Giovanni Bosco Zimatore

New natural history of interferon‐β–treated relapsing multiple sclerosis

To investigate the impact of interferon‐beta (IFNβ) on disease progression in relapsing‐remitting multiple sclerosis patients.

Age‐related disability in multiple sclerosis

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

Real-life impact of early interferonβ therapy in relapsing multiple sclerosis

Recent findings support greater efficacy of early vs. delayed interferon beta (IFNβ) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFNβ treatment in definite relapsing‐remitting MS (RRMS) and to assess the optimal time to initiate IFNβ treatment with regard to the greatest benefits on disability progression.

Localised 1H-MR spectroscopy for metabolic characterisation of diffuse and focal brain lesions in patients infected with HIV

OBJECTIVES To evaluate the role of proton MR spectroscopy (1H-MRS) in detecting metabolic changes in diffuse or focal lesions in the brain of patients infected with HIV. METHODS Sixty HIV seropositive patients (25 with HIV related encephalopathies, 20 with toxoplasmosis, eight with progressive multifocal leukoencephalopathies (PMLs), and seven with lymphomas) and 22 HIV seronegative neurological controls were examined with a combined MRI and1H-MRS technique using a Siemens 1.5 Tesla Magnetom. Spectra (Spin Echo sequence, TE 135 ms) were acquired by single voxel, localised on focal lesions in toxoplasmosis, PML, lymphomas, and HIV encephalopathies and on the centrum semiovale of neurological controls. Choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), lactate, and lipids were evaluated in each spectrum and NAA/Cr, NAA/Cho, and Cho/Cr ratios were calculated. RESULTS A significant decrease in NAA/Cr and NAA/Cho ratios were found in all HIV diagnostic groups in comparison with neurological controls (p<0.003), suggesting neuronal or axonal damage independent of brain lesion aetiology. However, the NAA/Cr ratio was significantly lower in PML and lymphomas than in HIV encephalopathies (p<0.02) and toxoplasmosis (p<0.05). HIV encephalopathies, lymphomas, and toxoplasmosis showed a significant increase in the Cho/Cr ratio in comparison with neurological controls (p<0.03) without between group differences. The presence of a lipid signal was more frequent in lymphomas (71%) than in other HIV groups (Fisher’s test, p=0.00003). The presence of mobile lipid resonance together with a high Cho/Cr ratio in lymphomas may be related to an increased membrane synthesis and turnover in tumour cells. A lactate signal (marker of inflammatory reaction), was found in all but one patient with PML lesions (75%), but had a lower incidence in the other HIV diagnostic groups (Fisher’s test, p=0.00024). CONCLUSION 1H-MRS shows a high sensitivity in detecting brain involvement in HIV related diseases, but a poor specificity in differential diagnosis of HIV brain lesions. Nevertheless, the homogeneous metabolic pattern that characterises PML suggests the usefulness of 1H-MRS as an adjunct to MRI in differentiating CNS white matter lesions, such as HIV encephalopathies, from PML.

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

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

The brief international cognitive assessment for multiple sclerosis (BICAMS): normative values with gender, age and education corrections in the Italian population

BackgroundBICAMS (Brief International Cognitive Assessment for Multiple Sclerosis) has been recently developed as brief, practical and universal assessment tool for cognitive impairment in MS subjects. It includes the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT2) and the Brief Visuospatial Memory Test-Revised (BVMT-R) . In this study we aimed at gathering regression based normative data for the BICAMS battery in the Italian population.MethodsHealthy subjects were consecutively recruited among patient friends and relatives. Corrections for demographics were calculated using multivariable linear regression models. Test-retest reliability was assessed using the Pearson correlation coefficient.ResultsThe BICAMS battery was administered to 273 healthy subjects (180 women, mean age 38.9 ± 13.0 years, mean education 14.9 ± 3.0 years). Test-retest reliability was good for all the tests.ConclusionsThe study provided normative data of the BICAMS for the Italian population confirming good test-retest reliability which can facilitate the use of the battery in clinical practice, also for longitudinal patient assessments.

Acute changes in blood-CSF barrier permselectivity to serum proteins after intrathecal methotrexate and CNS irradiation

SummaryTen children affected by acute lymphoblastic leukaemia without CNS involvement were treated with a CNS prophylaxis protocol. Intrathecal methotrexate and CNS irradiation (60Co) administered at different times both induced an increase in blood-CSF barrier permeability to serum proteins (albumin, IgG, alpha2 macroglobulin). The relationship between permeability coefficients of proteins was analysed by theoretical porous or vesicular blood-CSF barrier models. The analysis indicated that both therapeutic procedures affect endothelial pinocytosis. An increase in radius of pinocytotic vesicles from 400 to 1500 Å seemed the most relevant change. The damage of endothelial barrier permselectivity could be involved in acute and late delayed toxic effects of intrathecal methotrexate and of CNS irradiation.

Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis

The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patients choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting.

Age at onset in multiple sclerosis

Abstract Age at onset of multiple sclerosis (MS) can vary from childhood to adult life. Many reports have been carried out over the years concerning the role of age at onset in determining the disease outcome. In a sporadic MS population of 1463 patients with homogeneous clinical and demographic features, derived from three Italian neurological centres (Bari, Cagliari and Sassari), we analysed the relative weights of current age and age at onset on disease severity according to the expanded disability status scale (EDSS) score, by fixing the disease duration.The results of present study demonstrate that clinical disability in MS in influenced by the patients age (p<0.01) and not by the age at onset. Therefore, these data do not confirm the hypothesis that an early age at onset should be considered a favourable prognostic factor of the disease outcome.

Intrathecal IgG synthesis in multiple sclerosis: Comparison between isoelectric focusing and quantitative estimation of cerebrospinal fluid IgG

SummaryIsoelectric focusing of CSF and serum IgG followed by crossed immuno isoelectric focusing and direct immunofixation as well as quantitative assay of IgG and albumin were performed in 64 clinically definite multiple sclerosis patients. Intrathecal IgG synthesis was calculated according to the CSF IgG index and de novo CNS IgGsyn. Isoelectric focusing showed abnormal IgG fractions in CSF indicating increased intrathecal synthesis of oligoclonal IgG in 99% of patients. Only 62% and 70% of multiple sclerosis patients showed values of CSF IgG indices and de novo CNS IgGsyn higher than in controls. Increased intrathecal IgG synthesis was indicated more frequently by de novo CNS IgGsyn in patients with a normal CSF IgG index than by the CSF IgG index in patients with normal de novo CNS IgGsyn. All patients with blood CSF barrier damage had increased de novo CNS IgGsyn, but only 40% had an increased CSF IgG index. Isoelectric focusing seemed to be a more sensitive method to detect an increased intrathecal oligoclonal IgG synthesis than quantitative methods. Identification of abnormal IgG fractions can be performed easily and with more reproducible results by direct immunofixation than by crossed immuno isoelectric focusing. The formula for de novo CNS IgGsyn seemed more sensitive and less influenced by blood-CSF barrier damage than the CSF IgG index to detect increased intrathecal IgG synthesis in multiple sclerosis patients. No correlation was found between the CSF IgG pattern or amounts and age, duration, clinical course or therapy of the disease.ZusammenfassungBei 64 klinisch bestimmten Fällen von multipler Sklerose wurde die isoelektrische Fokussierung von CSF und Serum-IgG, gefolgt von „crossed“ immuno-isoelektrischer Fokussierung und direkter Immunofixierung, sowohl bei der quantitativen Bestimmung als auch bei Albumin, durchgeführt. Die IgG-intrathekal-Synthese wurde entsprechend dem CSF-IgG-Index und de-novo-CNS-IgGsyn berechnet. Bei 99% der Patienten zeigte die isoelektrische Fokussierung abnorme Fraktionen im CSF an, ein Hinweis auf eine erhöhte intrathekale Synthese von oligoklonalem IgG. Nur bei 62–70% der Multiple-Sklerose-Fälle waren die Werte des CSF-IgG-Index und de-novo-CNS-IgGsyn höher als bei Vergleichskontrollen. Eine erhöhte intrathekale Synthese wurde häufiger von de-novo-CNS-IgGsyn bei Patienten mit normalem CSF-IgG-Index als von CSF-IgG-Index bei Patienten mit normalem de-novo-CNS-IgGsyn angezeigt. Bei allen Patienten mit Störung der Blut-CSF-Schranke war de-novo-CNS-IgGsyn erhöht, dagegen wurde bei nur 40% eine Erhöhung des CSF-IgG-Index festgestellt. Im Vergleich zu den quantitativen Verfahren scheint die isoelektrische Fokussierung die genauere Methode zur Feststellung einer erhöhten Intrathekal-oligoklonal-IgG-Synthese zu sein. Abnorme IgG-Fraktionen werden eher durch direkte Immunofixierung einfacher und mit wenig voneinander abweichenden Resultaten festgestellt als durch immunoisoelektrische Fokussierung. Die Formel für die de-novo-CNS-IgGsyn scheint sensibler und weniger durch Störungen der Blut-CSF-Schranke beeinflußbar zu sein als der CSF-IgG-Index bei der Bestimmung erhöhter Intrathekal-IgG-Synthese bei Fällen von multipler Sklerose. Es wurde kein Zusammenhang zwischen der CSF-IgG-Zusammensetzung und den Werten zum Alter, der Krankheitsdauer, dem klinischen Verlauf und der Behandlungstherapie des Kranken gefunden.