Therapeutic Advances in Neurological Disorders最新文献

Hereditary spastic paraplegia (HSP) groups rare, clinically and genetically heterogeneous neurodegenerative disorders, characterized by progressive lower-limb spasticity and weakness. Over the past decades, diagnostic strategies have evolved from pure clinical assessment to the integration of molecular tools, with next-generation and long-read sequencing (LRS) substantially increasing diagnostic yield and refining genotype-phenotype correlations. Neuroimaging provides complementary information, especially in specific subtypes such as SPG11 and SPG15, supporting diagnosis and guiding testing. Treatment has historically focused on symptomatic care, including physiotherapy, antispastic agents, and botulinum toxin, with dalfampridine explored for gait improvement in selected patients. More recently, research has expanded into disease-modifying avenues, such as drug repurposing (e.g., statins in SPG5, menatetrenone in ALS2) and early gene-based interventions in ultra-rare subtypes. At the same time, advances in technology, ranging from quantitative imaging and digital gait analysis to induced pluripotent stem cell models and artificial intelligence, are beginning to influence both clinical management and trial design. This review traces the trajectory of HSP care from its historical foundations to present standards and emerging innovations, outlining how technological progress is shaping realistic prospects for future therapeutic strategies.

Background: The prognostic significance of resting heart rate (HR) in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO) after endovascular treatment (EVT) remains to be elucidated.

Objectives: To determine whether HR is differentially associated with functional outcomes in patients dichotomized by anterior (ACS) or posterior circulation stroke (PCS) after successful reperfusion.

Design: A multicenter retrospective cohort study.

Methods: We retrospectively analyzed consecutive successfully recanalized LVO-AIS patients with complete HR recordings at admission, 30 min, 12 h, 24 h, and 48 h post-EVT. A good outcome was defined as modified Rankin Scale (mRS) 0-2 for ACS or mRS 0-3 for PCS at 3 months. Binary logistic regression and receiver operating characteristic analyses were used to assess associations and predictive performance.

Results: Among 505 patients (362 ACS, 143 PCS), lower HR at 12, 24, and 48 h post-EVT was independently associated with good outcomes in both groups. HR showed higher predictive accuracy for PCS (AUC: 0.872-0.885) than for ACS (AUC: 0.732-0.762).

Conclusion: HR following EVT independently predicts functional outcome in LVO patients, demonstrating stronger predictive value for PCS than ACS. These results highlight the potential of HR monitoring in post-EVT management.

Chimeric antigen receptor T-cell (CAR-T) therapy has become an established treatment for several haematological malignancies in relapse and is being evaluated for new indications. An important clinical challenge associated with the use of CAR-T therapy, however, is the common development of neurotoxicity. Different neurotoxicity syndromes have been reported. The best-known form of CAR-T neurotoxicity is immune effector cell-associated neurotoxicity syndrome, which can be associated with various findings on magnetic resonance imaging (MRI), including cerebral oedema and leptomeningeal enhancement. Other manifestations of neurotoxicity include movement disorders, myelopathy, cranial nerve palsies and ischaemic strokes. MRI plays a key role in the diagnosis and management of patients with suspected neurotoxicity. It can be used to support the diagnosis, exclude differential diagnoses and forms part of the grading of neurotoxicity. Other roles for MRI after CAR-T therapy include assessment of potential longer-term effects of therapy and neurotoxicity, and the evaluation of patients with emerging indications for CAR-T therapy. We recommend performing a baseline MRI brain prior to CAR-T therapy where feasible, as this greatly aids in the interpretation of neuroimaging findings. Here, we discuss the established and potential roles of neuroimaging in the context of neurotoxicity secondary to CAR-T therapy.

Background: The quality and clinical outcomes of mechanical thrombectomy (MT) performed at thrombectomy-capable stroke centers (TSCs) versus comprehensive stroke centers (CSCs) remain insufficiently characterized.

Objective: To compare MT outcomes between TSCs and CSCs and to develop and externally validate an online tool for individualized prognosis and decision support.

Design: Retrospective cohort study including derivation and external validation cohorts from multiple stroke centers.

Method: Patients with anterior circulation large vessel occlusion who underwent MT within 24 h were analyzed. Inverse probability of treatment weighting (IPTW) and multivariable logistic regression estimated the effects of stroke center certification. Sensitivity analyses using alternative model specifications, patient subsets, and predefined subgroups assessed robustness and heterogeneity. A prognostic model was developed using least absolute shrinkage and selection operator regression after IPTW, externally validated using 2023-2024 data from different centers, and deployed as a Shiny-based online tool predicting 90-day modified Rankin Scale outcomes (0-2 for independence, 0-5 for survival).

Results: The median age was 69 years (interquartile range (IQR) 60-77) in the derivation cohort (n = 975) and 72 years (IQR 64-80) in the validation cohort (n = 484). Functional outcomes and survival probabilities were similar between cohorts. After IPTW and adjustment, logistic regression showed CSCs were associated with higher 3-month survival (OR, 1.70 (95% CI: 1.31-2.22)). Sensitivity and subgroup analyses validated findings. The online prediction model, incorporating eight variables, demonstrated strong discriminative ability for functional outcomes (C-statistic 0.77 (95% CI: 0.73-0.81)) and survival (C-statistic 0.77 (95% CI: 0.71-0.82).

Conclusion: CSCs were significantly associated with a higher probability of survival compared to TSCs, while no significant difference was observed in favorable functional outcomes. An online multivariable model could predict clinical outcomes and guide decision-making between TSCs and CSCs in routine clinical practice.

Background: Cladribine (CLAD) stands as an oral disease modifying treatment (DMT) for multiple sclerosis (MS) patients, distinguished by its unique dosing regimen and mechanism of action. However, real-world data on its effectiveness remain limited, particularly regarding the clinical and therapeutical management beyond the 2-year treatment schedule.

Objectives: The aim of our study was to explore the effectiveness profile of CLAD in individuals with MS (pwMS). We assessed the proportion of patients achieving no evidence of disease activity (NEDA-3) status and identified variables associated with better outcomes.

Design: In this retrospective study, we collected clinical and magnetic resonance imaging (MRI) data of MS patients across 10 MS Clinics in Central Italy who started CLAD between 2018 and 2023.

Methods: We evaluated the annualized relapse rate (ARR) during treatment, and the proportion of patients who experienced relapses, radiological activity, and confirmed disability progression. Additionally, we estimated the proportion of patients achieving NEDA-3 among those with a minimum follow-up of 3 months and explored baseline variables associated with NEDA status.

Results: We collected data from 1094 patients with a mean follow-up of 25.1 months, of whom 79% completed the second CLAD cycle. The mean age was 37.7 years (SD 9.7), and the mean disease duration was 6.5 years, with 40.5% being treatment naïve. Despite a significant reduction of the ARR from 0.91 to 0.04 (p < 0.01) following CLAD treatment, 8.9% of patients presented at least one relapse, while 22.0% and 7.9% of patients experienced radiological activity or disability progression, respectively. Across the entire study cohort, 70.2% of patients maintained the NEDA-3 status. Younger age (HR = 0.98, p < 0.001) and higher expanded disability status scale score (HR = 1.11, p = 0.049) were associated with a higher risk of not achieving the NEDA-3 status. Additionally, we included 131 patients who were older than 50 years at the time of CLAD initiation. Among the cohort, 116 patients switched to another DMT after CLAD, primarily anti-CD20 monoclonal antibodies following disease reactivation.

Conclusion: This postmarketing experience confirms the effectiveness of CLAD in the treatment of pwMS, with a significant reduction in ARR and a high proportion of patients remaining free from disease activity. By contrast, some patients required an escalation strategy mainly with anti-CD20 monoclonal antibodies because of persisting disease activity.

Therapeutic plasma exchange (PLEX) is a powerful and fast-acting immunomodulating therapy that is underutilized for autoimmune neurological disorders. Here, we present the largest collection of real-world experiences with PLEX procedures to date in the treatment of autoimmune neurological conditions, supporting its safety and clinical benefits with patient cases and corresponding patient videos. Our collective real-world experience with PLEX spans over 67 years, 90,210 procedures, and includes nine double-blind randomized controlled and unblinded studies serving as principal investigators. Case histories and videos of our patients demonstrate when and how PLEX should be used, identify barriers to using PLEX, and ways to overcome these barriers. Specific protocol details are shared of how to treat an acute or chronic phase of a disease. If used appropriately and early in the disease course for both acute and chronic progressive phases, PLEX can safely change the trajectory of many autoimmune neurological disorders in both outpatient and inpatient settings.

Background: Switching disease-modifying therapies (DMTs) is common in relapsing-remitting multiple sclerosis (RRMS). Vertical switching to higher-efficacy agents generally outperforms horizontal switching within the same efficacy tier, yet horizontal switches remain frequent where escalation is impractical.

Objectives: To compare real-world outcomes after horizontal versus vertical DMT switches and to identify predictors of successful horizontal switching.

Design: Retrospective, registry-based observational study.

Methods: Adults with RRMS who switched DMTs in the MSBase Registry (2010-2023) were analyzed. Horizontal switches were defined as transitions within efficacy tiers, and vertical switches as transitions to a higher tier. Propensity score matching (1:1) generated balanced cohorts. Multivariable mixed-effects models with a random intercept for patients were used to evaluate associations with outcomes. The primary outcome was no evidence of disease activity (NEDA-3) during the treatment period; secondary outcomes included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) change, confirmed disability worsening (CDW), confirmed disability improvement (CDI), and progression independent of relapse activity (PIRA). Predictors of successful horizontal switching were explored using logistic regression.

Results: A total of 4934 matched switches (2467 pairs) were analyzed. Vertical switching achieved higher NEDA-3 rates than horizontal switching (45.8% vs 33.7%) and was associated with lower ARR, reduced CDW risk, and more frequent CDI; differences in EDSS progression and PIRA were not significant. Among horizontal switchers, 33.7% achieved NEDA-3. Success was associated with lower baseline EDSS, fewer prior relapses, and later-line switching. Outcomes varied by destination therapy: anti-CD20 agents had the highest success (≈50%), followed by cladribine (≈43%) and natalizumab (≈41%), whereas interferon and glatiramer acetate performed the poorest. Switches toward anti-CD20 therapies generally yielded better outcomes than other within-tier changes.

Conclusion: Vertical switching should be preferred when treatment modification is required, particularly for patients with active disease. However, a subset of patients can achieve disease stability after horizontal switching, especially those with lower disability and fewer prior relapses. The dynamics of horizontal switching may further influence outcomes, warranting prospective validation.

Background: Despite significant achievements in healthcare quality improvement for ischemic stroke and transient ischemic attack (TIA), the advancements and challenges of patient adherence to secondary prevention medications remain unclear.

Objectives: We aimed to investigate adherence rates of secondary prevention medication and identified the key determinants in Chinese patients with ischemic stroke or TIA.

Design: This is an observational study.

Methods: Using the China National Stroke Registry (CNSR) database from 2007 to 2018, this observational study included patients with ischemic stroke or TIA who were admitted to the hospital within 7 days of symptom onset. The study outcome was the patient adherence to secondary prevention medications, which was defined as the consistent use of prescribed antithrombotic, lipid-modulating, antidiabetic, and antihypertensive medications post-discharge using an "all-or-none" approach. We calculated adherence rates in 3 and 12 months. Logistic regression models were used to evaluate influencing factor patterns and challenges in the improvement of patient adherence.

Results: A total of 12,873 patients from CNSR I and 15,099 patients from CNSR III were included. Patient adherence rates for secondary prevention medications increased from 66.97% in CNSR I to 80.76% in CNSR III (p < 0.0001) in 3 months, and from 35.08% to 59.81% (p < 0.0001) in 12 months. Patient age, the National Institute of Health stroke scale score at admission, disease diagnosis, the Trial of Org 10172 in Acute Stroke Treatment classification, family income per capita, alcohol consumption, dyslipidemia history, hypertension history, diabetes history, and heart disease history appeared to exhibit a significant association with adherence.

Conclusion: In spite of the remarkable progress in patient adherence to secondary prevention of stroke from 2007 to 2018, challenges remain in sustaining quality improvement initiatives, necessitating further improvements by addressing disease severity, lifestyle, medical history, and socioeconomic factors.

Background: Lasmiditan, an oral 5-HT_1F receptor agonist, has been recently approved for acute migraine treatment. While its efficacy was confirmed in randomized clinical trials, scarce data is available regarding effectiveness and tolerability in the real-world setting.

Objectives: To evaluate lasmiditan effectiveness and tolerability in the real-world setting in 16 Italian headache centers.

Design: LasmiDitan as Acute migRaine Treatment (DART) study is a prospective, multicentric, observational study.

Methods: We enrolled 58 participants with migraine (84.5% females, age 49.0 (45.2-52.9) years, 24.1% with chronic migraine) reporting 9.4 (7.4-11.3) monthly migraine days. Participants were instructed to treat their migraine attacks with oral lasmiditan 50 or 100 mg. Using an ad hoc electronic diary, participants prospectively collected migraine attack features at baseline and every 30 min after lasmiditan administration, up to 2 h post-dose. The primary outcome was 2-h pain freedom for the first-treated attack after lasmiditan intake. We also collected the occurrence of treatment-emergent adverse events (AE) after administration.

Results: Overall, participants treated 100 attacks, of which 58 first-treated attacks. Regarding first-treated attacks, 44.8% of subjects rated migraine intensity as severe at lasmiditan intake. Pain freedom 2-h post-dosing was reported in 32.8% (19/58) of individuals and was associated with baseline pain intensity, being higher in subjects treating a mild/moderate attack (p = 0.044). Conversely, it was not influenced by timing of intake (p = 0.375), dosage (p = 0.727), or previous triptan failure (p = 0.351). Regarding all-treated attacks, pain freedom 2-h post-dosing was 37.0% (37/100). At least one AE was reported by 53.4% of participants (31/58), predominantly asthenia, dizziness, somnolence, anxiety or agitation, and paresthesia. Tolerability was rated as good-to-excellent by 51.8% of subjects.

Conclusion: Our study supports clinical effectiveness of oral lasmiditan 50 and 100 mg for the treatment of acute migraine attacks. Lasmiditan effectiveness was not associated with the previous triptan failure and may therefore represent a valuable therapeutic option in subjects who did not benefit from, or have contraindications to, triptans.

Trail registration: The study was preregistered on clinicaltrial.gov, NCT05903040 (https://clinicaltrials.gov/study/NCT05903040?cond=migraine&intr=lasmiditan&rank=5).

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is the most frequently observed autoimmune neuropathy in patients with diabetes mellitus (DM). While intravenous immune globulin (IVIG) is a well-established treatment for CIDP, its efficacy in diabetic patients remains uncertain due to their exclusion from prior randomized trials, largely because of concerns about confounding diabetic axonal neuropathy.

Objectives: To evaluate the effectiveness of IVIG therapy in CIDP patients with diabetes mellitus (CIDP-DM) compared to those without diabetes (CIDP).

Design: Multi-center, prospective, observational study after at least 3 monthly infusions of IVIG therapy.

Methods: Thirty-six patients meeting diagnostic criteria for CIDP were enrolled and stratified into CIDP or CIDP-DM. All patients were followed for a minimum of 3 months after initiating IVIG therapy. Clinical outcomes were assessed at baseline (visit #1) and after 3 monthly IVIG infusions (visit #4) using the adjusted Inflammatory Neuropathy Cause and Treatment Disability Score, the Rasch-built Overall Disability Scale, and the Chronic Acquired Polyneuropathy Patient-reported Index, measured at baseline and at the point of maximal improvement.

Results: No significant differences were observed in clinical outcomes, treatment-related adverse events, or tolerance between CIDP and CIDP-DM groups, indicating comparable effectiveness of IVIG therapy. However, subgroup analyses revealed that longer duration of diabetes and elevated HbA1c levels were associated with delayed response to IVIG, likely due to cumulative axonal degeneration.

Conclusion: Despite the small number of enrolled patients, IVIG appears equally effective in CIDP patients with and without diabetes. Earlier initiation of IVIG treatment should be considered in CIDP-DM patients to mitigate potential delays in therapeutic response associated with a possibly chronic diabetic neuropathy-related component.