Multiple Sclerosis: Pozzilli C

Sørensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, Polman C, Pozzilli C, Ross C, Anonymous00318. · Danish Multiple Sclerosis Research Centre, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Eur J Neurol. · Pubmed #16241970 No free full text.

Abstract: Therapy-induced binding and neutralizing antibodies is a major problem in interferon (IFN)-beta treatment of multiple sclerosis. The objective of this study was to provide guidelines outlining the methods and clinical use of the measurements of binding and neutralizing antibodies. Systematic search of the Medline database for available publications on binding and neutralizing antibodies was undertaken. Appropriate publications were reviewed by one or more of the task force members. Grading of evidence and recommendations was based on consensus by all task force members. Measurements of binding antibodies are recommended for IFN-beta antibody screening before performing a neutralizing antibody (NAB) assay (Level A recommendation). Measurement of NABs should be performed in specialized laboratories with a validated cytopathic effect assay or MxA production assay using serial dilution of the test sera. The NAB titre should be calculated using the Kawade formula (Level A recommendation). Tests for the presence of NABs should be performed in all patients at 12 and 24 months of therapy (Level A recommendation). In patients who remain NAB-negative during this period measurements of NABs can be discontinued (Level B recommendation). In patient with NABs, measurements should be repeated, and therapy with IFN-beta should be discontinued in patients with high titres of NABs sustained at repeated measurements with 3- to 6-month intervals (Level A recommendation).

Pozzilli C, Petsas N, Prosperini L. · No affiliation provided · Expert Rev Neurother. · Pubmed #19271936 No free full text.

This publication has no abstract.

Gasperini C, Cefaro LA, Borriello G, Tosto G, Prosperini L, Pozzilli C. · S Camillo-Forlanini Hospital, Department of Neuroscience, Viale dell'Università 30, 00185 Rome, Italy. · Expert Opin Emerg Drugs. · Pubmed #18764723 No free full text.

Abstract: BACKGROUND: Therapy for multiple sclerosis (MS) has changed dramatically over the past decade, yielding significant progress in the treatment of relapsing/remitting and secondary progressive MS. Disease-modifying treatments are now widely available, and their beneficial effects on relapse rates, MRI outcomes and, in some cases, relapse-related disability have been shown in several clinical studies. However, as these treatments are only partially effective in halting the MS disease process and in clinical practice are frequently associated with injection-related side effects and suboptimal patient adherence, new oral therapeutic approaches are warranted. OBJECTIVE: The aim of the present paper is to present new promising results from emerging oral drugs for multiple sclerosis. METHODS: This review focuses on advances in current and novel oral treatment approaches for MS. Nevertheless, most of the data were obtained from Phase I/II clinical trials, we need further confirmation of their safety and efficacy profile from longer Phase III clinical trials. RESULTS: Several pivotal reports have provided promising results for new oral therapies evaluating the safety and efficacy of new agents including fingolimod, fumaric acid, cladribine, teriflunomide and laquinomid. CONCLUSIONS: It is unknown whether these oral drugs could be used as first-line treatment for MS; this will depend mostly on their safety profile. Alternatively, these drugs could be used as add-on treatment for failed first-line therapy, or as an effective induction agent.

Pozzilli C, Prosperini L. · S. Andrea Hospital, La Sapienza University, Via di Grottarossa, 1035, 00189, Rome, Italy. · Neurol Sci. · Pubmed #18690494 No free full text.

Abstract: Interferon beta (IFNbeta) and glatiramer acetate (GA) showed a relevant impact in modifying the clinical course of relapsing-remitting multiple sclerosis. However, not all treated patients experience a satisfied response to therapy in terms of suppression of relapse and slowing disability progression.At the present time none of the proposed criteria of response to disease modifying therapies (DMTs) have been validated. Clinical parameters, such as relapse rate and disability progression assessing with EDSS scale, may represent two useful indicators of therapeutic response, but their value in predicting the long-term response to DMTs is weak.

Pozzilli C, Prosperini L, Sbardella E, Paolillo A. · Department of Neurological Sciences, La Sapienza University, Viale dell'Università 30, I-00185 Rome, Italy. · Neurol Sci. · Pubmed #16998723 No free full text.

Abstract: Multiple sclerosis (MS) is a life-long disease that typically affects young adults. The introduction of disease-modifying therapy has changed the clinical and social burden of the disease. Safety, tolerability and efficacy profiles of Interferon beta (IFNbeta) therapy in MS have been widely highlighted both in trial settings and in daily clinical practice. However, there is a relative lack of information on the long-term period: all pivotal trials must be considered short-term in a disease with an average duration of 30-40 years and post-marketing studies suffer from some limitations. Moreover, current available IFNbeta preparations are only partially effective and are difficult to administer, which has led to poor patient compliance. Over the treatment period, a problem could be the development of neutralising antibodies (NAbs) against the drug, which have been related to lessening treatment benefits. Despite these restrictions, IFNbeta still remains the first choice treatment in MS.

Tomassini V, Pozzilli C. · Department of Neurological Sciences, La Sapienza University, Rome, Italy. · Expert Opin Pharmacother. · Pubmed #16634709 No free full text.

Abstract: Several lines of evidence suggest that gender affects the susceptibility and course of multiple sclerosis. A higher disease prevalence, as well as an overall better prognosis, in women than men is observed. This sex dimorphism may be explained by the effect of sex hormones on brain damage and repair mechanisms. Experimental, clinical and MRI evidence confirms a pathogenetic link between sex hormones and multiple sclerosis, also suggesting sex-specific effects of hormones in multiple sclerosis pathology and therapy. A gender-based approach to multiple sclerosis could provide further benefits for its treatment and management.

Mainero C, Pantano P, Caramia F, Pozzilli C. · Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, 02129, USA. · J Neurol Sci. · Pubmed #16626753 No free full text.

Abstract: Deficits in memory and attention frequently occur during the course of multiple sclerosis (MS). In patients with MS the severity of cognitive manifestations is not closely related to indices of structural brain damage on both conventional and non conventional magnetic resonance imaging (MRI). It is conceivable that the ability of the brain to compensate for tissue impairment or loss may contribute to the maintenance of normal performance despite scattered brain lesions. Accordingly, using functional MRI (fMRI), patients with multiple sclerosis showed a greater extent of brain activation during motors tasks than controls. Changes in functional organization of the cerebral cortex have also been reported by fMRI studies comparing the activation patterns during cognitive tasks in patients with MS and in healthy subjects. Differences in patients' selection, activation paradigm, experimental design and MR acquisition parameters make, however, the results obtained from fMRI studies difficult to be compared and may explain, at least partially, some discrepant findings. Nevertheless, fMRI studies provide a new interesting way of understanding how the brain can change its functional organization in response to MS pathology, and might be useful in the study of the effects of either rehabilitation or pharmacological agents on brain plasticity.

Pozzilli C, Marinelli F, Romano S, Bagnato F. · Department of Neurological Sciences, La Sapienza University, V.le Università 30, 00185 Rome, Italy. · J Neurol Sci. · Pubmed #15261560 No free full text.

Abstract: Corticosteroids (Cs) are widely used for treatment of multiple sclerosis (MS) acute relapses because of the potent immunosuppressive and anti-inflammatory properties. As for patients with relapsing-remitting (RR) MS, short-term administrations of Cs markedly less severity of symptoms and promote faster recovery of clinical attacks. Chronic administrations of Cs significantly diminish the formation of T1 hypointense lesions and the progression of brain atrophy. As for patients with secondary progressive MS treatment with Cs delays the time to onset of sustained disability. Finally the association between methylprednisolone and interferon beta (IFNbeta) leads the recovery of active lesions at greater extent and reduces the formation of neutralizing antibodies (NABs) against IFNbeta in patients with RRMS.

Bagnato F, Pozzilli C. · Neuroimmunology Branch, National Institutes of Neurological Disease and Stroke, National Institutes of Health, Bethesda, MD, 20892-1400 USA. · Expert Opin Investig Drugs. · Pubmed #12831350 No free full text.

Abstract: Diminished efficacy in terms of clinical relapses and lesion load on magnetic resonance images for patients developing neutralising antibodies (NAbs) to recombinant IFN-beta may be found in multiple sclerosis. NAbs become detectable over the first few years of therapy, disappearing during the treatment course in some patients and persisting longer in some others. Therefore, the administration of concomitant therapies to recombinant IFNbeta to prevent the formation of NAbs could be indicated mainly in the latter group of patients at the early stage of the treatment. Among those therapies, steroids meet the best criteria in terms of either safety or impact on the development of NAbs, at the present time.

Pozzilli C, Romano S, Cannoni S. · Department of Neurological Science, University of Rome, La Sapienza, Italy. · J Rehabil Res Dev. · Pubmed #12051462 No free full text.

Abstract: Multiple sclerosis (MS) is a chronic disease affecting the central nervous system, usually leading to early disablement in young adults. At least 350,000 persons in Europe have the disease. Wide variations exist both between and within European countries in the incidence and prevalence of the disease as well as in the general standard of care for MS patients. The needs, well-being, and social participation of people with MS are systematically influenced by their physical and cultural environment and the nature of the community services. Moreover, the rate of introduction of the new disease-modifying therapy also widely differs from country to country. This article helps clinical researchers to understand better the differences in epidemiology and in the current treatment of MS in Europe.

Bastianello S, Paolillo A, Giugni E, Giuliani S, Evangelisti G, Luccichenti G, Angeloni U, Colonnese C, Salvetti M, Gasperini C, Pozzilli C, Fieschi C. · Department of Neurological Sciences, University of Rome 'La Sapienza', Rome, Italy. · J Neurovirol. · Pubmed #10871800 No free full text.

Abstract: Over the last 10 - 15 years, magnetic resonance imaging techniques have had a major impact in understanding and managing multiple sclerosis. The present review briefly summarises the current usefulness of spinal cord MRI in MS disease, examining the frequency, distribution and main characteristics of spine MS plaques; the differential diagnosis with other spinal cord disease was also described. Finally we considered how newer imaging sequences when added to semi-automated quantitative methods, may give us a putative tool to reliably quantify subtle changes which develop on the spinal cord of MS patients over time.

Ristori G, Montesperelli C, Perna A, Cannoni S, Battistini L, Borsellino G, Riccio P, Pesole G, Chersi A, Pozzilli C, Buttinelli C, Salvetti M. · First Chair of Neurology, Dept. Neurosciences, Università "La Sapienza", Rome, Italy. · J Neuroimmunol. · Pubmed #10854659 No free full text.

Abstract: Increasing evidences show a global immune disregulation in multiple sclerosis (MS). The possible involvement of myelin and non-myelin (auto-)antigens in the autoaggressive process as well as the disregulation of both adaptive and innate immunity challenge the concept of specific immunotherapy. T cells at the boundary between innate and adaptive immunity, whose immunoregulatory role is becoming increasingly clear, have recently been shown to bear relevance for MS pathogenesis. Global immune interventions (and type I interferons may be considered as such) aimed at interfering with both innate and acquired immune responses seem to be a most promising therapeutic option in MS.

Pozzilli C, Gherardi M, Patrucco L, Cannoni S, Haggiag S, Faroni J. · Department of Neurological Science, University La Sapienza, Rome, Italy. · Electroencephalogr Clin Neurophysiol Suppl. · Pubmed #10689509 No free full text.

This publication has no abstract.

Ghezzi A, Amato MP, Capobianco M, Gallo P, Marrosu MG, Martinelli V, Milanese C, Moiola L, Milani N, La Mantia L, Patti F, Pozzilli C, Trojano M, Comi G, Zaffaroni M, Anonymous00157. · Centro Studi Sclerosi Multipla, Ospedale di Gallarate, Via Pastori 4, I-20013, Gallarate, Italy. · Neurol Sci. · Pubmed #17603763 No free full text.

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

Pozzilli C, Prosperini L, Sbardella E, De Giglio L, Onesti E, Tomassini V. · Department of Neurological Sciences, La Sapienza University, Viale dell'Università 30, I-00185, Rome, Italy. · Neurol Sci. · Pubmed #16388353 No free full text.

Abstract: Safety, tolerability and efficacy profiles of interferon beta (IFNbeta) therapy in relapsing multiple sclerosis (MS) has been widely verified both in trial settings and in daily clinical practice. However, for a variable percentage of treated patients, it remains only partially effective. In this study, we reported the post-marketing experience of the efficacy of IFNbeta therapy for a large cohort of MS patients regularly attending the MS Outpatient Clinic of "La Sapienza University" in Rome. In this cohort we also sought clinical and paraclinical variables responsible for the clinical course of MS during IFNbeta therapy. Patients that received treatment with one of the IFNbeta formulations for at least 1 year were included. Clinical outcomes (i. e., relapses and disability score) were monitored throughout the entire study period. Magnetic resonance imaging (MRI) scans were performed twice for each subject: at baseline and after 1 year of therapy. The occurrence of more than one relapse during the study period or a sustained disability progression in the Expanded Disability Status Scale (EDSS) score were considered as criteria for the definition of suboptimal clinical response to IFNbeta therapy. During IFNbeta therapy (number of patients 242, mean length of treatment 4.3+/-2.3 years) a reduction in the annualised relapse rate of 59% (p<0.001) was observed. Eighty-six patients (35%) fulfilled the criterion for defining "suboptimal responder" on the basis of relapses, and 69 (28.5%) did the same on the basis of EDSS sustained progression. Twenty-seven (11.1%) patients showed both an EDSS progression and two or more relapses. The presence of T1-enhancing lesions and new T2 hyperintense lesions on the scan performed after the first year of therapy were the best MRI features associated with both the occurrence of relapses during the treatment period (OR for enhancing lesions and relapses 3.6; OR for new T2 lesion and relapses 2.8). The present post-marketing experience confirms the efficacy of IFNbeta in modifying the natural course of MS and encourages the use of paraclinical variables measuring subclinical disease activity as surrogate markers to monitor the clinical course of MS during IFNbeta therapy.

Tomassini V, Paolillo A, Russo P, Giugni E, Prosperini L, Gasperini C, Antonelli G, Bastianello S, Pozzilli C. · Dept. of Neurological Sciences, La Sapienza University, viale dell'Università, 30, 00185 Rome, Italy. · J Neurol. · Pubmed #16151600 No free full text.

Abstract: OBJECTIVES: The aim of this study was to identify clinical, magnetic resonance imaging (MRI) and biological markers predictive of long-term clinical response to interferon beta (IFN beta) therapy in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Sixty-eight patients treated with IFN beta were followed over a 6-year period. Relapse rate and disability progression were evaluated throughout the study. We considered suboptimal clinical response to be either the presence of sustained disability progression, or more than two relapses. Baseline and 12-month demographic, clinical and MRI findings, as well as the development of neutralizing antibodies (NAbs) against IFN beta during the first year of therapy were analyzed as predictors of long-term clinical outcome. RESULTS: "Black holes" on MRI were the best baseline predictor of disability progression (odds ratio [OR] 6.8; p < 0.001). At 1 year, both male gender (OR 4.9; p = 0.009) and NAbs (OR 7.3; p = 0.003) were independently associated with a high risk of developing subsequent disability. The presence of gadolinium enhancement, both at baseline (OR 4.7; p = 0.005) and on the 1-year MRI scan (OR 7.9; p = 0.002), was the unique variable associated with the number of relapses over the study period. CONCLUSIONS: Variables assessable within the first year of treatment significantly influence relapse rate and disability progression in patients with RRMS treated with IFN beta. These findings may help clinicians to make decisions regarding therapy regimen over time, and highlight the need for a prognostic algorithm.

Avolio C, Filippi M, Tortorella C, Rocca MA, Ruggieri M, Agosta F, Tomassini V, Pozzilli C, Stecchi S, Giaquinto P, Livrea P, Trojano M. · Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy. · Mult Scler. · Pubmed #16042227 No free full text.

Abstract: Matrix metalloproteinase-9 (MMP-9) is involved in blood-brain barrier (BBB) disruption in active multiple sclerosis (MS), while MMP-2 seems to be associated with the chronic progressive phase of the disease. Recombinant interferon beta-1a (rIFNbeta-1a) is effective in restoring the BBB. We studied the relationships between serum MMP-9, MMP-2, TIMP-1 and TIMP-2 and different magnetic resonance imaging (MRI) measures of disease activity in MS patients during treatment with rIFNbeta-1a. Twenty-one relapsing-remitting (RR) MS patients underwent longitudinally simultaneous blood withdrawals and MRI (before and after standard dose (SD) and triple dose (TD) of gadolinium (Gd)) examinations before and during 48 weeks of rIFNbeta-1a (Rebif 22 mcg three times a week) treatment. Serum MMP-9, MMP-2, TIMP-1 and TIMP-2 were measured, MMP-9 to TIMP-1 and MMP-2 to TIMP-2 ratios were calculated and the numbers of Gd-SD, Gd-TD, new-Gd-SD, new-Gd-TD and new-T2 lesions counted. Serum MMP-9/TIMP-1 ratio (P < 0.0001), as well as the numbers of 'active' lesions (P ranging from 0.0004 to 0.005) decreased during treatment Moreover, serum MMP-9/TIMP-1 ratio proved to be a good positive predictor (estimate = 0.85; P < 0.05) of the numbers of MRI Gd-TD active lesions. These data confirm that serum MMP-9/TMIP-1 ratio may be viewed as a reliable marker and may be predictive of MRI activity in RR MS.

Fazekas F, Sørensen PS, Filippi M, Ropele S, Lin X, Koelmel HW, Fernandez O, Pozzilli C, O'Connor P, Enriquez MM, Hommes OR, Anonymous00202. · Department of Neurology, Medical University of Graz, Graz, Austria. · Mult Scler. · Pubmed #16042226 No free full text.

Abstract: BACKGROUND: Monthly application of high-dose intravenous immunoglobulin (IVIG) to patients with secondary progressive multiple sclerosis (MS) showed no clinical benefit in the European Study on Immunoglobulin in MS (ESIMS). Magnetic resonance imaging (MRI) results may provide insights into the morphologic consequences of such treatment. METHODS: A total of 318 patients (mean age 44 +/- 7 years) were enrolled in 31 European and Canadian centres and treated monthly with 1 g/kg body weight of IVIG or equivalent amounts of albumin 0.1% for 27 months. MRI was performed at baseline and after 12 and 24 months and comprised of conventional dual-echo T2-weighted and T1-weighted scans before and after application of 0.1 mmol/kg Gd-DTPA. RESULTS: Similar to clinical variables, MRI measures at baseline were well comparable between treatment groups except for a somewhat lower mean number of contrast-enhancing lesions and number of active scans in IVIG-treated patients. Over the trial period there was almost no change of the T2-lesion load and the 'black hole' volume in both treatment groups and the cumulative number of contrast-enhancing lesions were similar. There was only a trend for fewer new or enlarged T2-lesions in IVIG patients, which disappeared after correction for the imbalance in the number of contrast-enhancing lesions at baseline. Brain volume in terms of a partial cerebral fraction decreased significantly less with IVIG than placebo treatment (final visit: -0.62 -/+ 0.88% versus -0.88 +/- 0.91%; P=0.009). This difference remained statistically significant with correction for active lesions at baseline (P=0.02) and was seen primarily in male patients and those with an Expanded Disability Status Scale score > or = 6 and no relapses in the two years before the study. CONCLUSION: The absence of significant differences in conventional MRI measures between both treatment groups parallels the negative clinical results of ESIMS. The causes for and possible long-term clinical effects of a lower rate of brain volume loss in IVIG patients should be explored further.

Ghezzi A, Amato MP, Capobianco M, Gallo P, Marrosu G, Martinelli V, Milani N, Milanese C, Moiola L, Patti F, Pilato V, Pozzilli C, Trojano M, Zaffaroni M, Comi G, Anonymous00201. · Centro Studi Sclerosi Multipla, Ospedale di Gallarate, Gallarate, Italy. · Mult Scler. · Pubmed #16042224 No free full text.

Abstract: OBJECTIVE: Immunomodulatory drugs (IDs) (interferon beta (IFNgamma) and glatiramer acetate (GA)) reduce relapse rate and disease progression in relapsing remitting multiple sclerosis (RRMS) but extensive data are not available on the effectiveness and tolerability of these drugs in childhood or adolescence. The aim of this study was to evaluate the impact of IFNbeta and GA in MS patients treated before 16 years of age. METHODS: A research group (Immunomodulatory Treatment of Early onset MS (ITEMS)) was promoted in Italy to collect a large series of patients affected by clinically definite and RRMS and treated with IDs before 16 years of age. Fifteen centres recognized subjects suitable for inclusion: 76 patients (52 females) were collected with a mean age at onset of 12.4 (SD 2.5) years, a mean disease duration of 18.6 (SD 14.7) and a relapse rate of 3.1 (SD 2.9). RESULTS: Results were evaluated in 65 (45 females) subjects with a pretreatment and a treatment duration >3 months: 38 were treated with IFNbeta-1a once weekly (Avonex), 18 with IFNbeta three times weekly (16 with Rebif, 2 with Betaferon) and nine with GA (Copaxone).The mean pretreatment period was respectively 20, 18 and 9.2 months. The treatment duration lasted respectively 23.3, 40.7 and 33.3 months. The mean annualized relapse rate decreased dramatically during the treatment: from 2.4 to 0.4 in the Avonex group, from 3.2 to 0.8 in the Rebif-Betaferon group and from 2.8 to 0.25 in the GA group. The mean final EDSS scores were respectively (in brackets the initial scores): 1.3 (1.4), 1.6 (1.8) and 0.6 (1.1). In the whole group, the final score was unchanged or reduced in all subjects except eight. Clinical side effects were recorded in 41/65 subjects (mainly in subjects treated with IFNbeta), abnormal laboratory findings were observed in 13/65 subjects: they were transient in most cases. IFNgamma was stopped in six cases: in four because of inefficacy and in two cases because of side effects. CONCLUSIONS: Sixty-five clinically definite MS subjects were treated during childhood or adolescence with IDs. The treatment reduced the relapse rate and the progression of the disease in most cases. Side effects were common in subjects treated with IFNbeta but were well tolerated in most cases.

Sormani MP, Bruzzi P, Beckmann K, Kappos L, Miller DH, Polman C, Pozzilli C, Thompson AJ, Wagner K, Filippi M. · Neuroimaging Research Unit, Dept. of Neurology, Scientific Institute and University Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. · J Neurol. · Pubmed #16021360 No free full text.

Abstract: Whereas the effect of interferons (IFNs) on magnetic resonance imaging (MRI) outcome measures in patients with multiple sclerosis (MS) has been convincingly shown, little work has been done to define the between-patient heterogeneity of treatment response. Our aim was to assess the distribution of the effect of IFNbeta-1b in terms of reduction of active T2 lesions in patients with MS. Using a fixed and a random effects model, we investigated the distribution of active T2 lesions reduction over a three-year follow up in response to treatment with 250 mcg IFNbeta-1b every other day in 695 patients with a complete MRI data-set of the 718 (97 %) enrolled in the European, multicenter, randomised, double-blind, placebo-controlled trial of secondary progressive MS. The two statistical models consistently showed that the between-patient response to IFNbeta-1b, in terms of reduction of active T2 lesions, is highly heterogeneous. Whereas treated patients have a high probability (more than 65%) of showing an active T2 lesion reduction equal to or greater than 60%, there is also a 7% probability for treated patients not to show any reduction of MRI-detected disease activity during the course of the trial or even to have an increase of T2 active lesions. This study might be regarded as a first step toward the definition of markers potentially useful to identify IFNbeta treatment responders and non-responders with regard to T2 lesion activity.

Hommes OR, Sørensen PS, Fazekas F, Enriquez MM, Koelmel HW, Fernandez O, Pozzilli C, O'Connor P. · European Charcot Foundation, Nijmegen, Netherlands. · Lancet. · Pubmed #15451222 No free full text.

Abstract: BACKGROUND: Several double-blind placebo-controlled trials of relapsing-remitting multiple sclerosis have shown beneficial effects of intravenous immunoglobulin (IVIG) on relapse rate and disability. The European Study on Intravenous Immunoglobulin in Multiple Sclerosis set out to test IVIG in the secondary progressive phase of the disease. METHODS: 318 patients with clinically definite secondary progressive multiple sclerosis (mean age 44 years [SD 7]) were randomly assigned IVIG 1 g/kg per month (n=159) or an equivalent volume of placebo (albumin 0.1%; n=159) for 27 months. After baseline investigation, clinical assessments were made every 3 months and MRI was repeated after 12 months and 24 months. The primary outcome was confirmed worsening of disability as defined by the time to first confirmed progression on the expanded disability status scale (EDSS). Analyses were by intention to treat. FINDINGS: 19 patients in the IVIG group and 39 in the placebo group terminated study treatment prematurely but were included in the analyses. IVIG treatment had no beneficial effect on time to confirmed EDSS progression (hazard ratio 1.11 [95% CI 0.80-1.53] for IVIG versus placebo). The annual relapse rate was 0.46 in both groups. No significant differences between the treatment groups were found in any of the other clinical outcome measures or in the change of T2-lesion load over time. The treatment was generally well tolerated, although deep venous thrombosis, pulmonary embolism, or both occurred in seven patients with risk factors for thromboembolism (IVIG six, placebo one). INTERPRETATION: Treatment with IVIG in this study did not show any clinical benefit and therefore cannot be recommended for patients with secondary progressive multiple sclerosis.

Pozzilli C, Palmisano L, Mainero C, Tomassini V, Marinelli F, Ristori G, Gasperini C, Fabiani M, Battaglia MA. · Department of Neurological Sciences, La Sapienza University, Rome, Italy. · Mult Scler. · Pubmed #15327043 No free full text.

Abstract: Caregivers of persons with multiple sclerosis (MS) exhibit less satisfaction with quality of life with respect to the general population. To assess the relationship between depression in caregivers and health status profiles of MS patients, we examined data from 133 patients and their respective caregivers, as a part of a prospective randomized trial aimed to investigate the effectiveness of home-based care. Patients were evaluated at baseline and one year later with measures of physical and psychological impairment and health status (SF-36 Health Survey). Caregivers' psychological morbidity was assessed by the Profile of Mood State (POMS) at the same time points. An improvement of patients' health status as measured in four out of eight SF-36 dimensions was observed over the study period, while psychological morbidity of their caregivers did not change significantly. Depression in caregivers was related to physical, emotional and health status of the patients at baseline and/or at 12-month follow-up. Changes in the degree of depression of caregivers were also associated with changes in disability and health status of the patients. This study confirms and extends in a home-care setting previous findings on relationships between patients' status and depression in caregivers. It suggests that the caregiver is an appropriate and independent target for more focused therapeutic strategies.

Solari A, Motta A, Mendozzi L, Pucci E, Forni M, Mancardi G, Pozzilli C, Anonymous00397. · Laboratory of Epidemiology, National Neurological Institute C. Besta, via Celoria 11, 20133 Milan, Italy. · J Neurol Sci. · Pubmed #15240203 No free full text.

Abstract: CONTEXT: Cognitive compromise is one of the main contributing factors to activity and participation restrictions in people with multiple sclerosis (MS). Computer-aided programs are used for retraining memory and attention, but data on the efficacy of these interventions are scarce. OBJECTIVE: To assess the efficacy of computer-aided retraining of memory and attention in people with MS impaired in these abilities. DESIGN AND SETTING: Randomized, double-blind, controlled trial. PARTICIPANTS: Outpatients (n=82) with subjective complaints of poor attention or memory, confirmed by a score <80th percentile in at least two tests of the Brief Repeatable Battery of Neuropsychological Tests (BRBNT). INTERVENTIONS: Participants were randomized to two computer-assisted retraining interventions: memory and attention (study arm), and visuo-constructional and visuo-motor coordination (control arm). Both groups received 16 training sessions over 8 weeks. OUTCOME MEASURES: Improvement of 20% or more in at least two BRBNT test scores at 8 weeks compared to baseline (primary end point). Changes in depression and health-related quality of life. RESULTS: An improvement occurred in 45% of study patients vs. 43% of control patients (odds ratio 1.07, 95% confidence interval 0.44-2.64). The study treatment was better than the control treatment only on the word list generation test (p=0.016). CONCLUSIONS: This trial does not support the efficacy of specific memory and attention retraining in MS.

Mainero C, Inghilleri M, Pantano P, Conte A, Lenzi D, Frasca V, Bozzao L, Pozzilli C. · Section of Clinical Neurology, Department of Neurological Sciences, University of Rome La Sapienza, Italy. · Neurology. · Pubmed #15184612 No free full text.

Abstract: BACKGROUND: 3,4-diaminopyridine (3,4-DAP), a potassium (K+) channel blocker, improves fatigue and motor function in multiple sclerosis (MS). Although it was thought to do so by restoring conduction to demyelinated axons, recent experimental data show that aminopyridines administered at clinical doses potentiate synaptic transmission. OBJECTIVE: To investigate motor cerebral activity with fMRI and transcranial magnetic stimulation (TMS) after a single oral dose of 3,4-DAP in patients with MS. METHODS: Twelve right-handed women (mean +/- SD age 40.9 +/- 9.3 years) underwent fMRI on two separate occasions (under 3,4-DAP and under placebo) during a simple motor task with the right hand. FMRI data were analyzed with SPM99. After fMRI, patients underwent single-pulse TMS to test motor threshold, amplitude, and latency of motor evoked potentials, central conduction time, and the cortical silent period; paired-pulse TMS to investigate intracortical inhibition (ICI) and intracortical facilitation (ICF); and quantitative electromyography during maximal voluntary contraction. RESULTS: FMRI motor-evoked brain activation was greater under 3,4-DAP than under placebo in the ipsilateral sensorimotor cortex and supplementary motor area (p < 0.05). 3,4-DAP decreased ICI and increased ICF; central motor conduction time and muscular fatigability did not change. CONCLUSION: 3,4-DAP may modulate brain motor activity in patients with MS, probably by enhancing excitatory synaptic transmission.

Mainero C, Caramia F, Pozzilli C, Pisani A, Pestalozza I, Borriello G, Bozzao L, Pantano P. · Section of Clinical Neurology, Department of Neurological Sciences, University of Rome "La Sapienza", Rome, Italy. · Neuroimage. · Pubmed #15006652 No free full text.

Abstract: Functional magnetic resonance imaging (fMRI) data on motor function have shown adaptive functional changes related to brain injury in multiple sclerosis (MS). We investigated whether patients with MS have altered fMRI activation patterns during attention and memory tasks, and whether functional changes in the brain correlate with the extent of overall tissue damage on conventional MRI. Twenty-two right-handed patients with relapsing-remitting MS (RRMS) and no or only mild deficits at neuropsychological testing and 22 matched healthy subjects were scanned during the Paced Auditory Serial Addition Test (PASAT) and a recall task. fMRI data were analyzed using Statistical Parametric Mapping (SPM99). The relation between fMRI changes during both tasks and T2 lesion load was investigated. During both tasks, patients exhibited significantly greater brain activation than controls and recruited additional brain areas. Task-related functional changes were more significant in patients whose performance matched that of controls than in patients with a lower performance. During the PASAT, brain functional changes involved the right supplementary motor area and cingulate, the bilateral prefrontal, temporal and parietal areas, whereas during the recall task they involved the prefrontal and temporal cortex and basal ganglia bilaterally, and the left thalamus. In patients, activation in specific brain areas during performance of both tasks positively correlated with T2 brain lesions. Patients with RRMS exhibit altered patterns of activation during tasks exploring sustained attention, information processing and memory. During these tasks, fMRI activity is greater in patients with better cognitive function than in those with lower cognitive function. Functional changes in specific brain areas increase with increasing tissue damage suggesting that they may also represent adaptive mechanisms that reflect underlying neural disorganization or disinhibition, possibly associated with MS.