M. G. Marrosu

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.

Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene

Charcot-Marie-Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN), is a clinically and genetically heterogeneous condition. Mutations of the myelin protein zero (MPZ) gene have been associated with CMT1B, Déjerine-Sottas disease, and congenital hypomyelination, which are inherited demyelinating neuropathies characterized by different clinical severity. HMSN type II (HMSN II) or CMT2, the axonal form of CMT, is genetically heterogeneous. Linkage to 1p35-p36 (CMT2A), 3q(CMT2B), and 7p (CMT2D) chromosomes has been reported in the disease; however, most HMSN II families do not link to any of the reported loci. In a large HMSN II Sardinian family, we found a missense mutation in the chromosome 1q MPZ gene. This Ser44Phe mutation was located in exon 2 and was present in the heterozygous state in all affected individuals. This is the first example of an HMSN II family showing an MPZ point mutation. The MPZ gene Ser 44Phe mutation found in the HMSN II family presented in this study suggests that genetic analysis of HMSN II families should also include the MPZ gene, previously not considered to be involved in the axonal form of HMSN.

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.

Sardinian multiple sclerosis is associated with HLA‐DR4 A serologic and molecular analysis

HLA haplotypes in 45 unrelated Sardinian multiple sclerosis patients and in six multiplex families were defined, using both serologic and restriction fragment length polymorphism (RFLP) analysis. In unrelated MS patients, we found an association with HLA-DR4 (p < 0.01, relative risk = 2.5) and DQw3 (p < 0.04, relative risk = 2.2). Using a β-DR cDNA probe, we observed no variation of the DR4 RFLP profile in sporadic or related MS patients compared with DR4-specific pattern in controls. Using a β-DQ cDNA probe, we identified two DQw3 patterns (DQw3.1 and DQw3.2) with similar frequency in patients and in controls. No specific RFLPs were observed in association with different disease courses. The frequency of haplotype sharing in affected members of multiplex families was not different from that expected by chance. This study shows that Sardinian MS patients carry predominantly the HLA-DR4 allele, in contrast to the DR2 prevalence reported in Caucasian populations. The lack of association with HLA haplotypes in affected members of multiplex families may indicate that genetic factors outside the HLA system play a substantial role in families with MS.

Pregnancy and fetal outcomes after interferon-β exposure in multiple sclerosis

Objective: To assess pregnancy and fetal outcomes after in utero exposure to interferon-β (IFNβ) in all pregnancies occurring in women with multiple sclerosis (MS) during the study period, with a specific focus on the risk of spontaneous abortion. Methods: In this cohort study, data were gathered through a standardized, semi-structured interview. Patients who discontinued IFNβ less than 4 weeks from conception (exposed) were compared with those who had discontinued the drug at least 4 weeks from conception or who were never treated (not exposed). Possible confounders were handled through multivariate analyses adjusted for propensity score (PS). Results: We collected data on 396 pregnancies in 388 women, 88 classified as exposed (mean exposure 4.6 ± 5.8 weeks). IFNβ exposure was not associated with an increased risk of spontaneous abortion (PS-adjusted odds ratio [OR] 1.08, 95% confidence interval [CI] 0.4 to 2.9, p = 0.88), although it was associated with both lower baby weight (PS-adjusted β −113.8, p < 0.0001) and length (PS-adjusted β −1.102, p < 0.0001). Proportion of spontaneous abortion in exposed patients fell within the range expected for the Italian population in the same period. IFNβ exposure (PS-adjusted OR 2.11, 95% CI 1.18 to 3.78, p = 0.012) and cesarean delivery were the only predictors of preterm delivery. In the exposed group, we did not observe any significant fetal complications, malformations, or developmental abnormalities over a median follow-up of 2.1 years. Conclusions: Our findings point to the relative safety of IFNβ exposure times of up to 4 weeks and can assist neurologists facing therapeutic decisions in women with MS with a pregnancy plan.

Breastfeeding is not related to postpartum relapses in multiple sclerosis

Objective: To assess the relationship between breastfeeding and risk of puerperal relapses in a large cohort of patients with multiple sclerosis (MS). Methods: We prospectively followed-up pregnancies occurring between 2002 and 2008 in women with MS, recruited from 21 Italian MS centers, and gathered data on breastfeeding through a standardized interview. The risk of relapses after delivery was assessed using the Cox regression analysis. Results: A total of 302 out of 423 pregnancies in 298 women resulted in full-term deliveries. Patients were followed up for at least 1 year after delivery. The time-dependent profile of the relapse rate before, during, and after pregnancy did not differ between patients who breastfed and patients who did not. In the multivariate analysis, adjusting for age at onset, age at pregnancy, disease duration, disability level, and relapses in the year prior to pregnancy and during pregnancy, treatment with disease-modifying drugs (DMDs), and exposure to toxics, the only significant predictors of postpartum relapses were relapses in the year before pregnancy (hazard ratio [HR] = 1.5; 95%confidence interval [CI] 1.3–1.9; p < 0.001) and during pregnancy (HR = 2.2; 95% CI 1.5–3.3; p < 0.001). Conclusions: In our sample, postpartum relapses were predicted only by relapses before and during pregnancy. Therefore, the reported association between breastfeeding and a lower risk of postpartum relapses may simply reflect different patient behavior, biased by the disease activity. Our results can assist neurologists facing the breastfeeding issue in mother counseling and shared decision-making. Especially, among patients with high risk of postpartum relapses, breastfeeding may not be feasible and early postpartum treatment should be an option.

Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the FEMIMS study

Background Improved prognosis in women with multiple sclerosis (MS) undergoing immunosuppressive treatment with mitoxantrone (MITO) has led to an increased interest in the effect of such treatments on fertility. FErtility and Mitoxantrone In MS (FEMIMS) is a collaborative retrospective study aimed at evaluating the impact of MITO treatment on fertility in women with MS. Methods Occurrence of chemotherapy-induced amenorrhea (CIA) was evaluated in 189 women with MS treated with MITO before the age of 45. An “ad hoc” questionnaire, paying particular attention to onset of CIA either during or post-MITO treatment, was administered to each patient. The probability of CIA was calculated using a multivariate logistic regression analysis taking into account age at exposure, cumulative dose, and use of estroprogestinic (EP) drugs during treatment. Results Forty-eight (26%) patients presented CIA following MITO. The probability of CIA was increased by 2%/mg/m2 of cumulative dose and by 18% for each year of age, whereas it was reduced by administration of EP during treatment. Conclusions MITO treatment may affect reproductive capacity in women with MS. Patients of childbearing age should be properly counseled before MITO treatment and EP therapy should be administered to reduce the risk of CIA.

Communicating the diagnosis of multiple sclerosis - a qualitative study

Studies on communicating the diagnosis of multiple sclerosis (MS) are few, and all reveal communication and information deficits. We explored the personal experience of diagnosis communication of people with MS and health professionals, using a qualitative methodology. Data were obtained from two sets of focus group meetings (FGM) with people with MS (total 23; 16 females; age range: 23-70) and one FGMs with health professionals (four neurologists, three psychologists, two nurses). The methods of framework analysis were applied to meeting transcripts to identify key topics and categories. The experience of communicating/receiving an MS diagnosis was highly varied; all patients reported the moment as powerfully evocative and unforgettable. Very poor levels of support and information were sometimes given. Although diagnosis communication had improved in more recent experience, all felt it should be further improved with appropriate setting (privacy, no interruptions, sufficient time), information tailored to the individual, and continuity of care. Such improvements imply a more meaningful patientneurologist relationship, and also structural and organisational changes. Multiple Sclerosis 2007; 13: 763-769. http://msj.sagepub.com

Treatment of early-onset multiple sclerosis with intramuscular interferonβ-1a: Long-term results

The objective was to evaluate the safety, tolerability and effectiveness of intramuscular (IM) interferon beta-1a (IFNβ-1a; Avonex, Biogen) 30 mg once a week in patients with onset of symptoms of multiple sclerosis (MS) in childhood or adolescence. Patients with a diagnosis of definite MS according to McDonald’s criteria, relapsing course according to Lublin’s criteria, onset of symptoms of MS before 16 years of age, and who had received IM IFNβ-1a therapy before 16 years of age were eligible for the study if they had a pretreatment and treatment duration of at least 6 months. Clinical and laboratory evaluations were performed every 3 months. A total of 52 patients were identified as receiving treatment with IM IFNβ-1a 30 mg once a week before 16 years of age. Mean age at onset of symptoms of MS was 11.7±2.7 years, mean disease duration was 25.9±30.3 months, mean annualised relapse rate was 1.9±1.1 and mean Expanded Disability Status Scale (EDSS) score was 1.5±1.1. After a mean (±SD) treatment duration of 42.9±19.9 months, annualised relapse rate decreased to 0.4±0.5. Final EDSS score was 1.3±1.1. Adverse events were recorded for 35 (67%) patients (flulike syndrome, 33%; headache, 29%; myalgia, 21%; fever, 11%; fatigue, 6%; nausea and vomiting, 6%; and skin reaction, 4%); most were transient. IM IFNβ-1a was effective and well tolerated in these paediatric patients with MS.

HLA‐DQB1 genotype in Sardinian multiple sclerosis Evidence for a key role of DQB1 *0201 and *0302 alleles

We studied HLA-DQB1 haplotypes in 103 unrelated multiple sclerosis (UMS) patients and in 26 related (RMS) patients from 12 families from Sardinia, Italy, where the disease was associated with the HLA-DR4 allele. Using polymerase chain reaction and allele-specific oligonucleotide probes, we found in UMS an increased frequency of the DQB1 *0201 (p = 0.010) and DQB1 *0302 (p = 0.025) alleles, whereas the DQB1 *0301 allele was significantly decreased (p = 0.027). In RMS, only the DQB1 *0302 allele was increased (p = 0.047), and no difference was found in the DQB1 *0301 allele. For DQB haplotypes, an increased frequency of DQB1 *0302/*0502 (p = 0.026) and a decreased frequency of DQB1 *0201/*0601 (p = 0.009) and DQB1 *0502/*0502 (p = 0.025) was found in UMS patients, whereas RMS patients showed an increased frequency of DQB1 *0301/*0302 (p = 0.005). Because DQB1 *0201 and *0302 alleles are increased in Caucasian MS patients, where the disease is related to HLA-DR2 and where a primary association with the HLA-DR2, DQB1 *0602 allele has been reported, we conclude that Caucasian and Sardinian populations share HLA-DQB1 *0201 and *0302 alleles in genetic susceptibility to MS.