Maria Liguori

Multiple Sclerosis Severity Score Using disability and disease duration to rate disease severity

Background: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. Methods: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. Results: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. Conclusion: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Course and prognosis in early-onset MS Comparison with adult-onset forms

Objectives: To establish the prognostic role of clinical and demographic factors in a hospital-based cohort of MS patients categorized by age at clinical onset and clinical course. Methods: Eighty-three patients with MS had a clinical onset of the disease in childhood (age <16 years; early-onset MS [EOMS]) and 710 in adult age (between 16 and 65 years; adult-onset MS [AOMS]). Patients were followed for a mean period of observation of 5 years. Univariate and multivariate analyses of clinical and demographic predictors for rapid progression and disability were performed using a stepwise Cox regression model with time-dependent covariates. Results: In EOMS, the Expanded Disability Status Scale (EDSS) evaluated at last clinical examination was lower than in AOMS, despite a longer disease duration. The probability to reach growth disability and progression was significantly lower in EOMS than in AOMS. Median times to reach EDSS score of 4 and secondary progression were longer in EOMS than in AOMS, but the age at both endpoints was significantly lower in EOMS. In EOMS and AOMS, an irreversible disability was related to a secondary progressive course, a sphincteric system involvement at onset, and an older age at onset (in EOMS only for the group >14 years); in AOMS, other unfavorable factors were a pyramidal involvement at onset and a high relapse frequency in the first 2 years. The risk of entering secondary progression was significantly influenced by a high number of relapses in EOMS and by a higher age at onset and a short interattack interval in AOMS. Conclusion: A slower rate of progression of disease characterized EOMS patients, suggesting more plasticity to recover in developing CNS, but the early clinical manifestation cannot be considered a positive prognostic factor.

Multiple sclerosis in childhood: clinical features of 149 cases

From the retrospective study of 3375 patients affected by clinically definite or probable multiple sclerosis (MS), 149 patients were collected with onset of the disease before the age of 16 years (4.4%). Female/male ratio was higher than that of the adult onset MS (AOMS) population (2.2 vs 1.6) particularly at ages of onset after 12 years (3.0, P=0.007 vs AOMS). Among initial symptoms, those suggesting brainstem dysfunction (25%) were more frequent compared to other systems and compared to AOMs symptoms; motor and sensory disturbances were slightly less frequent (respectively 17.5% and 18.3%). Optic neuritis appeared in 16.5% of cases with onset in childhood and in 16.2% of cases with AOMS, cerebellar disturbances respectively in 9.1 % and 7.7%. The first interattack interval and the clinical course of early onset MS did not differ significantly from AOMS. In early onset MS patients with disease duration < 8 years, cases with EDSS > 6 were slightly more frequent than in the AOMS group (P=0.04). The frequency of cases for different levels of disability was similar for disease duration > 8 years.

Prospective study of multiple sclerosis with early onset

Fifty-four subjects (36 females and 18 males) affected by clinically definite multiple sclerosis (MS) and with onset of the disease at 15 years of age or before were prospectively studied in five Italian MS centres. Female/male ratio was 4.7 in subjects with age ≥12 years, suggesting a role of hormonal changes in triggering MS onset. The mean follow-up duration was 10.9-5.6 years. The functional systems more frequently involved at onset were the pyramidal and brainstem (both in 28% of cases). The onset was monosymptomatic in 31 subjects (57%). The course was relapsing-remitting in 39 subjects (72%) and relapsing-progressive in 15 (28%). Disability was assessed by the Expanded Disability Status Scale (EDSS): the mean score after 8 years of follow up was 3.5 (-2.5). The score was <4 in 68% of cases, between 4 and 6 in 8% of cases, > 6 in 24% of cases. Disability after 8 years was highly predicted by disability in the first year (p=0.008). There was a tendency to a worse prognosis in relation to the number of relapses in the first 2 years (p=0.08). The outcome was not influenced by the characteristics of symptoms at onset, age and gender.

Changes of serum sICAM-1 and MMP-9 induced by rIFNβ-1b treatment in relapsing-remitting MS

OBJECTIVE To correlate changes in serum levels of intercellular adhesion molecule-1 (sICAM-1) and matrix metalloproteinases (MMP) with clinical and MRI evidence of disease activity in MS patients receiving treatment with interferon-beta (rIFNbeta)-1b. BACKGROUND rIFNbeta reduces the frequency of gadolinium-enhancing (Gd+) MRI in relapsing-remitting MS (RRMS). Its mechanism of action on improving the integrity of the blood-brain barrier remains unclear. METHODS sICAM-1 and MMP-9 and MMP-2 serum levels were longitudinally (24 months) investigated (ELISA; zymography) in correlation with the modifications of the integrated area under the curve of Expanded Disability Status Scale scores normalized to entry baseline (deltaEDSS AUC) and of GD+ MRI scans, and with neutralizing antibodies (NAB) to rIFNbeta-1b production (MxA) in 36 RRMS patients. RESULTS During the first 12 months of treatment, levels of sICAM-1 increased and MMP-9 decreased significantly. After 12 months, levels returned toward baseline. Levels of sICAM-1 and MMP-9 were significantly negatively correlated. MMP-2 levels did not change significantly during the same period. During the second semester of the study, deltaEDSS AUC was significantly reduced. The percentage of patients with Gd+ MRI decreased significantly in the first (33%), second (29%), third (20%), and fourth (28%) semesters of treatment compared to baseline (62%). The NAB+ patients (14%) tended to have lower sICAM-1 levels at the ninth month; a higher MMP-9 activity at the sixth, 12th, and 18th months; and a greater deltaEDSS AUC in the third semester of treatment in comparison with the NAB- patients. CONCLUSIONS These results show that rIFNbeta-1b therapy increases sICAM-1 serum levels and reduces serum MMP-9 activity.

Age‐related disability in multiple sclerosis

There is evidence that the clinical course of multiple sclerosis is age related. The present study evaluated the relationship between age and rate of disability progression in a large hospital‐based cohort of definite cases of multiple sclerosis (n= 1,463). Patients were followed every 6 to 12 months for a total period of observation of 11,387.8 person‐years. Expanded Disability Status Scale scores increased significantly with increasing current age and longer duration of disease (p=0.007). Median times to reach Expanded Disability Status Scale scores of 4.0 and 6.0, assessed using an extended Kaplan–Meier method with age as a categorical time‐varying covariate, were significantly longer among patients aged 20 to 35 years compared with patients aged 36 to 50 and 51 to 65 years (p < 0.0001). Significant associations were observed between mean Expanded Disability Status Scale scores and age at disease onset, current age, and the interaction of age at disease onset and current age (p < 0.001). Current age had a greater effect (59% of variability in the model) on disease severity than did age at disease onset. Furthermore, a multiplicative effect on Expanded Disability Status Scale score was observed for age at disease onset and current age combined, indicating a faster rate of disease progression in older patients. In conclusion, the results of the current study demonstrate the impact of age on rate of disability progression in multiple sclerosis and suggest that an age‐adjusted progression index may be a more relevant criterion for defining differences between multiple sclerosis groups.

Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis

Abstract.Background:Cognitive impairment may occur at any time during the course of multiple sclerosis (MS), and it is often a major cause of disability in patients with the disease. The APOE-ε4 allele is the major known genetic risk factor for late onset familial and sporadic Alzheimer’s Disease (AD), and it seems to be implicated in cognitive decline in normal elderly persons.Objective:To investigate the clinical and genetic variables that can be associated with the cognitive decline in patients with MS.Methods:Five-hundred and three patients with clinically definite MS underwent a battery of neuropsychological tests and, according to the number of failed tests, were divided into cognitively normal and impaired. All patients were genotyped for APOE gene polymorphisms.Results:Fifty-six percent of MS patients showed, to different extents, cognitive impairment. Cognitive decline was predominant in men and was associated with disease duration, Kurtzke Expanded Disability Status Scale (EDSS) score, a low level of education, and, interestingly, the ε4 allele of the APOE gene. By contrast, cognitive impairment in women was independent of any investigated variable.Conclusion:The findings demonstrate that clinical and genetic factors play a role in men affected by MS developing cognitive impairment.

Serum and CSF anti-GM1 antibodies in patients with Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy.

High titers of antibodies directed against gangliosides, especially GM1, are found in the serum of patients with a variety of polyneuropathies, including those of the inflammatory type. We assayed anti-GM1 IgG and IgM levels in the serum and cerebrospinal fluid (CSF) of 23 patients with Guillain-Barré syndrome (GBS) and 10 with chronic inflammatory demyelinating polyneuropathy (CIDP) to investigate whether this immune response may also be localized within the intrathecal compartment and correlate with clinical parameters such as time interval since disease onset, disability score, preceding infectious episodes, and GM1 therapy. When compared to the control group, anti-GM1 IgG was increased in the serum of 39% of GBS and 10% of CIDP patients, whereas anti-GM1 IgM was elevated in 17% of GBS and none of the CIDP patients. In both patient groups, however, anti-GM1 antibody levels were more frequently elevated in CSF than paired sera: they belonged to the IgG class in 48% of GBS and 50% of CIDP patients, and to the IgM class in 48% of GBS and 55% of CIDP patients. In the GBS group, anti-GM1 IgM serum levels inversely correlated with time elapsed between sample collection and onset of disease (P < 0.05), whereas serum anti-GM1 IgG levels positively correlated with the loss of functional ability (P < 0.005). Increased anti-GM1 antibodies in GBS serum were not associated with clinical or serological evidence of infectious antecedents nor with previous GM1 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

HLA-multiple sclerosis association in Continental Italy and correlation with disease prevalence in Europe

The association with HLA-DRB1 alleles was tested in 609 Continental Italian MS patients and 836 controls. The phenotype frequency of DRB1*15 in the patients was significantly higher (0.316 vs. 0.112; p(c)<10(-6); Odds Ratio (OR)=3.64) with no dose effect. DRB1*10 was also significantly increased (OR=2.19; p(c)=0.047) and DRB1*07 decreased (OR=0.60; p(c)=1.3 x 10(-3)) independently of DR15 and of each other. We did not detect an influence of the DR phenotype on disease course, age at onset/diagnosis, gender or familiarity. No association with Class I was detected in a random subset of patients and controls. A comparison of the HLA association data in Northern and Southern European populations shows a parallel between disease prevalence and DR15 frequency.

Interferon beta in relapsing-remitting multiple sclerosis: an independent postmarketing study in southern Italy.

This independent, population-based surveillance study monitored the efficacy and safety of interferon beta (IFNb) products in 1033 patients with relapsing -remitting multiple sclerosis (RRMS) from 15 centres in Italy. Relapses, Expanded Disability Status Scale (EDSS) scores, and adverse events were evaluated for up to 24 months. Data of patients with a baseline EDSS score 5-3.5 are reported. The proportions of relapse-free patients were similar among the groups at 12 and 24 months (P =0.10). IFNb products produced significant reductio ns from baseline in relapse rates at 12 and 24 months (P B-0.001), with no differences among treatments (P =0.2). There were no significant differences in mean EDSS change among groups at 12 or 24 months. The IFNb-1b group showed a higher incidence of adverse events during the first year of treatment (P B-0.05) than IFNb-1a groups, and more withdrawals (10%) compared with Avonex (5%) at 24 months. IFNb products are equally effective in low disability RRMS, but IFNb-1a may have a more favorable efficacy/tolerability ratio.