Vittorio Martinelli

Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study

BACKGROUND Interferon beta reduces activity in multiple sclerosis as measured clinically and by magnetic resonance imaging (MRI). We assessed the effect of interferon beta-1a on the occurrence of relapses in patients after first presentation with neurological events, who are at high risk of conversion to clinically definite multiple sclerosis. METHODS Eligible patients had had a first episode of neurological dysfunction suggesting multiple sclerosis within the previous 3 months and had strongly suggestive brain MRI findings. Patients were randomly assigned interferon beta-1a 22 microg or placebo subcutaneously once weekly for 2 years. Neurological and clinical assessments were done every 6 months and brain MRI every 12 months. Analyses excluded one patient assigned placebo who received no study injections. FINDINGS 241 (78%) of 308 randomised patients received study treatment for 2 years; 278 (90%) remained in the study until termination. 57 (85%) of 67 who stopped therapy did so after conversion to clinically definite multiple sclerosis. Fewer patients developed clinically definite multiple sclerosis in the interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047). The time at which 30% of patients had converted to clinically definite multiple sclerosis was 569 days in the interferon group and 252 in the placebo group (p=0.034). The annual relapse rates were 0.33 and 0.43 (p=0.045). The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment. INTERPRETATION Interferon beta-1a treatment at an early stage of multiple sclerosis had significant positive effects on clinical and MRI outcomes.

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial

BACKGROUND Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. METHODS In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. FINDINGS All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). INTERPRETATION Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. FUNDING Teva Pharmaceutical Industries, Israel.

Relation between MR abnormalities and patterns of cognitive impairment in multiple sclerosis

Objective This study correlated the extent of abnormalities detected by different magnetic resonance imaging (MRI) techniques [proton density (PD)-weighted, T1-weighted, and magnetization transfer imaging (MTI)] with the overall cognitive, frontal lobe, and memory impairments in patients with MS. Patients There were 30 clinically definite MS patients, with different disease courses. Exclusion criteria: psychoactivelsteroid treatments, mood disorders, acute relapse phase. Main Outcome Measures Neuropsychological test results. Total (TLL) and frontal (FLL) lesion loads assessed from PD-weighted, T1-weighted (22 patients), and MTI (22 patients) MRI scans. Average lesion MT ratios (MTR) and analysis of the MTR histograms from brain tissue axial slabs on MTI scans. Results Patients with frontal lobe deficits (n = 15) or memory impairment (n = 17) had a higher TLL on PD scans (p = 0.04 and p = 0.01, respectively). Patients with frontal lobe deficits had higher FLL on PD scans (p = 0.01) and TLL on MTI (p = 0.03) scans. No significant relationships between the extent of T1-weighted lesion loads and the presence of any neuropsychological impairment. Mean MTR of both MS lesions and whole brain tissue was lower in patients with frontal lobe impairment (p = 0.04). MRI lesion loads correlated significantly with some neuropsychological test scores. Conclusions Lesion loads on PD-weighted MRI and MTI-derived measures are associated with cognitive decline in MS patients. Overall macroscopic and microscopic brain damage is more important than the corresponding regional brain disease in determining deficits of selective cognitive domains.

Clinical characteristics, course and prognosis of relapsing Devic’s Neuromyelitis Optica

Abstract.Objectives:To evaluate the clinical characteristics, course and prognosis of Devic’s neuromyelitis optica (DNO), to evaluate the prognostic role of demographic and clinical features, to evaluate the current DNO diagnostic criteria.Methods:Demographic, clinical, CSF and MRI data of patients affected by DNO were collected from fifteen Italian MS centres. Inclusion criteria were: 1) two or more acute episodes of neurological dysfunction indicating involvement of the optic nerve and spinal cord, in a simultaneous or subsequent temporal relationship; 2) no evidence of lesions beyond the optic nerve or the spinal cord; 3) brain MRI at onset negative or non-specific for multiple sclerosis (MS) (white matter lesions ≤ 2). Disability was scored by means of Kurtzke’s Expanded Disability Status Scale (EDSS).Results:46 patients with relapsing DNO were included, 37 females and 9 males, with mean age at onset of 40.1 ± 16.3 years (range 12–77 years). The follow up duration was 8.8 ± 3.5 years, the mean annualised relapse rate was 1.3 ± 1.2. After 5, 10 and 15 years EDSS 3.0 was reached respectively by 65%, 82 % and 86% of cases, EDSS 6.0 respectively by 42%, 53 % and 69% of cases, EDSS 10 respectively by 8%, 12% and 23% of cases. The probability of reaching EDSS 3 was statistically correlated with age at onset, interval between the first and 2nd attack, and relapse rate. The probability of reaching EDSS 6.0 was correlated with the residual EDSS at onset and to relapse rate.During the follow up, brain white matter lesions appeared in 8 subjects. Spinal cord MRI showed lesions extending across 3 or more segments in 39 subjects, only 1 lesion involving 1 segment in 4 subjects, and was normal in 3 subjects. One or more CSF abnormalities were found at least once in 29/44 patients (65.9 %), the most frequent findings being pleocytosis (38.6 %), oligoclonal bands (34.1 %), high protein level (25 %), and high albumin ratio (20.5 %).Conclusions:DNO has a poor prognosis in most cases. Compared with MS, DNO patients have a higher age at onset, females are more frequently affected, the course is more severe. Brain and spinal cord MRI permit the differentiation of DNO from MS. CSF supports the probability of DNO if it shows increased cells and proteins.

Cortical adaptation in patients with MS: a cross-sectional functional MRI study of disease phenotypes

BACKGROUND Movement-associated cortical reorganisation is known to occur in multiple sclerosis (MS). We aimed to define the development of such cortical reorganisation by comparing data from patients with different disease phenotypes. METHODS We studied patients with different phenotypes of MS: 16 patients with a clinically isolated syndrome (CIS), 14 patients with relapsing-remitting MS (RRMS) and no disability, 15 patients with RRMS and mild clinical disability, and 12 patients with secondary progressive MS (SPMS). Patients did a simple motor task with their unimpaired dominant hand during MRI, which was compared across the phenotype groups. FINDINGS Patients with a CIS activated more of the contralateral primary sensorimotor cortex than those with RRMS and no disability, whereas patients with RRMS and no disability activated more of the supplementary motor area than those with a CIS. Patients with RRMS and no disability activated more of the primary sensorimotor cortex, bilaterally, and more of the ipsilateral supplementary motor area than patients with RRMS and mild clinical disability. Conversely, patients with RRMS and mild clinical disability activated more of the contralateral secondary somatosensory cortex and inferior frontal gyrus, and the ipsilateral precuneus. Patients with RRMS and mild clinical disability activated more of the contralateral thalamus and of the ipsilateral secondary somatosensory cortex than those with SPMS. However, patients with SPMS activated more of the inferior frontal gyrus, bilaterally, the middle frontal gyrus, bilaterally, the contralateral precuneus, and the ipsilateral cingulate motor area and inferior parietal lobule. INTERPRETATION Movement-associated cortical reorganisation in patients with MS seems to vary across individuals at different stages of disease. Our study suggests that early in the disease course more areas typically devoted to motor tasks are recruited. Then bilateral activation of these regions is seen, and late in the disease course, areas that healthy people recruit to do novel or complex tasks are activated.

Cognitive dysfunction in patients with mildly disabling relapsing–remitting multiple sclerosis: an exploratory study with diffusion tensor MR imaging

Previous studies assessing the magnetic resonance imaging (MRI) correlates of cognitive dysfunction in multiple sclerosis (MS) achieved conflicting results. Diffusion tensor (DT)-MRI provides metrics that are sensitive to the macro- and microscopic MS lesion load with increased specificity to the more destructive aspects of MS pathology than conventional imaging. We performed an exploratory study to assess the magnitude of the correlation between quantities derived from DT-MRI and measures of cognitive impairment in patients with relapsing-remitting (RR) MS.T2, T1, DT-MRI scans of the brain and an extensive battery of neuropsychological tests (exploring language, complex reasoning, attention and memory) were obtained from 34 RRMS patients. We measured T2 and T1 lesion volumes (LV) and brain volume. Average lesion mean diffusivity (D) and fractional anisotropy (FA) were calculated. D and FA histograms from the brain tissue (BT), the normal-appearing brain tissue (NABT), the normal-appearing white matter (NAWM) and the normal-appearing gray matter (NAGM) were also obtained. Nine patients (26.5%) were found to be cognitively impaired. Moderate correlations were found between symbol digit modalities test, verbal fluency test and 10/36 spatial recall test scores and T2 LV, T1 LV and average lesion, WBT, NABT, NAWM and NAGM values (r values ranging from -0.30 to -0.53). No correlations were found between any of the neuropsychological test scores and brain volume, average lesion FA and WBT FA.DT-MRI provides quantitative metrics that seem to reflect the severity of language, attention and memory deficits in patients with RRMS. This study also suggests that the extent and the intrinsic nature of the macroscopic lesions as well as the damage of the NAWM and NAGM all contribute to the neuropsychological deficits of RRMS patients.

The prevalence of pain in multiple sclerosis A multicenter cross-sectional study

In a multicenter cross-sectional study, the authors assessed pain in patients with multiple sclerosis (MS) using a symptom-oriented approach. Out of 2,077 questionnaires, we used 1,672 for data analysis. Pain and frequencies included trigeminal neuralgia 2%, Lhermitte’s sign 9%, dysesthetic pain 18.1%, back pain 16.4%, and painful tonic spasms 11%. Comparison between different groups showed significant differences for age, Expanded Disability Status Scale, disease duration, and disease course, but not for sex. This study underlines the relevance of pain in the clinical history of MS.

Brain MRI correlates of cognitive impairment in primary and secondary progressive multiple sclerosis.

Brain magnetic resonance imaging (MRI) and an extensive battery of neuropsychological tests exploring frontal functions, short and long-term memory, visuo-spatial skills, attention and language were applied to 14 patients with primary progressive multiple sclerosis (PPMS) and 17 patients with secondary progressive MS (SPMS). Patients with PPMS and SPMS did not differ in degree of physical disability, but cognitive deficits were found in 9/17 (53%) patients with SPMS and in only 1/14 (7%) of those with PPMS (p = 0.01). Patients with SPMS had higher total (p = 0.004), periventricular (p = 0.008) and non-periventricular (p = 0.04) MRI lesion loads than patients with PPMS. In detail, patients with SPMS had greater involvement of frontal (p = 0.05) and occipital (p = 0.02) horns, trigones (p = 0.04), third ventricle (p = 0.03), basal ganglia (p = 0.02), parietal (p = 0.02), temporal (p = 0.004) and occipital (p = 0.03) lobes. Patients with SPMS and neuropsychological deficits had higher non-periventricular lesion loads than patients with SPMS who did not have such deficits (p = 0.005). Our results indicate that both neuropsychological and brain MRI abnormalities are more extensive in patients with SPMS. Since physical disability was similar for both groups, disability in PPMS may be predominantly due to spinal cord involvement.

A voxel-based morphometry study of grey matter loss in MS patients with different clinical phenotypes

To assess regional grey matter (GM) changes in a large cohort of multiple sclerosis (MS) patients with different clinical phenotypes, using voxel-based morphometry (VBM) and their correlation with the extent of global and regional T2 lesion volumes (LV), we acquired conventional MRI scans from 71 MS patients with different clinical phenotypes (26 with relapsing-remitting [RR] MS, 27 with secondary progressive [SP] MS and 18 with primary progressive [PP] MS), 28 patients with a clinically isolated syndrome (CIS) suggestive of MS, and 21 controls. No GM loss was found in CIS patients. Compared to CIS patients, those with RRMS had a significant GM loss in the right pre and postcentral gyri. Compared to RRMS, SPMS patients had a significant GM loss in several regions of the fronto-parieto-temporo-occipital lobes, the cerebellum and superior and inferior colliculus, bilaterally, and deep GM structures. Compared to PPMS, SPMS patients had a significant GM loss in the postcentral gyrus, the cuneus, the middle occipital gyrus, the thalamus, the cerebellum, and the superior and inferior colliculus. In all MS groups, regional GM loss was strongly/moderately correlated with brain T2 LV. In SPMS and PPMS patients, a correlation was found between cortical regional GM loss and T2 LV of the corresponding or adjacent lobes. In MS patients, GM volume loss follows different patterns of regional distribution according to the clinical phenotype of the disease, is likely secondary to the presence and topography of focal WM inflammatory-demyelinating lesions, and is more evident in the progressive forms of the disease.

MRI and magnetization transfer imaging changes in the brain and cervical cord of patients with Devic’s neuromyelitis optica

Objectives: To assess MRI and magnetization transfer (MT) imaging changes in the brain and cervical cord from patients with Devic’s neuromyelitis optica (DNO), and to compare them with those from patients with MS. Background: In MS, MT imaging detects changes within the normal-appearing brain tissue (NABT). MS lesions in the cord usually are isointense on T1-weighted images. No study has investigated these two aspects in patients with DNO. Methods: The authors obtained dual echo, fast fluid-attenuated inversion recovery, T1-weighted, and MT scans of the brain from 8 DNO patients, 10 MS patients, and 9 healthy volunteers. T2-weighted, short-tau inversion recovery, T1-weighted, and MT scans of the cervical cord also were obtained. The authors identified lesions visible on the different scans and quantified the volumes for those in the brain. MT ratio (MTR) histogram analysis of the NABT and of the entire cervical cord also was performed. Results: No brain abnormalities were found on the T2-weighted scans from healthy volunteers and from seven DNO patients. No significant difference was found for any of the NABT-MTR histogram metrics between DNO patients and controls, whereas MS patients had a significantly lower histogram average MTR and peak height. No abnormalities were seen on any of the scans of the cervical cord from healthy volunteers. All DNO patients had a single lesion longer than two vertebral segments. Five of them were hypointense on T1-weighted scans. The authors identified 24 cord lesions from MS patients: 22 were shorter than two vertebral segments and none was hypointense. There was no difference in cervical cord MTR histogram metrics between DNO and MS patients. Conclusions: This study demonstrates that patients with Devic’s neuromyelitis optica (DNO) and MS have different imaging characteristics of the brain and cervical cord. This provides further evidence that DNO is a clinical entity separate from MS.