Clinical features of Sjogren's syndrome in patients with multiple sclerosis.

OBJECTIVES: To assess the frequency of clinical features of Sjogren's syndrome (SS) in patients with multiple sclerosis (MS) receiving treatment with disease-modifying drugs (DMDs) or naïve to treatment and the possible association with clinical, cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) parameters. METHODS: A multicentre cross-sectional observational study was designed, based on a structured neurologist-administered questionnaire to 440 patients. RESULTS: Twenty-eight of 230 (12%) patients receiving treatment with DMDs (DMDs(+)) and 14 of 210 (6.6%) treatment-naïve patients (DMDs(-) ) showed clinical features of SS. Four primary SS were diagnosed, two of which were DMDs(+) and two were DMDs(-) . Sicca symptoms were significantly associated with higher EDSS scores (P = 0.018), a low frequency of gadolinium-enhanced MRI-positive lesions (P = 0.018) and cerebral disturbances (P = 0.001). CONCLUSIONS: Screening for the clinical features of SS should be performed in patients with MS both receiving treatment with immunomodulatory drugs and without therapy.

Natalizumab therapy of multiple sclerosis: recommendations of the Multiple Sclerosis Study Group--Italian Neurological Society.

Three years after the introduction of natalizumab (NA) therapy for the second line treatment of relapsing-remitting multiple sclerosis (MS), Italian MS centers critically reviewed the scientific literature and their own clinical experience. Natalizumab was shown to be highly efficacious in the treatment of MS. However, the risk of progressive multifocal leukoencephalopathy was confirmed and defined better. This article summarizes the MS-SIN Study Group recommendations on the use of NA in MS, with particular reference to the appropriate selection and monitoring of patients as well as to the management of adverse events.

Altered sensorimotor integration in multiple sclerosis: A combined neurophysiological and functional MRI study.

OBJECTIVE: To explore whether abnormal thalamic resting-state functional connectivity (rsFC) contributes to altered sensorimotor integration and hand dexterity impairment in multiple sclerosis (MS). METHODS: To evaluate sensorimotor integration, we recorded kinematic features of index finger abductions during somatosensory temporal discrimination threshold (STDT) testing in 36 patients with relapsing-remitting MS and 39 healthy controls (HC). Participants underwent a multimodal 3T structural and functional MRI protocol. RESULTS: Patients had lower index finger abduction velocity during STDT testing compared to HC. Thalamic rsFC with the precentral and postcentral gyri, supplementary motor area (SMA), insula, and basal ganglia was higher in patients than HC. Intrathalamic rsFC and thalamic rsFC with caudate and insula bilaterally was lower in patients than HC. Finger movement velocity positively correlated with intrathalamic rsFC and negatively correlated with thalamic rsFC with the precentral and postcentral gyri, SMA, and putamen. CONCLUSIONS: Abnormal thalamic rsFC is a possible substrate for altered sensorimotor integration in MS, with high intrathalamic rsFC facilitating finger movements and increased thalamic rsFC with the basal ganglia and sensorimotor cortex contributing to motor performance deterioration. SIGNIFICANCE: The combined study of thalamic functional connectivity and upper limb sensorimotor integration may be useful in identifying patients who can benefit from early rehabilitation to prevent upper limb motor impairment.

Real-life impact of early interferon beta therapy in relapsing multiple sclerosis.

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.

Involvement of the limbic system in multiple sclerosis patients with depressive disorders.

This study investigates the relationship between depression and both anatomic and cerebral blood flow abnormalities in multiple sclerosis (MS) patients. Ten nondepressed MS patients were compared with 10 depressed MS patients matched for age, sex, and functional disability. Both groups were evaluated by means of neuropsychological tests, magnetic resonance imaging, and single-photon emission tomography imaging. There was no difference between the two groups with regard to the global cognitive score. Magnetic resonance imaging data showed no significant differences in the number, side, location, and area of the demyelinating lesions between the two groups; however, regional cerebral blood flow asymmetries in the limbic cortex did distinguish the two groups. Analysis of variance showed a significant effect of depression on the perfusion asymmetries in the limbic cortex. Finally, perfusion asymmetries in limbic cortex significantly correlated with depression test scores. Our findings suggest that depression in MS patients could be induced by a disconnection between subcortical and cortical areas involved in the function of the limbic system.

A one-year study on the pharmacodynamic profile of interferon-beta1a in MS.

Interferon (IFN)-beta1a induction of neopterin and beta2-microglobulin (beta2-MG) were evaluated over 1 year in patients with MS. Neopterin and beta2-MG levels peaked 24 to 48 hours after weekly injections of IFNbeta1a over the entire study period. Predose levels of neopterin decreased significantly, consistent with a long-term decrease in IFNgamma expression and macrophage activation during IFNbeta-1a treatment. Predose levels of beta2-MG increased, the significance of which is as yet unclear.

Effect of steroids on Gd-enhancing lesions before and during recombinant beta interferon 1a treatment in relapsing remitting multiple sclerosis.

The aim of this study was to investigate whether a concomitant treatment with recombinant interferon beta 1a (rIFN beta-1a) modifies the effect of steroids on the blood-brain barrier (BBB) in relapsing remitting MS patients, as evaluated by enhanced MRI of the brain. We evaluated 19 patients with a clinical relapse treated only with intravenous methylprednisolone (IVMP; 1 g daily for 6 days), and 10 patients who experienced a clinical relapse and were treated with IVMP (1 g daily for 6 days) during an rIFN beta-1a treatment period. The number and volume of enhancing lesions were analyzed on four serial MR images obtained at monthly intervals (one scan before and three scans after IVMP treatment). A significant reduction in the mean number and volume of enhancing lesions was seen in the first scan after IVMP treatment in all patients. However, while persistently low enhancement was seen in the follow-up scans of patients treated with rIFN beta-1a, a rebound effect (i.e., increase in the number and volume of gadolinium-enhancing lesions) was observed in the other patients during the follow-up. These data suggest that rIFN beta-1a prolongs the beneficial effect of steroids on the BBB.

Noninvasive assessment of mitoxantrone cardiotoxicity in relapsing remitting multiple sclerosis.

Multiple sclerosis is the most common cause of neurologic disability in young adults. Recent reports have suggested that Mitoxantrone might be a candidate for clinical trials in multiple sclerosis patients. The authors studied 20 patients with relapsing remitting multiple sclerosis to evaluate cardiac toxicity during a one-year follow-up period. Patients were divided into 2 groups: group A, mitoxantrone treated patients (cumulative dose of 96 mg/m2); group B, placebo patients. The clinical course of multiple sclerosis was assessed using the Expanded Disability Status Scale and the number of relapses during the follow-up. Each patient had an electrocardiogram and a spectral and color flow Doppler echocardiographic examination at enrollment, and 6 and 12 months later, to investigate cardiac toxicity. The mean exacerbation rate was reduced significantly in group A patients. No significant differences in the electrocardiograms or the echocardiographic parameters of systolic and diastolic function were noted between the two groups or in group A during the follow-up. Mitoxantrone treatment seems able to improve the clinical course of relapsing remitting multiple sclerosis patients. It does not show any cardiac toxicity in selected patients at this dosage.

Clinical and MRI assessment of disease activity in patients with multiple sclerosis after influenza vaccination.

We investigated the possible effects of influenza vaccination on disease activity in multiple sclerosis (MS). Six patients were evaluated clinically during the year preceding and the year following influenza vaccination. Gadolinium-enhanced magnetic resonance imaging (Gd-MRI) was performed one day before and at days 15 and 45 after vaccination. Cumulatively, we did not observe increases in clinical or MRI disease activity following vaccination, with the exception of one case. This was the patient with the highest clinical disease activity during the year preceding vaccination. These results support and supplement previous observations, indicating that influenza vaccination is a safe procedure in multiple sclerosis. Nevertheless, it should be used with caution in patients with active/progressing disease.

Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting multiple sclerosis: 24-month clinical and MRI outcome.

We designed a randomized, placebo-controlled, multicentre trial involving 51 relapsing-remitting multiple sclerosis patients to determine the clinical efficacy of mitoxantrone treatment over 2 years. Patients were allocated either to the mitoxantrone group (27 patients receiving I.V. infusion of mitoxantrone every month for 1 year at the dosage of 8 mg/m2) or to the placebo group (24 patients, receiving I.V. infusion of saline every month for 1 year) using a centralized randomization system. Disability at entry and at 12-24 months was evaluated by four blinded neurologists trained in the application of the Kurtzke Expanded Disability Scale (EDSS). In addition, the number and clinical characteristics of the exacerbations over the 24 months were recorded by the local investigators. MRI, at 0, 12 and 24 months, was performed with a 0.2 T permanent unit. MRI data were analysed by two blinded neuroradiologists. All patients underwent a clinical evaluation. A statistically significant difference in the mean number of exacerbations was observed between the mitoxantrone group and placebo group both during the 1st and the 2nd year. Although there was no statistically significant benefit in terms of mean EDSS progression over 2 years, the proportion of patients with confirmed progression of the disease, as measured by a one point increase on the EDSS scale, was significantly reduced at the 2nd year evaluation in the mitoxantrone group. Forty-two (23 mitoxantrone, 19 placebo) patients underwent all MRI examinations during the 24-month period. We observed a trend towards a reduction in the number of new lesions on T2-weighted images in the mitoxantrone group. Our study suggests that mitoxantrone might be effective in reducing disease activity, both by decreasing the mean number of exacerbations and by slowing the clinical progression sustained by most patients after 1 year from the end of treatment.

Fast spin-echo and fast fluid-attenuated inversion-recovery versus conventional spin-echo sequences for MR quantification of multiple sclerosis lesions.

PURPOSE: To compare fast spin-echo (FSE) and fast fluid-attenuated inversion recovery (FLAIR) sequences with conventional spin-echo (CSE) MR imaging in the quantification of the number and volume of multiple sclerosis lesions. METHODS: In 30 patients with relapsing-remitting multiple sclerosis, we calculated the total number and volume of lesions detected with each of the three sequences using a semiautomated program. RESULTS: On CSE sequences, we calculated a total of 2,583 lesions with a global volume of 836.3 cm3. With FSE sequences, we observed a 16% relative reduction in the number of lesions detected and a 25% relative reduction in global volume as compared with CSE. With fast FLAIR sequences, we detected a significantly lower number and volume of infratentorial lesions, whereas at the cortical/subcortical level the lesions were both more numerous and bulkier than on CSE sequences. Finally, we observed a higher lesion/white matter contrast, a significant reduction in time required for the quantification of lesion load, and a very low interobserver variability in favor of fast FLAIR sequences. CONCLUSION: Despite its limitations in the detection of infratentorial lesions, the fast FLAIR sequence in conjunction with a semiautomated quantification program provides a reliable means to evaluate the total lesion burden in patients with MS.

Brain atrophy in relapsing-remitting multiple sclerosis: relationship with 'black holes', disease duration and clinical disability.

Recent MRI studies in multiple sclerosis have highlighted the potential role of brain atrophy evaluation as a putative marker of disease progression. In the present study, we evaluated the supratentorial and infratentorial brain volume in patients with relapsing remitting multiple sclerosis (RR MS) and in healthy subjects. Moreover, we determined whether brain volumes of MS patients are associated with different aspects of brain MRI abnormalities and clinical findings. Two-dimensional acquired MRI was performed on 52 relapsing-remitting multiple sclerosis and 30 healthy subjects. The volume of supratentorial and infratentorial structures was measured in selected representative slices. Gd-enhancement, T2 hyperintense, T1 hypointense (i.e. 'black holes') total lesion load, as well as the area of corpus callosum was calculated in the MS group and related to brain volume measures. Correlations between MRI parameters and clinical features were also considered. MS patients had significantly lower supratentorial, infratentorial brain volume and corpus callosum area than healthy subjects (P<0.01). Supratentorial brain volume was significantly related to corpus callosum area (r=0.58; P<0.01) and T1 hypointense lesion load (r=0.48; P<0.01), but not with T2 hyperintense lesion load. Infratentorial/supratentorial ratio was significantly associated with disease duration and EDSS score (r=-0.34; P=0.02 and r=-0.49; P<0.01, respectively). This study documents that brain atrophy is an early MRI finding in RR MS and it is closely related to 'black holes' burden. The use of relative values (infratentorial/supratentorial ratio) may increase the conspicuity of correlation between clinical and MRI findings.

Anterior corpus callosum atrophy and verbal fluency in multiple sclerosis.

To determine whether different portions of the corpus callosum (CC) are responsible for transferring the information of specific cognitive modalities, eighteen females with relapsing-remitting Multiple Sclerosis (MS) were studied using neuropsychological procedures and Magnetic Resonance Imaging (MRI). Measures of both anterior and posterior CC areas were obtained in patients with MS as well as in eighteen age and sex matched healthy controls. MRI scans were additionally analyzed for each patient in order to evaluate the extent of demyelinating lesions in both periventricular and subcortical areas. Patients with MS exhibited a significant decrease in both the anterior and posterior CC areas compared with normal subjects. The results of statistical analysis showed that, even when the effect of demyelinating lesions was taken into account within a regression equation, the atrophy of anterior CC area strongly affected the performance on verbal fluency task. These data emphasize the importance of the anterior CC area for the interhemispheric transfer of cognitive information associated with verbal fluency.

A controlled trial of mitoxantrone in multiple sclerosis: serial MRI evaluation at one year.

We present the results of a randomized double-blinded placebo controlled, multicenter trial, of low-dose mitoxantrone (MX), after one year, in 25 patients with relapsing-remitting multiple sclerosis, who had serial enhanced magnetic resonance imaging (MRI). Treatment groups were balanced for age, gender, duration of illness and neurological disability. Five of the 13 MX patients and 10 of the 12 placebo patients had exacerbations during treatment (p < 0.02). The mean change in the extended disability status scale was not significantly different between the MX and placebo treatment groups. Serial Gadolinium-DTPA enhanced MRI detected no significant difference between the MX treated and placebo groups in the mean total number of new, enlarging, or Gadolinium-DTPA enhancing lesions; there was a trend toward a reduction of new, enlarging and Gadolinium-DTPA enhancing lesions in MX patients. Despite this ameliorating effect, the results indicate that serial Gadolinium-DTPA enhanced MRI, performed over one year in a limited number of patients, could not provide conclusive evidence for a role of MX therapy in relapsing-remitting multiple sclerosis.

Circadian variation in the onset of acute cerebral ischemia: ethiopathogenetic correlates in 80 patients given angiography.

In a continuous series of 80 acute ischemic hemispheric strokes, the onset of symptoms was between 6:01 a.m. and noon in 45% of cases, between noon and 6:00 p.m. in 22.5%, between 6:01 p.m. and midnight in 31.25%, and between midnight and 6:00 a.m. in 1.25% (p less than 0.0001). By means of angiography and computerized tomography, and by detection of arterial and cardiac sources of emboli, four stroke subtypes were identified. Embolic and thrombotic strokes had their most frequent onset between 6:01 a.m. and noon (45% and 71%, respectively), whereas strokes of unknown origin and lacunar strokes were randomly distributed between 6:01 p.m. and midnight. The morning activation of the catecholaminergic system can account for this pattern of circadian onset of ischemic stroke.

Trigeminal neuralgia and pain related to multiple sclerosis.

Although many patients with multiple sclerosis (MS) complain of trigeminal neuralgia (TN), its cause and mechanisms are still debatable. In a multicentre controlled study, we collected 130 patients with MS: 50 patients with TN, 30 patients with trigeminal sensory disturbances other than TN (ongoing pain, dysaesthesia, or hypoesthesia), and 50 control patients. All patients underwent pain assessment, trigeminal reflex testing, and dedicated MRI scans. The MRI scans were imported and normalised into a voxel-based, 3D brainstem model that allows spatial statistical analysis. The onset ages of MS and trigeminal symptoms were significantly older in the TN group. The frequency histogram of onset age for the TN group showed that many patients fell in the age range of classic TN. Most patients in TN and non-TN groups had abnormal trigeminal reflexes. In the TN group, 3D brainstem analysis showed an area of strong probability of lesion (P<0.0001) centred on the intrapontine trigeminal primary afferents. In the non-TN group, brainstem lesions were more scattered, with the highest probability for lesions (P<0.001) in a region involving the subnucleus oralis of the spinal trigeminal complex. We conclude that the most likely cause of MS-related TN is a pontine plaque damaging the primary afferents. Nevertheless, in some patients a neurovascular contact may act as a concurring mechanism. The other sensory disturbances, including ongoing pain and dysaesthesia, may arise from damage to the second-order neurons in the spinal trigeminal complex.

Post-marketing of disease modifying drugs in multiple sclerosis: an exploratory analysis of gender effect in interferon beta treatment.

BACKGROUND: There are a few and conflicting results from randomised controlled trials (RCTs) pertaining to the influence of gender in response to currently used disease modifying drugs in Multiple Sclerosis (MS). Observational studies may be especially valuable for answering effectiveness questions in subgroups not studied in RCTs. OBJECTIVE: To conduct a post-marketing analysis aimed to evaluate the gender effect on Interferon beta (IFNbeta) treatment response in a cohort of relapsing (RR) MS patients. METHODS: A cohort of 2570 IFNbeta-treated RRMS was prospectively followed for up to 7 years in 15 Italian MS Centers. Cox proportional hazards regression models were used to assess gender differences for risk of reaching 1st relapse and risk of progression by 1 point on Expanded Disability Status Scale (EDSS) score. Gender effects were also explored by a propensity score (PS) matching algorithm, and a tree-growing technique. RESULTS: The multivariate Cox Regression analyses showed that male patients had a significant (p=0.0097) lower risk for 1st relapse and a trend (p=0.0897) for a higher risk to reach 1 point EDSS progression than females. The PS matched multivariate Cox Regression confirmed these results. The RECPAM analysis showed that male sex conferred a significant reduction in the risk for 1st relapse (HR=0.86; 95% CI=0.76-0.98; p=0.0226) in the subgroup with a low pre-treatment number of bouts, and a significant increase in the risk for 1 point EDSS progression (HR=1.33; 95% CI: 1.00-1.76; p<0.05) in the subgroup with a delayed treatment, but a still young age at the start of treatment. CONCLUSION: The results of this exploratory analysis seem to suggest that male patients do not respond to IFNbeta treatment in the same way of females.

An exploratory study on interferon beta dose effect in reducing size of enhancing lesions in multiple sclerosis.

Sixty-two patients with multiple sclerosis (MS) were imaged monthly over a six-month (ie, seven monthly magnetic resonance images [MRI]) natural history period (NHP). Thereafter, patients were randomized to receive 11 or 33 mug of subcutaneously injected interferon beta 1a (IFNp-1 a) with imaging monthly for nine months and at months 12, 18 and 24 of therapy phase (TP). In the present exploratory post hoc analysis, the authors evaluated IFNbeta-1a dose effect on reducing the size of contrast-enhancing lesions (CELs). MRIs performed at months 0, 3 and 6 of NHP and at months 3, 6, 9, 18 and 24 of TP were analysed. While a significant reduction in mean number of CELs was observed in both treatment groups of patients, the mean total volume and size of CELs was reduced only in patients undergoing therapy with 33 mug of IFNbeta-1a. The latter suggests a significant dose effect exerted by IFNbeta-1a in the evolution of CELs' dimensions during therapy.