V. Brescia Morra

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.

Cognitive impairment and its relation with disease measures in mildly disabled patients with relapsing–remitting multiple sclerosis: baseline results from the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study

Background Cognitive impairment is a common symptom of multiple sclerosis (MS), but the association between cognitive impairment and magnetic resonance imaging (MRI) disease measures in patients with relapsing–remitting (RR) MS is unclear. Objectives To study the prevalence of cognitive impairment and its relation with MRI disease measures in mildly disabled patients with RRMS. Methods Patients aged 18–50 years with RRMS (McDonald criteria) and an Expanded Disability Status Scale (EDSS) score ≤4.0, who were enrolled in the Cognitive Impairment in Multiple Sclerosis (COGIMUS) study, underwent baseline standardized MRI complete neurological examination and neuropsychological testing. Results A total of 550 patients were enrolled, 327 of whom underwent MRI assessments. Cognitive impairment (impaired performance in ≥3 cognitive tests) was present in approximately 20% of all patients and in the subgroup who underwent MRI. T2 hyperintense and T1 hypointense lesion volumes were significantly higher in patients with cognitive impairment (defined as impaired performance on at least three tests of the Rao’s battery) than those without. EDSS score was also significantly higher in cognitively impaired than in cognitively preserved patients. Disease duration, depression, and years in formal education did not differ significantly between cognitively impaired and cognitively preserved patients. T2 lesion volume, performance intelligence quotient, and age were significant predictors of cognitive impairment in this population. Weak correlations were found between performance on individual cognitive tests and specific MRI measures, with T1 and T2 lesion volumes correlating with performance on most cognitive tests. Conclusions Cognitive impairment occurs in approximately one-fifth of mildly disabled patients with MS and is associated with specific MRI disease measures. Assessment of cognitive function at diagnosis could facilitate the identification of patients who may benefit from therapeutic intervention with disease-modifying therapies to prevent further lesion development.

Effects of immunomodulatory treatment with subcutaneous interferon beta-1a on cognitive decline in mildly disabled patients with relapsing-remitting multiple sclerosis

The objective of this study was to assess the effects of subcutaneous (sc) interferon beta-1a (IFNβ-1a) on cognition in mildly disabled patients with relapsing—remitting multiple sclerosis (RRMS). Patients aged 18—50 years with RRMS (McDonald criteria; Expanded Disability Status Scale score ≤4.0) were assigned IFNβ therapy at the physician’s discretion and underwent standardized magnetic resonance imaging, neurological examination and neuropsychological testing at the baseline and regular intervals for up to three years. This analysis included 459 patients who received sc IFNβ-1a (44 mcg: n = 236; 22 mcg: n = 223; three-year follow up was available for 318 patients). The hazard ratio for cognitive impairment over three years (44 mcg versus 22 mcg) was 0.68 (95% confidence interval [CI]: 0.480—0.972), suggesting a 32% lower risk with the higher dose treatment. At year 3, the proportion of patients who were cognitively impaired increased slightly from 23.5% at the baseline to 24.8% in the IFNβ-1a 22 mcg treatment group, but remained stable at 15.2% in the IFNβ-1a 44 mcg treatment group. The proportion of patients with cognitive impairment at year 3 was significantly higher in the 22 mcg group than in the 44 mcg group (P = 0.03), although a trend was also seen at the baseline (P = 0.058). Multivariate logistic regression (corrected for baseline cognitive deficits) indicated that treatment with the higher dose of IFNβ-1a was predictive of lower cognitive impairment at three years (odds ratio: 0.51, 95% CI: 0.26—0.99) compared with the lower dose of IFNβ-1a. These findings suggest that sc IFNβ-1a may have dose-dependent cognitive benefits in mildly disabled patients with RRMS, and may support early initiation of high-dose IFNβ-1a treatment.

Safety and efficacy of natalizumab in children with multiple sclerosis

Objective: To describe the effect of natalizumab in the treatment of subjects with active multiple sclerosis (MS) treated before the age of 18 years. Methods: Nineteen pediatric subjects with MS (mean age 14.6 ± 2.2 years, mean number of attacks 5.2 ± 1.9 during the pretreatment phase of 27.7 ± 19.7 months, median pretreatment Expanded Disability Status Scale score [EDSS] 2.5, range 1.0–5.0) were treated with natalizumab at the dose of 300 mg every 28 days. After treatment initiation, patients were reassessed clinically every month; brain MRI was performed at baseline and every 6 months. Results: Patients received a median number of 15 infusions (range 6–26). A transient reversible worsening of preexisting symptoms occurred in 1 subject during and following the first infusion. All the patients remained relapse-free during the whole follow-up. The median EDSS decreased from 2.5 to 2.0 at the last visit (p < 0.001). EDSS remained stable in 5 cases, decreased by at least 0.5 point in 6 cases, and decreased by at least 1 point in 8 cases. At baseline, the mean number of gadolinium-enhancing lesions was 4.1 (range 1–20). During the follow-up, no gadolinium-enhancing lesions were detected (p = 0.008); 3 patients developed new T2-visible lesions at month 6 scan but the overall number of T2 lesions remained stable during the subsequent follow-up. Transient and mild side effects occurred in 8 patients. Conclusions: Natalizumab was well-tolerated in all subjects. A strong suppression of disease activity was observed in all subjects during the follow-up. Classification of evidence: This study provides Class IV evidence that natalizumab, 300 mg IV once every 28 days, decreased EDSS scores in pediatric patients with MS over a mean treatment period of 15.2 months.

A clinical comparison of trigeminal neuralgic pain in patients with and without underlying multiple sclerosis.

Despite clinical similitude, there is a tendency to consider trigeminal pain in multiple sclerosis (MS) as a distinct condition. To evaluate clinical differences in trigeminal pain presentation in patients with and without underlying MS, we compared clinical characteristics of facial pain found in 15 consecutive MS patients with those reported by 13 consecutive subjects diagnosed with classical trigeminal neuralgia. The only significant difference between MS and non-MS neuralgic patients was the age of onset of pain (43.4±10.5 in MS vs. 59.6±11.50 in non-MS patients, p=0.000629, unpaired Student’s t-test). No differences were observed for side, duration and quality of pain, trigeminal branches involved, presence of trigger areas or factors, pain refractive period, remitting-relapsing or chronic course. There was only a trend without statistical significance in interval pain and trigeminal hypoesthesia, more frequent in MS population. Only one patient in the MS group presented with long-lasting episodes (45–60 min) of atypical odontalgia. Our findings support the view of a common pathogenetic mechanism underlying TN in the two groups, possibly related to demyelination of the trigeminal entry root in the pons. Typical TN in MS patients should be considered as “symptomatic trigeminal neuralgia”.

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.

Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity

Background The approval of 9-δ-tetrahydocannabinol and cannabidiol (THC:CBD) oromucosal spray (Sativex) for the management of treatment-resistant multiple sclerosis (MS) spasticity opened a new opportunity for many patients. The aim of our study was to describe Sativex effectiveness and adverse events profile in a large population of Italian patients with MS in the daily practice setting. Methods We collected data of all patients starting Sativex between January 2014 and February 2015 from the mandatory Italian medicines agency (AIFA) e-registry. Spasticity assessment by the 0–10 numerical rating scale (NRS) scale is available at baseline, after 1 month of treatment (trial period), and at 3 and 6 months. Results A total of 1615 patients were recruited from 30 MS centres across Italy. After one treatment month (trial period), we found 70.5% of patients reaching a ≥20% improvement (initial response, IR) and 28.2% who had already reached a ≥30% improvement (clinically relevant response, CRR), with a mean NRS score reduction of 22.6% (from 7.5 to 5.8). After a multivariate analysis, we found an increased probability to reach IR at the first month among patients with primary and secondary progressive MS, (n=1169, OR 1.4 95% CI 1.04 to 1.9, p=0.025) and among patients with >8 NRS score at baseline (OR 1.8 95% CI 1.3–2.4 p<0.001). During the 6 months observation period, 631(39.5%) patients discontinued treatment. The main reasons for discontinuation were lack of effectiveness (n=375, 26.2%) and/or adverse events (n=268, 18.7%). Conclusions Sativex can be a useful and safe option for patients with MS with moderate to severe spasticity resistant to common antispastic drugs.

Long-term clinical experience with weekly interferon beta-1a in relapsing multiple sclerosis

Post‐marketing surveillance studies are needed to assess the long‐term safety, compliance and clinical efficacy of interferon beta‐1a (IFNβ‐1a) therapy in multiple sclerosis (MS) patients. The goals of this study were to (i) assess the safety, compliance and clinical efficacy of long‐term intramuscular (i.m.) IFNβ‐1a therapy in a large cohort of patients, and (ii) suggest possible predictors of therapeutic response. A total of 255 patients were included in the study. Mean time on therapy was 31.7 ± 19.3 months. Within 3 years, 31% of patients discontinued treatment, mainly for disease activity. No significant sustained blood analysis alteration was observed over time, apart from a decrease of cholesterol levels. After 3 years of treatment, mean Expanded Disability Status Scale (EDSS) scores increased by 0.4 points compared with baseline. The mean annual relapse rate was reduced compared with baseline. Patients with ≤2 relapses in the previous 2 years and with baseline EDSS scores of ≤2 had a longer estimated time to first relapse and to progression and first relapse, respectively. These results confirm the safety and suggest a sustained effectiveness of i.m. IFNβ‐1a, extending the reported follow‐up period to 6.3 years, and hypothesize the presence of possible predictors of clinical outcome.