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DIANA FERRARO
CULTORE DELLA MATERIA
Dipartimento di Scienze Biomediche, Metaboliche e Neuroscienze sede ex-Neuroscienze
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Pubblicazioni
2021
- A multicenter survey on access to care in Multiple Sclerosis-related trigeminal neuralgia
[Articolo su rivista]
Ferraro, D.; Annovazzi, P.; Lanzillo, R.; Calabrese, M.; Fantozzi, R.; De Luca, G.; Cordioli, C.; Paolicelli, D.; Ragonese, P.; Gajofatto, A.; Lo Fermo, S.; Cavalla, P.; Tortorella, C.; Pesci, I.; Gallo, A.; Pinardi, F.; Di Filippo, M.; Maniscalco, G. T.; Nociti, V.; Radaelli, M.; Tomassini, V.; Buscarinu, M. C.; Moccia, M.; Camera, V.; Cocco, E.; Gasperini, C.; Solaro, C.
abstract
The prevalence of trigeminal neuralgia (TN) in patients with Multiple Sclerosis (MS) is higher than in the general population and its management can be particularly challenging due to a number of reasons including high recurrence rates, lack of MS-specific treatment guidelines and uncertainties about pain pathophysiology. Aim of this cross-sectional, multicentre survey was to gather information on the current treatment modalities and options of MS-related TN across 23 Italian MS centres. Initial medical management (carbamazepine or oxcarbazepine) of MS-related TN was fairly homogeneous throughout Italian centres. The most commonly available surgical procedure was microvascular decompression, but the frequency and types of surgical procedures available locally differed considerably throughout MS centers, and were unavailable in one quarter of them. This survey reveals some of the issues that could hamper an optimal patient management and underlines the need for a consensus on MS-related TN to support health-care professionals in their approach to this challenging condition and to facilitate the development of local guidelines aimed at ensuring equity in access to care and treatment optimization.
2021
- A voxel-based lesion symptom mapping analysis of chronic pain in multiple sclerosis
[Articolo su rivista]
Plantone, D.; Vollono, C.; Pardini, M.; Primiano, G.; Myftari, V.; Vitetta, F.; Sola, P.; Mirabella, M.; Ferraro, D.
abstract
Background: Pain is one of the most disabling symptoms in multiple sclerosis. Chronic pain in multiple sclerosis is often neuropathic in nature, although a clear-cut distinction with nociceptive pain is not easy. Objective: The aim of our study was to analyze the MRIs of multiple sclerosis patients with chronic pain in order to explore possible associations with lesion sites, on a voxel-by-voxel basis. Materials and methods: We enrolled patients aged > 18 years with multiple sclerosis in accordance with the 2010 McDonald criteria. Patients meeting criteria for persistent pain (frequent or constant pain lasting > 3 months) were included in the “pain group”. The other patients were included in the “no pain group”. We outlined lesions on FLAIR MRI scans using a semi-automated edge finding tool. To detect the association between lesion localization and persistent pain, images were analysed with the voxel-based lesion symptom mapping methods implemented in the (nonparametric mapping software included into the MRIcron. Results: We enrolled 208 MS patients (140 F, mean age 55.2 ± 9.4 years; 176 RR, 28 progressive MS; mean EDSS 2.0 + 2.0). Pain group included 96 patients and no pain group 112 patients. Lesions of the right dorsolateral prefrontal area were significantly more prevalent in patients without pain, whereas periventricular posterior lesions were significantly more prevalent in patients with persistent pain. Conclusion: Our data suggest a role of the right dorsolateral prefrontal cortex in the modulation of pain perception and in the occurrence of chronic pain in MS patients. Our data also support a hemispheric asymmetry in pain perception and modulation.
2021
- Antibiotic Use and Risk of Multiple Sclerosis: A Nested Case-Control Study in Emilia-Romagna Region, Italy
[Articolo su rivista]
Baldin, E.; Zenesini, C.; Antonazzo, I. C.; Bartolomei, I.; Caniatti, L.; Costa, M.; Curti, E.; Ferraro, D.; Foschi, M.; Granella, F.; Guareschi, A.; Immovilli, P.; Lugaresi, A.; Malagu, S.; Mancinelli, L.; Montepietra, S.; Mussuto, V.; Neri, W.; Pasquinelli, M.; Pellegrino, L.; Pesci, I.; Poluzzi, E.; Pugliatti, M.; Ravasio, A.; Riise, T.; Salvi, F.; Santangelo, M.; Sireci, F.; Sola, P.; Strumia, S.; Tsantes, E.; Vignatelli, L.; Vitetta, F.; Viti, B.; D'Alessandro, R.
abstract
Introduction: Known risk factors for multiple sclerosis (MS) include smoking, a low vitamin D status, obesity, and EBV, while the inflammatory feature of the disease strongly suggests the presence of additional infectious agents. The association between use of antibiotics and MS risk that could shed light on these factors is still undetermined. We aimed to evaluate the association between antibiotics and MS risk, in the Emilia-Romagna region (RER), Italy. Methods: All adult patients with MS seen at any RER MS center (2015-2017) were eligible. For each of the 877 patients included, clinical information was collected and matched to 5 controls (RER residents) (n = 4,205) based on age, sex, place of residence, and index year. Information on antibiotic prescription was obtained through the linkage with the RER drug prescription database. Results: Exposure to any antibiotic 3 years prior to the index year was associated with an increased MS risk (OR = 1.52; 95% CI = 1.29-1.79). Similar results were found for different classes. No dose-response effect was found. Discussion/Conclusions: Our results suggest an association between the use of antibiotics and MS risk in RER population. However, further epidemiological studies should be done with information on early life and lifestyle factors.
2021
- Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study
[Articolo su rivista]
Di Gregorio, M.; Torri Clerici, V. L. A.; Fenu, G.; Gaetani, L.; Gallo, A.; Cavalla, P.; Ragonese, P.; Annovazzi, P.; Gajofatto, A.; Prosperini, L.; Landi, D.; Nicoletti, C. G.; Di Carmine, C.; Totaro, R.; Nociti, V.; De Fino, C.; Ferraro, D.; Tomassini, V.; Tortorella, C.; Righini, I.; Amato, M. P.; Manni, A.; Paolicelli, D.; Iaffaldano, P.; Lanzillo, R.; Moccia, M.; Buttari, F.; Fantozzi, R.; Cerqua, R.; Zagaglia, S.; Farina, D.; De Luca, G.; Buscarinu, M. C.; Pinardi, F.; Cocco, E.; Gasperini, C.; Solaro, C. M.; Di Filippo, M.
abstract
Background and purpose: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS. Methods: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected. Results: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11–68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1–10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0–7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03–1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02–2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18–9.5, p < 0.001) at baseline. Conclusions: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.
2021
- Determinants of therapeutic lag in multiple sclerosis
[Articolo su rivista]
Roos, I.; Leray, E.; Frascoli, F.; Casey, R.; Brown, J. W. L.; Horakova, D.; Havrdova, E. K.; Debouverie, M.; Trojano, M.; Patti, F.; Izquierdo, G.; Eichau, S.; Edan, G.; Prat, A.; Girard, M.; Duquette, P.; Onofrj, M.; Lugaresi, A.; Grammond, P.; Ciron, J.; Ruet, A.; Ozakbas, S.; De Seze, J.; Louapre, C.; Zephir, H.; Sa, M. J.; Sola, P.; Ferraro, D.; Labauge, P.; Defer, G.; Bergamaschi, R.; Lebrun-Frenay, C.; Boz, C.; Cartechini, E.; Moreau, T.; Laplaud, D.; Lechner-Scott, J.; Grand'Maison, F.; Gerlach, O.; Terzi, M.; Granella, F.; Alroughani, R.; Iuliano, G.; Van Pesch, V.; Van Wijmeersch, B.; Spitaleri, D. L. A.; Soysal, A.; Berger, E.; Prevost, J.; Aguera-Morales, E.; Mccombe, P.; Castillo Trivino, T.; Clavelou, P.; Pelletier, J.; Turkoglu, R.; Stankoff, B.; Gout, O.; Thouvenot, E.; Heinzlef, O.; Sidhom, Y.; Gouider, R.; Csepany, T.; Bourre, B.; Al Khedr, A.; Casez, O.; Cabre, P.; Montcuquet, A.; Wahab, A.; Camdessanche, J. -P.; Maurousset, A.; Patry, I.; Hankiewicz, K.; Pottier, C.; Maubeuge, N.; Labeyrie, C.; Nifle, C.; Coles, A.; Malpas, C. B.; Vukusic, S.; Butzkueven, H.; Kalincik, T.
abstract
Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups. Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation. Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants. Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2–34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3–36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5–65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2–61.5). Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
2021
- Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing–remitting multiple sclerosis
[Articolo su rivista]
Tsantes, E.; Curti, E.; Ferraro, D.; Lugaresi, A.; Baldi, E.; Montepietra, S.; Immovilli, P.; Simone, A. M.; Mancinelli, L.; Strumia, S.; Vitetta, F.; Foschi, M.; Ferri, C.; Ferrarini, C.; Sola, P.; Granella, F.
abstract
Background and purpose: Dimethyl fumarate (DMF) causes a mean lymphocyte count drop of approximately 30% in relapsing–remitting multiple sclerosis (RRMS) patients. The relationship between this reduction and DMF effectiveness is controversial. The objective was to investigate if the decrease in absolute lymphocyte count (ALC) from baseline during DMF treatment is associated with clinical and magnetic resonance imaging (MRI) disease activity. A secondary aim was to evaluate ALC variations over time in a real-life cohort of DMF-treated patients. Methods: Demographic, laboratory, clinical and MRI data were collected in this observational multicentre study, conducted on RRMS patients treated with DMF for at least 6 months. Multivariate Cox models were performed to evaluate the impact of 6-month ALC drop on time to no evidence of disease activity (NEDA-3) status loss. NEDA-3 is defined as absence of clinical relapses, MRI disease activity and confirmed disability progression. Results: In all, 476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed up to 5-year follow-up. A greater lymphocyte decrease was associated with a lower risk of NEDA-3 status loss (hazard ratio 0.87, P = 0.01). A worse outcome in patients with lower ALC drop (<11.5%), compared with higher tertiles (11.5%–40.5% and >40.5%), was observed (P = 0.008). The nadir of ALC drop (−33.6%) and 35% of grade III lymphopaenia cases occurred after 12 months of treatment. Conclusion: A higher lymphocyte count drop at 6 months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.
2021
- Effect of Disease-Modifying Therapy on Disability in Relapsing-Remitting Multiple Sclerosis Over 15 Years
[Articolo su rivista]
Kalincik, T.; Diouf, I.; Sharmin, S.; Malpas, C.; Spelman, T.; Horakova, D.; Havrdova, E. K.; Trojano, M.; Izquierdo, G.; Lugaresi, A.; Prat, A.; Girard, M.; Duquette, P.; Grammond, P.; Jokubaitis, V.; van der Walt, A.; Grand'Maison, F.; Sola, P.; Ferraro, D.; Shaygannejad, V.; Alroughani, R.; Hupperts, R.; Terzi, M.; Boz, C.; Lechner-Scott, J.; Pucci, E.; Van Pesch, V.; Granella, F.; Bergamaschi, R.; Spitaleri, D.; Slee, M.; Vucic, S.; Ampapa, R.; McCombe, P.; Ramo-Tello, C.; Prevost, J.; Olascoaga, J.; Cristiano, E.; Barnett, M.; Saladino, M. L.; Sanchez-Menoyo, J. L.; Hodgkinson, S.; Rozsa, C.; Hughes, S.; Moore, F.; Shaw, C.; Butler, E.; Skibina, O.; Gray, O.; Kermode, A.; Csepany, T.; Singhal, B.; Shuey, N.; Piroska, I.; Taylor, B.; Simo, M.; Sirbu, C. -A.; Sas, A.; Butzkueven, H.
abstract
OBJECTIVE: To test the hypothesis that immunotherapy prevents long-term disability in relapsing-remitting multiple sclerosis (MS), we modeled disability outcomes in 14,717 patients. METHODS: We studied patients from MSBase followed for ≥1 year, with ≥3 visits, ≥1 visit per year, and exposed to MS therapy, and a subset of patients with ≥15-year follow-up. Marginal structural models were used to compare the cumulative hazards of 12-month confirmed increase and decrease in disability, Expanded Disability Status Scale (EDSS) step 6, and the incidence of relapses between treated and untreated periods. Marginal structural models were continuously readjusted for patient age, sex, pregnancy, date, disease course, time from first symptom, prior relapse history, disability, and MRI activity. RESULTS: A total of 14,717 patients were studied. During the treated periods, patients were less likely to experience relapses (hazard ratio 0.60, 95% confidence interval [CI] 0.43-0.82, p = 0.0016), worsening of disability (0.56, 0.38-0.82, p = 0.0026), and progress to EDSS step 6 (0.33, 0.19-0.59, p = 0.00019). Among 1,085 patients with ≥15-year follow-up, the treated patients were less likely to experience relapses (0.59, 0.50-0.70, p = 10-9) and worsening of disability (0.81, 0.67-0.99, p = 0.043). CONCLUSION: Continued treatment with MS immunotherapies reduces disability accrual by 19%-44% (95% CI 1%-62%), the risk of need of a walking aid by 67% (95% CI 41%-81%), and the frequency of relapses by 40-41% (95% CI 18%-57%) over 15 years. This study provides evidence that disease-modifying therapies are effective in improving disability outcomes in relapsing-remitting MS over the long term. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with relapsing-remitting MS, long-term exposure to immunotherapy prevents neurologic disability.
2021
- Efficacy of mechanical thrombectomy in patients with ischemic stroke and cancer
[Articolo su rivista]
Ciolli, L.; Bigliardi, G.; Ferraro, D.; Maffei, S.; Vandelli, L.; Dell'Acqua, M. L.; Rosafio, F.; Picchetto, L.; Laterza, D.; Vincenzi, C.; Meletti, S.; Vallone, S.; Zini, A.
abstract
Cancer-related coagulopathy is a known cause of stroke and can lead to formation of thrombi with a unique composition. The effectiveness of mechanical thrombectomy in cancer patients is still unknown. The aim of the study was to evaluate the rate of successful reperfusion and the clinical outcome in cancer patients with stroke treated with endovascular therapies, compared to patients without cancer. We performed a retrospective analysis of consecutive patients with ischemic stroke treated with endovascular therapies at our hospital between January 2008 and January 2016. A sub-group analysis was performed including only patients with cryptogenic stroke. We included in the final analysis 14 patients with active cancer and 267 patients without cancer. Successful reperfusion was achieved in 79% of patients without cancer, and 71% of patients with active cancer (P = 0.68). Patients with cryptogenic stroke and active cancer had a lower reperfusion rate compared to patients with cryptogenic stroke without active cancer, although not significantly so (2/4 cancer patients, 50% vs 37/50, 74%, p: 0.31). Mortality rate was higher among cancer patients. Hemorrhagic transformation occurred in similar proportions in the two groups. Endovascular treatment in cancer patients seems, thus, effective.
2021
- Exit Strategies in Natalizumab-Treated RRMS at High Risk of Progressive Multifocal Leukoencephalopathy: a Multicentre Comparison Study
[Articolo su rivista]
Zanghi, A.; Gallo, A.; Avolio, C.; Capuano, R.; Lucchini, M.; Petracca, M.; Bonavita, S.; Lanzillo, R.; Ferraro, D.; Curti, E.; Buccafusca, M.; Callari, G.; Barone, S.; Pontillo, G.; Abbadessa, G.; Di Francescantonio, V.; Signoriello, E.; Lus, G.; Sola, P.; Granella, F.; Valentino, P.; Mirabella, M.; Patti, F.; D'Amico, E.
abstract
The main aim of the study is to evaluate the efficacy and safety profile of ocrelizumab (OCR), rituximab (RTX), and cladribine (CLA), employed as natalizumab (NTZ) exit strategies in relapsing–remitting multiple sclerosis (RRMS) patients at high-risk for progressive multifocal leukoencephalopathy (PML). This is a multicentre, retrospective, real-world study on consecutive RRMS patients from eleven tertiary Italian MS centres, who switched from NTZ to OCR, RTX, and CLA from January 1st, 2019, to December 31st, 2019. The primary study outcomes were the annualized relapse rate (ARR) and magnetic resonance imaging (MRI) outcome. Treatment effects were estimated by the inverse probability treatment weighting (IPTW), based on propensity-score (PS) approach. Additional endpoint included confirmed disability progression (CDP) as measured by Expanded Disability Status Scale and adverse events (AEs). Patients satisfying predefined inclusion and exclusion criteria were 120; 64 switched to OCR, 36 to RTX, and 20 to CLA. Patients from the 3 groups did not show differences for baseline characteristics, also after post hoc analysis. The IPTW PS-adjusted models revealed that patients on OCR had a lower risk for ARR than patients on CLA (ExpBOCR 0.485, CI 95% 0.264–0.893, p = 0.020). This result was confirmed also for 12-month MRI activity (ExpBOCR 0.248 CI 95% 0.065–0.948, p = 0.042). No differences were found in other pairwise comparisons (OCR vs RTX and RTX vs CLA) for the investigated outcomes. AEs were similar among the 3 groups. Anti-CD20 drugs were revealed to be effective and safe options as NTZ exit strategies. All investigated DMTs showed a good safety profile.
2021
- Microglia activation: A role for mitochondrial DNA?
[Articolo su rivista]
Pinti, M.; Ferraro, D.; Nasi, M.
abstract
2021
- Modulation of tregs and inkt by fingolimod in multiple sclerosis patients
[Articolo su rivista]
Ferraro, D.; De Biasi, S.; Simone, A. M.; Orlandi, R.; Nasi, M.; Vitetta, F.; Pinti, M.; Fogliani, M.; Meletti, S.; Cossarizza, A.; Sola, P.
abstract
The altered numbers and functions of cells belonging to immunoregulatory cell networks such as T regulatory (Tregs) and invariant Natural Killer T (iNKT) cells have been reported in Multiple Sclerosis (MS), an immune-mediated disease. We aimed to assess the frequencies of Tregs and iNKT cells in MS patients throughout a one-year treatment with fingolimod (FTY) and to correlate immunological data with efficacy and safety data. The percentage of Tregs (defined as Live Dead-CD3 + CD4 + FoxP3 + CD25++/CD127− cells) increased steadily throughout the year, while there was no significant difference in the absolute number or percentage of iNKT cells (defined as CD3 + CD14−CD19− Vα24-Jα18 TCR+ cells). However, out of all the iNKT cells, the CD8+ iNKT and CD4−CD8− double-negative (DN) cell percentages steadily increased, while the CD4+ iNKT cell percentages decreased significantly. The mean percentage of CD8+ T cells at all time-points was lower in patients with infections throughout the study. The numbers and percentages of DN iNKT cells were more elevated, considering all time-points, in patients who presented a clinical relapse. FTY may, therefore, exert its beneficial effect in MS patients through various mechanisms, including the increase in Tregs and in iNKT subsets with immunomodulatory potential such as CD8+ iNKT cells. The occurrence of infections was associated with lower mean CD8+ cell counts during treatment with FTY.
2021
- Prediction of on-treatment disability worsening in RRMS with the MAGNIMS score
[Articolo su rivista]
Kunchok, A.; Lechner-Scott, J.; Granella, F.; Trojano, M.; Alroughani, R.; Sola, P.; Ferraro, D.; Lugaresi, A.; Onofrj, M.; Ozakbas, S.; Izquierdo, G.; Grammond, P.; Luis Sanchez-Menoyo, J.; Van Wijmeersch, B.; Boz, C.; Pucci, E.; Mccombe, P.; Grand'Maison, F.; Spitaleri, D.; Vucic, S.; Hupperts, R.; Jokubaitis, V.; Sormani, M. P.; Butzkueven, H.; Kalincik, T.
abstract
Background: The magnetic resonance imaging in multiple sclerosis (MAGNIMS) score combines relapses and magnetic resonance imaging (MRI) lesions to predict disability outcomes in relapsing–remitting multiple sclerosis (RRMS) treated with interferon-β. Objective: To validate the MAGNIMS score and extend to other disease-modifying therapies (DMTs). To examine the prognostic value of gadolinium contrast-enhancing (Gd+) lesions. Methods: This RRMS MSBase cohort study (n = 2293) used a Cox model to examine the prognostic value of relapses, MRI activity and the MAGNIMS score for disability worsening during treatment with interferon-β and three other DMTs. Results: Three new T2 lesions (hazard ratio (HR) = 1.60, p = 0.028) or two relapses (HR = 2.24, p = 0.002) on interferon-β (for 12 months) were predictive of disability worsening over 4 years. MAGNIMS score = 2 (1 relapse and ⩾3 T2 lesions or ⩾2 relapses) was associated with a greater risk of disability worsening on interferon-β (HR = 2.0, p = 0.001). In pooled cohort of four DMTs, similar associations were seen (MAGNIMS score = 2: HR = 1.72, p = 0.001). Secondary analyses demonstrated that the addition of Gd+ to the MAGNIMS did not materially improve its prediction of disability worsening. Conclusion: We have validated the MAGNIMS score in RRMS and extended its application to three other DMTs: 1 relapse and ⩾3 T2 lesions or ⩾2 relapses predicted worsening of disability. Contrast-enhancing lesions did not substantially improve the prognostic score.
2021
- Serum neurofilament light as biomarker of seizure-related neuronal injury in status epilepticus
[Articolo su rivista]
Giovannini, G.; Bedin, R.; Ferraro, D.; Vaudano, A. E.; Mandrioli, J.; Meletti, S.
abstract
Biomarkers of neuronal damage in status epilepticus (SE) would be of great relevance for clinical and research purposes. In a retrospective cross-sectional study, serum neurofilament light chain (NfL) levels were measured in patients with SE (30 subjects), patients with drug-resistant epilepsy (30 subjects), and healthy controls (30 subjects). Serum NfL levels were higher in patients with SE (median = 26.15 pg/ml) compared to both epilepsy patients (median = 7.35 pg/ml) and healthy controls (median = 6.81 pg/ml; p <.001). In patients with SE, serum NfL levels showed a high correlation with cerebrospinal fluid (CSF) NfL (τ =.68, p <.001) as well as with CSF total tau (t-tau) levels (τ =.627, p <.001); they were higher in SE lasting >24 h (p =.013), in refractory/superrefractory SE (p =.004), and in patients who died within 30 days or who presented a worsening of clinical conditions (p =.001). Values of >28.8 pg/ml predicted 30-day clinical worsening or death (odds ratio [OR] = 10.83, 95% confidence interval [CI] = 1.96–59.83, p =.006) and SE refractoriness (OR = 9.33, 95% CI = 1.51–57.65, p =.016). In conclusion, serum NfL levels are increased in SE and correlate with SE treatment response, duration, and outcomes, therefore representing a promising biomarker of seizure-related neuronal damage.
2021
- The effectiveness of natalizumab vs fingolimod–A comparison of international registry studies
[Articolo su rivista]
Andersen, J. B.; Sharmin, S.; Lefort, M.; Koch-Henriksen, N.; Sellebjerg, F.; Sorensen, P. S.; Hilt Christensen, C. C.; Rasmussen, P. V.; Jensen, M. B.; Frederiksen, J. L.; Bramow, S.; Mathiesen, H. K.; Schreiber, K. I.; Horakova, D.; Havrdova, E. K.; Alroughani, R.; Izquierdo, G.; Eichau, S.; Ozakbas, S.; Patti, F.; Onofrj, M.; Lugaresi, A.; Terzi, M.; Grammond, P.; Grand Maison, F.; Yamout, B.; Prat, A.; Girard, M.; Duquette, P.; Boz, C.; Trojano, M.; Mccombe, P.; Slee, M.; Lechner-Scott, J.; Turkoglu, R.; Sola, P.; Ferraro, D.; Granella, F.; Shaygannejad, V.; Prevost, J.; Skibina, O.; Solaro, C.; Karabudak, R.; Wijmeersch, B. V.; Csepany, T.; Spitaleri, D.; Vucic, S.; Casey, R.; Debouverie, M.; Edan, G.; Ciron, J.; Ruet, A.; Seze, J. D.; Maillart, E.; Zephir, H.; Labauge, P.; Defer, G.; Lebrun, C.; Moreau, T.; Berger, E.; Clavelou, P.; Pelletier, J.; Stankoff, B.; Gout, O.; Thouvenot, E.; Heinzlef, O.; Al-Khedr, A.; Bourre, B.; Casez, O.; Cabre, P.; Montcuquet, A.; Wahab, A.; Camdessanche, J. -P.; Marousset, A.; Patry, I.; Hankiewicz, K.; Pottier, C.; Maubeuge, N.; Labeyrie, C.; Nifle, C.; Leray, E.; Laplaud, D. A.; Butzkueven, H.; Kalincik, T.; Vukusic, S.; Magyari, M.
abstract
Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at re-evaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab- and 1479 fingolimod treated patients. The on-treatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion: The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.
2021
- Transition to secondary progression in relapsing-onset multiple sclerosis: Definitions and risk factors
[Articolo su rivista]
Iaffaldano, P.; Lucisano, G.; Patti, F.; Brescia Morra, V.; De Luca, G.; Lugaresi, A.; Zaffaroni, M.; Inglese, M.; Salemi, G.; Cocco, E.; Conte, A.; Ferraro, D.; Galgani, S.; Bergamaschi, R.; Pozzilli, C.; Salvetti, M.; Lus, G.; Rovaris, M.; Maniscalco, G. T.; Logullo, F. O.; Paolicelli, D.; Achille, M.; Marrazzo, G.; Lovato, V.; Comi, G.; Filippi, M.; Amato, M. P.; Trojano, M.
abstract
Background: No uniform criteria for a sensitive identification of the transition from relapsing–remitting multiple sclerosis (MS) to secondary-progressive multiple sclerosis (SPMS) are available. Objective: To compare risk factors of SPMS using two definitions: one based on the neurologist judgment (ND) and an objective data-driven algorithm (DDA). Methods: Relapsing-onset MS patients (n = 19,318) were extracted from the Italian MS Registry. Risk factors for SPMS and for reaching irreversible Expanded Disability Status Scale (EDSS) 6.0, after SP transition, were estimated using multivariable Cox regression models. Results: SPMS identified by the DDA (n = 2343, 12.1%) were older, more disabled and with a faster progression to severe disability (p < 0.0001), than those identified by the ND (n = 3868, 20.0%). In both groups, the most consistent risk factors (p < 0.05) for SPMS were a multifocal onset, an age at onset >40 years, higher baseline EDSS score and a higher number of relapses; the most consistent protective factor was the disease-modifying therapy (DMT) exposure. DMT exposure during SP did not impact the risk of reaching irreversible EDSS 6.0. Conclusion: A DDA definition of SPMS identifies more aggressive progressive patients. DMT exposure reduces the risk of SPMS conversion, but it does not prevent the disability accumulation after the SP transition.
2021
- Treatment response score to glatiramer acetate or interferon beta-1a
[Articolo su rivista]
Bovis, Francesca; Kalincik, Tomas; Lublin, Fred; Cutter, Gary; Malpas, Charles; Horakova, Dana; Kubala Havrdova, Eva; Trojano, Maria; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Onofrj, Marco; Lugaresi, Alessandra; Izquierdo, Guillermo; Eichau, Sara; Patti, Francesco; Terzi, Murat; Grammond, Pierre; Bergamaschi, Roberto; Sola, Patrizia; Ferraro, Diana; Ozakbas, Serkan; Iuliano, Gerardo; Boz, Cavit; Hupperts, Raymond; Grand'Maison, Francois; Oreja-Guevara, Celia; van Pesch, Vincent; Cartechini, Elisabetta; Petersen, Thor; Altintas, Ayse; Soysal, Aysun; Ramo-Tello, Cristina; Mccombe, Pamela; Turkoglu, Recai; Butzkueven, Helmut; Wolinsky, Jerry S.; Solaro, Claudio; Pia Sormani, Maria
abstract
OBJECTIVE: To compare the effectiveness of glatiramer acetate (GA) vs intra-muscular Interferon beta-1a (IFNbeta-1a)), we applied a previously published statistical method, aimed at identifying patients' profiles associated with efficacy of treatments.METHODS: Data from 2 independent multiple sclerosis datasets, a randomized study (the CombiRx trial, evaluating GA vs IFNbeta-1a and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors.RESULTS: The overall ARR ratio of GA vs IFNbeta-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration and EDSS) detected differential response of GA vs IFNbeta-1a: in the trial, patients with the largest benefit from GA vs IFNbeta-1a (lower score quartile) had an ARR ratio of 0.40 (95%confidence interval [CI] = 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI = 0.61-1.34) and those in the upper quartile of 1.14 (95%CI = 0.59-2.18) (heterogeneity p = 0.012); this result was validated on MSbase, with the corresponding ARR ratios of 0.58 (95% CI = 0.46-0.72), 0.92 (95% CI = 0.77-1.09) and 1.29 (95% CI = 0.97-1.71); heterogeneity p < 0.0001).CONCLUSIONS: We demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFNbeta-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.
2020
- Association of Sustained Immunotherapy with Disability Outcomes in Patients with Active Secondary Progressive Multiple Sclerosis
[Articolo su rivista]
Lizak, N.; Malpas, C. B.; Sharmin, S.; Havrdova, E. K.; Horakova, D.; Izquierdo, G.; Eichau, S.; Lugaresi, A.; Duquette, P.; Girard, M.; Prat, A.; Larochelle, C.; Trojano, M.; Grand'Maison, F.; Grammond, P.; Sola, P.; Ferraro, D.; Hupperts, R.; Bergamaschi, R.; Boz, C.; Van Pesch, V.; Spitaleri, D.; Terzi, M.; Kalincik, T.
abstract
Importance: It is unclear whether relapses and disease-modifying therapies are associated with the rate of disability accumulation in patients with secondary progressive multiple sclerosis (SPMS). Objective: To examine the association of relapses with the rate of disability accumulation in patients with SPMS and to assess whether treatment before or during the secondary progressive phase can slow the progression of disability accumulation. Design, Setting, and Participants: In this observational cohort study, patient data were prospectively collected from the MSBase international registry between January 1, 1995, and February 1, 2018. Among 53680 patients in the MSBase registry, 4997 patients with SPMS (using the Lorscheider definition) were identified. Of those, 1621 patients were eligible for study inclusion based on sufficient follow-up before and after the onset of SPMS. Data were analyzed from November 15, 2017, to January 13, 2020. Exposures: The association between disability accumulation and several clinical and demographic variables, including relapses and exposure to immunotherapy, was evaluated. Main Outcomes and Measures: Two outcomes were analyzed as measures of disability accumulation during SPMS: the rate of disability accumulation during the secondary progressive phase (change relative to the reference population of patients with MS and absolute change) and the risk of becoming wheelchair dependent. A third outcome, the cumulative risk of experiencing confirmed disability progression events, was used for a secondary analysis. Outcomes were evaluated using multivariable mixed models (ie, linear and Cox models). Results: Of 1621 patients eligible for inclusion, 1103 patients (68.0%) were female, with a mean (SD) age at MS onset of 33.9 (10.6) years. A total of 661 patients (40.8%) experienced superimposed relapses during SPMS. Therapy receipt and relapses during early relapsing-remitting MS were not associated with disability accumulation during the secondary progressive phase. Higher relapse rates during the secondary progressive disease stage were associated with an increased risk of becoming wheelchair dependent (hazard ratio [HR], 1.87; 95% CI, 1.17-3.00; P =.009). Among patients who experienced superimposed relapses during SPMS, greater receipt of disease-modifying therapies was significantly associated with a reduced rate of disability progression and a lower risk of becoming wheelchair dependent. Conclusions and Relevance: In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target. Disease-modifying therapy was associated with improvements in disability outcomes among patients with active relapses during SPMS. The study's results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.
2020
- Cell-based assays for the detection of MOG antibodies: a comparative study
[Articolo su rivista]
Gastaldi, M.; Scaranzin, S.; Jarius, S.; Wildeman, B.; Zardini, E.; Mallucci, G.; Rigoni, E.; Vegezzi, E.; Foiadelli, T.; Savasta, S.; Banfi, P.; Versino, M.; Benedetti, L.; Novi, G.; Mancardi, M. M.; Giacomini, T.; Annovazzi, P.; Baroncini, D.; Ferraro, D.; Lampasona, V.; Reindl, M.; Waters, P.; Franciotta, D.
abstract
Background: The detection of antibodies to myelin oligodendrocyte glycoprotein (MOG) is fundamental for the identification of MOG antibody-associated disorders (MOGAD), and the differential diagnosis of acquired demyelinating syndromes of the CNS, among which multiple sclerosis (MS). We compared the diagnostic performance of four cell-based assays (CBAs) for their detection. Methods: Consecutive sera from 204 patients with ‘possible MOGAD’ (55), MS (112), and other neurological disorders (OND, 37) were tested for MOG-IgG with a live-CBA with anti-heavy-and-light chain secondary-antibody (LCBA-IgGH+L), and a live-CBA for IgG1 (LCBA-IgG1). A subgroup of 71 patients was additionally tested with a live-CBA with anti-Fcγ secondary-antibody (LCBA-IgGFcγ), and a commercial fixed-CBA with anti-Fcγ secondary-antibody (FCBA-IgGFcγ). Results: Fifty-seven/204 patients (27.9%) were MOG-IgG-positive. Sensitivity was 89.1% (CI:77.8–95.9) and specificity 93.3% (CI:88.0–96.7) for LCBA-IgGH+L, and 74.6% (CI:61.0–85.3) and 100% (CI:97.6–100) for LCBA-IgG1. Eighteen of 57 (31%) samples showed discrepant results (all negative on LCBA-IgG1); of these, three with ‘possible MOGAD’ showed high-titer MOG-IgG (≥ 1:640), and positivity for MOG-IgG2, whereas 15/18 had low-titer MOG-IgG (1:160/1:320) and mixed diagnoses (5 ‘possible MOGAD’, 6 MS, 4 OND). In the subgroup analysis, sensitivity was 92.3% (CI:79.1–98.4) and specificity 97.0% (CI:83.8–99.9) for LCBA-IgGFcγ, and 87.2% (CI:72.6–95.7) and 97.0% (CI:83.8–99.9) for FCBA-IgGFcγ. Conclusions: LCBA-IgG1 showed the highest specificity but can miss MOG-IgG2 reactivities, whose meaning warrants further investigations. Titration of samples tested with LCBA-IgGH+L/ IgGFcγ is important for meaningful interpretation of the results. In the subgroup analysis, LCBA-IgGFcγ yielded the highest accuracy, and FCBA-IgGFcγ good specificity, but it was at risk of false-negative results.
2020
- Cerebrospinal fluid kappa and lambda free light chains in oligoclonal band‐negative patients with suspected multiple sclerosis
[Articolo su rivista]
Ferraro, Diana; Trovati, Alice; Bedin, Roberta; Natali, Patrizia; Franciotta, Diego; Santangelo, Mario; Camera, Valentina; Vitetta, Francesca; Varani, Manuela; Trenti, Tommaso; Gastaldi, Matteo; De Biasi, Sara; Nasi, Milena; Pinti, Marcello; Meletti, Stefano; Sola, Patrizia
abstract
Cerebrospinal fluid (CSF) free light kappa chains (kappa FLC) may be a more sensitive marker of intrathecal IgG synthesis compared to oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a Multiple Sclerosis (MS) diagnosis in a group of OCB-negative patients with suspected MS.
2020
- Characteristics and treatment of Multiple Sclerosis-related trigeminal neuralgia: An Italian multi-centre study
[Articolo su rivista]
Ferraro, D.; Annovazzi, P.; Moccia, M.; Lanzillo, R.; De Luca, G.; Nociti, V.; Fantozzi, Riccardo; Paolicelli, D.; Ragonese, P.; Gajofatto, A.; Boffa, L.; Cavalla, P.; Lo Fermo, S.; Buscarinu, M. C.; Lorefice, L.; Cordioli, C.; Calabrese, M.; Gallo, A.; Pinardi, F.; Tortorella, C.; DI FILIPPO, Marcello; Camera, V.; Maniscalco, G. T.; Radaelli, M.; Buttari, F.; Tomassini, V.; Cocco, E.; Gasperini, C.; Solaro, C.
abstract
The prevalence of trigeminal neuralgia (TN) in Multiple Sclerosis (MS) patients is higher than in the general population and its management can be particularly challenging. Our aim is to describe the characteristics, treatment and prognostic factors of MS-related TN in a retrospective multicentre study.
2020
- Clinical and therapeutic predictors of disease outcomes in AQP4-IgG+ neuromyelitis optica spectrum disorder
[Articolo su rivista]
Kunchok, Amy; Malpas, Charles; Nytrova, Petra; Havrdova, Eva Kubala; Alroughani, Raed; Terzi, Murat; Yamout, Bassem; Hor, Jyh Yung; Karabudak, Rana; Boz, Cavit; Ozakbas, Serkan; Olascoaga, Javier; Simo, Magdolna; Granella, Franco; Patti, Francesco; Mccombe, Pamela; Csepany, Tunde; Singhal, Bhim; Bergamaschi, Roberto; Fragoso, Yara; Al-Harbi, Talal; Turkoglu, Recai; Lechner-Scott, Jeannette; Laureys, Guy; Oreja-Guevara, Celia; Pucci, Eugenio; Sola, Patrizia; Ferraro, Diana; Altintas, Ayse; Soysal, Aysun; Vucic, Steve; Grand'Maison, Francois; Izquierdo, Guillermo; Eichau, Sara; Lugaresi, Alessandra; Onofrj, Marco; Trojano, Maria; Marriott, Mark; Butzkueven, Helmut; Kister, Ilya; Kalincik, Tomas
abstract
Aquaporin-4-IgG positive (AQP4-IgG+) Neuromyelitis Optica Spectrum Disorder (NMOSD) is an uncommon central nervous system autoimmune disorder. Disease outcomes in AQP4-IgG+NMOSD are typically measured by relapse rate and disability. Using the MSBase, a multi-centre international registry, we aimed to examine the impact immunosuppressive therapies and patient characteristics as predictors of disease outcome measures in AQP4-IgG+NMOSD.
2020
- Delay from treatment start to full effect of immunotherapies for multiple sclerosis
[Articolo su rivista]
Roos, Izanne; Leray, Emmanuelle; Frascoli, Federico; Casey, Romain; Brown, J William L; Horakova, Dana; Havrdova, Eva K; Trojano, Maria; Patti, Francesco; Izquierdo, Guillermo; Eichau, Sara; Onofrj, Marco; Lugaresi, Alessandra; Prat, Alexandre; Girard, Marc; Grammond, Pierre; Sola, Patrizia; Ferraro, Diana; Ozakbas, Serkan; Bergamaschi, Roberto; Sá, Maria José; Cartechini, Elisabetta; Boz, Cavit; Granella, Franco; Hupperts, Raymond; Terzi, Murat; Lechner-Scott, Jeannette; Spitaleri, Daniele; Van Pesch, Vincent; Soysal, Aysun; Olascoaga, Javier; Prevost, Julie; Aguera-Morales, Eduardo; Slee, Mark; Csepany, Tunde; Turkoglu, Recai; Sidhom, Youssef; Gouider, Riadh; Van Wijmeersch, Bart; McCombe, Pamela; Macdonell, Richard; Coles, Alasdair; Malpas, Charles B; Butzkueven, Helmut; Vukusic, Sandra; Kalincik, Tomas
abstract
In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.
2020
- Diagnostic features of initial demyelinating events associated with serum MOG-IgG
[Articolo su rivista]
Orlandi, R.; Mariotto, S.; Ferrari, S.; Gobbin, F.; Sechi, E.; Capra, R.; Mancinelli, C. R.; Bombardi, R.; Zuliani, L.; Zoccarato, M.; Rossi, F.; Camera, V.; Ferraro, D.; Benedetti, M. D.; Reindl, M.; Gajofatto, A.
abstract
Background: Myelin oligodendrocyte glycoprotein (MOG)-IgG associated disorders are increasingly recognized as a distinct disease entity. However, diagnostic sensitivity and specificity of serum MOG-IgG as well as recommendations for testing are still debated. Materials and methods: Between October 2015 and July 2017 we tested serum MOG-IgG in 91 adult patients (49 females) with a demyelinating event (DE) not fulfilling 2010 McDonald criteria for MS at sampling, negative for neuromyelitis optica (NMO)-IgG and followed-up for at least 12 months. We assessed the sensitivity and specificity of a live-cell MOG-IgG assay for each final diagnosis at last follow-up, for the 2018 international recommendations for MOG-IgG testing, and for other combinations of clinical and laboratory characteristics. Results: Clinical presentations included acute myelitis (n = 48), optic neuritis (n = 36), multifocal encephalomyelitis (n = 4), and brainstem syndrome (n = 3). Twenty-four patients were MOG-IgG positive. Sensitivity and specificity of MOG-IgG test applied to the 2018 international recommendations were 28.4% and 86.7%, while they were 42.1% and 88.6% when applied to DE of unclear aetiology as defined above with two or more among: 1_no periventricular and juxtacortical MS-like lesions on brain MRI; 2_longitudinally extensive MRI optic nerve lesion; 3_no CSF-restricted oligoclonal bands; 4_CSF protein > 50 mg/dl. Conclusions: Simplified requirements compared to those currently proposed for MOG-IgG testing could facilitate the applicability of the assay in the diagnosis of adults with DEs of unclear aetiology.
2020
- Disability outcomes of early cerebellar and brainstem symptoms in multiple sclerosis
[Articolo su rivista]
Le, Minh; Malpas, Charles; Sharmin, Sifat; Horáková, Dana; Havrdova, Eva; Trojano, Maria; Izquierdo, Guillermo; Eichau, Sara; Ozakbas, Serkan; Lugaresi, Alessandra; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Larochelle, Catherine; Alroughani, Raed; Bergamaschi, Roberto; Sola, Patrizia; Ferraro, Diana; Grammond, Pierre; Grand' Maison, Francois; Terzi, Murat; Boz, Cavit; Hupperts, Raymond; Butzkueven, Helmut; Pucci, Eugenio; Granella, Franco; Van Pesch, Vincent; Soysal, Aysun; Yamout, Bassem I; Lechner-Scott, Jeannette; Spitaleri, Daniele LA; Ampapa, Radek; Turkoglu, Recai; Iuliano, Gerardo; Ramo-Tello, Cristina; Sanchez-Menoyo, Jose Luis; Sidhom, Youssef; Gouider, Riadh; Shaygannejad, Vahid; Prevost, Julie; Altintas, Ayse; Fragoso, Yara Dadalti; Mccombe, Pamela Ann; Petersen, Thor; Slee, Mark; Barnett, Michael H; Vucic, Steve; Van Der Walt, Anneke; Kalincik, Tomas
abstract
Background: Cerebellar and brainstem symptoms are common in early stages of multiple sclerosis (MS) yet their prognostic values remain unclear. Objective: The aim of this study was to investigate long-term disability outcomes in patients with early cerebellar and brainstem symptoms. Methods: This study used data from MSBase registry. Patients with early cerebellar/brainstem presentations were identified as those with cerebellar/brainstem relapse(s) or functional system score > 2 in the initial 2 years. Early pyramidal presentation was chosen as a comparator. Andersen-Gill models were used to compare cumulative hazards of (1) disability progression events and (2) relapses between patients with and without early cerebellar/brainstem symptoms. Mixed effect models were used to estimate the associations between early cerebellar/brainstem presentations and expanded disability status scale (EDSS) scores. Results: The study cohort consisted of 10,513 eligible patients, including 2723 and 3915 patients with early cerebellar and brainstem symptoms, respectively. Early cerebellar presentation was associated with greater hazard of progression events (HR = 1.37,p < 0.001) and EDSS (beta = 0.16,p < 0.001). Patients with early brainstem symptoms had lower hazard of progression events (HR = 0.89,p = 0.01) and EDSS (beta = -0.06,p < 0.001). Neither presentation was associated with changes in relapse risk. Conclusion: Early cerebellar presentation is associated with unfavourable outcomes, while early brainstem presentation is associated with favourable prognosis. These presentations may be used as MS prognostic markers and guide therapeutic approach.
2020
- Early clinical markers of aggressive multiple sclerosis
[Articolo su rivista]
Malpas, C. B.; Manouchehrinia, A.; Sharmin, S.; Roos, I.; Horakova, D.; Havrdova, E. K.; Trojano, M.; Izquierdo, G.; Eichau, S.; Bergamaschi, R.; Sola, P.; Ferraro, D.; Lugaresi, A.; Prat, A.; Girard, M.; Duquette, P.; Grammond, P.; Grand'Maison, F.; Ozakbas, S.; Van Pesch, V.; Granella, F.; Hupperts, R.; Pucci, E.; Boz, C.; Sidhom, Y.; Gouider, R.; Spitaleri, D.; Soysal, A.; Petersen, T.; Verheul, F.; Karabudak, R.; Turkoglu, R.; Ramo-Tello, C.; Terzi, M.; Cristiano, E.; Slee, M.; Mccombe, P.; Macdonell, R.; Fragoso, Y.; Olascoaga, J.; Altintas, A.; Olsson, T.; Butzkueven, H.; Hillert, J.; Kalincik, T.
abstract
Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.
2020
- Harmonization of real-world studies in multiple sclerosis: Retrospective analysis from the rirems group
[Articolo su rivista]
Moccia, M.; Annovazzi, P.; Buscarinu, M. C.; Calabrese, M.; Cavalla, P.; Cordioli, C.; Di Filippo, M.; Ferraro, D.; Gajofatto, A.; Gallo, A.; Lanzillo, R.; Laroni, A.; Lorefice, L.; Mallucchi, S.; Nociti, V.; Paolicelli, D.; Pinardi, F.; Prosperini, L.; Radaelli, M.; Ragonese, P.; Tomassini, V.; Tortorella, C.; Cocco, E.; Gasperini, C.; Solaro, C.
abstract
Background: Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies. In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group. Methods: RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ2). Results: Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ2=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ2=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ2=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ2=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ2=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p = 0.02; τ2=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p = 0.02; τ2=1.00). Discussion: We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.
2020
- Increased plasma levels of mitochondrial DNA and pro-inflammatory cytokines in patients with progressive multiple sclerosis
[Articolo su rivista]
Nasi, M.; Bianchini, E.; De Biasi, S.; Gibellini, L.; Neroni, A.; Mattioli, Marco; Pinti, M.; Iannone, A.; Mattioli, A. V.; Simone, A. M.; Ferraro, D.; Vitetta, F.; Sola, P.; Cossarizza, A.
abstract
The role of damage-associated molecular patterns in multiple sclerosis (MS) is under investigation. Here, we studied the contribution of circulating high mobility group box protein 1 (HMGB1) and mitochondrial DNA (mtDNA) to neuroinflammation in progressive MS. We measured plasmatic mtDNA, HMGB1 and pro-inflammatory cytokines in 38 secondary progressive (SP) patients, 35 primary progressive (PP) patients and 42 controls. Free mtDNA was higher in SP than PP. Pro-inflammatory cytokines were increased in progressive patients. In PP, tumor necrosis factor-α correlated with MS Severity Score. Thus, in progressive patients, plasmatic mtDNA and pro-inflammatory cytokines likely contribute to the systemic inflammatory status.
2020
- Informing MS patients on treatment options: a consensus on the process of consent taking
[Articolo su rivista]
Tortorella, C; Solaro, C; Annovazzi, P; Boffa, L; Buscarinu, M C; Buttari, F; Calabrese, M; Cavalla, P; Cocco, E; Cordioli, C; De Luca, G; Di Filippo, M; Fantozzi, R; Ferraro, D; Gajofatto, A; Gallo, A; Lanzillo, R; Laroni, A; Fermo, S Lo; Malucchi, S; Maniscalco, G T; Moccia, M; Nociti, V; Paolicelli, D; Pesci, I; Prosperini, L; Ragonese, P; Tomassini, V; Clerici, V L A Torri; Rodegher, M; Gherardi, M; Gasperini, C
abstract
In the last years, change in multiple sclerosis (MS) therapeutic scenario has highlighted the need for an improved doctor-patient communication in advance of treatment initiation in order to allow patient's empowerment in the decision-making process. Aims The aims of our project were to review the strategies used by Italian MS specialists to inform patients about treatment options and to design a multicentre shared document that homogenizes the information about disease-modifying treatment (DMTs) and the procedure of taking informed consent in clinical practice. Results The new resource, obtained by consensus among 31 neurologists from 27 MS Centres in Italy with the supervision of a medico-legal advisor, received the aegis of Italian Neurological Society (SIN) and constitutes a step toward a standardized decision process around DMTs in MS.
2020
- Inter-center agreement in the interpretation of oligoclonal bands
[Articolo su rivista]
Mariotto, S.; Ferraro, D.; Soldani, F.; Alberti, D.; Bedin, R.; Sola, P.; Gastaldi, M.; Franciotta, D.; Ferrari, S.
abstract
2020
- Kappa Index Versus CSF Oligoclonal Bands in Predicting Multiple Sclerosis and Infectious/Inflammatory CNS Disorders
[Articolo su rivista]
Ferraro, Diana; Bedin, Roberta; Natali, Patrizia; Franciotta, Diego; Smolik, Krzysztof; Santangelo, Mario; Immovilli, Paolo; Camera, Valentina; Vitetta, Francesca; Gastaldi, Matteo; Trenti, Tommaso; Meletti, Stefano; Sola, Patrizia
abstract
Cerebrospinal fluid (CSF) kappa free light chains (KFLC) are gaining increasing interest as markers of intrathecal immunoglobulin synthesis. The main aim of this study was to assess the diagnostic accuracy (AUC) of the kappa index (CSF/serum KFLC divided by the CSF/serum albumin ratio) compared to CSF oligoclonal IgG bands (OCB) in predicting Multiple Sclerosis (MS) or a central nervous system infectious/inflammatory disorder (CNSID).
2020
- Lymphocyte reconstitution after DMF discontinuation in clinical trial and real-world patients with MS
[Articolo su rivista]
Chan, Andrew; Rose, John; Alvarez, Enrique; Bar-Or, Amit; Butzkueven, Helmut; Fox, Robert J; Gold, Ralf; Gudesblatt, Mark; Haartsen, Jodi; Spelman, Tim; Wright, Katy; Ferraro, Diana; Sola, Patrizia; Hodgkinson, Suzanne; Kalincik, Tomas; Lechner-Scott, Jeannette; Mcguigan, Christopher; Spach, Karen; Chen, Chongshu; Fam, Sami; Wu, Fan; Miller, Catherine
abstract
Background Delayed-release dimethyl fumarate (DMF) has demonstrated robust efficacy in treating patients with relapsing-remitting multiple sclerosis. Decreases in absolute lymphocyte count (ALC) are a well-known pharmacodynamic effect of DMF treatment, but lymphocyte recovery dynamics are not well characterized after discontinuation of DMF. Methods Data sources included the Biogen DMF integrated clinical trial data set, a retrospective US chart abstraction study, and data from MSBase. We assessed rate and time course of lymphocyte reconstitution after DMF discontinuation. Results The majority of patients who developed lymphopenia while treated with DMF and subsequently discontinued treatment experienced ALC reconstitution. The median time to reach ALC >= 0.8 x 10(9)/L was 2-4 months after discontinuation for patients treated in real-world data sets; the median time to reach ALC >= 0.91 x 10(9)/L was 2 months after discontinuation in DMF clinical trials. Severity of lymphopenia on treatment and decline in ALC within the first 6 months did not affect the ALC reconstitution rate after DMF discontinuation; rather, on-treatment lymphopenia duration influenced the reconstitution rate. In patients with severe, prolonged lymphopenia for >= 3 years, lymphocyte reconstitution to >= 0.91 x 10(9)/L was 12-18 months vs 2-3 months in patients with lymphopenia persisting Conclusions The majority of patients who discontinued DMF due to lymphopenia experienced ALC reconstitution within 2-4 months following DMF discontinuation. This may help guide clinicians in managing patients who develop lymphopenia during DMF treatment. Prolonged lymphopenia on DMF treatment is associated with slow lymphocyte recovery after DMF discontinuation.
2020
- Mitochondrial damage-associated molecular patterns stimulate reactive oxygen species production in human microglia
[Articolo su rivista]
Nasi, Milena; De Gaetano, Anna; Bianchini, Elena; De Biasi, Sara; Gibellini, Lara; Neroni, Anita; Mattioli, Marco; Pinti, Marcello; Tartaro, Domenico Lo; Borella, Rebecca; Mattioli, Anna Vittoria; Chester, Johanna; Melegari, Alessandra; Simone, Anna Maria; Ferraro, Diana; Vitetta, Francesca; Sola, Patrizia; Cossarizza, Andrea
abstract
Microglia are the resident innate immune cells of the central nervous system and exert functions of host defence and maintenance of normal tissue homeostasis, along with support of neuronal processes in the healthy brain. Chronic and dysregulated microglial cell activation has increasingly been linked to the status of neuroinflammation underlying many neurodegenerative diseases, including multiple sclerosis (MS). However, the stimulus (or stimuli) and mechanisms by which microglial activation is initiated and maintained MS are still debated. The purpose of our research was to investigate whether the endogenous mitochondrial (mt)-derived damage-associated molecular patterns (MTDs) mtDNA, N-formyl peptides and cardiolipin (CL) contribute to these phenomena. We characterized the effects of the abovementioned MTDs on microglia activation in vitro (i.e. using HMC3 cells) by evaluating the expression of gene coding for proteins involved in their binding and coupled to downstream signaling pathways, the up-regulation of markers of activation on the cell surface and the production of pro-inflammatory cytokines and reactive oxygen species. At the transcriptional level, significant variations in the mRNA relative expression of five of eleven selected genes were observed in response to stimulation. No changes in activation of antigenic profile or functional properties of HMC3 cells were observed; there was no up-regulation of HLA-DR expression or increased secretion of tumor necrosis factor-α and interleukin-6. However, after stimulation with mtDNA and CL, an increase in cellular oxidative stress, but not in the mt ROS O2-, compared to control cells, were observed. There were no effects on cell viability. Overall, our data suggest that MTDs could cause a failure in microglial activation toward a pro-inflammatory phenotype, possibly triggering an endogenous regulatory mechanism for the resolution of neuroinflammation. This could open a door for the development of drugs selectively targeting microglia and modulating its functionality to treat MS and/or other neurodegenerative conditions in which MTDs have a pathogenic relevance.
2020
- Plasma neurofilaments correlate with disability in progressive multiple sclerosis patients
[Articolo su rivista]
Ferraro, Diana; Guicciardi, Claudio; De Biasi, Sara; Pinti, Marcello; Bedin, Roberta; Camera, Valentina; Vitetta, Francesca; Nasi, Milena; Meletti, Stefano; Sola, Patrizia
abstract
Cerebrospinal fluid (CSF) and blood neurofilaments (NFLs) are markers of axonal damage and are being investigated, mostly in relapsing-remitting (RR) MS, as a marker of disease activity and of response to treatment, while there are less data in progressive MS patients. Primary aim was to measure NFL in plasma samples of untreated patients with primary (PP) and secondary (SP) progressive MS and to correlate them with disability, disease severity, and prior/subsequent disability progression.
2020
- Risk of secondary progressive multiple sclerosis: A longitudinal study
[Articolo su rivista]
Fambiatos, A.; Jokubaitis, V.; Horakova, D.; Kubala Havrdova, E.; Trojano, M.; Prat, A.; Girard, M.; Duquette, P.; Lugaresi, A.; Izquierdo, G.; Grand'Maison, F.; Grammond, P.; Sola, P.; Ferraro, D.; Alroughani, R.; Terzi, M.; Hupperts, R.; Boz, C.; Lechner-Scott, J.; Pucci, E.; Bergamaschi, R.; Van Pesch, V.; Ozakbas, S.; Granella, F.; Turkoglu, R.; Iuliano, G.; Spitaleri, D.; Mccombe, P.; Solaro, C.; Slee, M.; Ampapa, R.; Soysal, A.; Petersen, T.; Sanchez-Menoyo, J. L.; Verheul, F.; Prevost, J.; Sidhom, Y.; Van Wijmeersch, B.; Vucic, S.; Cristiano, E.; Saladino, M. L.; Deri, N.; Barnett, M.; Olascoaga, J.; Moore, F.; Skibina, O.; Gray, O.; Fragoso, Y.; Yamout, B.; Shaw, C.; Singhal, B.; Shuey, N.; Hodgkinson, S.; Altintas, A.; Al-Harbi, T.; Csepany, T.; Taylor, B.; Hughes, J.; Jun, J. -K.; van der Walt, A.; Spelman, T.; Butzkueven, H.; Kalincik, T.
abstract
Background: The risk factors for conversion from relapsing-remitting to secondary progressive multiple sclerosis remain highly contested. Objective: The aim of this study was to determine the demographic, clinical and paraclinical features that influence the risk of conversion to secondary progressive multiple sclerosis. Methods: Patients with adult-onset relapsing-remitting multiple sclerosis and at least four recorded disability scores were selected from MSBase, a global observational cohort. The risk of conversion to objectively defined secondary progressive multiple sclerosis was evaluated at multiple time points per patient using multivariable marginal Cox regression models. Sensitivity analyses were performed. Results: A total of 15,717 patients were included in the primary analysis. Older age (hazard ratio (HR) = 1.02, p < 0.001), longer disease duration (HR = 1.01, p = 0.038), a higher Expanded Disability Status Scale score (HR = 1.30, p < 0.001), more rapid disability trajectory (HR = 2.82, p < 0.001) and greater number of relapses in the previous year (HR = 1.07, p = 0.010) were independently associated with an increased risk of secondary progressive multiple sclerosis. Improving disability (HR = 0.62, p = 0.039) and disease-modifying therapy exposure (HR = 0.71, p = 0.007) were associated with a lower risk. Recent cerebral magnetic resonance imaging activity, evidence of spinal cord lesions and oligoclonal bands in the cerebrospinal fluid were not associated with the risk of conversion. Conclusion: Risk of secondary progressive multiple sclerosis increases with age, duration of illness and worsening disability and decreases with improving disability. Therapy may delay the onset of secondary progression.
2020
- Simultaneous quantification of natural and inducible regulatory T-cell subsets during interferon-β therapy of multiple sclerosis patients
[Articolo su rivista]
Chiarini, Marco; Capra, Ruggero; Serana, Federico; Bertoli, Diego; Sottini, Alessandra; Giustini, Viviana; Scarpazza, Cristina; Rovaris, Marco; Torri Clerici, Valentina; Ferraro, Diana; Galgani, Simonetta; Solaro, Claudio; Conti, Marta Zaffira; Visconti, Andrea; Imberti, Luisa
abstract
The mechanisms underlying the therapeutic activity of interferon-β in multiple sclerosis are still not completely understood. In the present study, we evaluated the short and long-term effects of interferon-β treatment on different subsets of regulatory T cells in relapsing-remitting multiple sclerosis patients biologically responsive to treatment because of mixovirus resistance protein A inducibility.
2020
- Timing of high-efficacy therapy for multiple sclerosis: a retrospective observational cohort study
[Articolo su rivista]
He, Anna; Merkel, Bernd; Brown, James William L; Zhovits Ryerson, Lana; Kister, Ilya; Malpas, Charles B; Sharmin, Sifat; Horakova, Dana; Kubala Havrdova, Eva; Spelman, Tim; Izquierdo, Guillermo; Eichau, Sara; Trojano, Maria; Lugaresi, Alessandra; Hupperts, Raymond; Sola, Patrizia; Ferraro, Diana; Lycke, Jan; Grand'Maison, Francois; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Larochelle, Catherine; Svenningsson, Anders; Petersen, Thor; Grammond, Pierre; Granella, Franco; Van Pesch, Vincent; Bergamaschi, Roberto; McGuigan, Christopher; Coles, Alasdair; Hillert, Jan; Piehl, Fredrik; Butzkueven, Helmut; Kalincik, Tomas
abstract
2019
- "Better explanations" in multiple sclerosis diagnostic workup: A 3-year longitudinal study
[Articolo su rivista]
Calabrese, Massimiliano; Gasperini, Claudio; Tortorella, Carla; Schiavi, Gianmarco; Frisullo, Giovanni; Ragonese, Paolo; Fantozzi, Roberta; Prosperini, Luca; Annovazzi, Pietro; Cordioli, Cinzia; Di Filippo, Massimiliano; Ferraro, Diana; Gajofatto, Alberto; Malucchi, Simona; Lo Fermo, Salvatore; De Luca, Giovanna; Stromillo, Maria L; Cocco, Eleonora; Gallo, Antonio; Paolicelli, Damiano; Lanzillo, Roberta; Tomassini, Valentina; Pesci, Ilaria; Rodegher, Maria E; Solaro, Claudio
abstract
The exclusion of other diseases that can mimic multiple sclerosis (MS) is the cornerstone of current diagnostic criteria. However, data on the frequency of MS mimics in real life are incomplete.
2019
- Abnormal Circadian Modification of Aδ-Fiber Pathway Excitability in Idiopathic Restless Legs Syndrome
[Articolo su rivista]
Vollono, Catello; Della Marca, Giacomo; Testani, Elisa; Losurdo, Anna; Virdis, Daniela; Ferraro, Diana; Brunetti, Valerio; Rossini, Paolo M; Le Pera, Domenica; Mazza, Salvatore; Valeriani, Massimiliano
abstract
Restless legs syndrome (RLS) is characterized by unpleasant sensations generally localized to legs, associated with an urge to move. A likely pathogenetic mechanism is a central dopaminergic dysfunction. The exact role of pain system is unclear. The purpose of the study was to investigate the nociceptive pathways in idiopathic RLS patients. We enrolled 11 patients (mean age 53.2 ± 19.7 years; 7 men) suffering from severe, primary RLS. We recorded scalp laser-evoked potentials (LEPs) to stimulation of different sites (hands and feet) and during two different time conditions (daytime and nighttime). Finally, we compared the results with a matched control group of healthy subjects. The Aδ responses obtained from patients did not differ from those recorded from control subjects. However, the N1 and the N2-P2 amplitudes' night/day ratios after foot stimulation were increased in patients, as compared to controls (N1: patients: 133.91 ± 50.42%; controls: 83.74 ± 34.45%; p = 0.016; Aδ-N2-P2: patients: 119.15 ± 15.56%; controls: 88.42 ± 23.41%; p = 0.003). These results suggest that RLS patients present circadian modifications in the pain system, which are not present in healthy controls. Both sensory-discriminative and affective-emotional components of pain experience show parallel changes. This study confirms the structural integrity of Aδ nociceptive system in idiopathic RLS, but it also suggests that RLS patients present circadian modifications in the pain system. These findings could potentially help clinicians and contribute to identify new therapeutic approaches.
2019
- Anti-inflammatory disease-modifying treatment and disability progression in primary progressive multiple sclerosis: a cohort study
[Articolo su rivista]
Lorscheider, J.; Kuhle, J.; Izquierdo, G.; Lugaresi, A.; Havrdova, E.; Horakova, D.; Hupperts, R.; Duquette, P.; Girard, M.; Prat, A.; Grand'Maison, F.; Grammond, P.; Sola, P.; Ferraro, D.; Trojano, M.; Ramo-Tello, C.; Lechner-Scott, J.; Pucci, E.; Solaro, C.; Slee, M.; Van Pesch, V.; Sanchez Menoyo, J. L.; van der Walt, A.; Butzkueven, H.; Kappos, L.; Kalincik, T.
abstract
Background and purpose: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti-inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti-inflammatory disease-modifying treatment on disability outcomes in PPMS. Methods: Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease-modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention-to-treat and an as-treated approach in paired, pairwise-censored analyses. Results: Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on-study pairwise-censored follow-up was 3.4 years (quartiles 1.2–5.5). No difference in the hazard of experiencing 3-month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6–1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6–1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7–1.6, P = 0.69). Conclusion: Our pooled analysis of disease-modifying agents suggests that these therapies have no substantial effect on short- to medium-term disability outcomes in PPMS.
2019
- Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis
[Articolo su rivista]
Brown, J William L; Coles, Alasdair; Horakova, Dana; Havrdova, Eva; Izquierdo, Guillermo; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Trojano, Maria; Lugaresi, Alessandra; Bergamaschi, Roberto; Grammond, Pierre; Alroughani, Raed; Hupperts, Raymond; McCombe, Pamela; Van Pesch, Vincent; Sola, Patrizia; Ferraro, Diana; Grand'Maison, Francois; Terzi, Murat; Lechner-Scott, Jeannette; Flechter, Schlomo; Slee, Mark; Shaygannejad, Vahid; Pucci, Eugenio; Granella, Franco; Jokubaitis, Vilija; Willis, Mark; Rice, Claire; Scolding, Neil; Wilkins, Alastair; Pearson, Owen R; Ziemssen, Tjalf; Hutchinson, Michael; Harding, Katharine; Jones, Joanne; McGuigan, Christopher; Butzkueven, Helmut; Kalincik, Tomas; Robertson, Neil
abstract
Within 2 decades of onset, 80% of untreated patients with relapsing-remitting multiple sclerosis (MS) convert to a phase of irreversible disability accrual termed secondary progressive MS. The association between disease-modifying treatments (DMTs), and this conversion has rarely been studied and never using a validated definition.
2019
- Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis
[Articolo su rivista]
Kalincik, Tomas; Kubala Havrdova, Eva; Horakova, Dana; Izquierdo, Guillermo; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Grammond, Pierre; Onofrj, Marco; Lugaresi, Alessandra; Ozakbas, Serkan; Kappos, Ludwig; Kuhle, Jens; Terzi, Murat; Lechner-Scott, Jeannette; Boz, Cavit; Grand'Maison, Francois; Prevost, Julie; Sola, Patrizia; Ferraro, Diana; Granella, Franco; Trojano, Maria; Bergamaschi, Roberto; Pucci, Eugenio; Turkoglu, Recai; McCombe, Pamela A; Pesch, Vincent Van; Van Wijmeersch, Bart; Solaro, Claudio; Ramo-Tello, Cristina; Slee, Mark; Alroughani, Raed; Yamout, Bassem; Shaygannejad, Vahid; Spitaleri, Daniele; Sánchez-Menoyo, José Luis; Ampapa, Radek; Hodgkinson, Suzanne; Karabudak, Rana; Butler, Ernest; Vucic, Steve; Jokubaitis, Vilija; Spelman, Tim; Butzkueven, Helmut
abstract
Oral immunotherapies have become a standard treatment in relapsing-remitting multiple sclerosis. Direct comparison of their effect on relapse and disability is needed.
2019
- Conversion to secondary progressive multiple sclerosis: Patient awareness and needs. Results from an online survey in Italy and Germany
[Articolo su rivista]
Solari, A.; Giovannetti, A. M.; Giordano, A.; Tortorella, C.; Clerici, V. T.; Brichetto, G.; Granella, F.; Lugaresi, A.; Patti, F.; Salvetti, M.; Pesci, I.; Pucci, E.; Centonze, D.; Danni, M. C.; Bonavita, S.; Ferraro, D.; Gallo, A.; Gajofatto, A.; Nociti, V.; Grimaldi, L.; Grobberio, M.; Lanzillo, R.; Di Giovanni, R.; Gregori, S.; Manni, A.; Pietrolongo, E.; Bertagnoli, S.; Ronzoni, M.; Compagnucci, L.; Fantozzi, R.; Allegri, B.; Arena, S.; Buscarinu, M. C.; Sabattini, L.; Quartuccio, M. E.; Tsantes, E.; Confaloneri, P.; Tacchino, A.; Schiffmann, I.; Rahn, A. C.; Kleiter, I.; Uccelli, M. M.; Barabasch, A.; Heesen, C.; Borreani, C.; De Luca, G.; Giordano, A.; Giovannetti, A. M.; Gitto, L.; Heesen, C.; Solari, A.; Clerici, V. T.; Trojano, M.; Uccelli, M. M.
abstract
Background: Few studies have investigated the experiences of patients around the conversion to secondary progressive multiple sclerosis (SPMS). ManTra is a mixed-method, co-production research project conducted in Italy and Germany to develop an intervention for newly-diagnosed SPMS patients. In previous project actions, we identified the needs and experiences of patients converting to SPMS via literature review and qualitative research which involved key stakeholders. Aims: The online patient survey aimed to assess, on a larger and independent sample of recently-diagnosed SPMS patients: (a) the characteristics associated to patient awareness of SPMS conversion; (b) the experience of conversion; (c) importance and prioritization of the needs previously identified. Methods: Participants were consenting adults with SPMS since ≤5 years. The survey consisted of three sections: on general and clinical characteristics; on experience of SPMS diagnosis disclosure (aware participants only); and on importance and prioritization of 33 pre-specified needs. Results: Of 215 participants, those aware of their SPMS diagnosis were 57% in Italy vs. 77% in Germany (p = 0.004). In both countries, over 80% of aware participants received a SPMS diagnosis from the neurologist; satisfaction with SPMS disclosure was moderate to high. Nevertheless, 28–35%obtained second opinions, and 48–56% reported they did not receive any information on SPMS. Participants actively seeking further information were 63% in Germany vs. 31% in Italy (p < 0.001). Variables independently associated to patient awareness were geographic area (odds ratio, OR 0.32, 95% CI 0.13–0.78 for Central Italy; OR 0.21, 95% CI 0.08–0.58 for Southern Italy [vs. Germany]) and activity limitations (OR 7.80, 95% CI 1.47–41.37 for dependent vs. autonomous patients). All pre-specified needs were scored a lot or extremely important, and two prioritized needs were shared by Italian and German patients: “physiotherapy” and “active patient care involvement.” The other two differed across countries: “an individualized health care plan” and “information on social rights and policies” in Italy, and “psychological support” and “cognitive rehabilitation” in Germany. Conclusions: Around 40% of SPMS patients were not aware of their disease form indicating a need to improve patient-physician communication. Physiotherapy and active patient care involvement were prioritized in both countries.
2019
- Incidence of pregnancy and disease-modifying therapy exposure trends in women with multiple sclerosis: A contemporary cohort study
[Articolo su rivista]
Nguyen, Ai-Lan; Havrdova, Eva Kubala; Horakova, Dana; Izquierdo, Guillermo; Kalincik, Tomas; van der Walt, Anneke; Terzi, Murat; Alroughani, Raed; Duquette, Pierre; Girard, Marc; Prat, Alexandre; Boz, Cavit; Sola, Patrizia; Ferraro, Diana; Lugaresi, Alessandra; Lechner-Scott, Jeannette; Barnett, Michael; Grand'Maison, Francois; Grammond, Pierre; Ramo-Tello, Cristina; Turkoglu, Recai; Mccombe, Pamela; Pucci, Eugenio; Trojano, Maria; Granella, Franco; Spitaleri, Daniele; Van Pesch, Vincent; Soysal, Aysun; Oreja-Guevara, Celia; Verheul, Freek; Vucic, Steve; Hodgkinson, Suzanne; Slee, Mark; Ampapa, Radek; Prevost, Julie; Menoyo, Jose Luis Sanchez; Skibina, Olga; Solaro, Claudio; Olascoaga, Javier; Shaw, Cameron; Madsen, Klaus Gregaard; Naidoo, Kerisha; Hyde, Robert; Butzkueven, Helmut; Jokubaitis, Vilija
abstract
Abstract
BACKGROUND:
Exposure to disease-modifying therapy (DMT) during early pregnancy in women with relapsing-remitting MS (RRMS) may be increasing.
OBJECTIVE:
To retrospectively determine incidence of pregnancy, DMT exposure and pregnancy outcomes in women with RRMS.
METHODS:
We identified all women with RRMS aged 15-45 years in the MSBase Registry between 2005-2016. Annualised pregnancy incidence rates were calculated using Poisson regression models. DMT exposures and pregnancy outcomes were assessed.
RESULTS:
Of 9,098 women meeting inclusion criteria, 1,178 (13%) women recorded 1,521 pregnancies. The annualised incidence rate of pregnancy was 0.042 (95% CI 0.040, 0.045). A total of 635 (42%) reported pregnancies were conceived on DMT, increasing from 27% in 2006 to 62% in 2016. The median duration of DMT exposure during pregnancy was 30 days (IQR: 9, 50). There were a higher number of induced abortions on FDA pregnancy class C/D drugs compared with pregnancy class B and no DMT (p = 0.010); but no differences in spontaneous abortions, term or preterm births.
CONCLUSIONS:
We report low pregnancy incidence rates, with increasing number of pregnancies conceived on DMT over the past 12-years. The median duration of DMT exposure in pregnancy was relatively short at one month.
2019
- Mitochondrial functionality and metabolism in T cells from progressive multiple sclerosis patients
[Articolo su rivista]
De Biasi, Sara; Simone, Anna Maria; Bianchini, Elena; Lo Tartaro, Domenico; Pecorini, Simone; Nasi, Milena; Patergnani, Simone; Carnevale, Gianluca; Gibellini, Lara; Ferraro, Diana; Vitetta, Francesca; Pinton, Paolo; Sola, Patrizia; Cossarizza, Andrea; Pinti, Marcello
abstract
Patients with primary progressive (PP) and secondary progressive (SP) forms of multiple sclerosis (MS) exhibit a sustained increase in the number of Th1, T cytotoxic type-1 and Th17 cells in peripheral blood, suggesting that the progressive phase is characterized by a permanent peripheral immune activation. As T cell functionality and activation are strictly connected to their metabolic profile, we investigated the mitochondrial functionality and metabolic changes of T cell subpopulations in a cohort of progressive MS patients. T cells from progressive patients were characterized by low proliferation and increase of terminally differentiated/exhausted cells. T cells from PP patients showed lower Oxygen Consumption Rate and Extracellular Acidification Rate, lower mitochondrial mass, membrane potential and respiration than those of SP patients, a downregulation of transcription factors supporting respiration and higher tendency to shift towards glycolysis upon stimulation. Furthermore, PP effector memory T cells were characterized by higher Glucose transporter -1 levels and a higher expression of glycolytic-supporting genes if compared to SP patients. Overall, our data suggest that profound differences exist in the phenotypic and metabolic features of T cells from PP and SP patients, even though the two clinical phenotypes are considered part of the same disease spectrum.
2019
- The real-world effectiveness of natalizumab and fingolimod in relapsing-remitting multiple sclerosis. An Italian multicentre study
[Articolo su rivista]
Curti, Elisa; Tsantes, E.; Baldi, Elio; Caniatti, L. M.; Ferraro, D.; Sola, PIER GIACOMO; Granella, F.
abstract
Background: Both natalizumab and fingolimod are highly effective in the treatment of relapsing-remitting MS (RRMS). In the absence of head-to-head trials, some observational studies have compared their efficacy with conflicting results. Objectives: To investigate the efficacy of natalizumab and fingolimod in a cohort of RRMS patients in an observational, retrospective study. Methods: We included all consecutive RRMS patients who started natalizumab or fingolimod in three MS centres with a follow-up to 24 months and analysed clinical and brain MRI data after propensity score (PS) matching. Results: After 1:1 PS-matching, we retained 102 patients in both groups, with similar baseline features. After 24 months, although both drugs resulted highly effective, patients treated with natalizumab had a lower relapse risk (HR 0.59 CI 95% 0.35–1.00, p = 0.048) and higher time to first relapse. MRI-combined-unique-activity was found in 31.8% of natalizumab vs 43.2% of fingolimod treated patients (p = 0.28). We found a higher proportion of patients with confirmed regression of disability (19.2 vs 6.7%, p = 0.03) and 2-year no evidence of disease activity (NEDA-3, 39.0% vs 22.0%, p = 0.04) in the natalizumab group. Conclusions: Both drugs were highly effective in our cohort. Natalizumab proved superior in inducing regression of disability and 2-year-NEDA-3.
2018
- Acute coronary syndrome associated with alemtuzumab infusion in multiple sclerosis
[Articolo su rivista]
Ferraro, Diana; Camera, Valentina; Vitetta, Francesca; Zennaro, Mauro; Ciolli, Ludovico; Nichelli, Paolo Frigio; Sola, Patrizia
abstract
no abstract available
2018
- Association of Inflammation and Disability Accrual in Patients With Progressive-Onset Multiple Sclerosis
[Articolo su rivista]
Hughes, Jordana; Jokubaitis, Vilija; Lugaresi, Alessandra; Hupperts, Raymond; Izquierdo, Guillermo; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Grand'Maison, Francois; Grammond, Pierre; Sola, Patrizia; Ferraro, Diana; Ramo-Tello, Cristina; Trojano, Maria; Slee, Mark; Shaygannejad, Vahid; Boz, Cavit; Lechner-Scott, Jeanette; Van Pesch, Vincent; Pucci, Eugenio; Solaro, Claudio; Verheul, Freek; Terzi, Murat; Granella, Franco; Spitaleri, Daniele; Alroughani, Raed; Jun, Jae-Kwan; Fambiatos, Adam; Van der Walt, Anneke; Butzkueven, Helmut; Kalincik, Tomas
abstract
The role of inflammatory disease activity as a determinant of disability in progressive-onset multiple sclerosis (MS) remains contested.
2018
- Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis
[Articolo su rivista]
Kalincik, Tomas; Jokubaitis, Vilija; Spelman, Tim; Horakova, Dana; Havrdova, Eva; Trojano, Maria; Lechner Scott, Jeannette; Lugaresi, Alessandra; Prat, Alexandre; Girard, Marc; Duquette, Pierre; Grammond, Pierre; Solaro, Claudio; Grand'Maison, Francois; Hupperts, Raymond; Prevost, Julie; Sola, Patrizia; Ferraro, Diana; Terzi, Murat; Butler, Ernest; Slee, Mark; Kermode, Allan; Fabis Pedrini, Marzena; Mccombe, Pamela; Barnett, Michael; Shaw, Cameron; Hodgkinson, Suzanne; Butzkueven, Helmut
abstract
This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon β, fingolimod or natalizumab.
2018
- First-line disease-modifying drugs in relapsing-remitting multiple sclerosis: an Italian real-life multicenter study on persistence
[Articolo su rivista]
Ferraro, Diana; Camera, Valentina; Baldi, Eleonora; Vacchiano, Veria; Curti, Erica; Guareschi, Angelica; Malagù, Susanna; Montepietra, Sara; Strumia, Silvia; Santangelo, Mario; Caniatti, Luisa; Foschi, Matteo; Lugaresi, Alessandra; Granella, Franco; Pesci, Ilaria; Motti, Luisa; Neri, Walter; Immovilli, Paolo; Montanari, Enrico; Vitetta, Francesca; Simone, Anna Maria; Sola, Patrizia
abstract
The introduction of oral disease-modifying drugs (DMDs) in addition to the available, injectable, ones for Relapsing-Remitting Multiple Sclerosis (RRMS) could be expected to improve medication persistence due to a greater acceptability of the route of administration. Aim of the study was to compare the proportion of patients discontinuing injectable DMDs (interferon beta 1a/1b, pegylated interferon, glatiramer acetate) with those discontinuing oral DMDs (dimethylfumarate and teriflunomide) during an observation period of at least 12 months. Secondary aims were to compare the time to discontinuation and the reasons for discontinuation between the two groups and to explore the demographic and clinical factors associated with DMD discontinuation.
2018
- Intrathecal oligoclonal bands synthesis in multiple sclerosis: is it always a prognostic factor?
[Articolo su rivista]
Frau, Jessica; Villar, Luisa Maria; Sardu, Claudia; Secci, Maria Antonietta; Schirru, Lucia; Ferraro, Diana; Coghe, Giancarlo; Lorefice, Lorena; Fenu, Giuseppe; Bedin, Roberta; Sola, Patrizia; Marrosu, Maria Giovanna; Cocco, Eleonora
abstract
Oligoclonal IgM (OCMB) and IgG (OCGB) bands were found to be associated with poor multiple sclerosis (MS) prognosis.
2018
- Predictors of relapse and disability progression in MS patients who discontinue disease-modifying therapy
[Articolo su rivista]
Kister, Ilya; Spelman, Tim; Patti, Francesco; Duquette, Pierre; Trojano, Maria; Izquierdo, Guillermo; Lugaresi, Alessandra; Grammond, Pierre; Sola, Patrizia; Ferraro, Diana; Grand'Maison, Francois; Alroughani, Raed; Terzi, Murat; Boz, Cavit; Hupperts, Raymond; Lechner-Scott, Jeannette; Kappos, Ludwig; Pucci, Eugenio; Hodgkinson, Suzanne; Solaro, Claudio; Butzkueven, Helmut
abstract
Background: Discontinuation of disease-modifying therapies (DMTs) for MS is common. MSBase, a large global observational registry, affords a unique opportunity to investigate predictors of ‘post-DMT’ relapses and confirmed disability progression (CDP) in a diverse group of patients exposed to different DMTs. Materials/methods: Main inclusion criteria: clinician-confirmed MS diagnosis (2010 McDonald criteria); age ≥ 18 at index DMT start; ≥12 months on index DMT prior to discontinuation; ≥24 months of follow-up post-discontinuation; did not restart DMT for ≥6 months. Predictors of time to first relapse and 3-month CDP were analyzed using Cox proportional hazards regression adjusted for age, gender, baseline EDSS, EDSS stability and relapse-free period for ≥1 year prior to discontinuation, calendar epoch, index DMT and reason for discontinuation. Results: 4842 patients (74.2% female) from 20 MSBase Centers met our inclusion criteria. 3556 (73%) discontinued one of IFNβ preparations, 849 (18%) - glatiramer acetate, 308 (6%) - natalizumab and 129 (3%) – fingolimod; other DMTs were excluded because too few records were available. Overall post-discontinuation annualized relapse rate (95% CI) was 0.224 (0.219, 0.229) and CDP rate was 8.23 (7.72, 8.76) per 100 person-years. Risk of post-DMT relapse was higher in younger patients, female patients, those with moderate disability and a relapse within 1 year of discontinuation. Hazard of CDP increased with increasing disability at baseline and disease progression within 3 years prior to stopping DMT. Of all the DMTs, only natalizumab was associated with increased risk of both post-DMT relapse and CDP. Conclusions: Knowledge of post-DMT relapse and disability progression rates and predictors of post-DMT disease activity allows for a more informed discussion of DMT discontinuation in those patients who are considering this option.
2018
- Systematic assessment and characterization of chronic pain in multiple sclerosis patients
[Articolo su rivista]
Ferraro, Diana; Plantone, Domenico; Morselli, Franca; Dallari, Giulia; Simone, Anna M.; Vitetta, Francesca; Sola, Patrizia; Primiano, Guido; Nociti, Viviana; Pardini, Matteo; Mirabella, Massimiliano; Vollono, Catello
abstract
Pain is one of the most disabling clinical symptoms in patients with multiple sclerosis (MS). Several studies have already assessed the prevalence of pain in MS patients, reporting variable results, probably due to methodological differences. The aim of this single-centre cross-sectional study was to define the prevalence and characteristics of chronic pain in a population of MS patients using validated tools, and to analyse these data in relation to demographic and clinical features, including disease duration and disability (EDSS and its single functional system scores). Of 397 enrolled patients, 23 were excluded due to a Beckâs Depression Inventory Score > 19. In the remaining 374 patients, the overall prevalence of chronic pain was 52.1%, most frequently affecting the lower limbs (36.9%). Neuropathic pain was the most frequent type of chronic pain (89 patients, overall prevalence of 23.7%) and was associated with a sensory functional system involvement. Pain intensity was significantly higher in patients with neuropathic pain as opposed to patients with non-neuropathic pain. Patients with chronic pain and, in particular, patients with neuropathic pain had significantly higher EDSS scores than those without pain. Only 24% of patients with chronic pain and 33% of patients with neuropathic pain were on a specific long-lasting treatment for pain. The present study supports the routine assessment of neuropathic pain in MS patients, especially in those with a sensory functional system involvement, in order to avoid underdiagnosing and undertreating a potentially disabling condition.
2017
- A multicenter study on the diagnostic significance of a single cerebrospinal fluid IgG band
[Articolo su rivista]
Ferraro, Diana; Franciotta, Diego; Bedin, Roberta; Solaro, Claudio; Cocco, Eleonora; Santangelo, Mario; Immovilli, Paolo; Gajofatto, Alberto; Calabrese, Massimiliano; Di Filippo, Massimiliano; Orlandi, Riccardo; Simone, ANNA MARIA; Vitetta, Francesca; Capello, Elisabetta; Giunti, Debora; Murialdo, Alessandra; Frau, Jessica; Mariotto, Sara; Gallina, Antongiulio; Gasperini, Claudio; Sola, Patrizia
abstract
The analysis of paired cerebrospinal fluid (CSF) and serum samples with isolectric focusing (IEF) can yield different patterns which can be of aid in the differential diagnosis of central nervous system (CNS) disorders. Rarely, a single CSF-restricted IgG band, which is not included within these patterns, can be detected in association with inflammatory disorders, multiple sclerosis (MS) above all. However, the diagnostic meaning of this abnormality is still uncertain. The main aim of our multicenter study was to establish the frequency and disease associations of single CSF IgG bands. Differences in the CSF profiles between MS and other diseases, and the follow-up patterns were also evaluated. Medical records of patients who underwent CSF analysis, which included IEF, over a 11.5-year period were retrospectively scrutinized at the participating centers, which used similar IEF techniques. One hundred and fifty-one of 9422 CSF reports (1.6%) showed single CSF-restricted IgG bands. Of the 129 patients with a definite diagnosis, 58.2% had CNS inflammatory-demyelinating diseases (the most frequent being MS: 21.7%), 6.2% tumours, 5.4% inflammatory peripheral nervous system diseases and 30.2% miscellaneous diseases. At follow-up, 3 out of the 10 patients with a repeated CSF analysis had developed an oligoclonal band pattern. Our findings indicate that single CSF IgG bands tend to associate with diseases characterized by the involvement of intrathecal humoral immune responses, and strongly support the notion that this abnormality should be regularly reported, thus alerting clinicians of possible inflammatory disorders of the CNS.
2017
- Acute hemichorea as unusual first multiple sclerosis presentation
[Articolo su rivista]
Giovannini, Giada; Cavallieri, Francesco; Meletti, Stefano; Chiari, Annalisa; Mandrioli, Jessica; Ferraro, Diana; Valzania, Franco
abstract
Patient 1 was a 39-year-old woman with an unremarkable medical history who developed acute involuntary right arm and leg movements. Neurologic examination revealed moderate dysarthria and subcontinuous, choreic movements in her right limbs, prevailing in the arm, which worsened during postural tasks. She occasionally had ballistic movements in her right limbs and abnormal dystonic postures. Continuous peribuccal and tongue involuntary movements were noted. Moreover, bilateral upper limb ataxia, gait and trunk ataxia, and brisk right tendon reflexes were found. There was no strength or sensory loss (video 1 at Neurology.org/cp). Brain MRI revealed a tumefactive, T2/fluid-attenuated inversion recovery (FLAIR) hyperintense, T1 hypointense contrast-enhancing demyelinating lesion in the left cerebral peduncle, extending to the substantia nigra and subthalamic nucleus (STN) (figure, A-C). Multiple hyperintense T2/FLAIR, T1 hypointense, non-contrast-enhancing demyelinating lesions in the hemispheric and periventricular deep white matter, brainstem, and cerebellar hemispheres were also found. All serologic tests were within normal limits. Isoelectric focusing (IEF) revealed 9 CSF oligoclonal bands (OCBs). A diagnosis of multiple sclerosis (MS) was made and the patient was treated with high-dose methylprednisolone with improvement of symptoms.
2017
- Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS
[Articolo su rivista]
Lorscheider, Johannes; Jokubaitis, Vilija G; Spelman, Tim; Izquierdo, Guillermo; Lugaresi, Alessandra; Havrdova, Eva; Horakova, Dana; Trojano, Maria; Duquette, Pierre; Girard, Marc; Prat, Alexandre; Grand'Maison, François; Grammond, Pierre; Pucci, Eugenio; Boz, Cavit; Sola, Patrizia; Ferraro, Diana; Spitaleri, Daniele; Lechner Scott, Jeanette; Terzi, Murat; Van Pesch, Vincent; Iuliano, Gerardo; Bergamaschi, Roberto; Ramo Tello, Cristina; Granella, Franco; Oreja Guevara, Celia; Butzkueven, Helmut; Kalincik, Tomas
abstract
To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).
2017
- Cerebrospinal fluid anti-Epstein-Barr virus specific oligoclonal IgM and IgG bands in patients with clinically isolated and Guillain-Barré syndrome
[Articolo su rivista]
Ferraro, Diana; Galli, Veronica; Simone, ANNA MARIA; Bedin, Roberta; Vitetta, Francesca; Merelli, Elisa; Nichelli, Paolo Frigio; Sola, Patrizia
abstract
Epstein-Barr virus (EBV) has been implicated in multiple sclerosis (MS) pathogenesis. We aimed to assess the frequency of EBV-specific IgG and IgM oligoclonal bands (OCB) in cerebrospinal fluid (CSF) of 50 patients with clinically isolated syndrome (CIS) and in 27 controls with Guillain-Barré syndrome (GBS). Furthermore, we assessed correlations between the presence of OCB and CIS patients' CSF, MRI, and clinical variables. There was no difference in the proportion of CIS and GB patients with positivity for anti-EBV-specific IgG/IgM OCB. There were no correlations between OCB and analyzed variables, nor were they predictive of a higher disability at 3 years.
2017
- Definitive childlessness in women with multiple sclerosis: a multicenter study
[Articolo su rivista]
Ferraro, Diana; Simone, ANNA MARIA; Adani, Giorgia; Vitetta, Francesca; Mauri, Claudia; Strumia, Silvia; Senesi, Caterina; Curti, Erica; Baldi, Eleonora; Santangelo, Mario; Montepietra, Sara; Immovilli, Paolo; Guareschi, Angelica; Neri, Walter; Granella, Franco; Caniatti, Luisa; Tola, Maria Rosaria; Motti, Luisa; Pesci, Ilaria; Montanari, Enrico; Sola, Patrizia
abstract
The frequency of definitive childlessness in women with multiple sclerosis (MS) may be higher than in the general population. MS may also affect decisions on the delivery procedure and on breast-feeding issues. Aim of the study was to assess the frequency of childlessness and its possible causes, the proportion of cesarean deliveries (CD), and the frequency of breast-feeding in patients and controls who have reached the end of their reproductive period. Female MS patients (>43 years) and controls (>45 years) filled out a questionnaire. We enrolled 303 patients and 500 controls. MS was associated with a higher frequency of childlessness (22 vs 13%) and less patients were in a stable relationship (83 vs 89%). There was no difference in the reported rates of infertility and miscarriages, while elective abortions were more frequent in patients (20 vs 12%). MS did not significantly affect the frequency of CD or of breast-feeding. MS-related reasons for childlessness, reported by 16% of childless patients, included disability/fear of future disability, fear of genetically transmitting MS, fear of not starting/discontinuing treatments, and discouragement by physician. Definitive childlessness is more frequent in women with MS compared to controls. A portion of voluntary childlessness may be avoided through correct/tailored information to patients.
2017
- Diagnostics of anti-MAG antibody polyneuropathy
[Articolo su rivista]
Franciotta, Diego; Gastaldi, Matteo; Benedetti, Luana; Garnero, Martina; Biagioli, Tiziana; Brogi, Marco; Costa, Gianna; Fadda, Elisabetta; Andreetta, Francesca; Simoncini, Ornella; Giannotta, Claudia; Bazzigaluppi, Elena; Fazio, Raffaella; Bedin, Roberta; Ferraro, Diana; Mariotto, Sara; Ferrari, Sergio; Galloni, Elisabetta; De Riva, Valentina; Zardini, Elisabetta; Cortese, Andrea; Nobile orazio, Eduardo
abstract
This document presents the guidelines for anti-myelin-associated glycoprotein (MAG) antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of sponsoring Italian Association of Neuroimmunology (AINI) congresses. The main clinical information on anti-MAG antibody polyneuropathy, indications and limits of anti-MAG antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
2017
- Diagnostics of dysimmune peripheral neuropathies
[Articolo su rivista]
Franciotta, Diego; Gastaldi, Matteo; Benedetti, Luana; Pesce, Giampaola; Biagioli, Tiziana; Lolli, Francesco; Costa, Gianna; Melis, Cristina; Andreetta, Francesca; Simoncini, Ornella; Giannotta, Claudia; Bazzigaluppi, Elena; Fazio, Raffaella; Bedin, Roberta; Ferraro, Diana; Mariotto, Sara; Ferrari, Sergio; Galloni, Elisabetta; De Riva, Valentina; Zardini, Elisabetta; Cortese, Andrea; Nobile orazio, Eduardo
abstract
This document presents the guidelines for anti-ganglioside antibody testing that have been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Main clinical information on dysimmune peripheral neuropathies, indications and limits of anti-ganglioside antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.
2017
- Invariant natural killer T cells and mucosal-associated invariant T cells in multiple sclerosis
[Articolo su rivista]
Bianchini, Elena; DE BIASI, Sara; Simone, ANNA MARIA; Ferraro, Diana; Sola, Patrizia; Cossarizza, Andrea; Pinti, Marcello
abstract
Multiple sclerosis (MS) is a chronic progressive inflammatory demyelinating disorder of the central nervous system, and in several countries is a leading cause of permanent neurological disability in young adults, particularly women. MS is considered an autoimmune disease, caused by an aberrant immune response to environmental triggers in genetically susceptible subjects. However, the contribution of the innate or of the adaptive immune system to the development and progression of the disease has not yet been fully elucidated. Innate-like T lymphocytes are unconventional T cells that bridge the innate and adaptive arms of the immune system, because they use a T cell receptor to sense external ligands, but behave like innate cells when they rapidly respond to stimuli. These cells could play an important role in the pathogenesis of MS. Here, we focus on invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells, and we review the current knowledge on their biology and possible involvement in MS. Although several studies have evaluated the frequency and functions of iNKT and MAIT cells both in MS patients and in experimental mouse models, contradictory observations have been reported, and it is not clear whether they exert a protective or a pro-inflammatory and harmful role. A better understanding of how immune cells are involved in MS, and of their interactions could be of great interest for the development of new therapeutic strategies.
2017
- Percutaneous endoscopic gastrostomy, body weight loss and survival in amyotrophic lateral sclerosis: a population-based registry study
[Articolo su rivista]
Fasano, Antonio; Fini, Nicola; Ferraro, Diana; Ferri, Laura; Vinceti, Marco; Errals, ; Mandrioli, Jessica
abstract
Abstract
Objective: To assess the role of percutaneous endoscopic gastrostomy (PEG) insertion, and its timing, on ALS survival, and
to study prognostic factors of survival before and after PEG placement in a population-based setting. Methods: In this
observational population-based, registry study, we enrolled patients with newly- diagnosed ALS, according to the El
Escorial revised criteria, who were resident in the Emilia Romagna Region, and who developed severe dysphagia needing
enteral nutritional support. The primary outcome measure was tracheostomy-free survival after PEG recommendation.
Results: There were 210 patients needing PEG, out of an incident cohort of 545 patients from the Emilia Romagna Registry
for ALS, who were diagnosed between 2009 and 2013. One hundred and ninety-three patients were included in the study,
and 17 were excluded because they were already tracheostomized at the time of PEG placement. Of the 193 patients
included in the study, 152 underwent PEG, whereas 41 did not undergo the procedure. Patients who did not undergo
PEG, among the eligible ones, had the same tracheostomy-free survival from onset as patients who did (25 vs. 32 months,
p¼0.21). Tracheostomy-free survival from PEG recommendation was greater in patients who underwent PEG placement
than in patients who did not (6 vs. 2 months, p¼0.008). Median tracheostomy-free survival from PEG insertion was eight
months (95% CI5–12); 30 days after PEG placement, survival was 89.60%. At Cox multivariable analysis, the hazard of
death or tracheostomy after PEG insertion was significantly influenced by the difference between BMI at the time of the
PEG procedure and BMI at diagnosis (HR 1.05, 95% CI 1.02–1.08; p¼0.002). The hazard of death or tracheostomy was
not affected by the timing of PEG insertion. Conclusions: The present study, although it has some limitations, suggests a
gain of tracheostomy-free survival from the time of PEG recommendation for patients who undergo PEG placement, and,
among patients who undergo PEG, a greater survival if PEG is inserted before a significant weight loss occurs, and if
nutritional support avoids further weight loss. Should this association between prevention of weight loss and better clinical
outcome be confirmed by further studies, it would have important implications for disease management.
2017
- Platelet Function Testing in Patients with Acute Ischemic Stroke: An Observational Study
[Articolo su rivista]
Rosafio, Francesca; Lelli, Nicoletta; Mimmi, Stefano; Vandelli, Laura; Bigliardi, Guido; Dell'Acqua, Maria Luisa; Picchetto, Livio; Pentore, Roberta; Ferraro, Diana; Trenti, Tommaso; Nichelli, Paolo Frigio; Zini, Andrea
abstract
Background: The measurement of platelet reactivity in patients with stroke undergoing antiplatelet therapies is not commonly performed in clinical practice. We assessed the prevalence of therapy responsiveness in patients with stroke and further investigated differences between patients on prevention therapy at stroke onset and patients naive to antiplatelet medications. We also sought differences in responsiveness between etiological subtypes and correlations between Clopidogrel responsiveness and genetic polymorphisms. Methods: A total of 624 stroke patients on antiplatelet therapy were included. Two different groups were identified: "non-naive patients", and "naive patients". Platelet function was measured with multiple electrode aggregometry, and genotyping assays were used to determine CYP2C19 polymorphisms. Results: Aspirin (ASA) responsiveness was significantly more frequent in naive patients compared with non-naive patients (94.9% versus 82.6%, P < .0010). A better responsiveness to ASA compared with Clopidogrel or combination therapy was found in the entire population (P < .0010), in non-naive patients (P < .0253), and in naive patients (P < .0010). Multivariate analysis revealed a strong effect of Clopidogrel as a possible "risk factor" for unresponsiveness (odds ratio 3.652, P < .0001). No difference between etiological subgroups and no correlations between responsiveness and CYP2C19 polymorphisms were found. Conclusion: In our opinion, platelet function testing could be potentially useful in monitoring the biological effect of antiplatelet agents. A substantial proportion of patients with stroke on ASA were "resistant", and the treatment with Clopidogrel was accompanied by even higher rates of unresponsiveness. Longitudinal studies are needed to assess whether aggregometry might supply individualized prognostic information and whether it can be considered a valid tool for future prevention strategies.
2016
- Acute hemichorea as unusual first multiple sclerosis presentation: two case reports
[Abstract in Atti di Convegno]
Cavallieri, F; Giovannini, G; Menozzi, E; Meletti, S; Chiari, A; Mandrioli, J; Ferraro, D; Contardi, S; Nichelli, P; Valzania, F
abstract
2016
- Amyotrophic lateral sclerosis: a comparison of two staging systems in a population-based study
[Articolo su rivista]
Ferraro, Diana; Consonni, D.; Fini, N.; Fasano, Antonio; DEL GIOVANE, Cinzia; Emilia Romagna Registry for ALS, Group; Mandrioli, Jessica
abstract
Background and purpose: To compare two recently developed staging systems for amyotrophic lateral sclerosis (ALS) [King's College and Milano-Torino staging (MITOS) systems] in an incident, population-based cohort of patients with ALS. Methods: Since 2009, a prospective registry has been recording all incident cases of ALS in the Emilia Romagna region in Italy. For each patient, detailed clinical information, including the ALS functional rating scale score, is collected at each follow-up. Results: Our study on 545 incident cases confirmed that King's College stages occurred at predictable times and were quite evenly spaced out throughout the disease course (occurring at approximately 40%, 60% and 80% of the disease course), whereas MITOS stages were mostly skewed towards later phases of the disease. In the King's College system there was a decrease in survival and an increase in deaths with escalating stages, whereas in the MITOS system survival curves pertaining to intermediate stages overlapped and the number of deaths was fairly homogenous throughout most stages. Conclusions: The King's College staging system had a higher homogeneity (i.e. smaller differences in survival among patients in the same stage) and a higher discriminatory ability (i.e. greater differences in survival among patients in different stages), being more suitable for individualized prognosis and for measuring efficacy of therapeutic interventions.
2016
- Cerebrospinal fluid amounts of HLA-G in dimeric form are strongly associated to patients with MRI inactive multiple sclerosis
[Articolo su rivista]
Fainardi, Enrico; Bortolotti, Daria; Bolzani, Silvia; Castellazzi, Massimiliano; Tamborino, Carmine; Roversi, Gloria; Baldi, Eleonora; Caniatti, Maria Luisa; Casetta, Ilaria; Gentili, Valentina; Granieri, Enrico; Rizzo, Roberta; Tola, M. R.; Dallocchio, F.; Bellini, T.; Rotola, A.; Di Luca, D.; Seraceni, S.; Contini, C.; Sabbioni, S.; Negrini, M.; Tognon, M.; Antonelli, T.; Groppo, E.; Gentile, M.; Ceruti, S.; Manfrinato, M. R.; Trentini, A.; Miotto, E.; Ferracin, M.; Mazzoni, E.; Pietrobon, S.; Masini, I.; Rotondo, J. C.; Martini, F.; Baruzzi, A.; Roberto D'Alessandro, R.; Michelucci, R.; Salvi, F.; Stecchi, S.; Scandellari, C.; Terzano, G.; Granella, F.; Nichelli, Paolo Frigio; Sola, P.; Ferraro, Diana; Vitetta, F.; Simone, ANNA MARIA; Bedin, Roberta; Marcello, N.; Motti, L.; Montepietra, S.; Guidetti, D.; Immovilli, P.; Montanari, E.; Pesci, I.; Guareschi, A.; Greco, G.; Santangelo, M.; Mauro, A. M.; Malagù, S.; Rasi, F.; Spadoni, M.; Galeotti, M.; Fiorani, L.; Neri, W.; Ravasio, A.; Pasquinelli, M.; Gutman, S.; Monaldini, C.
abstract
Background: The relevance of human leukocyte antigen (HLA)-G in dimeric form in multiple sclerosis (MS) is still unknown. Objective: To investigate the contribution of cerebrospinal fluid (CSF) HLA-G dimers in MS pathogenesis. Methods: CSF amounts of 78-kDa HLA-G dimers were measured by western blot analysis in 80 MS relapsing-remitting MS (RRMS) patients and in 81 inflammatory and 70 non-inflammatory controls. Results: CSF amounts of 78kDa HLA-G dimers were more frequent in RRMS than in inflammatory (p<0.01) and non-inflammatory controls (p<0.001) and in magnetic resonance imaging (MRI) inactive than in MRI active RRMS (p<0.00001). Conclusion: Our findings suggest that HLA-G dimers may be implicated in termination of inflammatory response occurring in MS.
2016
- GASTROSTOMY, BODY WEIGHT
LOSS AND SURVIVAL IN AMYOTROPHIC
LATERAL SCLEROSIS: A POPULATIONBASED
STUDY
[Abstract in Rivista]
Fasano, A; Fini, N; Ferraro, D; Ferri, L; Vinceti, M; Mandrioli, J
abstract
2016
- Serum IgG against Simian Virus 40 antigens are hampered by high levels of sHLA-G in patients affected by inflammatory neurological diseases, as multiple sclerosis
[Articolo su rivista]
Rizzo, Roberta; Pietrobon, Silvia; Mazzoni, Elisa; Bortolotti, D.; Martini, Fernanda; Castellazzi, Massimiliano; Casetta, Ilaria; Fainardi, Enrico; Luca, Dario; Granieri, Enrico; Tognon, Mauro; Granieri, E.; Castellazzi, M.; Casetta, I.; Tola, M. R.; Fainardi, E.; Dallocchio, F.; Bellini, T.; Rizzo, R.; Rotola, A.; Di Luca, D.; Seraceni, S.; Contini, C.; Sabbioni, S.; Negrini, M.; Tognon, M.; Antonelli, T.; Groppo, E.; Gentile, M.; Baldi, E.; Caniatti, M. L.; Ceruti, S.; Manfrinato, M. R.; Trentini, A.; Miotto, E.; Ferracin, M.; Mazzoni, E.; Pietrobon, S.; Masini, I.; Rotondo, J. C.; Martini, F.; Baruzzi, A.; Roberto D'Alessandro, R.; Michelucci, R.; Salvi, F.; Stecchi, S.; Scandellari, C.; Terzano, G.; Granella, F.; Nichelli, Paolo Frigio; Sola, P.; Ferraro, Diana; Vitetta, F.; Simone, ANNA MARIA; Bedin, Roberta; Marcello, N.; Motti, L.; Montepietra, S.; Guidetti, D.; Immovilli, P.; Montanari, E.; Pesci, I.; Guareschi, A.; Greco, G.; Santangelo, M.; Mauro, A. M.; Malagù, S.; Rasi, F.; Spadoni, M.; Galeotti, M.; Fiorani, L.; Neri, W.; Ravasio, A.; Pasquinelli, M.; Gutman, S.; Monaldini, C.
abstract
Background: Many investigators detected the simian polyomavirus SV40 footprints in human brain tumors and neurologic diseases and recently it has been indicated that SV40 seems to be associated with multiple sclerosis (MS) disease. Interestingly, SV40 interacts with human leukocyte antigen (HLA) class I molecules for cell entry. HLA class I antigens, in particular non-classical HLA-G molecules, characterized by an immune-regulatory function, are involved in MS disease, and the levels of these molecules are modified according with the disease status. Objective: We investigated in serum samples, from Italian patients affected by MS, other inflammatory diseases (OIND), non-inflammatory neurological diseases (NIND) and healthy subjects (HS), SV40-antibody and soluble sHLA-G and the association between SV40-prevalence and sHLA-G levels. Methods: ELISA tests were used for SV40-antibodies detection and sHLA-G quantitation in serum samples. Results: The presence of SV40 antibodies was observed in 6 % of patients affected by MS (N = 4/63), 10 % of OIND (N = 8/77) and 15 % of NIND (N = 9/59), which is suggestive of a lower prevalence in respect to HS (22 %, N = 18/83). MS patients are characterized by higher sHLA-G serum levels (13.9 ± 0.9 ng/ml; mean ± St. Error) in comparison with OIND (6.7 ± 0.8 ng/ml), NIND (2.9 ± 0.4 ng/ml) and HS (2.6 ± 0.7 ng/ml) subjects. Interestingly, we observed an inverse correlation between SV40 antibody prevalence and sHLA-G serum levels in MS patients. Conclusion: The data obtained showed a low prevalence of SV40 antibodies in MS patients. These results seems to be due to a generalized status of inability to counteract SV40 infection via antibody production. In particular, we hypothesize that SV40 immune-inhibitory direct effect and the presence of high levels of the immune-inhibitory HLA-G molecules could co-operate in impairing B lymphocyte activation towards SV40 specific peptides.
2016
- iNKT cells in secondary progressive multiple sclerosis patients display pro-inflammatory profiles
[Articolo su rivista]
DE BIASI, Sara; Simone, ANNA MARIA; Nasi, Milena; Bianchini, Elena; Ferraro, Diana; Vitetta, Francesca; Gibellini, Lara; Pinti, Marcello; DEL GIOVANE, Cinzia; Sola, Patrizia; Cossarizza, Andrea
abstract
Background. Multiple Sclerosis (MS), an autoimmune disease with neurodegeneration and inflammation, is characterized by several
alterations of different T cell subsets. However, few data exist on the role of iNKT lymphocytes.
Objective. To identify possible changes in the phenotype of iNKT cells in patients with different clinical forms of MS, and find alterations in their polyfunctionality (i.e., ability to produce simultaneously up to 4 cytokines such as IL‐17, TNF‐α, IFN‐γ, IL‐4). Methods. We studied a total of 165 patients, 91 with a Relapsing Remitting form [RR; 31 were treated with interferon (IFN)1‐β, 25 with natalizumab (Nat), 29 with glatiramer acetate (Gla); 17 were newly-diagnosed RR without treatment, 19 not active RR without treatment]. Forty-four patients had a Progressive MS: 20 Primary Progressive (PP), 24 Secondary Progressive (SP). A total of 55 age- and sex-matched subjects represented healthy controls (CTR). Among fresh peripheral blood mononuclear cells (PBMC) iNKT cells were identified by flow cytometry. Moreover, the capability of iNKT cells to produce different cytokines (IL‐17, TNF‐α, IFN‐γ, and IL‐4) after in vitro stimulation were evaluated in 18 RR (11 treated with Nat and 7 with IFN), 4 PP, 6 SP and 16 CTR. Results. No main differences were found in iNKT cell phenotype among MS patients with different MS forms, or during different treatments. However, the polyfunctional response of iNKT cells showed Th1 and Th17 profiles. This was well evident in patients with secondary progressive form, who are characterized by high levels of inflammation and neurodegeneration, and exhibited a sustained increase in the production of Th17 cytokines. Patients treated with natalizumab displayed lower levels of iNKT cells producing IL‐17, TNF‐α and IFN‐γ.
Conclusion. Our data suggest that the progressive phase of the disease is characterized by permanent iNKT activation and a skewing towards an inflammatory phenotype. Compared to other treatments, natalizumab was able to modulate iNKT cell function.
2015
- Cerebrospinal fluid CXCL13 in clinically isolated syndrome patients: Association with oligoclonal IgM bands and prediction of Multiple Sclerosis diagnosis
[Articolo su rivista]
Ferraro, Diana; Galli, Veronica; Vitetta, Francesca; Simone, Anna Maria; Bedin, Roberta; Del Giovane, Cinzia; Morselli, Franca; Filippini, Maria Maddalena; Nichelli, Paolo Frigio; Sola, Patrizia
abstract
Cerebrospinal fluid (CSF) CXCL13 was shown to correlate with markers of intrathecal inflammation and CSF oligoclonal IgM bands (IgMOB) have been associated with a more severe Multiple Sclerosis (MS) course.We correlated CSF CXCL13 levels with clinical, MRI and CSF parameters, including CSF IgMOB, in 110 Clinically Isolated Syndrome (CIS) patients.CSF CXCL13 levels correlated with CSF cell count, total protein, IgG Index and with the presence of CSF IgGOB and IgMOB.CSF CXCL13 levels ≥. 15.4. pg/ml showed a good positive predictive value and specificity for a MS diagnosis and for a clinical relapse within one year from onset.
2015
- Methylprednisolone-induced toxic hepatitis after intravenous pulsed therapy for multiple sclerosis relapses
[Articolo su rivista]
Ferraro, Diana; Mirante, Vincenzo G.; Losi, Luisa; Villa, Erica; Simone, ANNA MARIA; Vitetta, Francesca; Federzoni, Lucia; Nichelli, Paolo Frigio; Sola, Patrizia
abstract
High-dose, intravenous methylprednisolone (MP) is the only recommended first-line treatment for multiple sclerosis relapses. However, there are increasing reports on liver toxicity induced by this treatment regimen. We report of 4 multiple sclerosis patients with no history of viral/metabolic liver disorders or alcohol/hepatotoxic drug intake, who developed hypertransaminasaemia following intravenous MP. In 2 of the patients, liver biopsy showed periportal fibrosis, piecemeal necrosis, and inflammatory cell infiltrates. A rechallenge test confirmed a causal association in 1 case. MP-induced liver toxicity may be more frequent than commonly thought and it is important to report this adverse reaction, which is potentially lethal, and to raise awareness on the potential hepatotoxicity of corticosteroid pulses.
2015
- TIMP-1 resistant matrix metalloproteinase-9 is the predominant serum active isoform associated with MRI activity in patients with multiple sclerosis
[Articolo su rivista]
Trentini, Alessandro; Manfrinato, Maria C.; Castellazzi, Massimiliano; Tamborino, Carmine; Roversi, Gloria; Volta, Carlo A.; Baldi, Eleonora; Tola, Maria R.; Granieri, Enrico; Dallocchio, Franco; Bellini, Tiziana; Fainardi, Enrico; Ferraro, Diana; Bedin, Roberta
abstract
Background: The activity of matrix metalloproteinase-9 (MMP-9) depends on two isoforms, an 82 kDa active MMP-9 modulated by its specific tissue inhibitor (TIMP-1), and a 65 kDa TIMP-1 resistant active MMP-9. The relevance of these two enzymatic isoforms in multiple sclerosis (MS) is still unknown. Objective: To investigate the contribution of the TIMP-1 modulated and resistant active MMP-9 iso-forms to MS pathogenesis. Methods: We measured the serum levels of the 82 kDa and TIMP-1 resistant active MMP-9 isoforms by activity assay systems in 86 relapsing-remitting MS (RRMS) patients, categorized according to clinical and magnetic resonance imaging (MRI) evidence of disease activity, and in 70 inflammatory (OIND) and 69 non-inflammatory (NIND) controls. Results: Serum levels of TIMP-1 resistant MMP-9 were more elevated in MS patients than in OIND and NIND (p < 0.05, p < 0.02, respectively). Conversely, 82 kDa active MMP-9 was higher in NIND than in the OIND and MS patients (p < 0.01 and p < 0.00001, respectively). MRI-active patients had higher levels of TIMP-1 resistant MMP-9 and 82 kDa active MMP-9, than did those with MRI inactive MS (p < 0.01 and p < 0.05, respectively). Conclusion: Our findings suggested that the TIMP-1 resistant MMP-9 seem to be the predominantly active isoform contributing to MS disease activity.
2014
- Aging with HIV infection: a journey to the center of inflammAIDS, immunosenescence and neuroHIV
[Articolo su rivista]
Nasi, Milena; Pinti, Marcello; DE BIASI, Sara; Gibellini, Lara; Ferraro, Diana; Mussini, Cristina; Cossarizza, Andrea
abstract
In the last years, a significant improvement in life expectancy of HIV+ patients has been observed in Western countries. The parallel increase in the mean age of these patients causes a parallel increase in the frequency of non-AIDS related complications (i.e., neurocognitive, cardiovascular, liver and kidney diseases, metabolic syndrome, osteoporosis, non-HIV associated cancers, among others), even when antiviral treatment is successful. Immune activation and persistent inflammation characterizes both HIV infection and physiological aging, and both conditions share common detrimental pathways that lead to early immunosenescence. Furthermore, HIV-associated neurocognitive disorders represent important consequences of the infection. The persistent systemic immune activation, the continuous migration of activated monocytes to the central nervous system and progressive patients' aging contribute to develop neuronal injuries, that are in turn linked to HIV-associated neurocognitive disorders, which can persist despite successful antiretroviral treatment.
2014
- False positive absent somatosensory evoked potentials in cardiac arrest with therapeutic hypothermia.
[Articolo su rivista]
Codeluppi, Luca; Ferraro, Diana; Marudi, Andrea; Valzania, F.
abstract
ND
2014
- Previous treatment influences fingolimod efficacy in relapsing-remitting multiple sclerosis: Results from an observational study
[Articolo su rivista]
Baldi, Eleonora; Guareschi, Angelica; Vitetta, Francesca; Senesi, Caterina; Curti, Erica; Montepietra, Sara; Simone, ANNA MARIA; Immovilli, Paolo; Caniatti, Luisa; Tola, Maria Rosaria; Pesci, Ilaria; Montanari, Enrico; Sola, Patrizia; Granella, Franco; Motti, Luisa; Ferraro, Diana
abstract
Objective: Fingolimod (FTY) is licensed as a disease-modifying treatment in highly active relapsing-remitting multiple sclerosis. The aim of the study was to evaluate the efficacy and safety of FTY in a real-life setting and to explore the possible role of clinical and MRI parameters, including previous treatment type, in predicting its efficacy. Methods: Clinical and MRI data was collected on 127 patients assigned to treatment with FTY in six multiple sclerosis centers in Emilia-Romagna, Italy, between August 2011 and June 2013. Results: During a mean follow-up period of 10 months (range 1-22), we observed a total of 47 relapses in 39 patients (30.7%); new T2 lesions or gadolinium-enhancing (Gd+) lesions were present at follow-up MRI in 32/71 patients (45%). Expanded disability status scale (EDSS) at the end of the follow-up period was not different when compared to the baseline EDSS. Serious adverse events occurred in three patients (2.4%). A higher proportion of patients previously treated with natalizumab showed clinical (41%) or MRI activity (54%). Previous treatment with natalizumab increased the risk of a relapse within 30 days (versus immunomodulatory drugs; OR: 4.3; p=0.011) and at survival analysis (versus remaining patients; HR: 1.9; p=0.046). Study limitations include a small population sample, a short observation period with variable timing of follow-up MRI and different baseline characteristics of patients previously treated with natalizumab compared to those treated with immunomodulatory drugs. Conclusions: This study confirms the efficacy of FTY in reducing relapse rate in patients previously treated with immunomodulatory drugs, while it seems to be less effective in patients discontinuing natalizumab. Due to the short duration of follow-up it is not possible to evaluate disability progression; however, no difference was observed between the groups. © 2014 Informa UK Ltd.
2014
- Severe anemia in a patient with multiple sclerosis treated with natalizumab
[Articolo su rivista]
Simone, ANNA MARIA; Ferraro, Diana; Vitetta, Francesca; Marasca, Roberto; Bonacorsi, Goretta; Pinelli, Giovanni; Federzoni, Lucia; Nichelli, Paolo Frigio; Sola, Patrizia
abstract
The paper is a case report of a 51-year-old woman with a 16-year history of relapsing-remitting multiple sclerosis, who developed a severe anemia following a treatment with natalizumab
2014
- Treatment of relapsing-remitting multiple sclerosis after 24 doses of natalizumab: evidence from an Italian spontaneous, prospective, and observational study (the TY-STOP Study)
[Articolo su rivista]
Clerico, Marinella; Schiavetti, Irene; De Mercanti, Stefania F; Piazza, Federico; Gned, Dario; Brescia Morra, Vincenzo; Lanzillo, Roberta; Ghezzi, Angelo; Bianchi, Anna; Salemi, Giuseppe; Realmuto, Sabrina; Sola, Patrizia; Vitetta, Francesca; Cavalla, Paola; Paolicelli, Damiano; Trojano, Maria; Sormani, Maria Pia; Durelli, Luca; Ferraro, Diana
abstract
IMPORTANCE The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS).OBJECTIVE To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS.DESIGN, SETTING, AND PARTICIPANTS The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab.INTERVENTIONS Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod.MAIN OUTCOMES AND MEASURES The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year.RESULTS No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery.CONCLUSIONS AND RELEVANCE This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug.
2013
- Biological markers in cerebrospinal fluid for axonal impairment in multiple sclerosis: Acetylcholinesterase activity cannot be considered a useful biomarker
[Articolo su rivista]
Antonelli, T.; Tomasini, M. C.; Castellazzi, M.; Sola, P.; Tamborino, C.; Ferraro, Diana; Ferraro, L.; Granieri, E.
abstract
An impairment of the cholinergic system activity has been demonstrated in multiple sclerosis (MS). The correlation between the cholinergic system and the cognitive dysfunction in MS has led to studies on the use of acetylcholinesterase inhibitors (AChEI). The acetylcholinesterase (AChE), essential enzyme for the regulation of turnover of acetylcholine, can be considered the most important biochemical indicator of cholinergic signaling in the nervous system. Besides its catalytic properties, AChE has a crucial role in the regulation of the immune function. Based on the role of the AChe in the regulation of cholinergic signaling in the nervous system, the aim of the present study is to evaluate the activity of AChE in different pathological conditions: MS, other inflammatory neurological disorders (OIND) and non-inflammatory neurological disorders (NIND). We measured AChE activity in CSF samples obtained from 34 relapsing-remitting MS patients and, as controls, 40 patients with other inflammatory neurological disorders (OIND) and 40 subjects with other non-inflammatory neurological disorders (NIND). Fluorimetric detection of the AChE in MS patients and in the controls showed no statistically significant differences: 1.507 ± 0.403 nmol/ml/min in MS patients, 1.484 ± 0.496 nmol/ml/min in OIND and 1.305 ± 0.504 nmol/ml/min in NIND. Similar results were obtained in another recent study, using a different method. Further studies must be conducted on a larger number of patients, with different degrees of cognitive impairment. However, AChE measured in CSF can probably not be considered a useful biomarker for the assessment of the functional alterations of cholinergic system in pathological conditions. © 2012 Springer-Verlag Italia.
2013
- Cerebrospinal fluid oligoclonal IgM bands predict early conversion to clinically definite multiple sclerosis in patients with Clinically Isolated Syndrome.
[Articolo su rivista]
Ferraro, Diana; Simone, ANNA MARIA; Bedin, Roberta; Galli, Veronica; Vitetta, F; Federzoni, L; D'Amico, Roberto; Merelli, E; Nichelli, Paolo Frigio; Sola, P.
abstract
We reviewed the records of 391 patients who had presented with a Clinically Isolated Syndrome and selected 205 who had performed a baseline spinal tap and MRI scan. We studied cerebrospinal fluid (CSF) and serum IgM oligoclonal bands (IgMOB) using agarose gel isoelectric focusing and analyzed the impact of baseline clinical, MRI and CSF variables on the risk of conversion to clinically definite multiple sclerosis, i.e. on the risk of a clinical relapse. At survival analysis, a lower age at onset, an onset with optic neuritis and the presence of CSF-restricted IgMOB increased the risk of a relapse. Only the presence of CSF-restricted IgMOB predicted a relapse within one year.
2013
- Frequent early multiple sclerosis relapses during treatment with fingolimod: a paradoxical effect?
[Articolo su rivista]
Ferraro, Diana; Federzoni, Lucia; Vitetta, F; Simone, ANNA MARIA; Cossarizza, Andrea; Nichelli, Paolo Frigio; Sola, P.
abstract
This is the case report of a multiple sclerosi patient who presented frequent relapses early after beginning a treatment with fingolimod
2013
- Recurrent varicella following steroids and fingolimod in a Multiple Sclerosis patient
[Articolo su rivista]
Ferraro, Diana; DE BIASI, Sara; Vitetta, F; Simone, A. M; Federzoni, Lucia; Borghi, Valentina; Cossarizza, Andrea; Nichelli, Paolo Frigio; Sola, P.
abstract
This is the case report of a multiple sclerosis patient who presented recurrent varicella following steroid and fingolimod therapy
2012
- Habituation to Pain in "Medication Overuse Headache": A CO2 Laser-Evoked Potential Study
[Articolo su rivista]
Ferraro, Diana; Vollono, C; Miliucci, R; Virdis, D; De Armas, L; Pazzaglia, C; Le Pera, D; Tarantino, S; Balestri, M; Di Trapani, G; Valeriani, M.
abstract
Objective.-Our aim was to investigate CO2 laser-evoked potential (LEP) habituation to experimental pain in a group of patients affected by medication-overuse headache, with a history of episodic migraine becoming chronic, before and after treatment, consisting in acute medication withdrawal and a preventive treatment cycle.Background.-One of the main features of LEPs in migraineurs is a lower habituation to repetitive noxious stimuli during the interictal phase.Methods.-LEPs were recorded to stimulation of both the right hand and the right perioral region in 14 patients and in 14 healthy subjects. The habituation of both the N1 and the vertex N2/P2 components was assessed by measuring the LEP amplitude changes across 3 consecutive repetitions of 30 trials each.Results.-In the 8 patients who had clinically improved after treatment, the N2/P2 amplitude habituation was significantly higher after treatment than before treatment following both hand (F = 43.2, P < .0001) and face stimulation (F = 6.9, P = .01). In these patients, the N2/P2 amplitude habituation after treatment was not different from that obtained in healthy controls (P = .18 and P = .73 for hand and face stimulation, respectively). On the contrary, in the patients who did not improve, the N2/P2 amplitude still showed reduced habituation after both hand (F = 3.1, P = .08) and face (F = 0.7, P = .4) stimulation.Conclusion.-The deficient habituation of the vertex N2/P2 complex was partly restored after successful treatment of medication-overuse headache, reflecting a modification in pain-processing pathways.
2012
- Paroxysmal ventricular tachicardia and pure right insular stroke.
[Articolo su rivista]
Zini, Andrea; Fioravanti, Valentina; Ferraro, Diana; Casoni, Federica; Cavazzuti, Milena; Nichelli, Paolo Frigio
abstract
Case report of a patient who developed a paroxysmal ventricular tachicardia after an ischemic stroke limited to the right insula.
2011
- Changing incidence and subtypes of ALS in Modena, Italy: A 10-years prospective study
[Articolo su rivista]
Georgoulopoulou, Eleni; Vinceti, Marco; F., Bonvicini; P., Sola; C. A., Goldoni; G. D., Girolamo; Ferraro, Diana; Nichelli, Paolo Frigio; Mandrioli, Jessica
abstract
We performed a prospective population-based study to describe the temporal pattern of the incidence and prevalence and the clinical features and phenotypes of ALS in Modena, Italy, from 2000 to 2009. From 2000 onwards, a prospective registry has been collecting all cases of incident ALS among residents in the province of Modena. This source was implemented by cases resulting from the provincial hospitals, and by death certificates. Based on 193 newly diagnosed cases, the crude average annual incidence rate of ALS was 2.9 cases per 100,000 person years (py); adjusted incidence rate was 2.8/100,000. The age-standardized incidence rates increased from 2.6 per 100,000 py in 2000-2004 to 2.9 per 100,000 py in 2005-2009, representing an annual increase of approximately 2% throughout the 10-year period. There was a constant increase in prevalence rates throughout the years of the study (from 5.8/100,000 on 31 December 2000 to 11.2/100,000 on 31 December 2009). Median life time was 29 months for patients diagnosed before the year 2000 and 36 months for patients diagnosed from 1 January 2000 (p < 0.01). Thus, we report incidence rates similar to those reported by recent European population based studies, but we observed an increasing trend over the 10 years of the study. The increasing incidence is not explained by aging of the population, and our study raises the question as to whether local environmental or genetic factors are driving this temporal trend. Along with an increasing incidence, we found an important increase in prevalence and survival probably related to access to mutidisciplinary clinics and improvements in symptomatic care of ALS.
2011
- Evidence of different spinal pathways for the warmth evoked potentials
[Articolo su rivista]
Valeriani, M.; Pazzaglia, C.; Ferraro, Diana; Virdis, D.; Rotellini, S.; Le Pera, D.; Testani, E.; Minciotti, I.; Balestri, M.; Vigevano, F.; Vollono, C.
abstract
Objective: To investigate the presence of multiple spinothalamic pathways for warmth in the human spinal cord. Methods: Laser evoked potentials to C-fiber stimulation (C-LEPs) were recorded in 15 healthy subjects after warmth stimulation of the dorsal midline at C5, T2, T6, and T10 vertebral levels. This method allowed us to calculate the spinal conduction velocity (CV) in two different ways: (1) the reciprocal of the slope of the regression line was obtained from the latencies of the different C-LEP components, and (2) the distance between C5 and T10 was divided by the latency difference of the responses at the two sites. In particular, we considered the C-N1 potential, generated in the second somatosensory (SII) area, and the late C-P2 response, generated in the anterior cingulate cortex (ACC). Results: The calculated CV of the spinal fibers generating the C-N1 potential (around 2.5. m/s) was significantly different (p<0.01) from the one of the pathway producing the P2 response (around 1.4. m/s). Conclusions: Our results suggest that the C-N1 and the C-P2 components are generated by two parallel spinal pathways. Significance: Warmth sensation is subserved by parallel spinothalamic pathways, one probably reaching the SII area, the other the ACC. © 2011 International Federation of Clinical Neurophysiology.
2011
- Isolated progressive cognitive impairment and depression in a patient with neuroradiological features suggestive of multiple sclerosis
[Articolo su rivista]
Ferraro, Diana; Simone, ANNA MARIA; Merelli, E.; Mandrioli, J:; Molinari, M. A.; Nichelli, Paolo Frigio; Sola, P.
abstract
We report the case of a woman who started complaining of depression, attention and memory problems at the age of 49. Over the following 6 years, serial neuropsychological assessments showed fluctuating, but overall progressively worsening, performances in tests exploring attention, working memory, language and executivefunctions. Cerebrospinal fluid (CSF) examination showed identical IgG oligoclonal bands in serum and CSF.Neurological examination, to date, only reveals minimal pyramidal and cerebellar signs. Although typical clinical and laboratory evidence indicating a diagnosis of multiple sclerosis (MS) in this patient is lacking, an extensive diagnostic work-up ruled out many other causes of leukoencephalopathy and neuroradiological features strongly suggest this diagnosis. Multiple sclerosis may present with cognitive or neuropsychiatric symptoms; this should be kept in mind, especially in younger patients, even in the absence of ‘‘classical’’ physical symptoms.
2011
- Primary progressive versus relapsing-onset multiple sclerosis: presence and prognostic value of cerebrospinal fluid oligoclonal IgM
[Articolo su rivista]
P., Sola; Mandrioli, Jessica; Simone, ANNA MARIA; Ferraro, Diana; Bedin, Roberta; R., Annecca; Venneri, Maria Grazia; Nichelli, Paolo Frigio; E., Merelli
abstract
Background: There is increasing evidence on cerebrospinal fluid (CSF) oligoclonal IgM (OCIgM) predicting a more aggressive disease course in relapsing-remitting Multiple Sclerosis (MS), while there is a scarcity of data for primary progressive MS (PPMS). Objective: Our aim was to investigate the presence and possible prognostic value of CSF OCIgM in a group of PPMS and in a group of relapsing-onset MS patients. The possible prognostic role of other clinical and biological factors was also evaluated. Methods: We calculated the impact of single clinical and biological factors, including CSF OCIgM at onset, on the probability of reaching an Expanded Disability Status Scale of 3 and 4 in 45 PPMS and 104 relapsing-onset MS patients. Results: CSF OCIgM were found in only 13% of PPMS patients and did not influence the time taken to reach an Expanded Disability Status Scale of 3 and 4. Conversely, they were present in 46% of relapsing-onset MS patients and increased the risk of reaching an Expanded Disability Status Scale of 4. Clinical factors with a negative prognostic value in PPMS were age at onset <30 years and onset with pyramidal symptoms, while onset with sensory symptoms in relapsing-onset MS predicted a more favourable course. Conclusion: This study confirms that, in relapsing-onset MS patients, the presence of CSF OCIgM at onset predicts a worse disease course. In the cohort of PPMS patients, however, CSF OCIgM were rare, suggesting that heterogeneous pathogenetic mechanisms may be involved in the different MS forms.
2011
- Semiautomated segmentation of the human spine based on echoplanar images
[Articolo su rivista]
G., Giulietti; Summers, Paul Eugene; Ferraro, Diana; Porro, Carlo Adolfo; B., Maraviglia; F., Giove
abstract
The number of functional magnetic resonance imaging (fMRI) studies performed on the human spinal cord (SC) has considerably increased in recent years. The lack of a validated processing pipeline is, however, a significant obstacle to the spread of SC fMRI. One component likely to be involved in any such pipeline is the process of SC masking, analogous to brain extraction in cerebral fMRI. In general, SC masking has been performed manually, with the incumbent costs of being very time consuming and operator dependent.To overcome these drawbacks, we have developed a tailored semiautomatic method for segmenting the echoplanar images (EPI) of human spine that is able to identify the spinal canal and the SC. The method exploits both temporal and spatial features of the EPI series and was tested and optimized on EPI images of cervical spine acquired at 3 T. The dependence of algorithm performance on the degree of EPI image distortion was assessed by computing the displacement warping field that best matched the EPI to the corresponding high-resolution T2 images. Segmentation accuracy was above 80%, a significant improvement over values obtained with similar approaches, but not exploiting temporal information. Geometric distortion was found to explain about 50% of the variance of algorithm classification efficiency.
2010
- A quantitative comparison of BOLD fMRI responses to noxious and innocuous stimuli in the human spinal cord
[Articolo su rivista]
Summers, Paul Eugene; Ferraro, Diana; Duzzi, Davide; Lui, Fausta; G. D., Iannetti; Porro, Carlo Adolfo
abstract
Recent studies have shown that functional magnetic resonance imaging (fMRI) can non-invasively assess spinal cord activity. Yet, a quantitative description of nociceptive and non-nociceptive responses in the human spinal cord, compared with random signal fluctuations in resting state data, is still lacking. Here we have investigated the intensity and spatial extent of blood oxygenation level dependent (BOLD) fMRI responses in the cervical spinal cord of healthy volunteers, elicited by stimulation of the hand dorsum (C6-C7 dermatomes). In a block design fMRI paradigm, periods (20 s each) of repetitive noxious (laser heat) or innocuous (brushing) stimulation were alternated with rest. To estimate the level of false positive responses, functional images were acquired during a separate run while subjects were at rest. In a first analysis of averaged peri-stimulus signals from all voxels within each half of the spinal cord, we found bilateral fMRI responses to both stimuli. These responses were significantly larger during noxious than during innocuous stimulation. No significant fMRI signal change was evident over corresponding time periods during the Rest run. In a second, general linear model analysis, we identified a voxel population preferentially responding to noxious stimulation, which extended rostro-caudally over the length (4 cm) of the explored spinal cord region. By contrast, we found no evidence of voxel populations responding uniquely to innocuous stimuli, or showing decreased activity following either kind of somatosensory stimulus. These results provide the first false-positive-controlled comparison of spinal BOLD fMRI responses to noxious and innocuous stimuli in humans, confirming and extending physiological information obtained in other species.
2010
- Cerebrospinal fluid oligoclonal IgM bands and disease outcome in Guillain-Barrè Syndrome
[Abstract in Atti di Convegno]
Ferraro, D; Simone, A; Santangelo, M; Venneri, M; Bedin, R; Galli, V; Mandrioli, J; Galassi, G; Malaguti, Mc; Nichelli, P; Sola, P
abstract
2010
- Cerebrospinal fluid oligoclonal IgM bands in guillain-Barrè syndrome
[Abstract in Atti di Convegno]
Ferraro, D; Simone, A; Venneri, Mg; Mandrioli, J; Bedin, R; Galassi, G; Malaguti, Mc; Nichelli, P; Sola, P
abstract
2010
- Mechanisms of neuropathic pain in patients with Charcot-Marie-Tooth 1 A: A laser-evoked potential study
[Articolo su rivista]
Pazzaglia, Costanza; Vollono, Catello; Ferraro, Diana; Virdis, Daniela; Lupi, Valentina; Le Pera, Domenica; Tonali, Pietro; Padua, Luca; Valeriani, Massimiliano
abstract
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy. The CMT1A type can be considered the typical phenotype of this disease. Although pain is not considered a relevant symptom in CMT patients by physicians and no study assessed it comprehensively, this symptom is frequently complained by patients. The objective of the present study was to investigate the nociceptive system in a sample of CMT1A patients suffering from pain by laser-evoked potentials (LEPs). Moreover, we also used a pain specific questionnaire in order to obtain patient-oriented data about their painful symptoms, the Neuropathic Pain Diagnostic Questionnaire (DN4). We evaluated 16 patients affected by CMT1A and 14 controls. All subjects underwent a standard LEP recording session (foot, hand, and face stimulation) and filled in the DN4. While the N2/P2 amplitude to foot stimulation was lower in CMT patients than in controls (p = 0.003), no difference in LEP amplitude to both hand and face stimulation was found between patients and healthy subjects (p > 0.05). This result is probably due to a length-dependent Aδ-fiber loss which involves mostly the longer fibers coming from the lower limb. In our patients, there was a significant association between a reduced N2/P2 amplitude to foot stimulation and a high DN4 score (p = 0.03), meaning that patients with highly probable neuropathic pain had also low N2/P2 amplitude values to painful foot stimulation. This suggests that in our CMT1A patients neuropathic pain is probably related to a reduction of the Aδ afferents. © 2010 International Association for the Study of Pain.
2010
- Optic nerve glioma mimicking optic neuritis
[Abstract in Atti di Convegno]
Georgoulopoulou, E; Malaguti, Mc; Mandrioli, J; Pinna, G; Carpeggiani, P; Maiorana, A; Mantovani, A; Monti, G; Barbi, F; Ferraro, D; Nichelli, P; Sola, P.
abstract
2010
- The abnormal recovery cycle of somatosensory evoked potential components in children with migraine can be reversed by topiramate
[Articolo su rivista]
Vollono, C; Ferraro, Diana; Miliucci, R.; Vigevano, F.; Valeriani, M.
abstract
The aim of this study was to compare the recovery cycle of somatosensory evoked potentials (SEPs) in children with migraine without aura before and after treatment with topiramate. Eleven migraine children were studied before and after a 3-month treatment with topiramate at the average dose of I.3 mg/kg/day. We calculated the SEP latency and amplitude modifications after paired electrical stimuli at 5, 20 and 40 ms interstimulus intervals, comparing them with a single stimulus condition assumed as baseline. In nine patients, who had a significant reduction in headache frequency after treatment, the recovery cycles of the P24 (P = 0.03) and N30 (P < 0.005) potentials were longer after than before topiramate treatment. In two migraineurs who did not show any improvement, the recovery cycles of the cortical SEP components were even shorter after treatment. Our results suggest that topiramate efficacy in paediatric migraine prophylaxis is probably related to restored cortical excitability. © International Headache Society 2009.
2009
- A novel SOD1 mutation in a young ALS patient associated with slowly progressive clinical course
[Abstract in Rivista]
Georgoulopoulou, E; Bragato, C; Gellera, C; Sola, P; Bigliardi, G; Bernabei, C; Ferraro, D; Mandrioli, J
abstract
2009
- A study of the CD45 exon 4 C77G polymorphism in a patient affected both by multiple sclerosis and pulmonary Langerhans' cell histiocytosis
[Abstract in Atti di Convegno]
Ferraro, D; Simone, A; Zucchini, P; Bavieri, M; Mandrioli, J; Nichelli, P; Sola, P
abstract
2009
- Cerebrospinal fluid oligoclonal IgM bands in Guillain-Barrè syndrome
[Abstract in Atti di Convegno]
Ferraro, D; Venneri, M; Mandrioli, J; Galassi, G; Bedin, R; Simone, A; Nichelli, P; Sola, P
abstract
2009
- Depression and progressive cognitive impairment as isolated clinical features in a patient with multiple sclerosis
[Abstract in Atti di Convegno]
Ferraro, D; Simone, A; Merelli, E; Mandrioli, J; Molinari, M; Nichelli, P; Sola, P
abstract
2009
- EBV and HHV6 in cerebrospinal fluid and serum of primary progressive multiple sclerosis
[Abstract in Atti di Convegno]
Ferraro, D; Merelli, E; Mandrioli, J; Simone, A; Annecca, R; Meacci, M; Gennari, W; Pecorari, M; Sola, P
abstract
2009
- Prognosis of primary progressive multiple sclerosis: do cerebrospinal fluid oligoclonal IgM bands play a role?
[Abstract in Atti di Convegno]
Mandrioli, J; Simone, A; Bedin, R; Merelli, E; Ferraro, D; Venneri, Mg; Annecca, R; Nichelli, P; Sola, P
abstract
2009
- Slowly progressive ALS associated with a novel SOD1 D11Y mutation
[Abstract in Atti di Convegno]
Georgoulopoulou, E; Gellera, C; Bragato, C; Sola, P; Bernabei, C; Ferraro, D; Mandrioli, J
abstract
2008
- Acute necrotizing encephalopathy: A relapsing case in a European adult [4]
[Articolo su rivista]
Fasano, Alfonso; Natoli, G. F.; Cianfoni, A.; Ferraro, Diana; Loria, G.; Bentivoglio, A. R.; Servidei, S.
abstract
A male adult presented with a relapsing case of acute necrotizing encephalopathy. Clinically he presented with lethargy. MRI showed predominant thalmic involvement. Anti-influenza antibodies indicated a recent infection
2008
- Charcot-Marie-Tooth and pain: Correlations with neurophysiological, clinical, and disability findings
[Articolo su rivista]
Padua, Luca; Cavallaro, Tiziana; Pareyson, Davide; Quattrone, Aldo; Vita, Giuseppe; Schenone, Angelo; Grandis, M; Benedetti, L; Caliandro, P; Pazzaglia, C; Irene, A; Mazza, O; Ferraro, D; Mignogna, T; Tonali, P; Fabrizi, Gm; Rizzuto, N; Laurà, M; Mazzeo, A; Majorana, G; Valentino, P; Nisticò, R.
abstract
Pain is not considered a relevant symptom in Charcot-Marie-Tooth (CMT) patients and no studies have comprehensively assessed it. We performed a multidimensional assessment in 211 consecutive CMT patients to evaluate the clinical features, quality of life (QoL) and disability. For QoL we used the SF-36, which comprises one domain called "Bodily Pain" (BP), which is a generic measure of intensity of pain. Results showed that pain is a relevant symptom related to gender, CMT subtypes, clinical picture, disability, and mildly to neurophysiological impairment. In our study the importance of pain was an occasional finding. Because of the study design we are not able to ascertain if pain is primarily due to the neuropathy or if it is due to the muscoloskeletal deformities arising as a consequence of the neuropathy. Our study underlined that pain should be considered as a relevant symptom in CMT patients and further studies should be performed. © Springer-Verlag Italia 2008.
2008
- Left thalamomegaly in a patient with partial epilepsy
[Articolo su rivista]
Della Marca, Giacomo; Vollono, Catello; Ferraro, Diana; Mariotti, Paolo; Mazza, Marianna; Ferini Strambi, Luigi; Mazza, Salvatore
abstract
Temporal lobe epilepsy (TLE) is associated with modification in thalamic structure and function. In particular, thalamic atrophy and hypometabolism can occur, affecting ipsilateral, contralateral thalami or both. We describe a 28-year-old epileptic woman, who presented peculiar neuroimaging findings, with enlargement of the thalamus contralateral to the epileptic focus. The patient was born from dystocic delivery, she presented partial motor seizures in the left side of the body, followed by generalisation, and the EEG showed a right temporal epileptic focus. Serial CT and MRI scan, performed along 11 years, showed a non-evolutive left thalamomegaly. 18-FDG PET showed reduced metabolic activity in the upper right temporal gyrus and in the ipsilateral thalamus. Thalamic asymmetry in our patient could be an occasional finding. © 2007 Elsevier B.V. All rights reserved.
2008
- Letter to Editor: Carpal tunnel syndrome due to an atypical deep soft tissue leiomyoma: The risk of misdiagnosis and mismanagement
[Articolo su rivista]
Granata, Giuseppe; Martinoli, Carlo; Pazzaglia, Costanza; Caliandro, Pietro; Padua, Luca; Ferraro, Diana
abstract
A response to Chalidis et al: Carpal tunnel syndrome due to an atypical deep soft tissue leiomyoma: The risk of misdiagnosis and mismanagement. © 2008 Granata et al; licensee BioMed Central Ltd.
2008
- Topiramate in the prevention of pediatric migraine: Literature review
[Articolo su rivista]
Ferraro, Diana; Trapani, Girolamo
abstract
Pediatric migraine is a disabling condition, which can cause a significant impact on quality of life. Currently, no drugs have been approved by the FDA for its preventive treatment. Our aim was to review the medical literature concerning the efficacy and tolerability of topiramate in the prophylactic treatment of migraine in children and adolescents. A total of five papers were reviewed: two randomized controlled trials (RCTs), a post-hoc subset analysis of adolescents who had been included in three RCTs carried out on adults and two open studies. Topiramate has been proven to reduce headache frequency and the accompanying disability. The frequency of side effects varied considerably among studies, the most frequent being weight loss, anorexia, abdominal pain, difficulties in concentrating, sedation and paresthesia. Since these adverse events, although often transitory, may be distressing for the child, we strongly recommend to assess the disability caused by the migraine episodes before deciding to initiate a prophylactic treatment. Nevertheless, dropout rates due to side effects in the studies were very low. © Springer-Verlag 2008.
2007
- Antiepileptic drugs in the preventive treatment of migraine in children and adolescents
[Articolo su rivista]
Vollono, Catello; Ferraro, Diana; Valeriani, Massimiliano
abstract
Migraine prevalence in childhood ranges from 2.7 to 10% causing a significant impact on quality of life. No drugs are currently approved for use in the prevention of pediatric migraine. Antiepileptic drugs such as valproate and topiramate have been approved for the preventive treatment of migraine in adults. The present study aimed at reviewing evidence on the efficacy and safety of antiepileptic drugs in the preventive treatment of migraine in children and adolescents. We searched PubMed from 1988 to May 2007 and reviewed, abstracted, and classified relevant literature. Thirteen studies were reviewed. Data from randomized controlled trials are available only for valproate and topiramate. They show that both topiramate and valproate are effective in reducing headache frequency, intensity, and duration. As for safety and tolerability, topiramate is well tolerated, while there are insufficient data regarding the tolerability of valproate. Open-label or retrospective studies suggest that levetiracetam, zonisamide, and gabapentin are effective, but further evidence is warranted to confirm these data. © 2007 Wiley-Liss, Inc.
2006
- Topiramate and triptans revert chronic migraine with medication overuse to episodic migraine
[Articolo su rivista]
Mei, Daniele; Ferraro, Diana; Zelano, Giovanni; Capuano, Alessandro; Vollono, Catello; Gabriele, Carbone; Di Trapani, Girolamo
abstract
OBJECTIVE: This is a randomized, double-blind versus placebo study aimed at evaluating the efficacy of topiramate (TPM) in reducing the number of days with headache and the amount of acute medication taken monthly in patients with chronic migraine with medication overuse. We also studied the efficacy of single triptans available in Italy in interrupting headache crises during preventive treatment. METHODS: The studied sample was made up of 50 subjects: 30 patients were randomized for treatment with TPM, 100 mg/d, and 20 for placebo. Subjects treated with TPM were further randomized to evaluate, in double-blind versus placebo, the efficacy of single triptans available in Italy. The double-blind phase consisted of a titration phase (4 weeks) and of a maintenance phase (8 weeks). OUTCOME MEASURES: The reduction in the number of days with headache per 28 days and the reduction in the amount of acute medication taken per 28 days throughout the clinical trial in the TPM group were compared with those of the placebo group; the number of patients who were pain-free at 2 hours after the triptan intake and the headache recurrence rate in the 22 hours after the pain-free condition in the triptan group were compared with those of the placebo group. We also looked at tolerability profile. RESULTS: The group treated with TPM had a significant reduction in the number of days with headache (P < 0.0001 vs placebo) and in the mean amount of acute medication taken (P < 0.0001 vs placebo); all triptans were superior to placebo; there were no significant differences between different triptans; the analgesic effect of triptans increased throughout the trial. CONCLUSIONS: Topiramate proved to be well tolerated and effective in reverting chronic migraine with medication overuse to episodic migraine. Copyright © 2006 by Lippincott Williams & Wilkins.
2005
- Multiple attack study on the available triptans in Italy versus placebo
[Articolo su rivista]
Vollono, C.; Capuano, A.; Mei, D.; Ferraro, Diana; Pierguidi, L.; Evangelista, M.; Di Trapani, Girolamo
abstract
The aim of the study is to evaluate the efficacy and tolerability of the five triptans that are commercially available in Italy (zolmitriptan 2.5 mg, rizatriptan 10 mg, sumatriptan 100 mg, almotriptan 12.5 mg and eletriptan 40 mg). The study was conducted in single-blind versus placebo and its duration was 18 months. At the Headache Centre of the 'Agostino Gemelli' Hospital in Rome we selected 42 patients, suffering from headache with and without aura (International Headache Society Committee on Headache Classification, 1988 Cephalalgia 8:1-96), whose headache frequency ranged between 1- and 4-monthly crises. For a total of 25 crises, for every five consecutive crises, a different triptan was taken. The end-points of the study were as follows: response at 2 h, 'pain free' at 2 h and 'sustained pain free' (at 24 h). The intra-patient consistency and the tolerability were also evaluated. Thirty patients completed the study and the statistical analysis was only applied to these patients. No substantial difference in terms of the efficacy of the triptans was noted; all triptans were well tolerated. These results suggest the possibility of testing different triptans in the same patient in order to identify the ideal drug for every patient. © 2005 EFNS.
2004
- Antiepileptic drugs in migraine prophylaxis: state of the art
[Articolo su rivista]
Capuano, A; Vollono, C; Mei, D; Pierguidi, L; Ferraro, Diana; Di Trapani, G.
abstract
Antiepileptic drugs have proven their efficacy in the prophylactic treatment of migraine. Our study comprises a clinical trial that examines the efficacy of gabapentin and topiramate and a description of the pharmacologic characteristics and the efficacy of tiagabine, lamotrigine, levetiracetam and zonisamide. Antiepileptic drugs have multiple modes of action which can explain their efficacy in reducing neuronal excitability which is proven in epilepsy and postulated in migraine. The relationship between epilepsy and migraine has, in fact, been much debated but never convincingly proven. Antiepileptic drugs could be useful in migraine prophylaxis as some of these have determined a reduction in the monthly frequency and intensity of crises in subjects suffering from migraine with and without aura. These are the aims that have been proposed by the U.S. Headache Consortium Evidence-Based Guidelines. Further double-blind placebo-controlled studies are necessary in order to assess their safety and efficacy.
2004
- Antiepileptic drugs in the treatment of headache: Neuroprotective effect or something else?
[Articolo su rivista]
Di Trapani, Girolamo; Mei, Daniele; Vollono, Catello; Capuano, Alessandro; Ferraro, Diana
abstract
The hypothesis that cortical hyperexcitability may play an important role in the physiopathology of migraine has lead to the therapeutic use of antiepileptic drugs in headache prophylaxis. Cortical hyperexcitability is due to an imbalance between neuronal inhibition, mediated by gamma-aminobutyrric acid (GABA), and neuronal excitement, mediated by excitatory aminoacids. It becomes therefore clear how cortical excitability may be modulated by acting on mechanisms such as the synthesis and metabolism of GABA and on targets such as GABA and glutamate receptors and on sodium and calcium channels. The question is, whether, thanks to their tolerability and rapidity of action, these should be considered as first-choice prophylaxis drugs rather than simply as alternative drugs. Thanks to their action on the key-mechanisms implicated in the genesis and maintenance of pain, valproic acid, gabapentin, topiramate, levetiracetam and lamotrigine have all the requisites in terms of efficacy, tolerability and rapidity of action that are requested from a drug in order to be considered a firstchoice drug rather than simply an alternative to the drugs currently used. The expansion, however, of medical areas in which antiepileptic drugs are prescribed and the growing number of patients using them, require an increased sensitivization in order to avoid their incorrect use. © Springer-Verlag Italia 2004.
2004
- Topiramate in migraine prophylaxis: A randomised double-blind versus placebo study
[Articolo su rivista]
Mei, D.; Capuano, Alessandro; Vollono, C.; Evangelista, M.; Ferraro, Diana; Tonali, P.; Di Trapani, G.
abstract
The objectives of this paper are to evaluate the efficacy and tolerability of topiramate, given at the dose of 100 mg/day, in the prophylactic treatment of migraine. The hypothesis that migraine is the result of a condition of neuronal hyperexcitability and the quest for drugs that are able to limit the number of crises justifies the attempt to utilise the new antiepileptic drugs in the prophylaxis of this pathology, which is so important due to its high prevalence and due to the high disability it causes. The study was randomised double-blind versus placebo, lasting 16 weeks, and was preceded by a run-in period of 4 weeks. One hundred and fifteen patients were randomly allocated to treatment with topiramate (TPM) or placebo: 35 patients completed the study in the TPM group and 37 patients in the placebo group. At the end of the double-blind phase of study, in the TPM group, we recorded a significant reduction in the frequency of migraine crises (from 5.26 at baseline to 2.60 in the last 4 weeks), a significant reduction in the quantity of symptomatic drugs taken as compared to the placebo control group (from 6.17±1.80 SD to 2.57±0.80) and a significant downward trend in the number of days of disability over the 16-week period of therapy. In the TPM group, side effects were transient and well tolerated. TPM has thus proven its efficacy and tolerability in the prophylaxis of migraine. © Springer-Verlag Italia 2004.
2003
- Occupational head injury and subsequent glioma
[Articolo su rivista]
Magnavita, N; Placentino, R. A.; Mei, D.; Ferraro, Diana; Di Trapani, G.
abstract
We report the case of a policeman who suffered a severe head injury to the right temporoparietal lobe while driving a police car. Four years later, the patient developed a neoplasm at the precise site of the meningocerebral scar. Histological examination confirmed a glioblastoma multiforme adjacent to the dural scar. Radiological documentation of the absence of tumor at the time of injury, exact localization of the neoplasm in the injured cerebral area, and latency of the cancer supported the hypothesis of a causal relationship with brain trauma. Physicians faced with brain neoplasms in adults should carefully investigate the patient's personal history of head trauma. When a relationship with occupational head injury is probable, reporting of suspect occupational illness is compelling.