Therapeutic Advances in Neurological Disorders最新文献

In multiple sclerosis (MS), increasing disability is considered to occur due to persistent, chronic inflammation trapped within the central nervous system (CNS). This condition, known as smoldering neuroinflammation, is present across the clinical spectrum of MS and is currently understood to be relatively resistant to treatment with existing disease-modifying therapies. Chronic active white matter lesions represent a key component of smoldering neuroinflammation. Initially characterized in autopsy specimens, multiple approaches to visualize chronic active lesions (CALs) in vivo using advanced neuroimaging techniques and postprocessing methods are rapidly emerging. Among these in vivo imaging correlates of CALs, paramagnetic rim lesions (PRLs) are defined by the presence of a perilesional rim formed by iron-laden microglia and macrophages, whereas slowly expanding lesions are identified based on linear, concentric lesion expansion over time. In recent years, several longitudinal studies have linked the occurrence of in vivo detected CALs to a more aggressive disease course. PRLs are highly specific to MS and therefore have recently been incorporated into the MS diagnostic criteria. They also have prognostic potential as biomarkers to identify patients at risk of early and severe disease progression. These developments could significantly affect MS care and the evaluation of new treatments. This review describes the latest knowledge on CAL biology and imaging and the relevance of CALs to the natural history of MS. In addition, we outline considerations for current and future in vivo biomarkers of CALs, emphasizing the need for validation, standardization, and automation in their assessment.

Background: Time elapsed from stroke onset and baseline infarct volume is influential on endovascular thrombectomy (EVT) outcomes.

Objectives: This study aimed to explore the utility of early infarct growth rate (EIGR) measured by apparent diffusion coefficient (ADC) in predicting symptomatic intracranial hemorrhage (sICH) of ischemic stroke patients after EVT.

Methods: We retrospectively analyzed patients from the prospectively maintained stroke registry admitted between January 2019 and March 2023, presenting with large vessel occlusive stroke in the anterior circulation. EIGR was defined as ischemic core volume on magnetic resonance perfusion imaging (ADC ⩽620 × 10^-6 mm²/s) divided by the time from stroke onset to imaging. sICH was diagnosed according to the Heidelberg Bleeding Classification within 72 h after the procedure.

Results: A total of 315 patients met the inclusion criteria. We observed sICH in 36 (11.4%) patients. After adjusting for the potential confounders, increased EIGR was confirmed to be independently associated with a higher risk of sICH (adjusted odds ratio, 1.033; 95% confidence interval (CI), 1.018-1.048; p = 0.001). Similar results were also confirmed when EIGR was analyzed as a categorical variable. Using a logistic regression model with restricted cubic splines, we found a linear correlation between EIGR and sICH risk (p = 0.001 for linearity). Furthermore, adding EIGR to a model containing conventional risk factors significantly improved risk reclassification for sICH (category-free net reclassification index, 0.393; 95% CI, 0.227-0.560; p = 0.001; integrated discrimination improvement, 0.245; 95% CI, 0.146-0.343; p = 0.001).

Conclusion: Increased EIGR may predict the sICH in ischemic stroke patients who receiving EVT.

Background: Myelin oligodendrocyte glycoprotein (MOG) IgG related optic neuritis (ON) which manifests as recurrent episodes and severe visual impairment remains a challenging issue in relapse prevention. Tocilizumab (TCZ), a human monoclonal antibody against IL-6R, may be an alternative treatment for the prevention of relapse in refractory MOG-ON patients.

Objectives: To investigate the efficacy and safety of Tocilizumab (TCZ) in patients with recurrent myelin oligodendrocyte glycoprotein IgG related optic neuritis (MOG-ON).

Design: We conducted an open-label, single-arm, nonrandomized, uncontrolled clinical trial at a tertiary neuro-ophthalmology center between April 1, 2021, and April 1, 2022.

Methods: Participants with relapsed MOG-ON, whose disease had been resistant to previous immunotherapies, received tocilizumab as monotherapy or as an add-on therapy and were followed up for at least 12 months. Annual recurrence rate (ARR), best corrected visual acuity (BCVA), and adverse events were recorded for analyses.

Result: Ten patients (7 females and 3 males) with relapsed MOG-ON were included with a mean (SD) ages of 28.6 (20.5) years old at disease onset and 30.9 (19.7) years at first TCZ administration, with a mean disease duration of 26.6 (11.3) months. Seven (70%) patients remained relapse-free, and the median (range) ARR dropped significantly from 1.9 (0.4-3.5) to 0.0 (0-4.0) during TCZ treatment (p = 0.006). Three patients experienced a relapse of ON at 2, 3, and 7 months after TCZ therapy. The median BCVA improved from 2.7 (2.0-3.0) logMAR at the nadir to 0.2 (0-2.0) logMAR at the last follow-up. Adverse effects included transient diarrhea (n = 1) and upper respiratory infection (n = 1).

Conclusion: This study supports that Tocilizumab therapy, with or without concomitant immunosuppression, is safe and effective in reducing relapses in MOG-ON patients who have failed immunosuppressive therapy or targeted B-cell therapy.

Trial registration: This trial is registered with the Chinese Clinical Trial Registry, number ChiCTR2100045273. (URL: https://www.chictr.org.cn/showproj.html?proj=124810).

Background: Good outcomes in stroke care require swift diagnostics, for which magnetic resonance imaging (MRI) as first-line brain imaging is superior to computed tomography scans. Reduced length of stay (LOS) in hospital and emergency departments (ED) may optimize resource use. Fast-track stroke MRI was implemented as the primary imaging technique for suspected stroke, in the ED at Copenhagen University Hospital-Herlev and Gentofte in 2020.

Objectives: We aimed to describe and compare LOS, MRI utilization, and the rate of strokes versus stroke-mimicking conditions on the stroke ward, before and after the implementation of fast-track MRI.

Design and method: In this cross-sectional study, we used data from admissions to the neurologic ED and associated non-comprehensive stroke unit. We compared two time periods, that is, January 1-December 31, 2019, and January 1-December 31, 2020, before and after the implementation of fast-track stroke MRI.

Results: There were 6650 admissions before and 7201 after implementation of fast-track stroke MRI. After implementation, we observed reductions in average LOS in hospitals from 56.0 to 38.6 h (p < 0.001), and LOS in ED from 9.17 to 8.63 h (p < 0.001). The use of inpatient MRI increased significantly, and the rate of acute ischemic stroke patients on the ward increased yet the rate of non-strokes remained unchanged. The association between shorter admissions and access to MRI remained (odds ratio 1.81, p < 0.001), after adjusting for sex, age, weekend admissions, and lockdown periods.

Conclusion: Fast-track stroke MRI in ED associated with reduced LOS in hospital.

Guillain-Barré syndrome (GBS) and its variants represent a spectrum of acute, immune-mediated polyneuropathies with heterogeneous clinical presentations and underlying etiologies. While infectious triggers are common precursors to these disorders, the association between viral infections and autoimmune neurological conditions remains an area of active investigation. Here, we report a case of GBS/Miller-Fisher syndrome overlap syndrome in an 80-year-old male presenting with dysarthria, dysphonia, ophthalmoplegia, areflexia, and postural instability following an upper respiratory tract infection. Cerebrospinal fluid analysis revealed the unexpected detection of herpes simplex virus type 1 DNA. Treatment with intravenous immunoglobulin therapy and acyclovir resulted in a progressive recovery of neurological symptoms. This case emphasizes the role of viral infections in differential diagnosis or as potential triggers for autoimmune neurological disorders highlighting the efficacy to addressed therapy in such complex cases.

An expansion in the availability of generic specialty disease modifying therapies (DMTs) for treatment of multiple sclerosis (MS) has increased recently. Generic specialty medications aim to provide greater access to molecules that alter the disease trajectory at lower costs. The US Food and Drug Administration requires generic products to contain between 90% and 110% of the stated active ingredient and an 80%-125% bioequivalence range. We present the clinical experiences and absolute lymphocyte counts (ALC) trends of six people with MS originally treated with Gilenya^® (fingolimod) 0.5 mg who were required to transition to generic fingolimod 0.5 mg by third-party administrators, and the medication content from recovered products. Six individuals with acute clinical exacerbations or disease advancement on MRI were identified during routine scheduled visits from a tertiary care center and consecutively included from January 2024 to August 2024. ALC trends were constructed for each individual during Gilenya^® and generic fingolimod treatment. These individuals experienced signs of disease advancement while on generic fingolimod 0.5 mg at approximately 1 year of treatment and elevations in ALC, a biological metric related to the mechanism of action of sphingsine-1-phosphate receptor modulation, were observed following the transition. High purity fingolimod for standardization tests, Gilenya^® 0.5 mg, and five recovered generic fingolimod 0.5 mg products were independently tested in an accredited laboratory. Gilenya^® 0.5 mg capsules had an average fingolimod content of 97.7% (standard deviation (SD) = 2.59%). Three recovered generic fingolimod 0.5 mg products used during relapses had an average content of 91.2% (3.25%), 81.6% (6.24%), and 72.5% (2.05%). Two generic fingolimod 0.5 mg products not associated with relapse activity revealed averages of 97.4% (1.82%) and 103.3% (3.77%). Subpotent generic specialty DMTs may not only result in greater risk for disease activity but may also expose individuals to the potential for disease rebound, depending on the mechanism of action.

Background: Combined first-line therapies have been frequently adopted for patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Plasma exchange (PE) or immunoadsorption (IA) was used as an add-on option following initial immunotherapies, including high-dose steroids and intravenous immunoglobulin (IVIG). However, whether a shorter delay of PE or IA can improve the early recovery prognosis of patients with anti-NMDAR encephalitis remains largely unknown.

Objective: To compare short-term clinical improvement between patients with early and late initiation of PE or IA in anti-NMDAR encephalitis.

Design: A retrospective study was conducted for patients admitted with anti-NMDAR encephalitis between January 2015 and December 2023 (n = 29), including 21 patients who received PE or IA as synergistic therapies.

Methods: The clinical prognosis was compared between the early PE/IA group and the late PE/IA group in the research. Primary outcome included changes in the Clinical Assessment Scale for Autoimmune Encephalitis (∆CASE) at 90 and 120 days after encephalitis onset. Secondary outcomes included changes in the modified Rankin scale (∆mRS) after 90 and 120 days from encephalitis onset, and the length of intensive care unit (ICU) stay for patients with severe anti-NMDAR encephalitis.

Results: The ∆CASE scores after 90 and 120 days from encephalitis onset revealed a significant difference between patients with early and late initiation of PE or IA (p ⩽ 0.05). A significant difference in the ∆mRS was also found between patients with early and late initiation of PE or IA in severe encephalitis (p ⩽ 0.05). No significant difference was found in the length of ICU admission (p = 0.101).

Conclusion: Our findings emphasize the importance of considering PE or IA as early as feasible for patients with anti-NMDAR encephalitis, even when steroids and IVIG are in use.

Background: Acute ischemic stroke (AIS) imposes a major healthcare burden. It is hypothesized that bacterial infection could influence atherosclerosis and thrombus formation, potentially contributing to AIS.

Objectives: We aim to systematically review all studies that have investigated the presence of bacterial signatures within thrombi retrieved following mechanical thrombectomy (MT) procedures in patients with AIS.

Design: This systematic review is designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 checklist.

Data sources and methods: A comprehensive search was conducted in the Web of Sciences, PubMed, Scopus, and Embase databases to identify relevant studies.

Results: The literature search and screening included 11 studies involving 674 patients, with 414 (61.4%) being male and 260 (38.6%) females. Among all the patients, 393 (58.3%) were positive for bacterial presence in their retrieved thrombi. The most utilized technique for bacterial signature detection was bacterial DNA extraction followed by polymerase chain reaction amplification of the 16S rRNA gene sequence. Staphylococcus aureus was the most studied bacteria among the studies analyzed.

Conclusion: Bacterial infections and the presence of bacteria within thrombi may significantly contribute to AIS by initiating or exacerbating atherosclerosis or thrombosis. Understanding the mechanisms by which bacteria affect vascular health is crucial for developing effective preventive and therapeutic strategies for stroke patients.

Background: The relationship between coronavirus disease 2019 (COVID-19) infection and multiple sclerosis (MS) relapse and disease progression remains unclear. Previous studies are limited by small sample sizes and most lack a propensity-matched control cohort.

Objective: To evaluate the effect of COVID-19 infection on MS disease course with a large propensity-matched cohort.

Design: This multi-centre cohort study analysed relapse and disability outcomes post-COVID-19 infection after balancing covariates using a propensity score matching method. The study period was from the 11th of September 2019 to the 16th of February 2023. The mean follow-up period was 1.7 years.

Methods: Data were retrieved from the MSBase Registry. Propensity scores were obtained based on age, sex, disease duration, baseline Expanded Disability Status Scale (EDSS), MS course, relapses pre-baseline, disease-modifying therapy (DMT) class and country. Primary outcomes were time to first relapse, annualised relapse rate (ARR) and time to confirm EDSS progression. Secondary outcomes were time to EDSS of 3, 4 or 6. Sensitivity analyses with baseline DMT classes were performed.

Results: The study included 2253 cases and 6441 controls. After matching, there were 2161 cases and an equal number of matched controls. Cases had a significantly higher ARR (ARR = 0.10 [95% CI 0.09-0.11]) compared to controls (ARR = 0.07 [95% CI 0.06-0.08]). Cases had a significantly greater hazard of time to first relapse compared to controls (hazard ratio (HR) = 1.54 [95% CI 1.29-1.84]). There was no association between COVID-19 infection and 24-week EDSS progression (HR = 1.18 [95% CI 0.92-1.52]), or time to EDSS of 3, 4 or 6. For patients on interferons and glatiramer acetate (BRACE), COVID-19 infection was associated with a greater hazard of time to first relapse (HR = 1.83 [95% CI 1.25-2.68]) and greater hazard of time to EDSS of 3 (HR = 2.04 [95% CI 1.06-3.90]) compared to patients on BRACE therapy without COVID-19 infection.

Conclusion: COVID-19 infection was associated with a significantly increased MS relapse rate and a shorter time to first relapse. There was no effect on confirmed EDSS progression over the short term. These results support ongoing COVID-19 risk minimisation strategies to protect patients with MS.

Background: Alemtuzumab is administered intravenously (IV) for relapsing-remitting multiple sclerosis (RRMS), with limited studies of subcutaneous (SC) treatment.

Objectives: We sought to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety profile of SC-administered alemtuzumab in people with progressive multiple sclerosis (PMS).

Design: SCALA was a phase I, open-label, randomized, parallel-group study with two 12-month periods and a safety monitoring phase to 60 months.

Methods: Of 29 screened participants, 24 were enrolled and randomized 2:1 to two 12 mg/day alemtuzumab treatments (60 and 36 mg total; SC:IV). Key inclusion criteria: ⩾18 years with a PMS diagnosis. Key exclusion criteria included RRMS diagnosis and prior treatment with anti-CD52 antibodies. Primary endpoint: CD3⁺ lymphocyte count. Secondary endpoints: PD and PK parameters.

Results: Demographics were broadly similar for participants in the SC (16) and IV (8) arms; more participants with primary PMS received SC (44%) versus IV (25%) treatment. After the first course, the mean CD3⁺ cell count/µL was reduced at month 1 in both arms (SC: baseline (BL) 1326 to 48 vs IV: BL 1155 to 84). Lymphocyte counts partially repopulated by month 12, with mean CD3⁺ cell counts/µL of SC 599 versus IV 528. The mean lymphocyte counts/µL decreased again after the second course at month 13 in both arms (SC: 90 vs IV: 129), with partial repopulation by month 24. Alemtuzumab serum concentrations were lower following SC administration relative to IV, with 32% bioavailability. There were no adverse events leading to permanent treatment discontinuation or death.

Conclusion: In SCALA, there were similar patterns of lymphocyte depletion and repopulation for participants receiving SC or IV alemtuzumab. In both arms, alemtuzumab had a manageable safety profile, with no emerging safety concerns. The general stabilization of neurological outcomes observed over 60 months underscores the potential long-term benefits of alemtuzumab treatment.

Trial registration: Clinicaltrials.gov identifier: NCT02583594.