Epstein-Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies.

BACKGROUND: The purpose of this study was to investigate intrathecal production and affinity distributions of Epstein-Barr virus (EBV)-specific antibodies in multiple sclerosis (MS) and controls. METHODS: Cerebrospinal fluid (CSF) and serum concentrations, quantitative intrathecal synthesis, oligoclonal bands (OCB) patterns and affinity distributions of anti-Epstein Barr virus (EBV) antibodies were evaluated in 100 relapsing-remitting MS (RRMS) patients and 200 age- and sex-matched controls with other inflammatory neurological disorders (OIND) and other noninflammatory neurological disorders (NIND). RESULTS: Levels of anti-EBNA-1 and anti-viral capsid antigen (VCA) IgG were different in both the CSF (P <0.0001 and P <0.01, respectively) and serum (P <0.001 and P <0.05, respectively) among the RRMS, OIND and NIND. An intrathecal synthesis of anti-EBNA-1 IgG and anti-VCA IgG, as indicated by the antibody index, was underrepresented in the RRMS, OIND and NIND (range 1 to 7%). EBV-specific OCB were detected in 24% of the RRMS patients and absent in the controls. High-affinity antibodies were more elevated in the RRMS and in the OIND than in the NIND for CSF anti-EBNA-1 IgG (P <0.0001) and anti-VCA IgG (P <0.0001). After treatment with increasing concentrations of sodium thiocyanate, the EBV-specific IgG OCB had low affinity in all 24 RRMS patients analyzed. CONCLUSIONS: Our findings do not support the potential role of an EBV persistent brain chronic infection in MS and suggest that an EBV-specific intrathecal oligoclonal IgG production can occur in a subset of MS patients as part of humoral polyreactivity driven by chronic brain inflammation.

Significant low prevalence of antibodies reacting with simian virus 40 mimotopes in serum samples from patients affected by inflammatory neurologic diseases, including multiple sclerosis.

Many investigations were carried out on the association between viruses and multiple sclerosis (MS). Indeed, early studies reported the detections of neurotropic virus footprints in the CNS of patients with MS. In this study, sera from patients affected by MS, other inflammatory (OIND) and non-inflammatory neurologic diseases (NIND) were analyzed for antibodies against the polyomavirus, Simian Virus 40 (SV40). An indirect enzyme-linked immunosorbent assay (ELISA), with two synthetic peptides, which mimic SV40 antigens, was employed to detect specific antibodies in sera from patients affected by MS, OIND, NIND and healthy subjects (HS). Immunologic data indicate that in sera from MS patients antibodies against SV40 mimotopes are detectable with a low prevalence, 6%, whereas in HS of the same mean age, 40 yrs, the prevalence was 22%. The difference is statistically significant (P = 0.001). Significant is also the difference between MS vs. NIND patients (6% vs. 17%; P = 0.0254), whereas no significant difference was detected between MS vs OIND (6% vs 10%; P>0.05). The prevalence of SV40 antibodies in MS patients is 70% lower than that revealed in HS.

Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study.

BACKGROUND: Most of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD. METHODS: Structured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models. RESULTS: Seventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected. CONCLUSIONS: Our data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.

Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study.

BACKGROUND: Only few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in multiple sclerosis (MS), we aimed to assess pregnancy and fetal outcomes after in utero exposure to GA, using the same dataset, with a specific focus on the risk of spontaneous abortion. MATERIALS AND METHODS: We recruited MS patients, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002-2008. Patients were divided into 2 groups: drug-exposed pregnancies (EP: suspension of the drug less than 4 weeks from conception); non-exposed pregnancies (NEP: suspension of the drug at least 4 weeks from conception or never treated pregnancies). All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders. Multivariate logistic and linear models were used for treatment comparisons. RESULTS: Data on 423 pregnancies were collected, 17 were classified as EP to GA, 88 as EP to IFNB, 318 as NEP. Pregnancies resulted in 16 live births in the GA EP, 75 live births in the IFNB EP, 295 live births in the NEP. GA exposure was not significantly associated with an increased risk of spontaneous abortion (OR = 0.44;95% CI 0.044-4.51;p = 0.49). Mean birth weight and length were not significantly different in pregnancies exposed to GA than in non exposed pregnancies (p = 0.751). The frequency of preterm delivery, observed in 4 subjects exposed to GA (25% of full term deliveries), was not significantly higher in pregnancies exposed to GA than in those non exposed (p > 0.735). These findings were confirmed in the multivariate analysis. There were neither major complications nor malformations after GA exposure. CONCLUSIONS: Data in our cohort show that mother's GA exposure is not associated with a higher frequency of spontaneous abortion, neither other negative pregnancy and fetal outcomes. Our findings point to the safety of in utero GA exposure and can support neurologists in the therapeutic counselling of MS women planning a pregnancy.

Epstein-Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis.

Cerebrospinal fluid and serum levels and intrathecal synthesis of anti-Epstein-Barr virus (EBV) IgG were measured by enzyme-linked immunosorbent assay in 80 relapsing-remitting multiple sclerosis patients grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. Eighty patients with other inflammatory neurological disorders (OIND) and 80 patients with non-inflammatory neurological disorders (NIND) served as neurological controls. Cerebrospinal fluid concentrations were higher in OIND than in multiple sclerosis (p < 0.0001) and NIND (p < 0.01) for anti-viral-capsid-antigen (anti-VCA) IgG, in multiple sclerosis than in NIND (p < 0.01) and in OIND than in NIND (p < 0.05) for anti-EBV nuclear antigen-1 (EBNA-1) IgG. Serum levels were more elevated in OIND than in multiple sclerosis (p < 0.05) and in MRI inactive than in MRI active multiple sclerosis (p < 0.0001) for anti-VCA IgG, and in multiple sclerosis than in OIND and NIND (p < 0.01) for anti-EBNA-1 IgG. Serum titres of anti-VCA and anti-EBNA-1 IgG were also positively (p < 0.05) and inversely (p < 0.001) correlated, respectively, with the Expanded Disability Status Scale. An intrathecal IgG production of anti-VCA and anti-EBNA-1 IgG, as indicated by Antibody Index, was present only in a limited number of multiple sclerosis patients and controls (range from 1.3 to 6.3%). These findings do not support a direct pathogenetic role of EBV-targeted humoral immune response in multiple sclerosis.

A possible paraneoplastic neuromyelitis optica associated with lung cancer.

Neuromyelitis optica is associated with antibodies to aquaporin-4 channels and has been classically defined as the occurrence of bilateral optic neuritis and transverse myelitis with no other neurological involvement. We describe here a 63-year-old woman who presented to our local hospital with an acute, bilateral visual loss followed by progressive paraparesis. Medical evaluations revealed a lung tumor and spinal MRI showed multiple cervical-dorsal hyperintense T(2) lesions with mild mass effect. Testing for NMO-Ig resulted positive. Patient's diagnosis was thus consistent with a possible paraneoplastic neuromyelitis optica associated with non-small cell lung cancer and evidence of NMO-Ig.

Pallidal stimulation for segmental dystonia: long term follow up of 11 consecutive patients.

Pallidal stimulation is a convincing and valid alternative for primary generalized dystonia refractory to medical therapy or botulinum toxin. However, the clinical outcome reported in literature is variable most likely because of heterogeneity DBS techniques employed and /or to clinical dystonic pattern of the patients who undergo surgery. In this study, we report the long term follow up of a homogeneous group of eleven subjects affected by segmental dystonia who were treated with bilateral stimulation of the Globus Pallidus pars interna (GPi) from the years 2000 to 2008. All the patients were evaluated, before surgery and at 6-12-24-36 months after the treatment, in accordance with the Burke Fahn Marsden Dystonia Rating Scale (BFMDRS). Our study indicates that DBS promotes an early and significant improvement at 6 months with an even and a better outcome later on. The analysis of specific sub items of the BFMDRS revealed an earlier and striking benefit not only as far as segmental motor function of the limbs but also for the complex cranial functions like face, (eyes and mouth), speech and swallowing, differently from results reported in primary generalized dystonia. Deep Brain Stimulation of GPi should be considered a valid indication for both generalized and segmental dystonia when other therapies appear ineffective.

Natalizumab: a country-based surveillance program.

Natalizumab is a humanized monoclonal antibody with a selective adhesion-molecule inhibitor effect, and a demonstrated efficacy in decreasing the frequency of relapses and progression of disability in relapsing-remitting multiple sclerosis (RR MS). After the approval of FDA and EMEA in MS cases unresponsive to immunomodulating therapy or in severe MS patients also not previously treated with interferons, and considering the concern on the possible side effects, an accurate program of surveillance was organized in our country by a combined effort of AIFA, Cineca, Department of Pharmacology of University of Bologna, and a group of neurologists appointed by the National Society of Neurology (SIN). After 15 months from the authorization of natalizumab therapy in MS, as of 31 March 2008, 908 cases have been treated with natalizumab and enrolled in this pharmaco-vigilance study. The mean age is 35 years, while the duration of disease is longer and disability is higher than that reported in the registrative study. Side effects are at the moment mild and similar to those previously described. At follow-up, the majority of treated cases are stable or ameliorated. The treatment was discontinued in 6% of patients.

Beneficial effect of interferon-beta 1b treatment in patients with relapsing-remitting multiple sclerosis is associated with an increase in serum levels of soluble HLA-I molecules during the first 3 months of therapy.

It has recently become clear that interferon-beta (IFN-beta) treatment is effective in ameliorating relapsing-remitting multiple sclerosis (RRMS) through an as yet unidentified mechanism. As there is no recognisable biological indicator to predict responsiveness to IFN-beta treatment, we have investigated fluctuations in serum sHLA-I levels in MS patients undergoing IFN-beta 1b therapy. Serum sHLA-I concentrations measured by enzyme-linked immunosorbent assay (ELISA) were assessed at baseline and, longitudinally, over a period of 18 months after the start of treatment in 29 RRMS patients grouped as responders and nonresponders according to their clinical response to IFN-beta 1b therapy. Thirty-nine healthy volunteers served as controls. Serum sHLA-I concentrations were significantly higher (p<0.001) in pretreated RRMS patients than in healthy donors. In MS patients, changes in mean serum levels of sHLA-I from baseline showed a temporal pattern characterized by a strong increase in the first trimester of treatment, a return toward basal values in the following 6 months, a slight decline at 12th and 15th months and a further moderate increase at the 18th month. Mean serum sHLA-I levels were significantly more elevated in responders than in nonresponders at the first (p<0.02), second (p<0.01), and at third (p<0.02) months after the beginning of treatment and significantly lower (p<0.01) at the time of relapses in comparison to baseline values. Overall, these results seem to indicate that IFN-beta 1b can modulate fluctuations in serum sHLA-I levels and argue in favour of a potential role for serum levels of sHLA-I as a sensitive marker to monitor response to IFN-beta treatment in MS.