A nurse-led, telephone-based patient support program for improving adherence in patients with relapsing-remitting multiple sclerosis using interferon beta-1a: Lessons from a consumer-based survey on adveva® PSP.

Background: Evidence suggests that organizational models that provide care interventions including patient support programs may increase patient adherence to multiple sclerosis (MS) therapies by providing tailored symptom management, informational support, psychological and/or social support, lifestyle changes, emotional adjustment, health education, and tailored coaching, thus improving patients' overall quality of life across the disease course. Objective: The main objective of this study was to describe MS patients' self-reported experience of a nurse-led, telephone-based PSP and to explore its potential role in improving disease and therapy management skills. Methods: Survey data were analyzed from a subset of patients relapsing-remitting MS (RRMS) using interferon beta-1a already registered in the adveva® PSP from three Italian multiple sclerosis centers with a consolidated experience in RRMS disease, treatment management, and PSP programs. Results: In total, 244 patient data at baseline were analyzed, of which 115 had a follow-up of at least 6 months. Results from this study provide an early view into the role of this PSP in improving the patients reported overall experience regarding disease management and injectable therapy, thus potentially ameliorating treatment adherence and decreasing health care cost. Moreover, study findings confirm the role of providing a patient-focused support by addressing non-medication-related topics in the PSP consultations. Indeed, patients involved in the adveva® PSP program reported a better psychological status in the follow up as demonstrated by an increased optimism regarding their future, tolerance of disease uncertainty, and their perceived ability to benefit from external help and social support (informal caregivers). Conclusions: As such, it is reasonable to conclude that the involvement in the adveva® PSP and the PSP's assistance in guiding patients on proper treatment self-management techniques is of great value to patients as it might contribute to improving engagement in their health care journey in terms of perceived self-care skills, emotional coping toward the future and the unpredictability of the disease course and their general attitudes toward the injection itself, involving pain tolerance.

Mapping the Progressive Treatment-Related Reduction of Active MRI Lesions in Multiple Sclerosis.

Objective: To assess treatment-related spatio-temporal dynamics of active MRI lesions in relapsing-remitting multiple sclerosis (RRMS) patients. Methods: We performed a post-hoc analysis of MRI data acquired at weeks 4, 8, 12, and 16, in RRMS patients from the multicenter randomized IMPROVE study, which compares patients treated with 44 mcg subcutaneous interferon ß-1a three times weekly (n = 120) versus placebo (n = 60). We created lesion probability maps (LPMs) of the cumulative combined unique active (CUA) lesions in each patient group at each time point. Group differences were tested in terms of lesion spatial distribution and frequency of occurrence. Results: Spatial distribution of CUA lesions throughout the study was less widespread in the treated than placebo group, with a 50% lower lesion accrual (24 vs. 48 cm3/month). Similar results were obtained with the WM tract analysis, with a reduction ranging from -47 to -66% in the treated group (p < 0.001). On voxel-wise analysis, CUA lesion frequency was lower in the treated group than the placebo group at week 4 (p = 0.07, corrected), becoming particularly pronounced (p ≤ 0.03, corrected) from week 8 onwards in large clusters of WM tracts, with peaks along fronto-parietal parts of the corticospinal tract, thalamic radiation, and superior longitudinal fascicle. Conclusion: LPM showed, in the short term, a treatment-related reduction of MRI lesion activity in RRMS patients in specific, clinically relevant brain locations. Such a quantitative approach might be a promising additional endpoint in future MS studies alongside the number and volume of WM lesions. Clinical Trial Registration: ClinicalTrials.gov identifier NCT00441103.

A Single Nucleotide ADA Genetic Variant Is Associated to Central Inflammation and Clinical Presentation in MS: Implications for Cladribine Treatment.

In multiple sclerosis (MS), activated T and B lymphocytes and microglial cells release various proinflammatory cytokines, promoting neuroinflammation and negatively affecting the course of the disease. The immune response homeostasis is crucially regulated by the activity of the enzyme adenosine deaminase (ADA), as evidenced in patients with genetic ADA deficiency and in those treated with cladribine tablets. We investigated in a group of patients with MS the associations of a single nucleotide polymorphism (SNP) of ADA gene with disease characteristics and cerebrospinal fluid (CSF) inflammation. The SNP rs244072 of the ADA gene was determined in 561 patients with MS. Disease characteristics were assessed at the time of diagnosis; furthermore, in 258 patients, proinflammatory and anti-inflammatory molecules were measured in the CSF. We found a significant association between rs244072 and both clinical characteristics and central inflammation. In C-carriers, significantly enhanced disability and increased CSF levels of TNF, IL-5 and RANTES was observed. In addition, lower CSF levels of the anti-inflammatory cytokine IL-10 were found. Finally, the presence of the C allele was associated with a tendency of increased lymphocyte count. In MS patients, ADA SNP rs244072 is associated with CSF inflammation and disability. The selective targeting of the ADA pathway through cladribine tablet therapy could be effective in MS by acting on a pathogenically relevant biological mechanism.

A pilot study on the use of interferon beta-1a in early Alzheimer's disease subjects.

Despite the fact that multiple sclerosis (MS) and Alzheimer's disease (AD) share common neuroimmunological features, interferon beta 1a (IFNß1a), the well-established treatment for the prevention of disease progression and cognitive decline in MS patients, has never been used in AD. We evaluated the safety and efficacy of IFNß1a in subjects affected by mild-to-moderate AD in a double-blind, randomized, placebo-controlled, multicenter pilot study. Forty-two early Alzheimer's patients were randomized to receive either a 22 mcg subcutaneous injection of IFNß1a or placebo three times per week. A treatment period of 28 weeks was followed by 24 weeks of observation. IFNß1a was well tolerated and adverse events were infrequent and mild to moderate. Although not statistically significant, a reduction in disease progression during follow-up was measured in IFNß1a-treated patients by the Alzheimer's Disease Assessment Scale cognitive subscale. Interestingly, the treatment group showed significant improvements in the Instrumental Activities of Daily Living and Physical Self-maintenance Scale. This study suggests that IFNß1a is safe and well tolerated in early AD patients, and its possible beneficial role should be further investigated in larger studies.

Cladribine interferes with IL-1ß synaptic effects in experimental multiple sclerosis.

Alterations of glutamate-mediated synaptic transmission occur in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the animal model of MS. Here we investigated whether intracerebroventricular (Icv) administration of cladribine has effects on EAE. Icv infusion of cladribine reduced the clinical deficits of EAE mice and reversed EAE-induced enhancement of excitatory postsynaptic current (sEPSC) frequency, a neurophysiological measure of glutamatergic synaptopathy associated with central inflammation. Cladribine failed to interfere with EAE-induced microglial and astroglial activation, but blocked EAE synaptic alterations by interfering with interleukin-1ß effects. Cladribine possesses neuroprotective properties in experimental MS that are independent of its peripheral immunosuppressant action.

Patient adherence to and tolerability of self-administered interferon ß-1a using an electronic autoinjection device: a multicentre, open-label, phase IV study.

BACKGROUND: Achieving good adherence to self-injected treatments for multiple sclerosis can be difficult. Injection devices may help to overcome some of the injection-related barriers to adherence that can be experienced by patients. We sought to assess short-term adherence to, and tolerability of, interferon (IFN) ß-1a administered via electronic autoinjection device in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: BRIDGE (RebiSmart to self-inject Rebif serum-free formulation in a multidose cartridge) was a 12-week, multicentre, open-label, single-arm, observational, Phase IV study in which patients self-administered IFN ß-1a (titrated to 44 µg), subcutaneously (sc), three times weekly, via electronic autoinjection device. Patients were assessed at baseline and 4-weekly intervals to Week 12 or early termination (ET) for: physical examinations; diary card completion (baseline, Weeks 4, 8 only); neurological examinations (baseline, Week 12/ET only); MS Treatment Concern Questionnaire (MSTCQ; Weeks 4, 8, 12 only); Convenience Questionnaire (Week 12 only); Hospital Anxiety and Depression Scale (HADS); and Paced Auditory Serial Addition Task (PASAT; baseline only). Adherence was defined as administration of ≥ 80% of scheduled injections, recorded by the autoinjection device. RESULTS: Overall, 88.2% (105/119; intent-to-treat population) of patients were adherent; 67.2% (80/119) administered all scheduled injections. Medical reasons accounted for 35.6% (31/87) of missed injections, forgetfulness for 20.6% (18/87). Adherence did not correlate with baseline Expanded Disability Status Scale (P = 0.821) or PASAT (P = 0.952) scores, or pre-study therapy (P = 0.303). No significant changes (baseline-Week 12) in mean HADS depression (P = 0.482) or anxiety (P = 0.156) scores were observed. 'Overall convenience' was the most important reported benefit of the autoinjection device. Device features associated with handling and ease of use were highly rated. Mean MSTCQ scores for 'flu-like' symptoms (P = 0.022) and global side effects (P = 0.002) significantly improved from Week 4-12. Mean MSTCQ scores for pain at injection site and injection pain increased from Week 4-12 (P < 0.001). Adverse events were mild/moderate. No new safety signals were identified. CONCLUSION: Convenience and ease of use of the autoinjection device may improve adherence and, therefore, outcomes, in patients with RRMS receiving sc IFN ß-1a. TRIAL REGISTRATION: EU Clinical Trials Register (EU-CTR; http://www.clinicaltrialsregister.eu): 2009-013333-24.

CD161(high)CD8+T cells bear pathogenetic potential in multiple sclerosis.

To identify differentially expressed genes in multiple sclerosis, microarrays were used in a stringent experimental setting-leukapheresis from disease-discordant monozygotic twins and gene expression profiling in CD4(+) and CD8(+) T-cell subsets. Disease-related differences emerged only in the CD8(+) T-cell subset. The five differentially expressed genes identified included killer cell lectin-like receptor subfamily B, member 1, also known as natural killer receptor protein 1a/CD161, presented by the International Multiple Sclerosis Genetics Consortium as one of the non-MHC candidate loci. Flow cytometric analysis on peripheral blood of healthy donors and patients with multiple sclerosis and rheumatoid arthritis confirmed an upregulation of CD161 at the protein level, showing also a significant excess of CD161(high)CD8(+) T cells in multiple sclerosis. This subset prevalently included chemokine (C-C motif) receptor 6(+), cytokine-producing, effector-memory T cells with proinflammatory profiles. It also included all circulating interleukin-17(+)CD8(+) T cells. In the CD161(high)CD8(+) subset, interleukin-12 facilitated proliferation and interferon-γ production, with CD161 acting as a co-stimulatory receptor. CD161(+)CD8(+)CD3(+) T cells producing interferon-γ were part of intralesional immune infiltrates and ectopic B cell follicles in autopsy multiple sclerosis brains. Variations of CD161 expression on CD8(+) T cells identify a subset of lymphocytes with proinflammatory characteristics that have not been previously reported in multiple sclerosis and are likely to contribute to disease immunopathology.

Differential patterns of interhemispheric functional disconnection in mild and advanced multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis may present altered patterns of connectivity between the two brain hemispheres. To date, only transcallosal connectivity between the two primary motor cortices (M1) has been investigated functionally in patients with multiple sclerosis. OBJECTIVES: The aim of this study was to investigate whether connectivity between the dorsal premotor cortex and the contralateral M1 was altered in patients with multiple sclerosis, and to see whether clinical progression is accompanied by exacerbated dorsal premotor cortex-M1 disconnectivity. METHODS: A twin-coil transcranial magnetic stimulation approach was used to investigate both excitatory and inhibitory interhemispheric connections between the left dorsal premotor cortex and the contralateral M1 in 18 multiple sclerosis patients without disability, in 18 multiple sclerosis patients with advanced disease and in 12 age-matched healthy subjects. To activate distinct inhibitory and facilitatory transcallosal pathways, the intensity of dorsal premotor cortex stimulation was adjusted to be either suprathreshold (110% of resting motor threshold) or subthreshold (80% of active motor threshold). RESULTS: Our sample of patients with multiple sclerosis showed altered patterns of interhemispheric dorsal premotor cortex-M1 functional connectivity even in the absence of clinical deficits. Facilitatory connections originating from dorsal premotor cortex were reduced in multiple sclerosis patients with or without disability, while inhibitory dorsal premotor cortex-M1 connections were altered only in disabled patients. CONCLUSIONS: The current study demonstrates that functional excitatory connectivity originating from non-primary motor areas is compromised in multiple sclerosis patients even in the absence of clinical disability. Clinical disease progression leads to an impairment of both excitatory and inhibitory transcallosal connections.

Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability.

BACKGROUND: Fatigue is a major problem in multiple sclerosis (MS), and its association with MRI features is debated. OBJECTIVE: To study the correlation between fatigue and lesion load, white matter (WM), and grey matter (GM), in MS patients independent of disability. METHODS: We studied 222 relapsing remitting MS patients with low disability (scores or=5; n=197) and low-fatigue groups (FSS

Predictors of quality of life among patients with multiple sclerosis: an Italian cross-sectional study.

The Functional Assessment of Multiple Sclerosis (FAMS) quality of life (QoL) instrument is a disease-specific, self-report questionnaire that was developed originally for US English-speaking patients. Here, the psychometric properties of the FAMS QoL questionnaire for Italian-speaking patients with multiple sclerosis (MS) are evaluated and compared with the results from the original FAMS validation survey (n=377). Eighteen Italian centers and 344 patients with MS participated in the study. The overall reliability (as expressed by Cronbach's alpha value) of the FAMS score, and its subscale scores, was always over the threshold of 0.8. Patients with benign MS showed a better overall QoL compared with patients with relapsing-remitting MS (RRMS; p=0.017), whereas patients with RRMS had a better QoL than patients with primary progressive MS (PPMS). No difference in QoL was found between patients with PPMS and those with secondary progressive MS. The Italian FAMS questionnaire is a valid measure to assess the QoL concerns of patients with MS. FAMS is also easy to administer and is well accepted by patients.

Adaptive cortical changes and the functional correlates of visuo-motor integration in relapsing-remitting multiple sclerosis.

Cortical reorganization has been demonstrated during performance of a motor task in patients with multiple sclerosis. Converging evidence suggests that changes in gray matter volume represent an early hallmark of the disease. We used functional MRI to investigate the role of cortical adaptive mechanisms in maintaining visuo-motor function in the face of structural damage. Two cohorts of patients with clinically definite relapsing-remitting multiple sclerosis were compared with healthy controls matched for demographic, motor and cognitive characteristics during the performance of a visuo-motor integration task. Direct comparison between the two groups demonstrated a greater response of the contralateral dorsal premotor cortex and of the ipsilateral superior parietal cortex in relapsing-remitting multiple sclerosis patients. The functional MRI changes in these areas were strongly correlated with decreased gray matter volumes and increased lesion burden, respectively. Our study demonstrated a selective involvement of the parieto-premotor circuitry in a relatively early stage of the disease, which was not influenced by clinical, motor or cognitive variables. Moreover these results confirm the potential for functional recovery and the adaptive role of these areas in the motor reorganization of multiple sclerosis patients.

Imaging brain damage in first-degree relatives of sporadic and familial multiple sclerosis.

OBJECTIVE: Our objective was to assess brain damage in first-degree relatives of patients with sporadic and familial multiple sclerosis (MS). METHODS: Asymptomatic first-degree relatives of sporadic (sMS, n = 152) and familial MS (fMS, n = 88) and healthy volunteers (NC, n = 56) underwent brain MRI and magnetization transfer (MT) imaging on a mobile MR scan. On MR examinations, we visually assessed white matter (WM) lesions and quantified WM lesion volumes, brain volumes, and MT ratio (MTr) in lesions and normal-appearing WM (NAWM). RESULTS: A lesional MR pattern similar to that of MS patients was found in 4% sMS and 10% fMS. In these WM lesions, MTr was lower (p < 0.0001) than in the WM of NC. In contrast, there was no difference in NAWM-MTr and brain volume values between the three groups. INTERPRETATION: Focal brain abnormalities indistinguishable from those of MS occur in asymptomatic first-degree relatives of MS patients. These are twice more frequent in fMS than in sMS but do not lead to the widespread tissue damage commonly found in MS patients. Although there is a genetic susceptibility to develop brain abnormalities suggestive of focal demyelination in first-degree relatives of MS patients, other factors are probably critical for the development of a diffuse, clinically relevant, pathology.

Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis.

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.

Effectiveness of interferon beta treatment in relapsing-remitting multiple sclerosis: an Italian cohort study.

RATIONALE, AIMS AND OBJECTIVES: Randomized clinical trials (RCTs) have provided evidence for the efficacy of interferon beta (IFNbeta) in the treatment of relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to evaluate the effectiveness of IFNbeta treatment in clinical practice. METHODS: This was a national, multicentre, observational study of patients with confirmed RRMS. Demographic, clinical and therapeutic data were retrospectively collected for each patient enrolled in the study. RESULTS: The study cohort consisted of 427 patients exposed to and 245 never exposed to IFNbeta treatment during the study period (for a total 2297 patient-years of follow-up). Among the exposed patients, 215 were initially untreated and then began IFNbeta later in the follow-up period; 137 of these patients were exposed to IFNbeta for more than 2 years. In these patients, IFNbeta treatment reduced the mean relapse rate by 24.2%[95% confidence interval (CI): 5.8-42.5%]. For 640 of the 672 patients enrolled in the study, it was possible to calculate the area under the disability/time curve compared to that present at baseline. A total of 117 (18.3%) patients displayed disability progression. Adjustment of the disability progression rates for potential confounders and/or for propensity scores by Poisson regression model resulted in relative risks for patients exposed to IFNbeta treatment compared to those never exposed to IFNbeta of 0.87 (95% CI: 0.56-1.34) after an exposure of < or = 2 years, and of 0.35 (95% CI: 0.21-0.60) after an exposure of >2 years. CONCLUSIONS: These findings suggest that the evidence from RCTs on the treatment of RRMS with IFNbeta has been effectively translated into routine clinical practice.

The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: a monthly MRI study after triple-dose gadolinium-DTPA.

OBJECTIVE: To examine the relationship between inflammation and brain atrophy in patients with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS). METHODS: Monthly triple-dose gadolinium (Gd/DTPA)-enhanced MRI scans over 6 months were obtained in 62 consecutive CIS patients with an abnormal baseline MRI scan. Subsequently MRI was performed at months 12 and 18. Patients who developed a clinically definite MS (i. e., a second clinical episode) ended the study at the time of the relapse. For each scan, the number and volume of newly active lesions (Gd-enhancement/new or newly enlarging T2 lesion that did not enhance), and the number and volume of T2 hyperintense lesions (T2-LL) and T1-black holes (T1-LL) were calculated. The percentage of brain volume changes (PBVC) was assessed using a fully automated technique (SIENA; Structural Image Evaluation using Normalization of Atrophy). RESULTS: Twenty-four (39%) developed clinically definite MS by month 18. Thirty-eight (61%) were relapsefree and completed the MRI follow-up. Relapse-free patients showed a progressive median increase between baseline and month 18 in T1-LL (25%, p<0.001), but not in T2-LL (8.5%, p=ns). PBVC decreased by 1.1% (p<0.001) in a time-dependent pattern (Kendall coefficient of concordance=0.85). Exploratory subgroup analyses showed a trend towards progressive decreases in brain volume in active patients (i. e., those with at least one newly active lesion during monthly MRI scanning; Spearman's R=-0.61; p<0.001), but not among inactive patients (Spearman's R=-0.10; p=0.53). Significant differences in median brain volume changes between the active and inactive patient groups were found at months 12 and 18; the difference detected at month 6 was not significant. The cumulative number and volume of new Gd-enhancing lesions developed during the 6 months of frequent MRI scanning were highly correlated with PBVC over the 18-month period (Spearman R values were 0.73 and 0.85, respectively). The strongest predictor of PBVC at 18 months was the cumulative volume of newly active lesions during frequent MRI scanning [ss=-0. 83, standard error (SE)=0.07, p<0.001]. CONCLUSIONS: This study shows that visible inflammation as detected by monthly, triple-dose Gd-enhanced MRI is an important factor in the pathogenesis of brain tissue loss in CIS patients. However, inflammation and brain atrophy do not proceed in parallel: atrophy appeared only after a delay of months following acute inflammation. Frequent MRI scanning allows for the detection of CIS patients who will develop brain atrophy in the short-term.

Cost-analysis of relapsing-remitting multiple sclerosis in Italy after the introduction of new disease-modifying agents.

BACKGROUND AND OBJECTIVE: During the last decade, several agents have proven to be effective in the treatment of relapsing-remitting multiple sclerosis (RRMS), for example interferon-beta (IFNß) and glatiramer acetate. This study aimed to perform a cost-analysis of the treatment of patients with RRMS in Italy after the introduction of these new agents. STUDY DESIGN: This was a retrospective observational study with systematic patient inclusion. METHODS AND RESULTS: Data gathered from 630 patients with confirmed RRMS over a 2-year period were evaluated. Overall, the direct cost over 2 years reached €11 073 100 thousand, corresponding to a per-patient cost of €17 576 (year of costing, 2001). The cost of disease-modifying agents represented approximately 77% of the total expenditure. IFNß accounted for 94% of the expense of disease-modifying agents, corresponding to a 2-year cost per patient of €20 223. Although glatiramer acetate and immunoglobulins were also associated with a high level of expense, these were prescribed in only 3.8% and 1.1% of patients, respectively. Using regression analyses, IFNß therapy, disability, number of days spent in hospital per year and the frequency of magnetic resonance imaging procedures were the main predictors of total costs. CONCLUSION: Based on the results of this study, IFNß treatment considerably modified the management of RRMS and was associated with a rise in cost of treatment per patient.

Teleradiology system accessible through a common web browser.

PURPOSE: To describe a teleradiology system accessible via a PC and a common web browser. MATERIAL AND METHODS: A dedicated system is connected to several radiological imagers (DR, US, CT, MR) with DICOM standard and TCP/IP protocol. The images are visualised in a common web browser on a remote PC by connecting to the dedicated web-site. Compressed images are visualised on a web page. Special toolbars allow specific operations to be performed on the images (brightness-contrast, zoom, distance measurement and ROI defining) and the communication with the radiological centre. RESULTS: The graphic interface is user-friendly and does not require any special knowledge, except for basic PC and internet surfing. Image compression can be set to preserve image quality, and image transfer is fast. CONCLUSIONS: The system presented overcomes the limitations of conventional teleradiology systems since it requires no special network or dedicated software, allowing for visualisation of a radiological examination on a PC and a common web browser.

Fate of neutralizing and binding antibodies to IFN beta in MS patients treated with IFN beta for 6 years.

An increasing number of evidence is showing that during prolonged treatment of relapsing-remitting multiple sclerosis (RRMS) with interferon (IFN) beta 1a or IFN beta 1b, the patients may develop serum anti-IFN antibody. It has been argued that some of the RRMS patients receiving IFN beta, who developed antibodies to IFN, lose them over time even though the treatment continues. To gain further insights into this issue, we performed a study to establish what happened to binding antibodies (BAB) and neutralizing antibodies (NAB) in 42 RRMS patients treated for 6 years with IFN beta 1a and/or IFN beta 1b. While the data of BAB analysis did not allow to reach definite conclusions, the results on NAB development confirm that the presence of this type of antibodies is transitory; in fact, most of the positive patients reverted to seronegative, although the IFN treatment is still ongoing; the only patients who were positive for NAB at 6 years of treatment are those whose serum contains high concentration of them. The paper also shows that patients lose antibodies to IFN independently on the type of IFN used for the treatment. In conclusion, the data indicate that the disappearance of the anti-IFN antibodies from the serum while the patients are still undergoing IFN treatment depends on the titer of antibodies but not on the type of IFN administered.

A longitudinal study of MR diffusion changes in normal appearing white matter of patients with early multiple sclerosis.

BACKGROUND AND PURPOSE: The stage at which normal appearing white matter (NAWM) abnormalities first appear in multiple sclerosis (MS) is not clear. The aim of our study was to monitor water diffusion changes over time in NAWM of patients with early MS. METHODS: Out of a consecutive series of patients enrolled in a MR study on clinically isolated syndrome (CIS), we selected 19 subjects who had completed a one year follow-up. The MR scans obtained at baseline and at 12 months were reviewed according to the new criteria on the diagnosis of MS. Lesion load on T2 and T1 weighted images and the trace of the apparent diffusion coefficient in NAWM were measured both at baseline and at 12 months in patients and in 12 healthy controls. RESULTS: In three patients the diagnosis of MS was done at baseline based on MR. Thirteen patients developed MS during the study and in three patients the diagnosis remained "possible MS." TADC in NAWM in patients was significantly higher than in controls at the 12 months' follow-up but not at baseline (controls mean tADC +/- sd = 0.745 +/- 0.02 mm(2)/sec x 10(-3); patients mean tADC(12) +/- sd = 0.767 +/- 0.02 mm(2)/sec x 10(-3); p < 0.02). TADC and T2 lesion load at 12 months were significantly correlated (p < 0.01). Patients exhibiting tADC(12) above a confidence interval had a significantly greater EDSS score at the same time period (EDSS(12) +/- sd = 1.9 +/- 0.5 and = 1.1 +/- 0.4 respectively; p < 0.01). CONCLUSIONS: This study suggests that diffusion MR cannot detect alterations in NAWM of patients with a CIS suggestive of MS. After one year, when most patients develop MS, diffusion MR abnormalities in NAWM become apparent. These abnormalities are correlated with T2 lesion load and may contribute to neurological impairment.