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OBJECTIVE: Recent findings support greater efficacy of early vs. delayed interferon beta (IFNbeta) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFNbeta treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFNbeta treatment with regard to the greatest benefits on disability progression. METHODS: A cohort of 2,570 IFNbeta-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFNbeta treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings. RESULTS: The lowest hazard ratios (HRs) for the three PS quintiles-adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR = 0.63; 95% CI = 0.48-0.85; p < 0.002), and the EDSS 4.0 milestone (HR = 0.56; 95% CI = 0.36-0.90; p = 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders. INTERPRETATION: Greater benefits on disability progression may be obtained by an early IFNbeta treatment in RRMS. Ann Neurol 2009;66:513-520. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the impact of interferon-beta (IFNbeta) on disease progression in relapsing-remitting multiple sclerosis patients. METHODS: A cohort of 1,504 relapsing-remitting multiple sclerosis (1,103 IFNbeta-treated and 401 untreated) patients was followed for up to 7 years. Cox proportional hazards regression adjusted for propensity score inverse weighting was used to assess the differences between the two groups for three different clinical end points: secondary progression (SP) and irreversible Expanded Disability Status Scale (EDSS) scores 4 and 6. Times from first visit and from date of birth were used as survival time variables. RESULTS: The IFNbeta-treated group showed a highly significant reduction in the incidence of SP (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.24-0.58 for time from 1st visit; HR, 0.36, 95% CI, 0.23-0.56 for time from date of birth; p < 0.0001), EDSS score of 4 (HR, 0.70, 95% CI, 0.53-0.94 for time from first visit; HR, 0.69, 95% CI, 0.52-0.93 for time from date of birth; p < 0.02), and EDSS score of 6 (HR, 0.60, 95% CI, 0.38-0.95 for time from first visit; HR, 0.54, 95% CI, 0.34-0.86 for time from date of birth; p

Data on fertility after autologous hematopoietic stem cell transplantation (aHSCT) in women with multiple sclerosis (MS) are inconclusive. This study aims to report on post-aHSCT menstrual resumption in a multi-center MS-women cohort. Out of 43 women, 30 (70%) recovered menses after a mean time of 6.8 months. Older age (odds ratio (OR) = 0.5, p < 0.0001) and previous pulsed cyclophosphamide (OR = 0.44, p = 0.005) were independently associated with a reduced menstrual recovery probability. Conditioning regimens' intensity resulted not associated with post-procedure amenorrhea. Our results highlight younger age as significantly associated with menses recovery; proper fertility counseling for MS women candidated to aHSCT both prior- and post-transplantation is therefore warranted.

Introduction: Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, involved in neuronal survival and synaptic plasticity. The BDNF Val66Met polymorphism is known to reduce BDNF expression and secretion; its role in multiple sclerosis (MS) is poorly investigated. Objectives and Methods: In this multicenter, retrospective study, we assessed the role of BDNF Val66Met polymorphism on cognitive and motor disability in MS patients consecutively referred to the University of Florence and the Hospital of Barletta. All patients underwent a genetic analysis for the presence of Val66Met polymorphism and a comprehensive neuropsychological examination on the Rao's Brief Repeatable Battery and the Stroop Color Word Test. Possible predictors of the Expanded Disability Status Scale (EDSS) score and number of failed neuropsychological tests were assessed through linear multivariable regression models. Results: Ninety-eight patients were recruited. Patients with the BDNF Val66Met polymorphism (35.7%) were more frequently males ( p = 0.020), more disabled ( p = 0.026) and, marginally, older ( p = 0.064). In the multivariable analysis, BDNF Val66Met polymorphism was associated with a better cognitive performance ( B = -1.1 ± 0.5, p = 0.027). Higher EDSS score was associated with a progressive disease course ( B = 3.4, p < 0.001) and, marginally, with the presence of the BDNF Val66Met polymorphism ( B = 0.56, p = 0.066). Discussion: Our results preliminarily suggest a protective role of BDNF Val66Met polymorphism against cognitive impairment in MS patients, possibly related to a detrimental effect of increased BDNF concentration in a neuroinflammatory environment., Competing Interests: EPr received compensation for travel grants, participation in advisory board, and/or speaking activities from Biogen, Merck Serono, Sanofi, Teva, and Novartis and serves on the editorial board of Frontiers in Neurology. LP received research support from Novartis, Biogen, and speaker honoraria from Teva. LR received research support from Novartis. GZ received travel funds and speaker honoraria from Sanofi-Genzyme, Novartis, Teva, Biogen, Almirall, Roche, and Merck. MA served on scientific advisory boards for and has received speaker honoraria and research support from Biogen Idec, Merck Serono, Bayer Schering Pharma, and Sanofi Aventis and serves on the editorial board of BMC Neurology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The Handling Editor declared a past co-authorship with some of the authors EPo, LR, and MA., (Copyright © 2021 Portaccio, Bellinvia, Prestipino, Nacmias, Bagnoli, Razzolini, Pastò, Niccolai, Goretti, Fonderico, Zimatore, Losignore, Sorbi and Amato.)

Objective: To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplantation in a large cohort of patients with MS., Methods: To be included, a minimum dataset (consisting of age, MS phenotype, Expanded Disability Status Scale [EDSS] score at baseline, information on transplantation technology, and at least 1 follow-up visit after transplantation) was required., Results: Two hundred ten patients were included (relapsing-remitting [RR] MS 122 [58%]). Median baseline EDSS score was 6 (1-9); mean follow-up was 6.2 (±5.0) years. Among patients with RRMS, disability worsening-free survival (95% confidence interval [CI]) was 85.5% (76.9%-94.1%) at 5 years and 71.3% (57.8%-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0% (59.4%-82.6%) and 57.2% (41.8%-72.7%) at 5 and 10 years, respectively. In patients with RRMS, EDSS significantly reduced after aHSCT ( p = 0.001; mean EDSS change per year -0.09 [95% CI -0.15% to -0.04%]). In patients with RRMS, the use of the BCNU+Etoposide+Ara-C+Melphalan (BEAM) + anti-thymocyte globulin (ATG) conditioning protocol was independently associated with a reduced risk of no evidence of disease activity 3 failure (hazard ratio 0.27 [95% CI 0.14-0.50], p < 0.001). Three patients died within 100 days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007., Conclusions: aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM + ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity., Classification of Evidence: This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients., (© 2021 American Academy of Neurology.)

Background: Subcutaneous recombinant interferon-beta 1a (IFN-β1a SC) is indicated for treatment of relapsing multiple sclerosis (RMS); however, it is associated with development of flu-like syndrome (FLS) in 75% of patients. No recommendations are available on whether evening or morning administration could induce better or worse FLS., Objective: Primary objective was to investigate whether morning administration of IFN-β1a 44 µg (Rebif) would affect the severity of FLS versus evening administration, in patients with RMS. Secondary objectives were to investigate whether timing of administration could lead to a better quality of life., Methods: Multicenter, open-label, 12-week, randomized, controlled, parallel-group, phase 4 study., Results: Of 217 patients screened at 29 Italian sites, 200 were included in the study. Among these, 104 patients were randomized to IFN-β1a SC administration in the morning and 96 in the evening. Morning administration resulted in higher FLS scores, as measured by the Multiple Sclerosis Treatment Concern Questionnaire, at week 4 (p = 0.0083) and week 8 (p = 0.0079); however, the difference was no longer significant at the end of 12 weeks., Conclusion: IFN-β1a evening injections in the first 8 weeks of treatment led to an improvement in FLS; when continuing therapy, time of administration could be decided according to patient's lifestyle and preference.

Background: Many potentially modifiable risk factors for MS are investigated. It is not known, however, if these factors also apply to MS-related cognitive impairment (CI), a frequent consequence of MS., Objective: The aim of our study was to assess risk factors for CI in MS patients, focusing on environmental exposures, lifestyle and comorbidities., Methods: We included MS patients referring to MS Centers in Florence and Barletta between 2014 and 2017. Neuropsychological performance was assessed through the Rao's battery and Stroop test, cognitive reserve (premorbid intelligence quotient-IQ) was evaluated using the National Adult Reading Test (NART). Potential risk factors were investigated through a semi-structured questionnaire., Results: 150 patients were included. CI was detected in 45 (30%) subjects and was associated with older age (p<0.005), older age at MS onset (p = 0.016), higher EDSS score (p<0.005), progressive disease course (p = 0.048) and lower premorbid IQ score (p<0.005). As for risk factors, CI was related with lower physical activity in childhood-adolescence (p<0.005). In women, hormonal therapy resulted to be protective against CI (p = 0.041). However, in the multivariable analysis, the only significant predictors of CI were older age (p<0.05; OR 1.06, 95% CI 1.02-1.10) and lower premorbid IQ (p<0.05; OR 0.93, 95% CI: 0.88-0.98). Removing IQ from the model, CI was associated with higher EDSS (p = 0.030; OR 1.25, 95% CI 1.02-1.53) and, marginally, previous physical activity (p = 0.066; OR 0.49, 95% CI: 0.23-1.05)., Conclusions: Our findings suggest that physical activity in childhood-adolescence could be a contributor to cognitive reserve building, thus representing a potential protective factors for MS-related CI susceptible to preventive strategies., Competing Interests: The authors have declared that no competing interests exist.

Objective: To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients., Methods: A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data., Results: In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06-1.55; 1.42, 1.10-1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60-0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42-0.83; 0.75, 0.71-0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46-7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening., Interpretation: This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729-739., (© 2017 American Neurological Association.)

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), patient's 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., (© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Recently, a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been developed as an international and standardized brief cognitive test, which is easily performed in everyday clinical practice for neuropsychological assessment in multiple sclerosis (MS). However, we need to gather more information about this tool compared to other neuropsychological batteries. The aim of our study is to compare the performance of BICAMS and Brief Repeatable Battery (BRB) in MS subjects., Methods: Tests of the BRB and BICAMS were administered to MS patients recruited from 11 Italian MS centres. Cognitive impairment (CI) was defined as the failure on at least two tests (scores below the fifth percentile) on the BRB and as the failure on at least one test of the BICAMS. The agreement between the performances on the two batteries was assessed through Cohen's K statistic. Finally we calculated the effects sizes for each test of the two batteries using Cohen's d., Results: The two batteries were administered to 192 MS patients (142 women, 50 men; mean age 41.4 ± 10.8 years, mean education 12.3 ± 3.5 years). Mean scores of patients were lower compared to those of healthy subjects in all the cognitive measures examined. Forty-six MS patients were identified as impaired and 48 as unimpaired on both of the batteries, when the Symbol Digit Modalities Test (SDMT) was included in the analysis. Cohen's K statistic was 0.46 which corresponds to a moderate accord. If the SDMT was excluded from the BRB, 37 MS patients were identified as impaired and 57 as unimpaired on both of the batteries. Cohen's K statistic was 0.3 which corresponds to a poor accord. The SDMT, the Paced Auditory Serial Addition Test (PASAT) 3 and 2 yielded higher d values (SDMT 0.83, PASAT 3 0.65, PASAT 2 0.84)., Conclusions: This study confirms the feasibility of BICAMS in everyday clinical practice for the identification of CI and highlights the good psychometric properties of the SDMT.

Background: BICAMS (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., Methods: Healthy 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., Results: The 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., Conclusions: The 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.

Background: Posterior cortical atrophy is a clinical syndrome that is characterized by the progressive loss of visuospatial integration and is associated with neurodegenerative conditions., Case Report: We describe a 60-year-old female with simultanagnosia, oculomotor apraxia, and optic ataxia for which she received an initial clinical diagnosis of posterior cortical atrophy. Three years later, she developed Balint's syndrome, Gerstmann's syndrome, left alien hand syndrome, smooth asymmetric (left) rigidity, cortical sensory loss, and spontaneous myoclonic jerks of the left arm, which suggested a final diagnosis of corticobasal syndrome., Discussion: This case report indicates that corticobasal syndrome may present with visuospatial deficits.

Background: Non-motor symptoms (NMS) in Parkinson's disease (PD) differ from those in essential tremor (ET), even before a definitive diagnosis is made. It is not clear whether patient's knowledge of the diagnosis and treatment influence their subsequent reporting of NMS., Methods: 1 year after a clinical and instrumental diagnosis, we compared the motor impairment (Movement Disorders Society (MDS)-Unified Parkinson's Disease Rating Scale-III) and non-motor symptoms (NMSQuest) in PD (n = 31) and ET (n = 21) patients., Results: PD patients reported more NMS than did the ET patients (p = 0.002). When compared to their baseline report, at follow-up, PD patients reported less nocturia (p = 0.02), sadness (p = 0.01), insomnia (p = 0.02), and restless legs (p = 0.04) and more nausea (p = 0.024), unexplained pain (p = 0.03), weight change (p = 0.009), and daytime sleepiness (p = 0.03). When compared to their baseline report, ET patients reported less loss of interest (p = 0.03), anxiety (p = 0.006), and insomnia (p = 0.02). Differences in reported weight change (p<0.0001) and anxiety (p = 0.001) between PD and ET patients were related to pharmacological side effects or to a reduction in the ET individuals., Discussion: The reporting of NMS is influenced by subjective factors, and might vary with the patient's knowledge of the diagnosis or the effectiveness of treatment.

Background: Non-motor symptoms (NMS) in Parkinson's disease (PD) are common, increase the patients' disability and have a significantly negative impact on their quality of life. Essential tremor (ET) is also affected by non-motor symptoms and often enters into the differential diagnosis with PD. Brain scintigraphy with [(123)I]β-CIT SPECT is a technique used to facilitate differential diagnosis between PD and ET., Methods: We evaluated both motor impairment (MDS-UPDRS-III) and non-motor symptoms (NMSQuest) in patients who underwent a [(123)I]β-CIT SPECT examination for diagnostic purposes. Both the clinical and the scintigraphic data obtained from the selected PD (n = 31) and ET (n = 22) patients were compared., Results: We did not detect a significant difference in the total number of NMS reported by either PD (10.4 ± 4.9) or ET patients (8.41 ± 3.3). PD patients reported more drooling (29%), hyposmia (32.2%), hallucinations (19.3%), difficulty in concentrating (51.6%), orthostatic dizziness (67.7%), falling (19.3%), vivid dreams (32.2%), REM sleep behavior disorder (58%), and diplopia (22.5%) compared with ET patients. PD patients who complained of drooling, orthostatic dizziness, and diplopia had greater denervation of the caudata than did the PD patients who did not report the same symptoms. The differences observed were not associated with differences in age, sex, UPDRS-III score, and the presence/absence of tremor., Conclusions: The declaration of non-motor symptoms is influenced by subjective factors that are widely suggestible. When analyzed early and before receiving a definitive diagnosis, PD patients complain of specific symptoms that seem to depend on different pathogenetic mechanisms., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Adult-onset focal dystonias (AOFDs) are non-task-specific or task-specific and may spread to other body segments of affected patients., Case Report: We report the case of a barber with non-task-specific craniocervical dystonia and a new occupational focal hand dystonia (while using scissors)., Discussion: Different AOFDs may develop and coexist in the same "vulnerable" patient. Hairdresser's dystonia is a rare task-specific dystonia.

The effects of Glatiramer Acetate (GA) in combination with Minocycline (MIN), a second-generation tetracycline, have been investigated on the course of EAE in mice, resulting in a significant reduction in disease severity and burden with attenuation of the inflammation, axonal loss and demyelination. Here we investigate the effects of combination therapy with GA and MIN on the induction, maturation and phenotyping of blood monocyte-derived dendritic cells (DCs) in Multiple Sclerosis (MS) patients. Hence the expressions of HLA-DR, CD11c, CD83 and CD1a were studied by flow cytometric analysis on immature (iDCs) and mature DCs (mDCs) from untreated and GA treated MS patients. Thirteen relapsing-remitting MS patients and 13 healthy controls (HCs) were included in the study. Ten of the MS patient group were re-tested after a 2 month period of GA treatment. The marker expressions on DC from untreated MS and HCs were studied in vitro in the absence or presence of GA and GA+MIN; and on DCs from GA treated MS patients without and with the in vitro addition of MIN. We found that in vitro GA alone or in combination with MIN downregulated DCs antigen presentation capability (HLA-DR), whereas the combination treatment only affected also myeloid DCs activation (CD83) in both MS and HCs. Prolonged GA treatment (in vivo for 2 months) affected antigen presentation capability by DCs, whereas when treated in vitro with MIN these cells also tended to reduce activation marker expression and myeloid phenotype acquisition (CD11c). The present data demonstrate possible combination effects of GA and MIN on peripheral blood monocyte-derived DCs in MS patients.

Objective: To investigate the impact of interferon-beta (IFNbeta) on disease progression in relapsing-remitting multiple sclerosis patients., Methods: A cohort of 1,504 relapsing-remitting multiple sclerosis (1,103 IFNbeta-treated and 401 untreated) patients was followed for up to 7 years. Cox proportional hazards regression adjusted for propensity score inverse weighting was used to assess the differences between the two groups for three different clinical end points: secondary progression (SP) and irreversible Expanded Disability Status Scale (EDSS) scores 4 and 6. Times from first visit and from date of birth were used as survival time variables., Results: The IFNbeta-treated group showed a highly significant reduction in the incidence of SP (hazard ratio [HR], 0.38, 95% confidence interval [CI], 0.24-0.58 for time from 1st visit; HR, 0.36, 95% CI, 0.23-0.56 for time from date of birth; p < 0.0001), EDSS score of 4 (HR, 0.70, 95% CI, 0.53-0.94 for time from first visit; HR, 0.69, 95% CI, 0.52-0.93 for time from date of birth; p < 0.02), and EDSS score of 6 (HR, 0.60, 95% CI, 0.38-0.95 for time from first visit; HR, 0.54, 95% CI, 0.34-0.86 for time from date of birth; p < or = 0.03) when compared with untreated patients. SP and EDSS scores of 4 and 6 were reached with significant delays estimated by times from first visit (3.8, 1.7, and 2.2 years) and from date of birth (8.7, 4.6, and 11.7 years) in favor of treated patients. Sensitivity analysis confirmed findings., Interpretation: IFN-beta slows progression in relapsing-remitting multiple sclerosis patients.

Apoptotic deletion of autoreactive T-cells is defective in patients with multiple sclerosis (MS). Glatiramer acetate (GA) treatment seems to restore apoptosis of detrimental T-cells. We analyzed the mitochondria membrane pro- (Bax) and anti-apoptotic (Bcl- 2) and cytosolic pro-apoptotic (Cyt-c, APAF-1) proteins expression in peripheral lymphocytes from relapsing-remitting (RR) MS patients during GA treatment. Blood samples were collected from 8 healthy controls (HCs) and from 8 RR MS patients prior to and every three months during the 9 months of GA treatment. Peripheral blood mononuclear cells (PBMNCs) Bcl-2, Bax, Cyt-c and APAF-1 were quantified by western blot followed by densitometric scanning and Bax/Bcl-2, cytosolic Cyt-c/Bcl-2 and APAF-1/Bcl-2 ratios were calculated. T-cells were in vitro tested for oxygen consumption by a respirometric analysis. Bax/Bcl-2, cytosolic Cyt-c/Bcl-2 and APAF-1/Bcl-2 ratios in untreated MS patients were significantly (p < 0.05) lower than in HCs. Bax/Bcl-2 ratio increased (p = 0.03) and Cyt-c/Bcl-2 ratio showed a trend to increase during the 9 months of GA treatment in MS patients. A reduction of 58% and 59% in oxygen consumption by PBMNCs was evident after GA treatment in vitro or when GA treated patients' cells were compared with those from HCs, respectively. Our findings suggest that GA exerts a regulatory effect on peripheral T lymphocytes through pro-apoptosis mechanisms involving mitochondria and cytosolic proteins.

This independent, population-based surveillance study monitored, in clinical practice, the efficacy of interferon beta (IFNbeta) products in 1173 patients with multiple sclerosis (MS) from the Department of Neurological and Psychiatric Sciences, University of Bari, Italy. Relapses and Expanded Disability Status Scale (EDSS) scores were evaluated for up to 6 years for Avonex, Betaferon and Rebif 22 groups, and for up to 3 years for the Rebif 44 group. IFNbeta products produced significant reductions from baseline in relapse rates at 2, 4 and >4 years (p<0.0001), with no differences among treatments (p=0.2). A modest significant (p<0.05) increase of EDSS was observed in all treatment groups from baseline to 48 months, followed thereafter by a plateau. The IFNbeta-1b group showed more withdrawals (19%) compared with Avonex (6%) and Rebif (7%) at 6 years.

This independent, population-based surveillance study monitored the efficacy and safety of interferon beta (IFNbeta) 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 < or = 3.5 are reported. The proportions of relapse-free patients were similar among the groups at 12 and 24 months (P = 0.10). IFNbeta products produced significant reductions from baseline in relapse rates at 12 and 24 months (P < 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 IFNbeta-1b group showed a higher incidence of adverse events during the first year of treatment (P < 0.05) than IFNbeta-1a groups, and more withdrawals (10%) compared with Avonex (5%) at 24 months. IFNbeta products are equally effective in low disability RRMS, but IFNbeta-1a may have a more favorable efficacy/tolerability ratio.

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 is influenced by the patient's 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.

Objectives: To confirm reduced human immunodeficiency virus type-1 (HIV-1) burden in the CSF of patients with progressive multifocal leukoencephalopathy (PML) and to verify whether this viral load coincides with the absence of inflammatory changes in the CSF., Methods: Paired CSF and plasma samples from 17 patients with PML, 26 with non-PML cerebral opportunistic infections, nine with HIV-1 leukoencephalopathy (HIVE), and 12 neurologically asymptomatic AIDS patients were subjected to HIV-RNA titration. Tumour necrosis factor (TNF)-alpha was also measured and the CSF albumin: serum albumin ratio (Q(Alb)) was calculated., Results: The CSF HIV-1 burden of patients with PML did not differ from that of neurologically asymptomatic patients (p=0.21), but was significantly lower than CSF burden of the remaining patients (non-PML opportunistic infections, p<0.001; HIVE, p<0.001). Q(Alb) was normal for all neurologically asymptomatic patients, for 86.6% patients with PML, and 62.5% patients with HIVE (p=0.09). Q(Alb) was altered in 91.6% patients with non-PML opportunistic infections. TNF-alpha in CSF was higher in patients with non-PML opportunistic infections (p<0.001) and those with HIVE (p<0.001) than in patients with PML who consistently had TNF-alpha concentrations<10 pg/ml., Conclusions: These results, while indicating a reduced HIV replication in CSF of patients with PML which might serve as a disease marker, emphasise the increased CSF HIV-RNA concentration in patients with HIVE and patients with non-PML opportunistic infections. Low concentrations of HIV-RNA in CSF coincide with reduced TNF-alpha concentrations, possibly due to particular features of PML compared with other opportunistic infections as it develops without detectable inflammatory changes in the CSF.

Objectives: To optimize the use of polymerase chain reaction (PCR) on cerebrospinal fluid (CSF) for the evaluation of central nervous system (CNS) white-matter lesions that along with clinical findings and magnetic resonance imaging (MRI) can allow a definite diagnosis to be made; also to evaluate treatment with zidovudine plus foscarnet., Design and Methods: Fifteen AIDS patients with uncertain CNS white-matter lesions were identified. HIV-1 RNA, cytomegalovirus (CMV) and JC virus (JCV) DNA were measured in a total of 29 CSF samples. The results were correlated with clinical and MRI findings and treatment with zidovudine plus foscarnet was evaluated., Results: Four and five out of 15 patients with CMV DNA > or = 1 : 625 and JCV DNA > or = 10(3) copies/microl detected in the CSF were diagnosed with CMV and progressive multifocal leukoencephalopathy (PML), respectively. Six patients who were CMV/JCV-negative with the highest levels of HIV RNA (median, 6.87 log10 copies/ml) in CSF were considered as having HIV-1 encephalitis. Neurological symptoms were non-supportive for diagnosis as was MRI in 11 out of 15 patients. Nine patients completed a 21-day course of zidovudine plus foscarnet. HIV RNA decreased irrespective of neurological diagnosis. All three HIV-1 encephalitis patients and two out of three patients with CMV leukoencephalopathy improved. In these two latter patients, relief of clinical symptoms coincided with decreased CMV DNA. JCV DNA remained unchanged and all three PML patients deteriorated., Conclusions: Measurement of CSF viral sequences supports the diagnosis of CNS white-matter lesions in AIDS patients. While effective therapy for PML remains elusive, treatment including zidovudine plus foscarnet may be a promising option for HIV-1 and CMV-related manifestations.

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 and 1H-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.

Seven paired HIV-1 isolates from peripheral blood mononuclear cells (PMCs) and cerebrospinal fluid (CSF) of infected subjects at various stages of the disease were studied for their capacity to replicate in continuous cell lines (Molt-3 and U-937 cells) and to induce cytopathic effects "in vitro". Obtained results indicate that paired HIV-1 isolates from PMCs and CSF of the same patient can differ in their replicative activity "in vitro", suggesting that, at least in some cases, CSF isolates may represent a distinct subtype of HIV-1.

Isoelectric 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 i 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.

Ten 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, alpha 2 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 A 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.

Isoelectric focusing and quantitative estimation of serum and CSF IgG were performed in 85 patients with idiopathic polyneuropathy (IP), subdivided according to the clinical course (acute, subacute, recurrent, chronic). Acute IP very frequently had an increase of oligoclonal and/or polyclonal serum IgG during the progressive phase and blood-CSF barrier damage accompanied by polyclonal IgG intrathecal synthesis during the stationary phase. Polyclonal IgG intrathecal synthesis was also present in several not acute IP and seemed to forecast unfavorable course. Oligoclonal IgG synthesis occurs very rarely within CSF but is a frequent finding in serum of patients with IP. Abnormalities of the IgG serum pattern are neither specific for any clinical course of IP nor of prognostic value. The possible significance of such findings is discussed.

Cerebrospinal fluid (CSF)/serum concentration gradients (Q) of individual proteins (albumin, IgG, alpha 2-macroglobulin) have been studied in controls and in patients in whom the lumbar CSF flow is altered (medullary compression) or the blood-CSF barrier (BCB) function impaired (acute idiopathic polyneuropathy and acute meningoencephalitis). The analysis of relationships among protein Q has been performed by total and multiple regressions and the actual BCB permeability to individual proteins has been interpreted according to the accepted theoretical porous or vesicular BCB models. The exponential Q-IgG vs. Q-albumin total regression, and the poor Q-alpha 2-macroglobulin vs. Q-albumin regression found in controls, together with the different multiple regressions among proteins and the high Q-IgG vs. Q-albumin partial regression coefficients found in medullary compression, acute idiopathic polyneuropathy and acute meningoencephalitis, indicated that different permeability mechanisms can be postulated. Heterogeneous, fairly independent permeability BCB mechanisms maintain the normal CSF/serum protein concentration gradient. Pinocytotic vesicles or pores of radius exceeding 1000-1500 A, probably located at the capillary endothelium, account for the main serum-derived CSF protein fraction(s) with large hydrodynamic radius (R). A more selective endothelial vesicular transport with a radius of 250 A transfers a negligible amount of protein from serum into CSF. Proteins with small R also enter the CSF through a set of selective pores of radius 120 A, probably at the level of the choroidal epithelium. Pinocytotic vesicles with a radius of 250 A and increased rate of formation induce the accumulation of proteins below an obstruction of lumbar CSF flow. An increased formation rate of vesicles with a radius of 450 A can explain the increased capillary permeability in nerve roots in acute idiopathic polyneuropathy. Loss of selectivity was the main feature of BCB in acute meningoencephalitis, and it seemed to be due to pores or vesicles with a radius larger than 1000-1500 A. The heterogeneity of BCB mechanisms must be taken into account when the intrathecal synthesis of a protein, also derived from serum (for example IgG), has to be measured.

CSF and serum of 80 HIV-seropositive patients in various stages of the disease were examined. Total as well as intrathecal IgG synthesis appeared to be frequently elevated in each diagnostic group. Abnormal CSF oligoclonal IgG fractions were significantly more frequent in asymptomatic patients. CSF pleocytosis was found with a lower percentage in neurological AIDS patients. In patients subdivided according to blood T helper cell count, the distribution of the abnormal CSF parameters confirms that the immunological response in the CNS is mediated by interaction with systemic immunity.