MRI lesion volume heterogeneity in primary progressive MS in relation with axonal damage and brain atrophy.

OBJECTIVES: To investigate whether axonal damage in primary progressive (PP) multiple sclerosis (MS), as measured by proton magnetic resonance spectroscopy (HMRS) imaging and brain atrophy, is a function of T2 weighted brain lesion volume. METHODS: 34 PP MS patients were divided into two categories: low (<3 cm(3), n = 18) or high (>or=3 cm(3), n = 16) T2 lesion load (LL). An Index of Brain Atrophy (IBA) was calculated and HMRS metabolite ratios were derived from a central brain area centred at the corpus callosum. RESULTS: Patient groups did not differ with regard to clinical characteristics and showed lower mean IBA and mean N-acetylaspartate:creatinine (NAA:Cr) ratios compared to healthy controls. CONCLUSION: PP patients with low and high brain T2LL have detectable brain atrophy and NAA:Cr reduction compared to healthy controls. In PP MS, T2 lesions alone are insufficient to explain the presence of brain atrophy and decrease in NAA:Cr.

3-D echo planar (1)HMRS imaging in MS: metabolite comparison from supratentorial vs. central brain.

UNLABELLED: To determine if metabolite ratios as measured by 3-dimensional echo planar spectroscopy imaging (3D-EPSI) from central brain regions of interest (ROI) centered at the corpus callosum reflect imaging metrics of large volumes of supratentorial brain (STB) from patients with multiple sclerosis. METHODS: 48 MS patients with relapsing-remitting, secondary progressive, and primary progressive disease underwent a 3D-EPSI sequence covering large volumes of STB. Metabolite ratios were first estimated from all voxels within a STB mask using a linear regression of N-acetylaspartate (NAA) over Creatine (Cr), NAA over choline (Cho) and Cho over Cr. Secondly, spectroscopic voxels from a central brain (CB) ROI centered at the corpus callosum were selected within the STB. Ratios were compared using Bland-Altman regression analysis and Spearman's correlation coefficients between STB versus central brain. Ratios from studied ROIs were correlated with the EDSS and compared to normal controls. RESULTS: Very strong correlations ranging from 0.884 and 0.938 (p < 0.0001) were found for all metabolite ratios between STB versus central brain. NAA/Cr ratios were similarly and negatively correlated with the EDSS across all ROIs, trends ranging from -0.257 to -0.314 (p < 0.1). NAA/Cr from all MS patients was similarly decreased compared to controls across all ROIs (p < 0.01). CONCLUSION: Metabolite ratios from a central brain ROI were statistically equivalent and highly correlated with ratios from the STB. The study of NAA/Cr using (1)HMRS from a central brain ROI centered at the corpus callosum seems to be representative of brainwide axonal changes in patients with MS.

A study of therapy-related acute leukaemia after mitoxantrone therapy for multiple sclerosis.

To evaluate the incidence of therapy-related acute leukaemia (t-AL) after single-agent mitoxantrone (MITO) treatment, we reviewed medical records of patients in three studies of single-agent MITO therapy for multiple sclerosis (MS) and existing literature on MITO therapy in MS, leukaemia, and solid tumors. Of 1378 MITO recipients in the three MS studies (mean cumulative dose of 60 mg/m2 and mean follow-up of 36 months), one patient had t-AL, an observed incidence proportion of 0.07% [95% confidence interval (CI) = 0.00-0.40%]. There were no cases of t-AL in published reports of nine additional studies of single-agent MITO therapy for MS. There was one published case report of acute promyelocytic leukoemia detected five years after initiating MITO therapy for MS. The observed incidence proportion of t-AL is very low in patients who received MITO as single-agent therapy for MS. Although these observations provide preliminary reassurance, extended follow-up of these patients and those who receive higher cumulative doses of MITO is required to define the long-term risk of t-AL after MITO therapy for MS.

Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS.

BACKGROUND: Mitoxantrone (MITO) is associated with dose-related cardiotoxicity when administered concomitantly with other cytotoxic agents with or without radiotherapy for leukemia and solid tumors. OBJECTIVE: To review observed cardiotoxicity of single-agent MITO therapy for MS. METHODS: Records of 1,378 patients from three clinical trials of MITO treatment for MS were reviewed for signs and symptoms of cardiac dysfunction and left ventricular ejection fraction (LVEF) results. Duration of follow-up was a median of 29 months (4,084 patient-years). RESULTS: No patients experienced congestive heart failure (CHF) before treatment. Cumulative MITO doses ranged from 2 to 183 mg/m(2) (mean 60.5 mg/m(2), median 62.5 mg/m(2)), and 141 patients received >100 mg/m(2). Two of 1,378 patients experienced CHF after initiating MITO therapy. Of 1,378 patients, 779 completed baseline and scheduled follow-up LVEF testing. Baseline LVEF was >50% in all 779 patients. Seventeen of 779 patients had asymptomatic LVEF of <50% (incidence proportion = 2.18%, 95% CI = 1.28 to 3.47%). Although the incidence of asymptomatic LVEF of <50% was not significantly related to monthly versus 3-monthly therapy, duration of therapy, age, or gender, asymptomatic LVEF of <50% trended higher with a cumulative dose of >/=100 mg/m(2) (5.0%) than with <100 mg/m(2) (1.8%) (p = 0.06). CONCLUSIONS: The observed incidence of CHF in patients with MS who received a mean cumulative dose of 60.5 mg/m(2) MITO was <0.20%. Continued monitoring of patients with MS who are receiving MITO is needed to determine whether the incidence of CHF increases with higher cumulative MITO doses and prolonged follow-up.

T2 relaxation time histograms in multiple sclerosis.

An accurate measurement of the transverse relaxation time T(2), and the histogram of T(2) in the brain parenchyma can be accomplished in vivo using a multi-echo magnetic resonance imaging sequence. An estimate of the error in the T(2) measurement is derived using copper sulfate doped water phantoms. Correction factors are calculated and applied to the signal intensity of each voxel prior to the in vivo T(2) evaluation. These corrected T(2) are in good agreement with the theoretical values calculated from copper sulfate concentrations. This technique is then applied to calculate T(2) histograms of the brain. The population studied was composed of normal volunteers and multiple sclerosis patients. The corrected T(2) histogram method discriminates the normal control population from the MS population, and also discriminates between relapsing-remitting patients and primary progressive or secondary progressive patients. Moreover using this approach we are able to detect in MS patients a global shift of the T(2) of the white mater toward higher values. The results of this study showed that the method is easy to implement and may be used to characterize MS pathology.

Linkage and association analysis of chromosome 19q13 in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune neurological disorder with a complex etiology. Sibling risk, twin, and adoption studies have demonstrated that genes play a vital role in susceptibility to MS. Numerous association and linkage studies have implicated the major histocompatibility complex (MHC) as one component of the genetic etiology, but additional loci remain to be identified. Genomic screens have suggested over 50 regions that might harbor these genes, but there has been little agreement between studies. The one region suggested by all four screens resides within chromosome 19q13. Allelic associations with several markers in this region have also been described. This region has now been examined in detail in an expanded dataset of MS families from the United States. Genetic linkage and association were tested with multiple markers in this region using both parametric and non-parametric analyses. Additional support for an MS susceptibility locus was observed, primarily in families with the MS-associated HLA-DR2 allele. While consistent, this effect appears to be modest with a maximum lambda(s) = 1.47, probably representing no more than 10% of the overall genetic effect in MS.

Treatment of depression is associated with suppression of nonspecific and antigen-specific T(H)1 responses in multiple sclerosis.

OBJECTIVE: To examine the relationship between depression, treatment of depression, and interferon gamma (IFN-gamma) production by peripheral blood mononuclear cells in patients with comorbid diagnoses of relapsing-remitting multiple sclerosis (MS) and major depressive disorder. DESIGN: A randomized comparative outcome trial of three 16-week treatments for depression. Assessments were conducted at baseline, week 8, and treatment cessation. SETTING: An academic outpatient treatment and clinical research center. PATIENTS: Fourteen patients who met the criteria for relapsing-remitting MS and major depressive disorder. INTERVENTIONS: Individual cognitive behavioral therapy, group psychotherapy, or sertraline therapy. MAIN OUTCOME MEASURES: Depression was assessed using the Beck Depression Inventory. Interferon gamma production by peripheral blood mononuclear cells was measured following stimulation with OKT3 or recombinant human myelin oligodendrocyte glycoprotein (MOG). Variability in immune assays was controlled using 8 nondepressed healthy subjects who were enrolled at times corresponding with the enrollment of MS patients. RESULTS: Results of the Beck Depression Inventory were significantly related to IFN-gamma production stimulated with OKT3 or MOG at baseline (P< or = .03 for all). Level of depression, OKT3-stimulated IFN-gamma production, and MOG-stimulated IFN-gamma production all declined significantly over the 16-week treatment period (P< or = .03 for all). Among controls, there were no significant changes over time in OKT3- or MOG-stimulated IFN-gamma, or in depression (P> or = .25 for all). CONCLUSIONS: These findings suggest that the production of the proinflammatory cytokine IFN-gamma by autoaggressive T cells in relapsing-remitting MS is related to depression and that treatment of depression may decrease IFN-gamma production. Thus, treatment of depression may provide a novel disease-modifying therapeutic strategy as well as a symptomatic treatment for patients with MS.

Injectable medication for the treatment of multiple sclerosis: the influence of self-efficacy expectations and injection anxiety on adherence and ability to self-inject.

The management of many chronic illnesses involves medications that must be injected on a frequent basis. With fewer support resources available, patients are increasingly being obliged to manage injectable medications themselves. Interferon beta-1a (IFNbeta-1a), recommended for the treatment of multiple sclerosis (MS), must be injected intramuscularly on a weekly basis. Patients are generally advised and taught to self-inject, if possible. This longitudinal study examined cognitive and affective contributions to the ability to self-inject and adherence to IFNbeta-1a over 6 months following initiation of medication. Participants were 101 patients with a relapsing form of MS. Injection self-efficacy expectations, injection anxiety, adherence expectations, method of injection administration, and 6-month adherence to IFNbeta-1a were fitted to a path analytic model. Pretreatment injection self-efficacy expectations were significantly related to 6-month adherence. This relation was mediated by the patient's ability to self-inject. Patients 'experienced level of injection anxiety was related to adherence but not to method of injection.

Comparative outcomes for individual cognitive-behavior therapy, supportive-expressive group psychotherapy, and sertraline for the treatment of depression in multiple sclerosis.

This study compared the efficacy of 3 16-week treatments for depression in 63 patients with multiple sclerosis (MS) and major depressive disorder (MDD): individual cognitive-behavioral therapy (CBT), supportive-expressive group therapy (SEG). and the antidepressant sertraline. Significant reductions were seen from pre- to posttreatment in all measures of depression. Intent-to-treat and completers analyses using the Beck Depression Inventory (BDI; A. T. Beck, C. H. Ward. M. Medelson. J. Mock, & J. Erbaugh, 1961) and MDD diagnosis found that CBT and sertraline were more effective than SEG at reducing depression. These results were largely supported by the BDI-18, which eliminates BDI items confounded with MS. However, the Hamilton Rating Scale for Depression (M. Hamilton, 1960) did not show consistent differences between treatments. Reasons for this inconsistency are discussed. These findings suggest that CBT or sertraline is more likely to be effective in treating MDD in MS compared with supportive group treatments.

Neuropsychological effects of interferon beta-1a in relapsing multiple sclerosis. Multiple Sclerosis Collaborative Research Group.

Cognitive dysfunction is common in multiple sclerosis (MS), yet few studies have examined effects of treatment on neuropsychological (NP) performance. To evaluate the effects of interferon beta-1a (IFNbeta-1a, 30 microg administered intramuscularly once weekly [Avonex]) on cognitive function, a Comprehensive NP Battery was administered at baseline and week 104 to relapsing MS patients in the phase III study, 166 of whom completed both assessments. A Brief NP Battery was also administered at 6-month intervals. The primary NP outcome measure was 2-year change on the Comprehensive NP Battery, grouped into domains of information processing and learning/memory (set A), visuospatial abilities and problem solving (set B), and verbal abilities and attention span (set C). NP effects were most pronounced in cognitive domains vulnerable to MS: IFNbeta-1a had a significant beneficial effect on the set A composite, with a favorable trend evident on set B. Secondary outcome analyses revealed significant between-group differences in slopes for Brief NP Battery performance and time to sustained deterioration in a Paced Auditory Serial Addition Test processing rate, favoring the IFNbeta-1a group. These results support and extend previous observations of significant beneficial effects of IFNbeta-1a for relapsing MS.

A longitudinal study of ventricular volume in early relapsing-remitting multiple sclerosis.

The specific aim of this study was to determine whether progressive brain atrophy could be detected within 18 months of establishing a diagnosis of relapsing-remitting multiple sclerosis (RRMS). Fifteen patients with clinically definite RRMS (mean disease duration from first symptom=6 months, mean EDSS=1.2) completed 6 - 14 monthly quantitative MRI sessions. The volume of the lateral ventricles was determined each month using a semi-automated thresholding technique from T1-weighted axial images. The number of new monthly gadolinium-enhancing (Gd+) lesions and EDSS scores were also recorded. Lateral ventricular volumes increased significantly during this study. When individual data were examined, statistically significant changes were observed in six of 15 patients. Monthly change in ventricular volume was related to baseline EDSS and total number of new Gd(+) lesions. These observations indicate brain atrophy, a putative imaging marker of diffuse demyelination and axonal loss, can occur as early as 18 months after first symptoms of RRMS, and is related to the baseline level of disability and to the number of new Gd+ lesions. Multiple Sclerosis (2000) 6 332 - 337

A longitudinal study of T1 hypointense lesions in relapsing MS: MSCRG trial of interferon beta-1a. Multiple Sclerosis Collaborative Research Group.

BACKGROUND: T1 hypointense lesions (T1 black holes) are focal areas of relatively severe CNS tissue damage detected by MRI in patients with MS. OBJECTIVE: To determine the natural history of T1 hypointense lesions in relapsing MS and the utility of T1 hypointense lesions as outcome measures in MS clinical trials. METHODS: MR studies were from the Multiple Sclerosis Collaborative Research Group trial. Longitudinal results are reported in 80 placebo- and 80 interferon beta-1a (IFNbeta-1a)-treated patients with mild to moderate disability relapsing-remitting MS. RESULTS: There was a small but significant correlation between T1 hypointense lesion volume and disability at baseline and on trial (r = 0.22, r = 0.28). In placebo patients there was a 29.2% increase in the mean volume of T1 hypointense lesions (median 124.5 mm3) over 2 years (p < 0.001 for change from baseline), as compared to an 11.8% increase (median 40 mm3) in the IFNbeta-1a-treated patients (change from baseline not significant). These treatment group comparisons did not quite reach significance. The most significant contributor to change in T1 hypointense lesions was the baseline number of enhancing lesions (model r2 = 0.554). Placebo patients with more active disease, defined by enhancing lesions at baseline, were the only group to show a significant increase in T1 hypointense lesion volume from baseline. CONCLUSION: The development of T1 hypointense lesions is strongly influenced by prior inflammatory disease activity, as indicated by enhancing lesions. These results suggest that treatment with once weekly IM IFNbeta-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.

Psychological stress and the subsequent appearance of new brain MRI lesions in MS.

OBJECTIVE: To examine the relationship between stressful life events and psychological distress, and the subsequent development of gadolinium-enhancing (Gd+) brain lesions. BACKGROUND: It has long been speculated that stressful life events and psychological distress are associated with disease exacerbation in MS. This is the first prospective longitudinal study of the relationship between stressful life events, psychological distress, and disease activity as measured by Gd+ brain MRI. METHODS: Thirty-six patients (mean age, 44.4 years; 22 women, 14 men) with relapsing forms of MS were assessed once every 4 weeks for 28 to 100 weeks. Assessments included Gd+ MRI, the Social Readjustment Rating Scale (SRRS), the Hassles Scale, and the Profile of Mood States. The SRRS was altered in the following manner: 1) three items that confounded with MS were eliminated, 2) endorsed items were rated for intensity, and 3) the scale was divided into three subscales: major negative events, conflict and disruption in routine, and positive life events. Data were analyzed using mixed-effects logistic regression to account for intrasubject correlations. Stress and distress measures were used to predict concurrent and future MRI activity. RESULTS: For the total sample of patients, increased conflict and disruption in routine was followed by increased odds of developing new Gd+ brain lesions 8 weeks later (odds ratio, 1.64; p = 0.00083). There was no strong evidence of a relationship between psychological stress or distress and clinical exacerbation. CONCLUSIONS: These data provide support for the notion that conflict and disruption in routine are related to subsequent disease activity in MS. However, this relationship is not sufficiently robust to predict clinical exacerbations reliably in individual patients.

1H MRSI comparison of white matter and lesions in primary progressive and relapsing-remitting MS.

OBJECTIVE: To compare brain metabolite levels in patients with primary progressive (PP) and relapsing remitting (RR) MS and controls. HYPOTHESES: (1) creatine (Cr), a putative marker of gliosis, is elevated and N-acetylaspartate (NAA), a putative marker of axonal density and functional integrity, is reduced in PPMS lesions and normal appearing white matter (NAWM) compared to control white matter; (2) The pattern of metabolite change in PPMS is different than in RRMS. METHODS: MRI and proton magnetic resonance spectroscopic imaging (1H MRSI) were collected from 15 PPMS patients, 13 RRMS patients, and 20 controls. RESULTS: Cr was increased in PPMS NAWM compared to controls (P=0.035), and compared to RRMS NAWM (P=0.038). Cr was increased in focal MRI lesions from PPMS compared to lesions from RRMS (P=0.044) and compared to control white matter (P=0.041). NAA was similarly reduced in PPMS and RRMS NAWM compared to control. NAA was similarly reduced in PPMS and RRMS lesions, compared to control white matter. CONCLUSIONS: Creatine is higher in PPMS than RRMS NAWM and focal lesions. This observation is consistent with the notion that progressive disability in PPMS reflects increased gliosis and axonal loss whereas disability in RRMS reflects the cumulative effects of acute inflammatory lesions and axonal loss.

Magnetization transfer ratio in new MS lesions before and during therapy with IFNbeta-1a.

OBJECTIVE: The authors examined the effect of 6.0 MIU interferon beta-1a (IFNbeta-1a) administered IM each week on the evolution of monthly magnetization transfer ratio (MTR) within new gadolinium-enhancing (Gd+) lesions in patients with very early relapsing-remitting (RR) MS. BACKGROUND: IFNbeta is an effective disease-modifying treatment for patients with RRMS. Among other effects, it has been shown to decrease the number of new Gd+ and T2-weighted lesions. MTR is a putative marker for irreversible tissue damage and evolution of MTR within a lesion may reflect recovery of tissue damage. It is not known whether IFNbeta-1a affects the recovery phase of lesions. METHODS: Eight untreated patients with RRMS who completed up to 14 monthly brain MRI sessions elected to initiate treatment with IFNbeta-1a. Four out of eight patients developed new Gd+ lesions during treatment. MTR of lesions at the time of appearance and subsequent rate of change of monthly MTR were compared before and after treatment (stratified Mann-Whitney test). RESULTS: The difference between MTR at appearance of 47 new Gd+ lesions before treatment versus 23 new Gd+ lesions during treatment was not significant. Twenty-two of 47 new Gd+ lesions before treatment and 11 of 23 new Gd+ lesions after treatment were monitored for up to 6 months. After appearance of new Gd+ lesions, the rate of increase in MTR was faster during therapy (p = 0.037). CONCLUSION: MTR abnormalities within new Gd+ lesions evolve at a faster rate during treatment with IFNbeta-1a than before initiating therapy. This is consistent with the hypothesis that IFNbeta-1a promotes resolution of new Gd+ lesions.

CC-chemokine receptor 5 polymorphism and age of onset in familial multiple sclerosis. Multiple Sclerosis Genetics Group.

Multiple sclerosis (MS) is a common disease of the central nervous system characterized by myelin loss and progressive neurological dysfunction. An underlying genetic susceptibility plays a clear role in the etiology of MS, likely acting in concert with an undefined environmental exposure. Full-genome screenings in multiplex MS families have identified several susceptibility regions, supporting a polygenic model for MS. Among these regions, evidence for weak linkage was observed at 3p/3cen suggesting the presence of an MS gene(s) of modest effect. Encoded here are two chemokine receptors, CCR5 and CCR2B. We examined the chromosome 3p21-24 region in 125 MS families (322 total affecteds and 200 affected sib-pairs), and performed genetic analyses of CCR5 and CCR2B loci and two nearby markers (D3S1289 and D3S1300) using both linkage- and association-based tests. No evidence of linkage to MS was observed for any of the tested markers. Affected relative-pair (SimIBD) and sib-pair analyses (ASPEX), and association testing (sib-TDT) for each locus were also not significant. However, age of onset was approximately 3 years later in patients carrying the CCR5delta32 deletion (P=0.018 after controlling for gender effects). Thus, chemokine receptor expression may be associated with differential disease onset in a subset of patients, and may provide a therapeutic target to modulate inflammatory demyelination.

Telephone-administered cognitive-behavioral therapy for the treatment of depressive symptoms in multiple sclerosis.

This study examined the efficacy of an 8-week telephone-administered cognitive-behavioral therapy (CBT) for the treatment of depressive symptomatology in multiple sclerosis (MS) patients. The treatment, Coping with MS (CMS), included a patient workbook designed to structure the treatment, provide visual aids, and help with homework assignments. Thirty-two patients with MS, who scored at least 15 on the Profile of Mood States Depression-Dejection scale, were randomly assigned to either the telephone CMS or to a usual-care control (UCC) condition. Depressive symptomatology decreased significantly in the CMS condition compared with the UCC condition. Furthermore, adherence to interferon beta-1a, a disease-modifying medication for the treatment of MS, was significantly better at the 4-month follow-up among patients who received CMS as compared with those in the UCC condition.

Drugs used to treat spasticity.

Spasticity is a common and disabling symptom for many patients with upper motor neuron dysfunction. It results from interruption of inhibitory descending spinal motor pathways, and although the pathophysiology of spasticity is poorly understood, the final common pathway is overactivity of the alpha motor neuron. Therapy for spasticity is symptomatic with the aim of increasing functional capacity and relieving discomfort. Any approach to treatment should be multidisciplinary, including physical therapy, and possibly surgery, as well as pharmacotherapy. It is important that treatment be tailored to the individual patient, and that both patient and care giver have realistic expectations. Pharmacotherapy is generally initiated at low dosages and then gradually increased in an attempt to avoid adverse effects. Optimal therapy is the lowest effective dosage. Baclofen, diazepam, tizanidine and dantrolene are currently approved for use in patients with spasticity. In addition, clonidine (usually as combination therapy), gabapentin and botulinum toxin have shown efficacy, however, more studies are required to confirm their place in therapy. Intrathecal baclofen, via a surgically implanted pump and reservoir, may provide relief in patients with refractory severe spasticity.