Diffusion MRI tractography has been used to map the axonal structure of the human brain, but its ability to detect neuronal injury is yet to be explored. Here we report differential tractography, a ...new type of tractography that utilizes repeat MRI scans and a novel tracking strategy to map the exact segment of fiber pathways with a neuronal injury. We examined differential tractography on multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis, and epileptic patients. The results showed that the affected pathways shown by differential tractography matched well with the unique clinical symptoms of the patients, and the false discovery rate of the findings could be estimated using a sham setting to provide a reliability measurement. This novel approach enables a quantitative and objective method to monitor neuronal injury in individuals, allowing for diagnostic and prognostic evaluation of brain diseases.
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•Conventional tractography maps all pathways and is insensitive to neuronal change.•Differential tractography compares two longitudinal scans to map neuronal injury.•Differential tractography tracks the exact segment with a decrease in anisotropy.•The injury pattern revealed can assist with diagnostic and prognostic evaluations.•The false discovery rate of the findings can be estimated using a sham analysis.
Differential tractography utilizes repeat diffusion MRI scans to identify the exact segment of tracks with a neuronal injury.
To examine the reliability, validity, and interpretability of 4 clinical measures in assessing the severity of balance dysfunction among people with cerebellar ataxia (CA) secondary to multiple ...sclerosis (MS).
Cross-sectional observation study.
Outpatient clinics.
Consecutive participants with CA secondary to MS (N=60).
Not applicable.
Balance was assessed and video recorded using the Berg Balance Scale (BBS), timed Up and Go (TUG) test, posture and gait subcomponent of the International Co-operative Ataxia Rating Scale (ICARS), and gait, stance, and sit subcomponents of the Scale for the Assessment and Rating of Ataxia (SARA). The videos were later used to estimate reliability. The Barthel Index, Expanded Disability Status Scale (EDSS), ICARS, and SARA were assessed, and disease duration was recorded.
Reliability was good for all 4 measures (intraclass correlation coefficient range, .95-.99). Internal consistency was moderate to good for all 4 measures (α range, .72-.94), with a moderate to good correlation between the measures of balance (Spearman ρ range, .72-.85) and poor to moderate correlation with disease severity (EDSS), functional independence (Barthel Index), and disease duration (Spearman ρ range, -.37 to .76). Minimal detectable change was derived for the BBS (3), posture and gait subcomponent of the ICARS (2), and gait, stance, and sit subcomponents of the SARA (2). Measures were able to discriminate between assistive walking device users and nonusers.
All 4 measures showed good reliability and acceptable validity; however, because of the item repetition in scoring of the posture and gait subcomponent of the ICARS and moderate construct, criterion, and convergent validity of the TUG, the BBS and gait, stance, and sit subcomponents of the SARA are recommended for balance assessment in clinical practice for people with CA secondary to MS.
Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. ...Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis.
We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972.
Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 95% CI 0·86–20·85; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 95% CI 1·05–23·20; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic.
We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab.
Biogen.
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