Roberta Lanzillo

Grey matter loss in relapsing-remitting multiple sclerosis: a voxel-based morphometry study.

Global grey matter (GM) loss has been reported in multiple sclerosis (MS). We addressed the question of if and where GM loss is localized by means of optimized voxel-based morphometry, applied to MRI studies of 51 patients with clinically defined relapsing-remitting MS and 34 age-matched normal subjects, segmented into normal and abnormal brain tissues using a multiparametric approach. Segmented GM volumes were subsequently compared on a voxel-by-voxel basis to highlight regions of relative GM loss (P < 0.05, corrected for multiple comparisons at AnCova). Additionally, localized differences in brain asymmetry between the MS and the control groups were assessed by comparing on a voxel-by-voxel basis maps of GM differences between the two hemispheres (P < 0.05 corrected for multiple comparisons). In MS patients, GM volume was significantly decreased at the level of the left fronto-temporal cortex and precuneus, as well as of anterior cingulate gyrus and of caudate nuclei bilaterally. The only cortical region of significant GM loss in the right hemisphere was located in the postcentral area. Furthermore, GM loss regions were colocalized with increased GM asymmetries (Left < Right) in MS, confirming a preferential left-sided GM loss. Caudate atrophy correlated with lesion load, while no correlation between cortical regional GM loss and disease duration, clinical status or lesion load emerged. Our findings suggest that in RR-MS cortical GM reduction preferentially involves left fronto-temporal structures and deep GM, the latter correlating preferentially to global lesion load.

Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing-remitting active multiple sclerosis patients: A longitudinal controlled trial of combination therapy

A large body of evidence suggests that, besides their cholesterol-lowering effect, statins exert anti-inflammatory action. Consequently, statins may have therapeutic potential in immune-mediated disorders such as multiple sclerosis. Our objectives were to determine safety, tolerability and efficacy of low-dose atorvastatin plus high-dose interferon beta-1a in multiple sclerosis patients responding poorly to interferon beta-1a alone. Relapsing—remitting multiple sclerosis patients, aged 18—50 years, with contrast-enhanced lesions or relapses while on therapy with interferon beta-1a 44 µg (three times weekly) for 12 months, were randomized to combination therapy (interferon + atorvastatin 20 mg per day; group A) or interferon alone (group B) for 24 months. Patients underwent blood analysis and clinical assessment with the Expanded Disability Status Scale every 3 months, and brain gadolinium-enhanced magnetic resonance imaging at screening, and 12 and 24 months thereafter. Primary outcome measure was contrast-enhanced lesion number. Secondary outcome measures were number of relapses, EDSS variation and safety laboratory data. Forty-five patients were randomized to group A (n = 21) or B (n = 24). At 24 months, group A had significantly fewer contrast-enhanced lesions versus baseline (p = 0.007) and significantly fewer relapses versus the two pre-randomization years (p < 0.001). At survival analysis, the risk for a 1-point EDSS increase was slightly higher in group B than in group A (p = 0.053). Low-dose atorvastatin may be beneficial, as add-on therapy, in poor responders to high-dose interferon beta-1a alone.

The glycopeptide CSF114(Glc) detects serum antibodies in multiple sclerosis

Synthetic glycopeptides have the potential to detect antibodies in multiple sclerosis (MS). In the present study, we analyzed the antibodies (IgM class, IgG class and IgG subclasses) to the synthetic glycopeptide CSF114(Glc) in the serum of 186 MS patients, 166 blood donors (BDs), 25 patients affected by meningitis/encephalitis, 41 affected by systemic lupus erythematosus (SLE) and 49 affected by rheumatoid arthritis (RA). The IgM antibody level to CSF114(Glc) was significantly increased in MS patients versus BDs (p<0.001) or versus other autoimmune diseases (SLE or RA, p<0.001). The IgG response was restricted to the subclass IgG2. IgM antibodies to CSF114(Glc) were found in 30% of relapsing/remitting MS patients and, at lower levels, in subjects affected by meningitis/encephalitis. The study of antibodies to CSF114(Glc) is a new, potential immunological marker of MS.

Effects of Bacille Calmette-GuÉrin after the first demyelinating event in the CNS

Objective: To evaluate Bacille Calmette-Guérin (BCG) effects after clinically isolated syndromes (CIS). Methods: In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-β-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months. Results: Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was significantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI] 0.308–0.956; p = 0.03) for gadolinium-enhancing lesions (the primary endpoint), 0.364 (95% CI 0.207–0.639; p = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI 0.046–0.416; p = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were −0.09 ± 0.72 vs 0.75 ± 1.81 (p = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 (p = 0.08), and −0.21 ± 1.03 vs 1.00 ± 2.49 (p = 0.02). After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52, 95% CI 0.27–0.99; p < 0.05), and more vaccinated people remained DMT-free (odds ratio = 0.20, 95% CI 0.04–0.93; p = 0.04). Conclusions: Early BCG may benefit CIS and affect its long-term course. Classification of evidence: BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence).

Treatment of Relapsing-Remitting Multiple Sclerosis After 24 Doses of Natalizumab: Evidence From an Italian Spontaneous, Prospective, and Observational Study (the TY-STOP Study)

IMPORTANCE The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS). OBJECTIVE To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab. INTERVENTIONS Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod. MAIN OUTCOMES AND MEASURES The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year. RESULTS No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery. CONCLUSIONS AND RELEVANCE This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug. TRIAL REGISTRATION Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.

In vivo dentate nucleus MRI relaxometry correlates with previous administration of Gadolinium-based contrast agents

AbstractObjectivesTo evaluate changes in T1 and T2* relaxometry of dentate nuclei (DN) with respect to the number of previous administrations of Gadolinium-based contrast agents (GBCA).MethodsIn 74 relapsing-remitting multiple sclerosis (RR-MS) patients with variable disease duration (9.8±6.8 years) and severity (Expanded Disability Status Scale scores:3.1±0.9), the DN R1 (1/T1) and R2* (1/T2*) relaxation rates were measured using two unenhanced 3D Dual-Echo spoiled Gradient-Echo sequences with different flip angles. Correlations of the number of previous GBCA administrations with DN R1 and R2* relaxation rates were tested, including gender and age effect, in a multivariate regression analysis.ResultsThe DN R1 (normalized by brainstem) significantly correlated with the number of GBCA administrations (p<0.001), maintaining the same significance even when including MS-related factors. Instead, the DN R2* values correlated only with age (p=0.003), and not with GBCA administrations (p=0.67). In a subgroup of 35 patients for whom the administered GBCA subtype was known, the effect of GBCA on DN R1 appeared mainly related to linear GBCA.ConclusionsIn RR-MS patients, the number of previous GBCA administrations correlates with R1 relaxation rates of DN, while R2* values remain unaffected, suggesting that T1-shortening in these patients is related to the amount of Gadolinium given.Key Points• In multiple sclerosis, previous Gadolinium administrations correlate with dentate nuclei T1 relaxometry. • Such correlation is linked to linear Gadolinium chelates and unrelated to disease duration or severity. • Dentate nuclei T2* relaxometry is age-related and independent of previous Gadolinium administrations. • Changes in dentate nuclei T1 relaxometry are not determined by iron accumulation. • MR relaxometry can quantitatively assess Gadolinium accumulation in dentate nuclei.

Epileptic seizures in multiple sclerosis: clinical and EEG correlations.

Abstract.Epileptic seizures occur more frequently in multiple sclerosis (MS) patients than in the general population. We evaluated clinical, electroencephalographic (EEG) and magnetic resonance imaging (MRI) findings, as well as EEG-MRI correlations and the response to antiepileptic drugs (AEDs) in 270 consecutive patients with definite MS referred to our Department from 1995 to 2002. Thirteen (4.8%) subjects experienced epileptic seizures. In four cases, seizures manifested within 1–2 years (“early-onset”), and in six cases within 8–23 years (“late-onset”) of MS diagnosis. Seizures were usually partial with secondary generalization. Thus, acute symptomatic seizures occurred in three cases. Epilepsy usually appeared late in the course of disease, although a single episode or a cluster of seizures can represent the onset symptom or a relapse of MS. Prognosis of epilepsy during the course of MS is usually good but the choice of AEDs remains a matter of debate.

Multiple sclerosis and headache co-morbidity. A case-control study

The prevalence of primary headache (PH) in a multiple sclerosis (MS) sample vs. control healthy subjects was investigated at a neurological clinic in 2004–2005: 122 of 238 (51%) MS patients and 57 of 238 (23%) controls proved to be affected by headache. The groups did not differ for the rates of PH types. Headache types of MS patients were comparable to those of PH patients that were observed at the same institute in a case-control comparison. First symptoms of headache preceded those of MS in two thirds of cases. Headache features did not significantly change after MS onset. Comorbidity of MS and PH could be explained by some common clinical and biological traits.

A voxel-based morphometry study of disease severity correlates in relapsing— remitting multiple sclerosis

Previous studies have shown a preferential loss of grey matter in fronto-temporal regions in patients with multiple sclerosis. Studies of correlates of disease severity are more controversial, because some studies have suggested an association between sensorimotor cortex atrophy and Expanded Disability Status Scale score, while others did not find such a correlation. The objective of this study was to assess the correlation of regional loss of grey matter and white matter with indexes of clinical and radiological severity in relapsing—remitting multiple sclerosis, including the Expanded Disability Status Scale and lesion load. Correlations between Expanded Disability Status Scale, lesion load and disease duration were assessed in 128 patients with relapsing—remitting multiple sclerosis (Expanded Disability Status Scale range 1.0—6.0) using optimized voxel-based morphometry. Bilateral loss of grey matter in sensorimotor cortices was correlated with Expanded Disability Status Scale, and tissue loss also involved adjacent white matter, extending along pyramidal tracts to the brainstem. Increasing lesion load was correlated with loss of deep grey matter and white matter. No specific region of grey matter or white matter showed a significant correlation with disease duration. These findings support the hypothesis that motor neuron involvement plays a major role in the progression of physical disability. Lesion load accrual affects mainly highly interconnected subcortical structures, while disease duration has a less significant impact on brain atrophy, probably owing to the inter-subject heterogeneity of the clinical course of the disease.

Cognitive impairment at diagnosis predicts 10-year multiple sclerosis progression:

Background: Cognitive impairment occurs from the early phases of multiple sclerosis (MS), and more frequently affects secondary progressive (SP) subjects than relapsing–remitting (RR). Objective: To investigate relationships between cognitive dysfunctions in newly diagnosed RRMS, and long-term MS-related outcomes. Methods: The present 10-year retrospective longitudinal study included 155 RRMS subjects, tested with the Rao Brief Repeatable Battery at MS diagnosis. The reaching of Expanded Disability Status Scale (EDSS) 4.0, and the SP conversion were recorded. Results: 67 subjects (43.2%) reached EDSS 4.0, and 34 subjects (21.9%) converted to SP during a follow-up period of 10.0±1.8 years. Subjects with cognitive impairment at diagnosis had a rate of reaching EDSS 4.0 more than three times greater (p<0.001; HR=3.183), and a rate of SP conversion more than two times greater, as compared to cognitively preserved subjects (p=0.008; HR=2.535). In particular, better scores in the Selective Reminding Test-Delayed Recall and in the Symbol Digit Modalities Test at baseline were associated with lower SP conversion rates during the follow-up period (p=0.018; HR=0.835; and p=0.001; HR=0.941, respectively). Conclusion: Cognitive impairment, with particular involvement of processing speed and memory, predicts disability progression and SP conversion in newly diagnosed RRMS, highlighting the importance of cognitive assessment from the beginning of MS.