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Higher-Level Gait Disorder (HLGD) is a type of gait disorder estimated to affect up to 6% of the older population. By definition, its symptoms originate from the higher-level nervous system, yet its association with brain morphology remains unclear. This study hypothesizes that there are patterns in brain morphology linked to HLGD. For the first time in the literature, this work investigates whether deep learning, in the form of convolutional neural networks, can capture patterns in magnetic resonance images to identify individuals affected by HLGD. To handle this new classification task, we propose setting up an ensemble of models. This leverages the benefits of combining classifiers instead of determining which network is the most suitable, developing a new architecture, or customizing an existing one. We introduce a computationally cost-effective search algorithm to find the optimal ensemble by leveraging a cost function of both traditional performance scores and the diversity among the models. Using a unique dataset from a large population-based cohort (VESPR), the ensemble identified by our algorithm demonstrated superior performance compared to single networks, other ensemble fusion techniques, and the best linear radiological measure. This emphasizes the importance of implementing diversity into the cost function. Furthermore, the results indicate significant morphological differences in brain structure between HLGD-affected individuals and controls, motivating research about which areas the networks base their classifications on, to get a better understanding of the pathophysiology of HLGD.

Background: Higher-level gait disorders (HLGDs) are slow, unsteady neurological GDs in older people. GDs can reduce quality of life (QoL) and cause depression. This has not been investigated in HLGD even though some HLGD causes are treatable, potentially affecting associated problems. We aimed to investigate gait and balance confidence, depressive symptoms and QoL in HLGD.

Methods: In a population (n=3769, 65-84y), 798 reported gait impairment (questionnaire) and were clinically examined together with 249 age- and sex-matched controls. Gait property groups were formed: 'HLGD', 'other neurological GD', 'non-neurological GD' or 'no GD'. Swedish Falls Efficacy Scale (FES(S)), Modified Gait Efficacy Scale (mGES), Euro Quality of Life 5-Dimension 5-Level index, Euro Quality of Life Visual Analogue Scale (EQ VAS) and Geriatric Depression Scale-15 (GDS-15) were compared.

Results: In the general population, 38% had GDs, of which 16% (n=87/561) were HLGDs, giving an HLGD prevalence of 5.8%; 26% (n=145/561) were other neurological GDs; and 59% (n=329/561) non-neurological GDs. HLGD had more depressive symptoms than non-neurological GD and no GD (GDS-15 HLGD, 3.9 +/- 3.4; non-neurological GD, 2.5 +/- 2.8; no GD, 1.4 +/- 2.0; p<0.05), lower EQ VAS (HLGD, 63 +/- 17; non-neurological GD, 71 +/- 18; no GD, 82 +/- 14; p<0.001), lower gait confidence (mGES HLGD, 60 +/- 22; non-neurological GD, 74 +/- 21; no GD, 90 +/- 13; p<0.001) and lower balance confidence (FES(S) HLGD, 93 +/- 32; non-neurological GD, 111 +/- 25; no GD, 124 +/- 13; p<0.001).

Conclusions: HLGDs are common and associated with reduced QoL, reduced confidence in gait and balance, and depressive symptoms, emphasising awareness of mental health among older people with slow unsteady gait.

Background: The placebo-controlled RINOMAX trial (NCT02950155) demonstrated superiority up to 12 months of rituximab over standard-of-care in new-onset generalized myasthenia gravis (MG), but benefit–risk over longer time frames remains unknown.

Methods: RINOMAX included 47 participants with a Quantitative Myasthenia Gravis (QMG) score ≥ 6. Twenty-five patients were randomized to a single intravenous infusion of 500 mg rituximab, and 22 to placebo of which 16 received rituximab after the double-blinded phase (7 ± 2.9 months). Data were extracted from the Swedish MG registry to track hospitalizations, treatments including rescue, and disease activity scores.

Results: Compared to the placebo arm, lower mean time-weighted QMG scores at 12 months (mean difference [MD]: 2.9, 95% CI: 0.9, 4.9; p = 0.005) and 24 months (MD: 2.6, 95% CI: 0.3, 4.9; p = 0.027) were observed in the RTX arm. The incidence rate of rescue from 48 weeks up to 5 years was numerically higher in the placebo arm than RTX (0.16 vs. 0.09/person-year; p = 0.121). Compared to delayed RTX, early exposure displayed lower QMG, risk of hospitalization (HR 0.24, 95% CI 0.07, 0.83), and rescue (HR 0.46, 95% CI 0.14, 1.57), but also the six patients never receiving RTX showed lower hospitalization risk (HR 0.08, 95% CI 0.01, 0.96). Corticosteroid doses were low globally throughout. Overall, 12.5% and 18.8% and of patients with early and delayed RTX, respectively, suffered a severe infection.

Conclusion: Disease activity and treatment burden, including hospitalization and rescue treatments, remained low, indicating a potential benefit of rituximab on the long-term disease trajectory. Infection risk with B cell depletion, however, remains a concern.

White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66–85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV’s stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.

BACKGROUND: Cerebral microbleeds (CMBs) are common in idiopathic normal pressure hydrocephalus (INPH) and have been suggested as radiological markers of a brain prone to bleeding. The presence of CMBs might be relevant when selecting patients for shunt surgery.

OBJECTIVE: To evaluate whether CMBs increases long-term risk of hemorrhagic complications and mortality or affects outcomes after cerebrospinal fluid shunt surgery in a cohort of patients with INPH.

METHODS: One hundred and forty nine shunted patients with INPH (mean age, 73 years) were investigated with MRI (T2* or susceptibility-weighted imaging sequences) preoperatively. CMBs were scored with the Microbleed Anatomic Rating Scale. Patients were observed for a mean of 6.5 years (range 2 weeks to 13 years) after surgery. Hemorrhagic events and death were noted. Improvement in gait was evaluated 3 to 6 months after surgery.

RESULTS: At baseline, 74 patients (50%) had CMBs. During follow-up, 7 patients (5%) suffered a hemorrhagic stroke and 43 (29%) suffered a subdural hematoma/hygroma with a median time from surgery of 30.2 months (IQR 50). Overall, having CMBs was not associated with suffering a subdural hematoma/hygroma or hemorrhagic stroke during follow-up with 1 exception that an extensive degree of CMBs (≥50 CMB) was more common in patients suffering a hemorrhagic stroke ( P = .03). CMBs were associated with increased mortality ( P = .02, Kaplan-Meier, log-rank test). The presence of CMBs did not affect gait outcome ( P = .28).

CONCLUSION: CMBs were associated with hemorrhagic stroke and mortality. CMBs do not seem to reduce the possibility of gait improvement after shunt surgery or contribute to the risk of hemorrhagic complications regarding subdural hematoma or hygroma.

IMPORTANCE: Rituximab is a third-line option for refractory generalized myasthenia gravis (MG) based on empirical evidence, but its effect in new-onset disease is unknown.

OBJECTIVE: To investigate the efficacy and safety of rituximab compared with placebo as an add-on to standard of care for MG.

DESIGN, SETTING, AND PARTICIPANTS: This randomized, double-blind, placebo-controlled study took place throughout 48 weeks at 7 regional clinics in Sweden. Key inclusion criteria were age older than 18 years, onset of generalized symptoms within 12 months or less, and a Quantitative Myasthenia Gravis (QMG) score of 6 or more. Patients were screened from October 20, 2016, to March 2, 2020. Key exclusion criteria included pure ocular MG, suspected thymoma, previous thymectomy, and prior noncorticosteroid immunosuppressants or high doses of corticosteroids.

INTERVENTIONS: Participants were randomized 1:1 without stratification to a single intravenous infusion of 500 mg of rituximab or matching placebo.

MAIN OUTCOMES AND MEASURES: Minimal disease manifestations at 16 weeks defined as a QMG score of 4 or less with prednisolone, 10 mg or less daily, and no rescue treatment.

RESULTS: Of 87 potentially eligible patients, 25 were randomized to rituximab (mean [SD] age, 67.4 [13.4] years; 7 [28%] female) and 22 to placebo (mean [SD] age, 58 [18.6] years; 7 [32%] female). Compared with placebo, a greater proportion with rituximab met the primary end point; 71% (17 of 24) in the rituximab group vs 29% (6 of 21) in the placebo group (Fisher exact test P = .007; probability ratio, 2.48 [95% CI, 1.20-5.11]). Secondary end points, comparing changes in Myasthenia Gravis Activities of Daily Living and Myasthenia Gravis Quality of Life at 16 weeks with QMG at 24 weeks did not differ between groups with censoring for rescue treatment (per-protocol analysis) but were in favor of active treatment when rescue treatment was taken into account by worst rank imputation (post hoc analysis). Rescue treatments were also more frequent in the placebo arm (rituximab: 1 [4%]; placebo, 8 [36%]). One patient in the placebo arm had a myocardial infarction with cardiac arrest and 1 patient in the active arm experienced a fatal cardiac event.

CONCLUSIONS AND RELEVANCE: A single dose of 500 mg of rituximab was associated with greater probability of minimal MG manifestations and reduced need of rescue medications compared with placebo. Further studies are needed to address long-term benefit-risk balance with this treatment.