Fatigue is not associated with raised inflammatory markers in multiple sclerosis

BACKGROUND: The pathogenesis of fatigue in patients with MS is poorly understood. OBJECTIVE: To test the hypothesis that fatigue in MS is related to inflammatory disease activity as measured by systemic markers of inflammation. METHODS: Fatigue as assessed by the Fatigue Questionnaire Scale (FQS) and Krupp's Fatigue Severity Scale (KFSS) was correlated with several inflammatory markers in 38 patients with MS (16 relapsing-remitting [RR; 7 of whom had benign MS), 9 secondary progressive [SP], 13 primary progressive [PP]). The markers included daily urinary neopterin excretion, a marker of interferon-gamma-activated macrophage activity, and serum C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) levels. Urinary neopterin excretion was measured daily for 2 weeks. RESULTS: No correlation was found between urinary neopterin excretion, CRP, or sICAM-1 and the fatigue scores. However, patients with a raised serum CRP level had higher KFSS, but not FQS, scores than patients with normal CRP levels (KFSS, 50 +/- 8 vs 41 +/- 14, p = 0.05; FQS, 13 +/- 4 vs 11 +/- 5, p = NS). When assessed using the FQS, patients with RR and SP MS were more fatigued than patients with PP MS (RR = 12.5 [4 to 23] vs SP = 13 [8 to 18] vs PP = 9 [7 to 14], p = 0.02). The patients with benign MS were as fatigued as patients with nonbenign disease. CONCLUSION: The pathogenesis of fatigue in MS is complex and does not appear to be directly related to systemic markers of inflammatory disease activity. Interestingly, patients with PP MS were less fatigued than patients with RR disease.     

Transferrin in patients with multiple sclerosis: a comparison among various subgroups of multiple sclerosis patients

OBJECTIVES: To compare cerebrospinal fluid (CSF) and serum transferrin (Tf) concentrations, transferrin quotient and index in various subgroups of MS patients. MATERIAL AND METHODS: CSF and serum transferrin concentrations, transferrin quotient QTf (i.e. CSF transferrin/serum transferrin x 10(3)) and index (QTf/Qalbumin) were determined in a group of 51 patients with clinically definite or probable multiple sclerosis (MS). Patients were subdivided according to the disease form (relapsing-remitting = RR, secondary progressive = SP, primary progressive = PP; patients with RR form were further subdivided into those in the attack and those in remission), disease severity (EDSS 0-5.5, EDSS 6.0-10.0), its treatment (non-treated - including patients treated with vitamins and/ or vasodilators only, treated - i.e. glucocorticoids and/or immunosuppressants and/or (exceptionally) beta-interferon), disease duration (0-2 years, >2-10 years, > 10 years) and sex. Correlation of transferrin values with age was also performed. RESULTS: Serum transferrin was somewhat lower and significantly more frequently subnormal in PP patients in comparison with the SP form and the RR form in remission. Transferrin index was significantly higher in the PP form than in the RR as well as the SP form. Transferrin quotient was significantly more frequently subnormal in patients in remission compared to those in the attack of the RR disease. CSF transferrin as well as transferrin quotient were more frequently subnormal in patients with short disease duration (0-2 years) than in patients with longer disease duration; these parameters, however, correlated also significantly with age. CSF transferrin and transferrin quotient were higher in male than in female patients. CONCLUSION: The authors conclude that evaluation of transferrin in MS patients - along with albumin - may help to differentiate among various MS subgroups, since there are significant differences among RR, SP and PP forms. For this purpose, however, other CSF protein fractions should be evaluated in parallel in order to obtain more complex information and to establish a panel of examinations enabling multiple statistical analyses. Transferrin evaluation in MS may also be of significant theoretical interest, since transferrin is known to be involved in the regulation of iron metabolism and it may have a protective role against the oxidative stress. Moreover, transferrin is a growth factor important for proliferation of activated T lymphocytes. By means of the use of transferrin quotient and especially transferrin index, it may be possible to estimate the proportion of intra-CNS-synthesized transferrin and/or rate of specific transferrin transport across the blood-CSF barrier. Further studies are, however, needed for such an evaluation.     

The relationship of brain and cervical cord volume to disability in clinical subtypes of multiple sclerosis: a three-dimensional MRI study

OBJECTIVES: Brain and cervical cord volume is a potentially valuable index marker of irreversible pathological processes in multiple sclerosis (MS). Volume in both brain and cervical cord regions in the same patients has only been investigated in a small number of subjects. We aimed at measuring volume in different parts of the central nervous system, and its relationship with clinical measures, in relapsing-remitting (RR) and secondary progressive (SP) MS patients. MATERIAL AND METHODS: Conventional dual echo and three-dimensional (3-D) magnetization prepared rapid acquisition gradient echo imaging was performed on 97 (49 RR and 48 SP) MS patients, and on 31 age- and gender-matched healthy controls. The volumes of the supratentorial brain, lateral ventricles, brainstem, cerebellum and upper cervical cord (UCC) were determined on 3-D magnetic resonance imaging. RESULTS: RR MS patients had significantly smaller supratentorial brain (P=0.002) and larger lateral ventricles (P=0.047) compared with controls, but no differences were found for cerebellum, brainstem and UCC volumes. Significantly smaller supratentorial brain (P<0.0001), cerebellum (P=0.007), brainstem (P=0.0004) and UCC (P<0.0001) volumes, and larger lateral ventricles (P<0.0001) were observed in SP MS patients than in controls. In RR MS, T2-lesion volume correlated with supratentorial (r=-0.46, P=0.0009), lateral ventricular (r=0.65, P<0.0001), cerebellar (r=-0.42, P=0.003) and brainstem (r=-0.35, P=0.01) volumes, but not with UCC volume (r=-0.18, P=0.22). In SP MS, apart from lateral ventricular volume (r=0.52, P=0.0002), none of the estimated structural volumes correlated with T2-lesion volume. The UCC volume correlated with brainstem volume in both RR MS (r=0.35, P=0.016) and SP MS (r=0.38, P=0.007). Multiple regression analysis showed that supratentorial brain volume in RR group, and UCC volume in SP group, were single significant contributors (P=0.01 and 0.04, respectively) to the Expanded Disability Status Scale of all factors entered into the regression model. CONCLUSION: Atrophy is confined to the supratentorial compartment early in the disease course corresponding to the RR stage, but becomes more pronounced in the brain and cervical spinal cord in the SP phase. The estimate of cervical cord volume for SP MS is relevant to functional disability and may be helpful in monitoring MS evolution in the progressive form of disease.     

The role of osteopontin: A shared pathway in the pathogenesis of multiple sclerosis and osteoporosis?

Osteopontin (OPN) was suggested to have a role in the pathophysiology of MS and in bone metabolism. However, we formerly reported increased presence of osteoporosis in MS patients independent of corticosteroid treatment, there is only limited information about the mechanism of bone loss. In this study, we investigated the role of OPN on bone mineral density in MS patients. Thirty-three relapsing-remitting (RR), 12 secondary progressive (SP), and 5 primary progressive (PP) MS patients and 30 healthy controls were prospectively enrolled. Students' t test, chi-square test, and Pearson correlations were used. The mean OPN level was 155.4+/-81.8 ng/ml in controls, and 15.9+/-36.2 ng/ml in MS patients (p<0.001).No statistical difference was observed among RR, SP and PPMS patients (p=0.162). No relationship was found between OPN levels and age at onset of disease (p=0.830), gender (p=0.785), MS subtypes (p=0.330), disease duration (p=0.744), or EDSS scores (p=0.633).About 34% of MS patients versus 10.3% of controls had osteoporosis (p=0.017).Osteopontin levels showed no significant correlation with osteoporosis in controls, but were lower in MS patients with osteoporosis in femur neck (r=0.85, p=0.010).The cumulative dose of corticosteroid treatment did not correlate with OPN levels (p=0.285).In conclusion, our results suggest that OPN may have a role as a shared cytokine in pathogenesis of MS and osteoporosis.     

Influence of CCR5 delta32 polymorphism on multiple sclerosis susceptibility and disease course

The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). We carried out an allelic association study using a deletion polymorphism in the coding region of the CCR5 gene in 331 relapsing-remitting (RR) and secondary progressive (SP) MS patients, 108 primary progressive (PP) MS patients and 230 healthy controls. Of the 331 RR and SPMS patients, 172 were recruited from specialist clinics and 159 from a population survey. Disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS) and used to calculate a progression index for each patient (defined as EDSS divided by duration of disease). No significant difference in distribution of the CCR5 delta32 allele was observed between the 331 RR/SPMS patients and controls, between the 108 PPMS patients and controls or between the PPMS and RR/SPMS groups. Furthermore, no differences in rate of disease progression were detected between carriers and noncarriers of the delta32 allele. In the population-based group of RR/SPMS patients, carriage of the CCR5 delta32 polymorphism was associated with a lower age at disease onset (mean age 26.562 versus 31.065 years, P = 0.003). However, no significant differences in age of onset were present in the PPMS group or in a second RRMS population. These results suggest that the CCR5 delta32 polymorphism is not a major determinant of susceptibility to develop MS in the population under study, and conflict with a previously reported association between CCR5 delta32 carriage and a better prognosis.     

Fatigue and its association with sociodemographic variables among multiple sclerosis patients

OBJECTIVE: To explore the relationship between fatigue, sociodemographic and clinical variables in a population of patients with multiple sclerosis (MS). RATIONALE: There is a need to identify empirical relationships with possible antecedents of fatigue among patients with MS. METHODS: A mailed questionnaire designed to survey sociodemographic variables and the Fatigue Severity Scale (FSS) was mailed to 502 individuals from the population of patients with definite MS in the city of Oslo. A total of 368 (73%) responded. Clinical data were collected from the Oslo City MS-Registry. RESULTS: The prevalence of fatigue in this population was 60.1%. The FSS score showed a negative correlation with education (r = -0.15, P < 0.01) and a positive correlation with age (r = 0.20, P < 0.001) and time since disease onset (r = 0.11, P < 0.05). When controlled for gender, level of education and time since disease onset, the data showed a positive relationship between fatigue and age (P < 0.001) among patients with primary progressive (PP) disease. This relationship between age and fatigue was not found among patients with relapsing-remitting/secondary progressive (RR/SP) disease. CONCLUSION: The negative relationship between level of formal education (FE) and fatigue among individuals with RR/SP disease suggests that behavioral factors may be among the antecedents of fatigue in this patient group. In contrast to normative data from the general population, our findings revealed no differences in fatigue related to gender Thus, this study supports the hypothesis that there are disease-specific antecedents of fatigue among patients with MS.     

Cognitive impairment in different MS subtypes and clinically isolated syndromes

OBJECTIVE: To investigate the pattern of cognitive impairment in patients with relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP) multiple sclerosis, and patients with clinically isolated syndrome (CIS) suggestive of MS, relative to control participants in the Greek population. METHODS: RR patients (N=75), SP patients (N=29), PP patients (N=23), CIS patients (N=33), and healthy control participants (N=43) were assessed by the Brief Repeatable Battery of Neuropsychological Tests (BRBN). RESULTS: The overall prevalence of cognitive dysfunction in our patients was 52.8% with CIS patients excluded and 47.5% with CIS patients included. All MS patients differed significantly from controls in all BRBN measures. Similar was the pattern of cognitive dysfunction in patients with CIS suggestive of MS, although verbal learning/memory capacity (as measured by the Selective Reminding Test) remained relatively spared. The comparisons between patient groups revealed some differences in the performance mainly in favor of CIS and RRMS patients. These differences largely disappeared after controlling for physical disability (EDSS). CONCLUSION: All MS subtypes patients exhibit a pattern of cognitive impairment running across the studied cognitive domains. The pattern of cognitive dysfunction in patients with CIS is similar with relative sparing of verbal learning.     

Intrathecal production of Chlamydia pneumoniae-specific high-affinity antibodies is significantly associated to a subset of multiple sclerosis patients with progressive forms

The purpose of this study was to provide further insight into the effective relevance of the association between Chlamydia pneumoniae and MS. We evaluated by ELISA technique cerebrospinal fluid (CSF) and serum levels of anti-C. pneumoniae IgG in 46 relapsing-remitting (RR), 14 secondary progressive (SP) and 11 primary progressive (PP) MS patients grouped according to clinical and Magnetic Resonance Imaging (MRI) evidence of disease activity. Fifty-one patients with other inflammatory neurological disorders (OIND) and 52 with non-inflammatory neurological disorders (NIND) were used as controls. A C. pneumoniae-specific intrathecal IgG synthesis as detected by the relative specific index was present in a small proportion of MS (17%), OIND (22%) and NIND (2%) patients and was significantly more frequent in MS and in OIND than in NIND (p<0.001) and in SP and PP MS than in RR MS patients (p<0.02). Among the patients with C. pneumoniae-specific intratecally produced antibodies, CSF high-affinity anti-C. pneumoniae IgG were found in the majority of SP or PP MS, occasionally in OIND, but not in RR MS and NIND patients. These findings confirm that the presence of a humoral immune response to C. pneumoniae within the central nervous system (CNS) is not selectively restricted to MS, but is shared by several inflammatory neurological conditions. In addition, our results suggest that an intrathecal production of C. pneumoniae-specific high-affinity IgG can occur in a subset of patients with MS progressive forms in which a C. pneumoniae brain chronic persistent infection may play an important pathogenetic role.     

Intracellular cytokine profile in T-cell subsets of multiple sclerosis patients: different features in primary progressive disease

OBJECTIVE: To evaluate the expression of cytokines in both CD4+ and CD8+ T cells derived from peripheral blood of untreated multiple sclerosis (MS) patients with either relapsing-remitting (RR), secondary progressive (SP) or primary progressive (PP) MS and healthy controls (HC). BACKGROUND: MS is an immune-mediated disease and cytokines hove been hypothesized to contribute significantly to disease progression. Compared to the relapse-onset (RR, SP) form of the disease, PPMS patients have different clinical, immunological and pathological features. Surprisingly, the ability of their circulating T cells to produce immunoregulatory cytokines has not been extensively studied so far. METHODS: Seventy-two MS patients (24 RR, 26 SP, 22 PP) and 34 HC were studied. Stimulated peripheral blood derived CD4+ and CD8+ T MS patients express significantly more CD4+ and CD8+ T cells were analyzed for IFN-gamma, IL-2, TNF-alpha, IL-4, IL-10 and IL-13 production. RESULTS: cells producing IFN-gamma compared to HC. Compared to the other forms of the disease, PPMS patients display a significant decrease in CD4+ T cells producing IL-2, IL-13 and TNF-alpha and a significant increase in CD8+ T cells producing IL-4 and IL-10. CONCLUSIONS: The data presented here demonstrate that patients with PPMS express less pro- and more anti-inflammatory cytokine producing T cells compared to the relapse-onset form of the disease, confirming the view on PPMS as a distinct disease entity.     

Primary and transitional progressive MS: a clinical and MRI cross-sectional study

BACKGROUND: Ten percent of patients with MS have a progressive course from onset with no history of relapses or remissions. A smaller subgroup follow a similar progressive course but have a single relapse at some point (transitional progressive [TP] MS). To date these patients have been excluded from receiving licensed treatments for MS and from most therapeutic trials. OBJECTIVE: To document the clinical and MRI characteristics of a large cohort of progressive patients, including 158 with primary progressive (PP) MS and 33 with TPMS. Data from a small reference group of 20 patients with secondary progressive (SP) MS are also presented for reference. METHODS: Patients were recruited from six European centers. All underwent a clinical assessment including scoring on the Expanded Disability Status Scale (EDSS) and MRI of the brain and spinal cord. RESULTS: The men-to-women ratio was 81:77 (51% men) in the PP group, 14:19 (42% men) in the TP group, and 5:15 (25% men) in the SP group. The mean age at disease onset was significantly higher in the PP group than it was in the other two groups (PP 40.2 years, TP 34.9 years, SP 28.7 years). On MRI the PP group had lower mean brain T2 and T1 hypointensity lesion loads than the SP group (T2 12.02 versus 27.74 cm3, p = 0.001; T1 4.34 versus 7.04 cm3, p = 0.015). The SP and TP cohorts had significantly more T2-weighted lesions in the spinal cord than the PP patients, and the SP cohort had the greatest degree of atrophy. There was a correlation in the PP and TP patients between EDSS score and brain and spinal cord atrophy (r = 0.3, 0.2, p < or = 0.006) but not with brain lesion load. The PP and TP patients who presented with spinal cord pathology had significantly lower brain T2 and T1 lesion loads than those with non-spinal cord presentations (p = 0.002). CONCLUSIONS: The monitoring of disease progression in PPMS is difficult, although measures of atrophy correlate with the EDSS and appear most promising. This study increases our understanding of this unique patient group, which will be further expanded with the acquisition of serial data.     

Multiple sclerosis: report on 200 cases from Iran

Clinical findings of 200 patients in Iran with definite multiple sclerosis (MS) according to Poser et al.'s criteria and positive findings on magnetic resonance imaging (MRI) have been reviewed. The clinical course was relapsing-remitting (RR) for 88%, primary progressive (PP) for 7% and secondary progressive (SP) for 5% of cases. The mean age of onset was 27 +/- 7.4 years for the whole group and 37.1 +/- 8.8 years for PPMS. The gender ratio was 2.5:1 female:male. Involvement of the pyramidal system was the most common mode of presentation. Five per cent of patients had positive family history for the disease, 14% of patients had benign MS and 12% with disease duration longer than five years had an Expanded Disability Status Scale < or = 2. The optico-spinal form was not a common form of presentation in the group.     

Correlation between brain MRI lesion volume and disability in patients with multiple sclerosis

In this study we evaluated the relationships between clinical variables and lesion volumes measured from magnetic resonance imaging (MRI) scans in a large cohort of multiple sclerosis (MS) patients. One hundred and thirty patients with MS entered the study: 36 patients had relapsing-remitting (RR), 39 benign (B), 42 secondary progressive (SP) and 13 primary progressive (PP) courses. There was a significant correlation (r=0.3; p=0.0006) between the total lesion load and the EDSS score when the whole cohort of patients was considered. This correlation increased (r=0.5) when only patients with RRMS and SPMS were considered. Our data indicate that a correlation between disability and MRI lesion volume in MS exists, but its strength is moderate.     

Selected issues of immunomodulating treatment in multiple sclerosis

Placebo-controlled or open trials of immunomodulating drugs shed more light upon pivotal clinical issues in relapsing-remitting and secondary progressive multiple sclerosis (RR MS, SP MS). Extension over 4 years of IFN beta-1b, IFN beta-1a s.c. and glatiramer acetate trials provided modest clinical benefit in RR MS patients. After 4-8 years of treatment an annual relapse rate decreased (0.20-0.57) and proportion of progression free RR MS patients increased significantly (56-65%). The percentages of SP MS patients without relapses increased markedly in EUSPMS, IMPACT, NASMPS and SPECTRIMS trials to 36-63. However, the treatments did not slow progression in two latter clinical investigations (p=ns). In most non-responders to IFN beta the second-line immunomodulating drugs brought about clinical improvement. About half of MS patients showed one year or longer adherence to the first immunomodulating drug and nearly one fifth benefited from the change of this drug to another immunotherapeutic agent.     

Cerebrospinal fluid C3 and C4 indexes in immunological disorders of the central nervous system

OBJECTIVES: Validation of cerebrospinal fluid (CSF) indexes as a measure for intrathecal C3 and C4 production. Examination of their role in differential diagnosis of immunological disorders of the central nervous system (CNS). MATERIAL AND METHODS: Correlative study in controls (low back pain without disk herniation) between the CSF/serum ratio (Q) for albumin, and Q C3 and Q C4. Comparative study of C3 and C4 indexes in patients with CNS dysfunction due to relapsing-remitting (RR) multiple sclerosis (MS), secondary progressive (SP) MS, systemic lupus erythematosus (SLE), and human immunodeficiency virus (HIV) infection. RESULTS: Strong and statistically highly significant correlations between Q albumin and Q C3 (r=0.89, P=0.0001), and Q C4 (r=0.68, P= 0.0001). In MS patients decreased mean values for serum (RR, SP) and CSF (RR) C3, and increased C3 index mean value (RR, SP). In CNS SLE increase of mean C3 and C4 index values. In CNS HIV increase of mean C3 and C4 index values, and CSF C3 and C4 concentrations. Most individual index values were within the reference range. CONCLUSION: CSF index is a valid tool to detect intrathecal C3 or C4 production. C3 or C4 index contributes little to the differential diagnosis of immunological CNS disorders. C3 might play a pathogenic role in various immunological CNS disorders.     

Differential patterns of memory performance in relapsing, remitting and secondary progressive multiple sclerosis

BACKGROUND: Memory dysfunction is common in multiple sclerosis (MS). A retrieval failure has been reported as the primary cause for the memory deficits, although some studies also described a faulty acquisition. AIMS: The aim of the study was to examine memory function in relapsing remitting (RR) and secondary progressive (SP) MS patients, analyze the patterns of performance and to investigate whether disease course influences this performance. DESIGN AND SETTINGS: Case-control prospective study conducted in a clinical setting. MATERIALS AND METHODS: Fifty-five RR, 23 SP MS patients and 80 normal subjects were evaluated with a comprehensive neuropsychological battery. Memory was assessed with tasks from the Signoret memory battery. Attention and executive function were also assessed. STATISTICAL ANALYSIS: Univariate analysis of variance, Mann-Whitney U-test, multivariate logistic regression and Chi-square test were used as appropriate. RESULTS: MS patients performed significantly worse than controls on almost all measures of memory (P < 0,001). MS subgroups differed in tasks of delayed recall (logical memory- P =0,019; wordlist delayed recall, P < 0,001), semantic cued recall (P < 0,001), recognition trials (P =0,006) rate of forgetting (P < 0,001) and confabulation and intrusion errors (P =0,004). CONCLUSIONS: Memory is consistently impaired in MS patients and disease course differentially affects the pattern of performance. SP patients show greater difficulties and a more pervasive pattern of dysfunction than RR patients. Delayed recall was the most affected memory measure and performance on this task discriminates between RR and SP MS patients. Relapsing remitting patients performed within the mildly impaired range while SP patients showed a moderate to severe impairment.     

Inflammation and atrophy in multiple sclerosis: MRI associations with disease course

Brain atrophy may be a useful surrogate marker of axonal loss and disease progression in multiple sclerosis (MS). Several studies have suggested that inflammatory disease activity is a risk factor for atrophy in the early stages of the disease, but may become less important later in the disease course. We aimed to investigate the relationships between atrophy and active inflammation at different stages of the disease course using brain volume measurements from magnetic resonance imaging (MRI) in patients with both relapsing-remitting (RR) (n=95) and secondary progressive (SP) (n=76) MS. Conventional dual echo and three-dimensional magnetization-prepared rapid-acquisition gradient echo imaging were performed in all patients and in 31 healthy controls. Supratentorial and infratentorial brain, and lateral ventricular volumes were determined using modern design stereology.Patients with SP MS had smaller supratentorial (p=0.003) and infratentorial brain volumes (p=0.0003), and larger lateral ventricles (p=0.02) than patients with RR MS. RR MS patients with T(1)-enhancing lesions had smaller supratentorial (p=0.02) and infratentorial (p=0.002) brain volumes and larger ventricles (p=0.002) than those without enhancing lesions. SP MS patients with enhancing lesions also had significantly larger lateral ventricles (p=0.03). Categorical analysis showed that more RR MS patients with enhancing lesions had smaller supratentorial brain (p=0.005), or larger lateral ventricular (p=0.028) volumes, and more SP MS patients with enhancing lesions had increased lateral ventricle volumes (p=0.013), than patients without enhancements. The number of enhancing lesions was significantly correlated with lateral ventricular volumes in both RR MS (r=0.39, p=0.0001) and SP MS (r=0.46, p<0.0001). Our data shows that the presence of active inflammation on a single MRI in the course of RR and SP MS, is associated with a higher risk and higher level of brain atrophy. These findings emphasise the important long-term relationship between inflammation and atrophy in MS and provide additional support for the strategy of early anti-inflammatory treatment to protect tissue integrity.     

Humoral and cellular immune responses to Copolymer 1 in multiple sclerosis patients treated with Copaxone

Little is known about the involvement of cytokines in the pathogenesis of primary progressive (PP) multiple sclerosis (MS). We evaluated in this cross-sectional study whether IL-18, IL-12p35, IL-12p40, TNF-, IFN-γ, IL-10, IL-4, TGF-β, IL-12Rβ1, and IL-12Rβ2 mRNA expression in unstimulated white blood cells showed significant differences between relapsing–remitting (RR), secondary progressive (SP) and PP MS patients, and healthy controls. All clinical subtypes showed unique mRNA expression patterns as compared to the controls. Both RR and SP patients displayed increased levels of IL-12p40, IL-18, and TGF-β mRNA compared to controls, whereas PP patients showed only increased IL-18 mRNA levels. Both in PP and SP patients, IFN-γ and IL-10 mRNA were decreased compared to RR patients and controls. PP patients were unique in that they showed decreased IL-12Rβ1 mRNA. In conclusion, our data show that the assessment of cytokine (receptor) mRNA profiles is useful to discriminate between the different clinical subtypes and suggest that different cytokines are involved in the pathogenesis of PP MS as compared to RR and SP MS.     

Early onset multiple sclerosis: a longitudinal study

OBJECTIVE: To evaluate the clinical course of MS in individuals with onset of MS before age 16. METHODS: Patients with onset of MS before age 16 (n = 116) with complete clinical information on the clinical course from the MS Clinic at The University of British Columbia (UBC) Site Hospital computerized database (MS-COSTAR) were included in this study. The data were compared to those from the Canadian natural history study for MS clinic attendees, regardless of age at onset. RESULTS: The mean duration of observation was 19.76 +/- 0.90 years; the mean age at MS onset was 12.73 +/- 0.25 years. Only three cases (2.6%) had a primary progressive (PP) MS course. To date, 60 (53.1%) of 113 subjects have developed secondary progressive (SP) MS. The 50% probability for SPMS was reached 23 years after onset. For patients with relapsing remitting (RR) or SPMS the mean disease duration from onset to the time of confirmed Expanded Disability Status Scale (EDSS) 3.0 was 16.03 +/- 1.17 years (at mean age 28.47 +/- 1.14); mean duration from onset to the time of EDSS 6.0 was 19.39 +/- 1.43 years (at mean age 32.32 +/- 1.44). Annual relapse rate was 0.54 +/- 0.05 per year. The correlation between the number of relapses during the first year of disease and the course of the disease was also significant. CONCLUSIONS: The prevalence of early onset MS (3.6%) in our study confirms the previous findings on early onset MS. A RR course was seen in the majority of cases of early onset MS. A high frequency of relapses, early age at permanent disability, and the presence of malignant cases raise the question of possible early use of disease-modifying therapy in patients with early onset MS.     

Brain atrophy in multiple sclerosis: impact of lesions and of damage of whole brain tissue

INTRODUCTION: In multiple sclerosis (MS), brain atrophy measurement on magnetic resonance imaging (MRI) reflects overall tissue loss, especially demyelination and axonal loss. We studied which factor contributes most to the development of brain atrophy extent and severity of lesions or damage of whole brain issue (WBT). METHODS: Eighty-six patients with MS [32 primary progressive (PP), 32 secondary progressive (SP)] and 22 relapsing-remitting (RR) were studied MRI included T1- and T2-weighted imaging to obtain hypointense T1 lesion volume (T1LV) and two brain volume measurements: 1) the parenchymal fraction (PF; whole brain parenchymal volume/intracranial volume) as a marker of overall brain volume, and 2) the ventricular fraction (VF; ventricular volume/intracranial volume) as a marker of central atrophy. From magnetization transfer ratio (MTR) histograms, the relative peak height (rHp) was derived as an index of damage of WBT (a lower peak height reflects damage of WBT). RESULTS: Multiple linear regression analysis revealed that damage of WBT explains most of the variance of PF (standardized coeffcient beta = 0.59, p < 0.001 for WBT and beta = -0.19, p < 0.05 for T1LV). These findings are independent of disease phase; even in RR patients, damage of WBT plays a dominant role in explaining the variance in overall brain volume. By contrast the variance in VF is explained by both T1LV and damage of WBT (standardized coefficient beta = 0.43, p < 0.001 for T1LV and beta =-0.38, p < 0.001 for WBT). CONCLUSION: This study shows that overall brain volume (PF) is best explained by damage of WBT, supporting the significance of nonfocal pathology in MS in producing tissue loss. Central atrophy (VP) is determined by both lesion volume and damage of WBT. Our results underline the importance of nonfocal pathology even in the early (RR) phase of the disease.