gene, termed DX alpha L (DQA2L), showed a strong negative association with MS. DX alpha L (DQA2L) is in strong linkage disequilibrium with DR1, 5(w11) 7, and a subset of DR4, all of which also showed a negative association with MS. Since DX alpha L (DQA2L) does not code for any known product, DR1, 5(11), 4, and 7 become candidates for disease resistance genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Defective suppressor cell function has previously been demonstrated in patients with multiple sclerosis (MS) with progressive disease and moderate degrees of disability. In the present study activated suppressor cell function was assessed in patients with documented progressive disease who, at the time of study, had experienced severe disability (Kurtzke score greater than or equal to 6.5) for at least 2 years. We found that mean suppressor levels were significantly increased in this patient group compared with the suppressor levels in the MS patient group with progressive disease but only moderate disability (Kurtzke score of less than or equal to 6.0 within 2 years of study) (59 +/- 8% vs 19 +/- 7%, respectively, p less than 0.01). The mean value in the latter group was significantly reduced compared with the mean value for normal control subjects (47 +/- 4%, p less than 0.01), a finding consistent with previous reports. The results of this study indicate that suppressor cell function, as measured by our assay system, need not be defective in MS patients who have become severely disabled from the progressive form of the disease. Whether the patients who are now severely disabled from progressive MS passed through a phase of disease associated with the same suppressor defects as found in the progressive patients currently with moderate disability will remain speculative until long-term longitudinal studies are performed.

Spasticity is a frequent and often disabling symptom in MS patients. Current drugs used as antispastic agents include Dantrolene Sodium, Baclofen and Diazepam. Tizanidine (5-chloro-4-(2imidazolin-2 yl amino)-2,1,3-benzothialdiazole) is a new antispasticity agent that has purported central action. A double blind placebo controlled trial was performed to study the efficacy of this drug in MS patients. Sixty-six patients entered an eight week therapeutic trial and fifty-nine completed the trial. Patients were assessed at 0, 2, 3 and 8 weeks of therapy for clinical effects. Electrophysiologic tests were performed at 0 and 8 weeks. A statistically significant benefit was noted in spastic muscle groups in the legs with concomitant significant reduction in hyperactive stretch reflexes and ankle clonus. Side effects most frequently cited included dry mouth and drowsiness. Two patients developed elevated liver function test that decreased with cessation of therapy. Other clinical details, side effects and electrophysiologic data will be presented. Tizanidine appears to reduce clinical spasticity and hyperreflexia in MS patients although no change in functional status was detected. Tizanidine may well serve as an alternate antispastic agent, alone or in combination with other agents.

A randomized, double-blind, placebo-controlled crossover study tested the efficacy of natural alpha interferon in altering exacerbating-remitting MS. Twenty-four patients with frequent exacerbations were treated for 6-month periods, beginning with either 5 X 10(6) IU of interferon daily or placebo. A 6-month washout period followed each treatment. Exacerbation rates were reduced during interferon and placebo phases compared with pre-study rates; a greater reduction occurred on interferon, particularly following placebo, possibly reflecting a learning phenomenon. Fifteen patients with a strictly exacerbating-remitting course had fewer and milder exacerbations on interferon compared with those on placebo, whereas 9 patients with a progressive component continued to have active disease. These results suggest that interferon might reduce exacerbations in certain patients and indicate guidelines for future trials of interferon in MS.

A battery of immunological functions was studied over a 2-year period in conjunction with a placebo-controlled trial of natural human alpha interferon in patients with multiple sclerosis. IgG synthesis was increased both systemically and intrathecally by administration of interferon; however, there were only minor changes in cerebrospinal fluid oligoclonal bands. Levels of helper and suppressor T lymphocytes fluctuated independently of clinical exacerbations, although mean helper/suppressor ratios were higher in multiple sclerosis patients than in controls and increased further during interferon treatment. Cerebrospinal fluid myelin basic protein and antibodies to basic protein were not affected by exacerbations or by interferon administration. Circulating IgG antibodies induced by interferon treatment appeared to be directed at a non-interferon contaminant of the preparation. None of the assays was a consistent indicator of disease activity or of clinical response to interferon.