Ruggero Capra

Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis

BACKGROUND Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. METHODS In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. RESULTS A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. CONCLUSIONS This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)

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.

Multiple Sclerosis: Effects of Cognitive Rehabilitation on Structural and Functional MR Imaging Measures—An Explorative Study

PURPOSE To evaluate brain changes after cognitive rehabilitation in patients with clinically stable relapsing-remitting (RR) multiple sclerosis (MS) by using neuropsychologic assessment and structural and functional magnetic resonance (MR) imaging techniques. MATERIALS AND METHODS The study was conducted with approval of the involved institutional review boards. Written informed consent was obtained from each participant. Twenty patients with RR MS and cognitive deficits at baseline were randomly assigned to undergo treatment (n = 10), which entailed computer-assisted cognitive rehabilitation of attention and information processing and executive functions, or to serve as a control subjects (n = 10) without cognitive rehabilitation. All patients underwent a standardized neuropsychologic assessment and MR imaging at baseline and after 12 weeks. Changes in gray matter (GM) volumes on three-dimensional T1-weighted images and changes in normal-appearing white matter (NAWM) architecture on diffusion-weighted images were assessed. Changes in functional activity at functional MR imaging during the Stroop task and at rest were also investigated by using linear models. RESULTS As compared with their performance at baseline, the patients in the treatment group improved at tests of attention and information processing and executive functions. Neither structural modifications to GM volume nor modifications to NAWM architecture were detected at follow-up in both groups. Functional MR imaging demonstrated modifications of the activity of the posterior cingulate cortex (PCC)/precuneus and dorsolateral prefrontal cortex (PFC) during the Stroop task, as well as modifications of the activity of the anterior cingulum, PCC and/or precuneus, left dorsolateral PFC, and right inferior parietal lobule at rest in the treatment group compared with the control group. In the treatment group, functional MR imaging changes were correlated with cognitive improvement (P < .0001 to .01). CONCLUSION Rehabilitation of attention and information processing and executive functions in RR MS may be effected through enhanced recruitment of brain networks subserving the trained functions.

L-Selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients

Objective: To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment. Methods: Patients were recruited from 10 European and US cohorts. Of 289 patients with multiple sclerosis (MS), 224 had been treated with natalizumab (18–80 months), 21 received other immune-modulatory treatments, and 28 were untreated. We had access to samples from 16 natalizumab PML patients. Eight of these patients had given blood before the diagnosis of PML. We also analyzed non-natalizumab-treated patients who developed PML (n = 10) and age- and sex-matched healthy donors (n = 31). All flow cytometric assessments were done on previously cryopreserved, viable peripheral blood mononuclear cells. Results: The percentage of l-selectin-expressing CD4+ T cells was significantly lower in patients treated long-term with natalizumab (40.2%) when compared with patients not receiving natalizumab treatment (47.2%; p = 0.016) or healthy controls (61.0%; p < 0.0001). An unusually low percentage (9-fold lower; 4.6%) was highly correlated with the risk of developing PML in the patient group with available pre-PML samples when compared with non-PML natalizumab-treated patients (p ≤ 0.0001). Samples were gathered between 4 and 26 months before PML diagnosis. Conclusions: The cell-based assessment of the percentage of l-selectin-expressing CD4 T cells could provide an urgently needed biomarker for individual PML risk assessment.

Brain involvement in systemic immune mediated diseases: magnetic resonance and magnetisation transfer imaging study

OBJECTIVE Magnetisation transfer imaging (MTI) provides information about brain damage with increased pathological specificity over conventional MRI and detects subtle abnormalities in the normal appearing brain tissue, which go undetected with conventional scanning. Brain MRI and MTI findings were compared in patients with multiple sclerosis (MS) and systemic immune mediated diseases (SIDs) affecting the CNS to investigate their roles in understanding the nature of brain damage in these diseases. METHODS Brain dual echo, T1 weighted and MTI scans were obtained in patients affected by systemic lupus erithematosus (SLE) with (NSLE, n=9) and without clinical CNS involvement (n=15), Behçets disease (BD) (n=5), Wegeners granulomatosis (WG) (n=9), and antiphospholipid antibody syndrome (APLAS) (n=6). Ten patients with clinically definite MS and 15 healthy controls also underwent the same scanning protocol. Brain MRI and MT ratio (MTR) images of the same subject were coregistered and postprocessed to obtain MTR histograms of the whole brain and of the NABT. RESULTS Brain hyperintense lesions were found in all patients with MS and with NSLE and in 5/15 patients with SLE, 5/9 with WG, 1/5 with BD, and 3/6 with APLAS. The lesion burden in the brain was significantly higher in patients with MS compared with all the other disease groups. All MTR histogram parameters were significantly different among patient subgroups. Patients with MS had significantly lower average MTR than all except patients with NSLE and significantly lower peak height and location than patients with SLE. patients with NSLE had significantly lower average MTR than patients with SLE. CONCLUSIONS Microscopic brain tissue damage is relevant in patients with MS, but, apart from patients with NSLE, it seems to be absent in systemic immune mediated diseases, even in the presence of macroscopic MRI lesions or clinical evidence of CNS involvement.

Corpus callosum damage and cognitive dysfunction in benign MS

Corpus callosum (CC), the largest compact white matter fiber bundle of the human brain involved in interhemispheric transfer, is frequently damaged in the course of multiple sclerosis (MS). Cognitive impairment is one of the factors affecting quality of life of patients with benign MS (BMS). The aim of this study was to investigate the relationship between the cognitive profile of BMS patients and the extent of tissue damage in the CC. Brain conventional and DT MRI scans were acquired from 54 BMS patients and 21 healthy controls. Neuropsychological tests (NPT) exploring memory, attention, and frontal lobe cognitive domains were administered to the patients. DT tractography was used to calculate the mean diffusivity (MD) and fractional anisotropy (FA) of the CC normal appearing white matter (NAWM). An index of CC atrophy was also estimated. Nine (17%) BMS patients fulfilled criteria for cognitive impairment. Compared with controls, BMS had significantly different CC diffusivity and volumetry (P < 0.001). Compared with cognitively preserved patients, those with CI had significantly higher CC lesion volume (LV) (P = 0.02) and NAWM MD (P = 0.02). The scores obtained at PASAT were significantly correlated with CC T2 LV, and NAWM FA and MD (r values ranging from −0.31 to 0.66, P values ranging from 0.04 to <0.001). Cognitive impairment in BMS is associated with the extent of CC damage in terms of both focal lesions and diffuse fiber bundle injury. MRI assessment of topographical distribution of tissue damage may represent a rewarding strategy for understanding the subtle clinical deficits of patients with BMS. Hum Brian Mapp 2009.

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.

Acute myeloid leukemia in Italian patients with multiple sclerosis treated with mitoxantrone.

Objectives: To evaluate the incidence and dose-dependency of mitoxantrone (MTX)-associated acute myelocytic leukemia (AML) in the network of Italian multiple sclerosis (MS) clinics. Methods: We performed a multicenter retrospective cohort study of patients treated with MTX in MS centers under the Italian national health care system between 1998 and 2008. Demographic, disease, treatment, and follow-up information were collected using hospital records. Results: Data were available for 3,220 patients (63% women) from 40 Italian centers. Follow-up (mean ± SD) was 49 ± 29 months (range 12–140 months). We observed 30 cases of AML (incidence 0.93% [95% confidence interval 0.60%–1.26%]). The mean cumulative dose was higher in patients with AML (78 vs 65 mg/m2, p = 0.028). The median interval from the start of therapy to AML diagnosis was longer than expected at 33 months (range 13–84 months); 8 patients (27%) developed AML 4 years or more after the first MTX infusion. The rate of mortality associated with AML was 37%. Conclusions: This higher than expected risk of AML and related mortality requires that treatment decisions must be made jointly between clinicians and patients who understand their prognosis, treatment options, and treatment-related risks. The now large exposed MS population must be monitored for hematologic abnormalities for at least 6 years from the end of therapy, to ensure the rapid actions needed for early diagnosis and treatment of AML.

Frequency and risk factors of mitoxantrone-induced amenorrhea in multiple sclerosis: the FEMIMS study

Background Improved prognosis in women with multiple sclerosis (MS) undergoing immunosuppressive treatment with mitoxantrone (MITO) has led to an increased interest in the effect of such treatments on fertility. FErtility and Mitoxantrone In MS (FEMIMS) is a collaborative retrospective study aimed at evaluating the impact of MITO treatment on fertility in women with MS. Methods Occurrence of chemotherapy-induced amenorrhea (CIA) was evaluated in 189 women with MS treated with MITO before the age of 45. An “ad hoc” questionnaire, paying particular attention to onset of CIA either during or post-MITO treatment, was administered to each patient. The probability of CIA was calculated using a multivariate logistic regression analysis taking into account age at exposure, cumulative dose, and use of estroprogestinic (EP) drugs during treatment. Results Forty-eight (26%) patients presented CIA following MITO. The probability of CIA was increased by 2%/mg/m2 of cumulative dose and by 18% for each year of age, whereas it was reduced by administration of EP during treatment. Conclusions MITO treatment may affect reproductive capacity in women with MS. Patients of childbearing age should be properly counseled before MITO treatment and EP therapy should be administered to reduce the risk of CIA.

Neuropsychological assessment in patients with relapsing-remitting multiple sclerosis and mild functional impairment: correlation with magnetic resonance imaging.

Forty one moderately impaired patients with clinically confirmed multiple sclerosis (MS) and a relapsing-remitting course were submitted to a neuropsychological battery and magnetic resonance imaging (MRI) to correlate the neuropsychological performances with the degree of cerebral demyelination. The neuropsychological results were indicative of a very mild overall impairment. The patients were subdivided into two groups (extensive periventricular demyelination or discrete lesions on MRI) and the results of neuropsychological tests compared. Patients with extensive periventricular demyelination had an inferior performance on concept formation, non-verbal reasoning and verbal memory tests.