Therapeutic Advances in Neurological Disorders最新文献

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.

Background: Alemtuzumab (ALEM) is a humanised monoclonal antibody that depletes circulating lymphocytes by selectively targeting CD52, which is expressed in high levels on T- and B-lymphocytes. This depletion is followed by lymphocyte repopulation and a cytokine expression shift towards a lesser inflammatory profile, both of which may contribute to prolonged efficacy. National recommendations for enrolling and treating multiple sclerosis (MS) patients with ALEM have been established. However, there are no recommendations in place for the treatment of MS reactivation after the ALEM treatment.

Objectives: To evaluate the effectiveness and safety of the use of ALEM and to analyse subsequent disease-modifying treatments (DMTs). A multidimensional prediction model was developed to make a patient-specific prognosis regarding the response to ALEM.

Design: A multicentre, prospective, non-controlled, non-interventional, observational cohort study.

Methods: Relapsing multiple sclerosis patients (RMSp) who received ⩾1 dose of ALEM were enrolled. In each treatment year, the following baseline and prospective data were collected: age, MS history, number, type and duration of previous disease-modifying treatment (PDMT), relapse rate (REL), expanded disability status scale (EDSS), magnetic resonance imaging and serious adverse events (AE). In cases of reactivation of MS, all data about the subsequent DMT were collected.

Results: A total of 142 RMSp from 10 MS Slovak Centres fulfilled the inclusion criteria. The average age was 35 years (standard error 8.56). The overall average EDSS was 3.87 (1.46) when ALEM was started. The average duration of PDMT was 6.0 (4.04) years, and the median number of PDMTs was 3 (0-5), while the patients were mostly treated with 2 or 3 DMTs (>65.00%). Post-ALEM treatment was needed in 39 cases (27.46%). The most frequent post-ALEM treatment indicated was ocrelizumab, followed by natalizumab (NAT), siponimod and cladribine. The ocrelizumab and NAT treatment bring little benefit to patients. Siponimod showed less EDSS increase in contrast to ocrelizumab and NAT. Another repopulation therapy, cladribine, may also be an effective option. Statistically significant predictors for the expected EDSS are age (p-value <0.0001), number of ALEM cycles (0.0066), high number of PDMT (0.0459) and the occurrence of relapses (<0.0001). There was no statistically significant effect on the patient's gender (0.6038), duration of disease-modifying treatment before alemtuzumab (0.4466), or the occurrence of AE (0.6668).

Conclusion: The study confirms the positive effect of ALEM on clinical and radiological outcomes. We need more data from long-term sequencing studies.

Background: Epidemiological research has failed to confirm laterality of lesion site as a neurobiological source of post-stroke psychopathology. However, acquired communication disorders have proved to be a key risk factor for depression, apart from established parameters such as pre-stroke psychopathology and physical immobility.

Objectives: The present work examines a new predictor of post-stroke psychopathology: psychological flexibility. This concept describes an accepting attitude toward irreversible loss following stroke while using remaining agency.

Design: Overall, 70 individuals engaged in a cross-sectional study conducted in the subacute stage after an ischemic or hemorrhagic event, a period with elevated prevalence of mental-health problems (2 weeks to 6 months after stroke).

Methods: Outcomes included standardized self-report and clinician-rated measures of depression, anxiety disorders, and general psychopathology (Beck Depression Inventory; Hospital Anxiety and Depression Scale; ICD-10 Symptom Rating; Hamilton Depression Rating Scale) alongside lack of psychological flexibility (Acceptance and Action Questionnaire II). The study design controlled for pre-stroke psychopathology and physical immobility (Barthel Index).

Results: Partial correlation analyses revealed a significant medium-to-large association between the entire set of clinical outcomes and lack of psychological flexibility (r ⩽ 0.62, p < 0.001). In moderator analyses, the magnitude of this association did not vary significantly with diagnosis of acquired communication disorders (i.e., aphasia, apraxia of speech or dysarthria; separately or combined).

Conclusion: The current results demonstrate a substantial link between post-stroke psychopathology and psychological flexibility. This finding opens new avenues for research on depression and other mental-health problems in stroke survivors with and without acquired communication disorders.

Registration: www.drks.de; identifier: DRKS00031204.

Background: Interferon-beta (IFN-β) still plays a fundamental role in immunomodulation of people with multiple sclerosis (MS) with low disease activity and in clinically isolated syndrome (CIS). In 2014, pegylated (PEG) interferon was licensed by the European Medicines Agency (EMA) for relapsing-remitting MS (RRMS), enabling a lower dosing frequency.

Objectives: Our retrospective study compares laboratory findings and adverse events between subcutaneous (sc.) PEG-IFN-β-1a and IFN-β-1a in RRMS and CIS patients.

Design: Patients with CIS or RRMS fulfilling the revised McDonald criteria from 2017 visiting the neurology department of the University Medical Center of the Johannes Gutenberg University Mainz from 2010 to 2019 and treated with sc. PEG-IFN-β-1a or sc. IFN-β-1a (n = 202) were screened for eligibility. Patients who underwent regular laboratory controls in-house were included in our analysis (n = 128).

Methods: We evaluate disease progression through clinical examination, relapse history, and magnetic resonance imaging (MRI) disease activity (gadolinium-enhancing or new T2 lesions). Relevant laboratory findings such as leukopenia (leukocyte count < 3.5/nl) and neutropenia (neutrophil count <43% of lymphocytes or <1500/µl) were assessed. Telephone interviews evaluated the side effects of the respective medication. A subgroup of patients was analyzed regarding neutrophil quantities and qualities.

Results: Patients treated with sc. PEG-IFN-β-1a had significantly lower leukocyte counts (p = 0.046) and higher incidences of leukopenia (p = 0.006) and neutropenia (p = 0.03) compared to sc. IFN-β-1a. Clinical and MRI disease activity showed no significant differences, but people treated with sc. PEG-IFN-β-1a reported more common adverse events such as joint/muscle pain, injection-site reaction, and infections. No serious adverse events were reported.

Conclusion: Treatment with sc. PEG-IFN-β-1a compared to unpegylated sc. IFN-β resulted in a significantly greater reduction in leukocyte and neutrophil levels with a higher incidence of side effects. We suggest mandatory monitoring of differential blood counts before and during treatment.

Background: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system affecting approximately 2.8 million people worldwide. In addition to genetic and environmental factors, various lifestyle factors contribute to disease development and progression.

Objectives: We performed a monocentric retrospective study and investigated the effect of lifestyle factors such as obesity, smoking, alcohol consumption, physical activity, and dietary habits on the degree of disability in a cohort of people with MS (pwMS) with an average onset of disease after the age of 55.

Design: This late-onset MS (LOMS) study group (n = 47) was characterized by a mean age of 60.9 years and a mean duration of disease of 5.0 years. The LOMS study group was compared with two control groups. The study participants in the "old control group" (C_old) were on average as old and in the "young control group" (C_young) as long suffering from MS as the pwMS in the LOMS group.

Methods: Data from medical documentation and a questionnaire were analyzed using descriptive frequency analyses and testing for correlation between different variables also by generalized estimating equations. The Expanded Disabilty Status Scale (EDSS) score and the progression index were used as a measure of disability.

Results: We found a significant association between smoking history and the current EDSS score in the C_young group, but not in the two older study groups. For physical activity, there was a significant negative correlation with EDSS score in the study group and the C_old group, alcoholic beverage consumption correlated with decreased EDSS in the C_old group. The intake of meat negatively correlated with the progression index in the LOMS group.

Conclusion: In summary, different life-style factors correlated with disability depending on patient age and disease duration. These life-style factors may be considered in the future counseling of pwMS at older ages.