Annals of Clinical and Translational Neurology最新文献

Background: While advances in endovascular thrombectomy (EVT) have led to high reperfusion rates, most patients treated with EVT do not avoid disability. Post-reperfusion hemorrhagic transformation (HT) is a potential target for improving outcomes. This study examined pretreatment blood-brain barrier (BBB) disruption in tissue that would subsequently become part of the final infarct to evaluate its role in post-EVT HT.

Methods: This post hoc analysis of the FRAME study, which enrolled patients with anterior large vessel occlusion who received EVT within 6 hours of onset, included patients if they had successful pretreatment MRI perfusion weighted imaging (PWI) and underwent successful EVT. BBB disruption was measured as the percent signal change due to gadolinium leakage on the PWI source images prior to thrombectomy. Mean permeability derangement (MPD) was defined as the average of all voxels in the stroke core that are two standard deviations above normal. The primary outcome was hemorrhagic transformation with parenchymal hematoma (PH).

Results: In total, 164 patients were included; mean age was 71 and 48% were female. PH occurred in 57 patients. Median MPD was 13.5% for patients with PH versus 3.6% for patients without (p < 0.0001). Elevated MPD was independently associated with PH with a 20% increased risk of PH for each 5% increase in MPD (OR 1.206; 95% CI 1.037:1.405; p = 0.0147, adjusted for NIHSS and procedure duration).

Conclusions: Even in patients who are successfully recanalized in an early time window, pretreatment BBB disruption in regions that go on to infarct is associated with an increased risk of post-EVT HT.

Objective: Subcutaneous ocrelizumab is being developed to provide treatment flexibility and additional choice to patients with multiple sclerosis. OCARINA I (NCT03972306) is an open-label, multicenter, Phase 1b, dose-finding study to investigate the pharmacokinetics, safety, tolerability, and immunogenicity of subcutaneous ocrelizumab and to select a dose for the Phase 3 OCARINA II study (NCT05232825).

Methods: Patients with relapsing or primary progressive multiple sclerosis (aged 18-65 years; Expanded Disability Status Scale score 0.0-6.5) were enrolled into two groups: previously treated with intravenous ocrelizumab (Group A) or naïve to ocrelizumab (Group B). Patients received single ascending doses of subcutaneous ocrelizumab up to 1200 mg. Following dose escalation, new patients in Group A were randomized (1:1) to receive a single 600 mg intravenous ocrelizumab dose or the candidate subcutaneous dose, which was predicted to result in similar exposure as the 600 mg intravenous dose while being safe and well tolerated. The area under the concentration-time curve for both formulations was used to select the subcutaneous ocrelizumab dose. Patients in all cohorts could enter a dose-continuation phase.

Results: Eighty-eight and 47 patients were enrolled into Group A and B, respectively; most patients were female (72.7%/63.0%), and mean age at baseline was 45.7 and 39.7 years, respectively. Subcutaneous ocrelizumab was well tolerated across all doses tested. The 920 mg subcutaneous ocrelizumab dose was selected for the OCARINA II study based on pharmacokinetic and safety data.

Interpretation: Subcutaneous ocrelizumab may provide patients with multiple sclerosis with an additional treatment option.

Objectives: Dysregulated RNA alternative splicing is the hallmark of myotonic dystrophy type 1 (DM1). However, the association between RNA mis-splicing and physical function in children with the most severe form of disease, congenital myotonic dystrophy (CDM), is unknown.

Methods: Eighty-two participants (42 adults with DM1 and 40 children with CDM) with muscle biopsies and measures of myotonia, motor function, and strength were combined from five observational studies. Data were normalized and correlated with an aggregate measure of alternative splicing dysregulation, [MBNL]_inferred, in skeletal muscle biopsies. Multiple linear regression analysis was performed to predict [MBNL]_inferred using clinical outcome measures alone. Similar analyses were performed to predict 12-month physical function using baseline metrics.

Results: Myotonia (measured via vHOT) was significantly correlated with RNA mis-splicing in our cross-sectional population of all DM1 individuals; CDM participants alone displayed no myotonia despite a similar range of RNA mis-splicing. Measures of motor performance and muscle strength were significantly associated with [MBNL]_inferred in our cohort of all DM1 individuals and when assessing children with CDM independently. Multiple linear regression analyses yielded two models capable of predicting [MBNL]_inferred from select clinical outcome assessments alone in all subjects (adjusted R² = 0.6723) or exclusively in children with CDM (adjusted R² = 0.5875).

Interpretation: Our findings establish significant correlations between skeletal muscle performance and a composite measure of alternative splicing dysregulation, [MBNL]_inferred, in DM1. The strength of these correlations and the development of predictive models will assist in designing efficacious clinical trials for individuals with DM1, particularly CDM.

Objectives: Many cases of cervical artery dissection are considered "spontaneous." Recent data suggest that while cervical artery dissection may proportionally explain more strokes in young patients, hospitalization for dissection increases with age, suggesting a potential role of acquired vascular disease. In this study, we hypothesized that traditional vascular risk factors and comorbidities are associated with cervical artery dissection.

Methods: We performed a retrospective cohort study using administrative claims data from a 5% sample of Medicare beneficiaries. Exposures of interest included traditional vascular risk factors and comorbidities: coronary artery disease, hyperlipidemia, hypertension, diabetes mellitus, heart failure, chronic kidney disease, chronic obstructive pulmonary disease, valvular heart disease, atrial fibrillation, tobacco use, and alcohol abuse. The primary outcome was a new diagnosis of cervical artery dissection. Marginal structural Cox models were used to characterize the association between the exposures and outcomes, adjusted for time-dependent confounding.

Results: Among 2,256,710 eligible Medicare beneficiaries, 730 (0.03%) developed cervical artery dissection. The following exposures were found to be significantly associated with the development of cervical artery dissection: hypertension (HR 1.84 [95% CI: 1.40-2.41]), alcohol use (HR 1.83 [1.52-2.21]), atrial fibrillation (HR 1.80 [1.53-2.11]), tobacco use (HR 1.80 [1.52-2.13]), coronary artery disease (HR 1.56 [1.33-1.82]), and valvular heart disease (HR 1.23 [1.05-1.45]).

Interpretation: In a large cohort of older people, several traditional vascular risk factors and comorbidities were associated with subsequent cervical artery dissection. Further studies exploring the role of such factors in the development of cervical artery dissection are warranted.

Objective: This study aimed to investigate the nature of subclinical Visual Snow Syndrome (VSS). We sought to develop a means of recruiting naïve participants with subclinical VSS symptoms to participate in research; and to understand whether subclinical VSS symptoms are stable across time. VSS is a recently characterised neurological condition, whose primary symptom is visual snow (dynamic noise in the visual field). There is evidence that VSS may be common in the general population and that it is unnoticed by many who experience it. To fully characterise VSS, it is important to understand whether (and how) subclinical VSS progresses to a clinical form.

Methods: Here, we present two related studies: Study 1 develops and validates the Melbourne Visual Snow Questionnaire (MVSQ), a tool for screening the general population for VSS symptoms; and Study 2 investigates the stability of subclinical VSS. We developed the MVSQ based on the results of other recent work investigating undiagnosed cases of VSS, and a validated questionnaire designed to identify people with tinnitus for research participation. We then tested the MVSQ in a population with clinical VSS, including assessing face validity (i.e., the extent to which people with clinical VSS believed the questionnaire accurately captured their symptoms). In Study 2, we deployed the MVSQ in a naïve sample of 155 participants, who completed the MVSQ twice, 6 weeks apart.

Results: The results of Study 1 indicated that the MVSQ was a viable method of recruiting people who experience VSS symptoms for research participation. It was deemed to have appropriate face validity and to pose little burden to those who completed it. In Study 2, VSS symptoms changed substantially across a 6-week period. Cohen's weighted kappa for diagnosis was 0.56, 95% CI [0.43, 0.69]. However, the impact of perceptual experiences was low and did not change over time, rank ICC = 0.71, 95% CI [0.59, 0.82].

Interpretation: The MVSQ is appropriate for assessing perceptual experiences in the general population. Determining the exact time scale across which symptoms fluctuate is important for understanding both clinical and subclinical cases of VSS.

Objective: Compare the diagnostic characteristics of intraepidermal nerve fiber density (IENFD) and confocal corneal microscopy (CCM) for distal symmetric polyneuropathy (DSP) and small fiber neuropathy (SFN).

Methods: Participants with obesity were recruited from bariatric surgery clinics and testing was performed prior to surgery. DSP and SFN were determined using the Toronto consensus definitions of probable neuropathy. IENFD was assessed from 3 mm punch biopsies of the distal leg and proximal thigh. CCM was performed on both eyes with manual and automated counting. The Michigan Neuropathy Screening Instrument questionnaire (MNSIq) was also completed. Diagnostic capability was determined using areas under the receiver operating characteristics curve (AUC) from logistic regression.

Results: We enrolled 140 participants (mean [standard deviation [SD]] age: 50.3 years [7.1], 77.1% female, BMI: 44.4 kg/m² [6.7]). In this population, 22.9% had DSP and 14.3% had SFN. Distal leg IENFD had the largest AUC (95% confidence interval) for DSP (0.78, 0.68-0.89) and SFN (0.85, 0.75-0.96). Proximal thigh IENFD (DSP: AUC: 0.59, 0.48-0.69, SFN: AUC: 0.59, 0.46-0.73) and CCM metrics (DSP: AUC range: 0.55-0.60, SFN: AUC range: 0.45-0.62) had poorer diagnostic capability than distal leg IENFD for DSP/SFN (P < 0.05). MNSIq had similar diagnostic capability to distal leg IENFD for both DSP/SFN (DSP: AUC: 0.76, 0.68-0.85, SFN: AUC: 0.81, 0.73-0.88). More participants (52%) preferred skin biopsies to CCM.

Interpretation: Distal leg IENFD was the best quantitative measure of DSP/SFN. CCM had poor diagnostic characteristics and fewer patients preferred this test to IENFD. The MNSIq had similar diagnostic characteristics to distal leg IENFD, indicating its value as a diagnostic tool in the clinical setting.

Clinical trial registration: clinicaltrials.gov: NCT03617185.

Objective: To systematically evaluate which lesion-based imaging features and methods allow for the best statistical prediction of poststroke deficits across independent datasets.

Methods: We utilized imaging and clinical data from three independent datasets of patients experiencing acute stroke (N₁ = 109, N₂ = 638, N₃ = 794) to statistically predict acute stroke severity (NIHSS) based on lesion volume, lesion location, and structural and functional disconnection with the lesion location using normative connectomes.

Results: We found that prediction models trained on small single-center datasets could perform well using within-dataset cross-validation, but results did not generalize to independent datasets (median R² _N1 = 0.2%). Performance across independent datasets improved using large single-center training data (R² _N2 = 15.8%) and improved further using multicenter training data (R² _N3 = 24.4%). These results were consistent across lesion attributes and prediction models. Including either structural or functional disconnection in the models outperformed prediction based on volume or location alone (P < 0.001, FDR-corrected).

Interpretation: We conclude that (1) prediction performance in independent datasets of patients with acute stroke cannot be inferred from cross-validated results within a dataset, as performance results obtained via these two methods differed consistently, (2) prediction performance can be improved by training on large and, importantly, multicenter datasets, and (3) structural and functional disconnection allow for improved prediction of acute stroke severity.

Objective: The association between gait speed and adverse outcomes after stroke has not been fully illustrated. This study aimed to explore the association of gait speed on long-term outcomes in minor stroke or transient ischemic attack (TIA).

Methods: We performed a longitudinal study with acute minor stroke or TIA based on a subgroup of the Third China National Stroke Registry data. The gait speed was evaluated using a 10-meter walking test at discharge and 3 months after the stroke onset. The primary outcomes were poor functional outcomes at 1 year, defined by a modified Rankin Score (mRS) of 2-6. Additional outcomes included all-cause death, ambulate dependency (mRS score 4-6), cognitive impairment (Montreal Cognitive Assessment <26), stroke recurrence, and composite vascular events.

Results: The study sample included a total of 1542 stroke patients with a median age of 60 (53-68). At 1-year follow-up, 140 (9.20%) patients experienced poor functional outcomes. Faster gait speed at discharge was associated with lower incidence of poor functional outcome (OR = 0.89; 95% CI, 0.84-0.94), cognitive impairment (OR = 0.93; 95% CI, 0.89-0.96), ischemic stroke recurrence (HR = 0.92; 95% CI, 0.87-0.98), and composite vascular events (HR =0.94; 95% CI, 0.89-0.99) at 1 year. Faster gait speed at 3 months was associated with lower incidence of poor functional outcome (OR = 0.90; 95% CI, 0.85-0.95), ambulate dependency (OR = 0.86; 95% CI, 0.77-0.97), and cognitive impairment (OR = 0.92; 95% CI, 0.88-0.95) at 1 year.

Interpretation: Our findings indicated that slow gait speed after minor stroke or TIA may be an independent predictor for long-term poor outcomes. Gait speed may be considered as a vital sign during follow-up in post-stroke patients.

Objective: Previous studies reveal heterogeneity in terms of paramagnetic rim lesions (PRL) associated tissue damage. We investigated the physiopathology and clinical implications of this heterogeneity.

Methods: In 103 MS patients (72 relapsing and 31 progressive), brain lesions were manually segmented on 3T 3D-FLAIR and rim visibility was assessed with a visual confidence level score (VCLS) on 3D-EPI phase. Using T1 relaxation time maps, lesions were categorized in long-T1 and short-T1. Lesion age was calculated from time of first gadolinium enhancement (N = 84 lesions). Results on clinical scores were validated in an extended cohort of 167 patients using normalized T1w-MPRAGE lesion values.

Results: Rim visibility (VCLS analysis) was associated with increasing lesional T1 (P/P_FDR < 0.001). Of 1680 analyzed lesions, 427 were categorized as PRL. Long-T1 PRL were older than short-T1 PRL (average 0.8 vs. 2.0 years, P/P_FDR = 0.005/0.008), and featured larger lesional volume (P/P_FDR < 0.0001) and multi-shell diffusion-measured axonal damage (P/P_FDR < 0.0001). The total volume of long-T1-PRL versus PRL showed 2× predictive power for both higher MS disability (EDSS; P/P_FDR = 0.003/0.005 vs. P/P_FDR = 0.042/0.057) and severity (MSSS; P/P_FDR = 0.0006/0.001 vs. P/P_FDR = 0.004/0.007). In random forest, having ≥1 long-T1-PRL versus ≥4 PRL showed 2-4× higher performance to predict a higher EDSS and MSSS. In the validation cohort, long-T1 PRL outperformed (~2×) PRL in predicting both EDSS and MSSS.

Interpretation: PRL show substantial heterogeneity in terms of intralesional tissue damage. More destructive, likely older, long-T1 PRL improve the association with MS clinical scales. This PRL heterogeneity characterization was replicated using standard T1w MRI, highlighting its potential for clinical translation.

Objective: We evaluated the effect of CHA₂DS₂-VASc score and prior use of oral anticoagulants (OACs) on endovascular treatment (EVT) in patients with acute ischemic stroke and atrial fibrillation (AF).

Methods: Patients with AF who received EVT in 353 centers in Japan (2018-2020) were included. The outcomes were symptomatic intracerebral hemorrhage (sICH), in-hospital mortality, functional independence, and successful and complete reperfusion. The effects of CHA₂DS₂-VASc score, its components, and prior use of OACs were assessed via a multiple logistic regression model.

Results: Of the 6984 patients, 780 (11.2%) used warfarin and 1168 (16.7%) used direct oral anticoagulants (DOACs) before EVT. Based on the CHA₂DS₂-VASc score, 6046 (86.6%) presented a high risk (≥2 for males and ≥3 for females) while 938 (13.4%) had intermediate to low risks. Higher CHA₂DS₂-VASc scores were associated with increased sICH, in-hospital mortality, and decreased functional independence, regardless of prior OACs. For patients with a high-risk category, prior DOACs increased the odds of successful and complete reperfusion (adjusted odds ratio [95% confidence interval (CI)], 1.27 [1.00-1.61] and 1.30 [1.10-1.53]). For those with integrated intermediate to low risks, neither prior warfarin nor DOAC affected the outcomes. Regardless of total CHA₂DS₂-VASc scores, patients with congestive heart failure or left ventricular dysfunction, hypertension, age >75 years, or female benefited similarly from prior DOAC use.

Interpretation: Prior DOAC use for patients with high- and selected intermediate-risk CHA₂DS₂-VASc scores increased prevalence of successful and complete reperfusion. These findings may provide supplemental evidence to introduce preventive DOAC for patients with AF.