A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. METHODS: Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. RESULTS: Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).

Health-related quality of life in multiple sclerosis: effects of natalizumab.

OBJECTIVE: To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. METHODS: HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300 mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-beta-1a) plus natalizumab 300 mg (n = 589), or IFN-beta-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. RESULTS: Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. INTERPRETATION: HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab.

[Cerebral venous thrombosis: a young woman case study]. / Przypadek zakrzepicy zatok zylnych mózgu u mlodej kobiety.

Cerebral venous sinus thrombosis is a rare, serious cerebrovascular disease with poor prognosis. It can be a sequel to various coagulation disturbances, head injuries or local inflammations. We report a case of a young woman with no risk factors detected, who developed a massive cerebral venous sinus thrombosis. She had progressively worsening symptoms, including left hemiplegia, aphasia, tonic-clonic seizures and unconsciousness. The diagnosis was supported by CT, MRI and angio-MRI findings. The intensive i.v. heparin and streptokinase treatment, as well as antibiotics, resulted in full remission of all patient's symptoms. The case emphasizes the necessity of early diagnosis and management of cerebral venous sinus thrombosis.

[Generalized choreic involuntary movements in the course of stroke: case report]. / Ruchy mimowolne pod postacia plasawicy uogólnionej w przebiegu udaru niedokrwiennego mózgu--opis przypadku.

Involuntary movements are rare ischemic stroke complication. Hemichorea, hemibalism and dystonia cases were described, especially during haemorrhage into basal ganglia and thalamus. The case of 73 years old woman is presented who was admitted to our Clinic cause of sudden choreatic involuntary movements occurrence within axial muscles and limbs. Computed Tomography showed ischemic focus in basal ganglia (head of caudate nucleus and lentiformis nucleus) and anterior branch of internal capsule. Cerebral angio--CT confirmed partial occlusion both medial arteries and atherosclerotical changes within the rest of cerebral arteries.

[Parkinsonism-ALS-dementia complex: case report]. / Zespól parkinsonizm-SLA-demencja--opis przypadku.

We are presenting a case of Parkinson-ALS-Dementia complex in 53 years old male. Outstanding bulbar signs with muscular atrophy of tongue, muscular atrophy of shoulder girdle together with massive fasciculations (myoclonus type descending from spinal cord) have been observed. Clear Parkinson's syndrome coexisted--bradykinesia, rigidity with cogwheel resistance, "masking" of the face, disturbances of body balance and significant vegetative signs. Moreover psychological testing has shown psycho-organic syndrome of frontal type, MRI scans proved the existence of slight brain general atrophy that is most prominent in frontal et temporal poles. Diseases of this kind occur all over the world sporadically. The case of ALS--dementia complex was observed in our clinic a year ago.

[A case or Leber hereditary optic neuropathy (LHON): differential diagnosis with post inflammatory atrophy of nerve II using the mtDNA analysis]. / Przypadek choroby lebera--róznicowanie z pozapalnym zanikiem nerwu II za pomoca analizy mtDNA.

The Leber hereditary optic neuropathy (LHON) is a disease due to a mtDNA mutation. The disorder results from enzymatic perturbations in the mitochondrial respiratory chain. Clinically the LHON may present as a progressive axonal atrophy of the optic nerves with or without other neurological symptoms. The process of reaching the diagnosis of the LHON by means of the molecular analysis of mtDNA is discussed.

The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL.

The AFFIRM and SENTINEL studies showed that natalizumab was effective both as monotherapy and in combination with interferon beta (IFNbeta)-1a in patients with relapsing multiple sclerosis (MS). Further analyses of AFFIRM and SENTINEL data were conducted to determine the efficacy of natalizumab in prespecified patient subgroups according to baseline characteristics: relapse history 1 year before randomization (1, 2, > or = 3), Expanded Disability Status Scale score (< or = 3.5, > 3.5), number of T2 lesions (< 9, > or = 9), presence of gadolinium-enhancing (Gd+) lesions (0, > or = 1), age (< 40, > or = 40) and gender (male, female). A post hoc analysis was conducted to determine the efficacy of natalizumab in patients with highly active disease (i. e., > or = 2 relapses in the year before study entry and > or = 1 Gd+ lesion at study entry). In both AFFIRM and SENTINEL studies natalizumab reduced the annualized relapse rates across all subgroups (except the small subgroups with < 9 baseline T2 lesions) over 2 years. In AFFIRM, natalizumab significantly reduced the risk of sustained disability progression in most subgroups. In SENTINEL, natalizumab significantly reduced the risk of sustained disability progression in the following subgroups: > or = 9 T2 lesions at baseline, > or = 1 Gd+ lesions at baseline, female patients and patients < 40 years of age. Natalizumab reduced the risk of disability progression by 64 % and relapse rate by 81 % in treatment- naive patients with highly active disease and by 58 % and 76 %, respectively, in patients with highly active disease despite IFNbeta-1a treatment. These results indicate that natalizumab is effective in reducing disability progression and relapses in patients with relapsing MS, particularly in patients with highly active disease.