Therapeutic Advances in Neurological Disorders最新文献

Background: Rescue stenting (RS) is a bailout strategy for failed thrombectomy. Optimal platelet inhibition strategy after RS remains unclear.

Objectives: We aimed to describe and compare different platelet inhibition strategies during/after RS.

Design: Retrospective cohort study across 34 international centers.

Methods: Patients with large vessel occlusion and RS after failed thrombectomy (2019-2023) were included. Periprocedural and postprocedural platelet inhibition strategies were described and compared, focusing on glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, single antiplatelet therapy (SAPT), and dual antiplatelet therapy (DAPT). We assessed the effects of platelet inhibition strategy and potentially covariates on the primary outcome of 90-day modified Rankin Scale (mRS) using ordinal shift analysis with proportional odds models.

Results: RS was performed in 589 patients (mean age 67.9 years, 60.8% male). Numerous combinations of platelet inhibitors were administered. Periprocedural GPIIb/IIIa inhibitors were used in 61.5% of patients. Postprocedural DAPT was administered to 80.5% and SAPT to 13.3%. Functional independence (mRS 0-2) was achieved in 40.7%, while 26.3% died within 90 days. Stent occlusion occurred in 20.5%, with 67.6% of these occlusions within 24 h. Postprocedural stent-occlusion was independently associated with worse functional outcome at 90 days (OR 4.1, 95% CI 2.3-7.2, p < 0.001). No significant association between periprocedural GPIIb/IIIa inhibitors, and 90-day mRS or stent occlusion was found. Postprocedural SAPT was associated with worse functional outcomes (adjusted odds ratio (aOR) 2.4, 95% CI 1.1-5.0, p = 0.02), higher mortality (aOR 2.1, 95% CI 1.05-4.0, p = 0.03), and increased stent occlusion rates (aOR 4.8, 95% CI 2.3-9.7, p < 0.001) compared to postprocedural DAPT. Symptomatic intracranial hemorrhage occurred in 6.8% of patients, with no significant difference between antiplatelet regimens.

Conclusion: Extensive heterogeneity exists in platelet inhibition strategies following RS. Stent occlusion is associated with worse clinical outcomes, and the first 24 h post-RS are critical for stent patency. Compared to SAPT, DAPT was associated with better functional outcome, lower mortality, and lower stent occlusion rates.

Orthostatic hypotension (OH) is a common, disabling manifestation of Parkinson's disease (PD) and a substantial driver of discomfort and functional disability. Clinicians caring for people with PD benefit from a working knowledge of many different treatment options for PD with OH, including medications and nonpharmacological treatments. This review provides clinicians a working understanding of PD OH management strategies that may help them in clinical practice. This includes a summary of clinical features, pathophysiological considerations, pharmacological and nonpharmacological treatments, and a proposed integrated approach to the PD patient with OH.

Parkinsonism-dominant multiple system atrophy (MSA-P) is typically a progressive disorder with poor responsiveness to levodopa and an unfavorable prognosis. However, in certain cases, the response to levodopa can be as robust as in Parkinson's disease (PD), with severe motor fluctuations developing during treatment. Unlike PD, no established therapy exists to maintain activities of daily living (ADLs) in such patients. We present three cases of young-onset MSA-P who demonstrated sustained levodopa responsiveness and were treated with levodopa-carbidopa intestinal gel (LCIG) following the emergence of disabling motor fluctuations. In all three patients, parkinsonism was the predominant symptom from onset until LCIG initiation, with only mild autonomic or cerebellar symptoms. Prior to LCIG introduction, their motor complications closely resembled those of advanced PD. LCIG therapy successfully reduced "off" time and dyskinesia in all cases. However, long-term follow-up revealed a gradual decline in ADLs due to disease progression. These cases suggest that LCIG may be a valuable treatment option for selected MSA-P patients with preserved levodopa responsiveness.

Background: Cladribine (CLAD), an immune reconstitution therapy for active multiple sclerosis (MS), can reduce intrathecal antibody production.

Objectives: In this study, we investigated the long-term impact of oral CLAD on protective antibody levels, essential for preventing infections and immune defense.

Design: Observational long-term study including a cohort of 15 CLAD-treated MS patients.

Methods: We longitudinally studied the humoral immunity to seven common pathogens (measles, mumps, varicella-zoster virus, diphtheria and tetanus toxin, rubella, hepatitis B virus (HBV)) and absolute immunoglobulin G (IgG) levels prior to CLAD treatment (baseline, BL; 12/2017-03/2020) and after an average of 73 months (long-term) follow-up to explore the impact on pre-existing IgG. At long-term, we assessed IgG response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evaluate potential inhibitory effects on the formation of new immunity.

Results: We found no CLAD associated loss of humoral immunity over up to 7 years. Pathogen-specific IgG antibodies were present in 60%-100% and 67%-100% of patients at BL and long-term, respectively. We found no decline in absolute IgG levels 73 months after starting CLAD treatment. Patients who received subsequent anti-CD20 treatment had significantly lower SARS-CoV-2 antibody levels (p = 0.011) compared to the rest of the cohort, which developed adequate anti-SARS-CoV-2 IgG. One patient had a clinically silent tick-borne encephalitis (TBE) infection mounting appropriate IgG and IgM. No severe COVID-19 cases occurred, and no new safety concerns were identified.

Conclusion: These long-term data suggest that CLAD treatment does not impact preexisting humoral immunity or antibody production toward novel antigens. Our results support the positive long-term safety profile of the drug.

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder characterized primarily by fluctuating skeletal muscle weakness affecting ocular, bulbar, truncal, limb, and respiratory muscles. The disease is typically mediated by anti-acetylcholine receptor (AChR) antibodies, and less commonly by anti-muscle-specific kinase) or anti-low-density lipoprotein receptor-related protein 4 antibodies. Despite significant advancements in diagnostics and immunotherapy, disparities in treatment access and practice variability remain prevalent in Israel. To address these gaps, updated national guidelines have been developed, integrating the latest international evidence and adapting it to the local healthcare landscape, regulation, and population diversity. This national guideline emphasizes precise diagnostic evaluation through comprehensive clinical assessment, standardized antibody testing, neurophysiological studies, and mediastinal imaging for thymic pathology assessment. Utilizing standardized scales, including MG activities of daily living, quantitative MG score, and MG Foundation of America post-intervention status, is crucial for disease staging and therapeutic decision-making. Therapeutic goals prioritize achieving full remission or a state of minimal manifestations of disease with negligible treatment-related side effects. Guidelines for treatment strategies are based on antibody status, disease severity, patient age, and comorbidities. Thymectomy is recommended for patients with generalized AChR antibody-positive MG, ideally within 2 years of disease onset. Pregnant women, older adults, children, and patients with cancer need specific immunotherapy approaches. Multidisciplinary care, structured patient education, and psychosocial support are integral to managing MG effectively. These national guidelines aim to standardize clinical practices, enhance patient outcomes, and reduce healthcare disparities in the management of MG across Israel.

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are autoimmune diseases characterized by immune-mediated damage to the central nervous system. Current treatments primarily focus on chronic immunosuppression. Immune tolerance induction offers a novel approach to restoring immune balance while minimizing systemic side effects. Central and peripheral immune tolerance mechanisms regulate autoreactive lymphocytes, ensuring immune homeostasis. Dysregulation of these pathways underpins NMOSD and MOGAD pathogenesis. Antigen-specific therapies targeting aquaporin-4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG) autoantigens include peptide-based vaccines and nanoparticle delivery systems, promoting T cell anergy and regulatory T cell (Treg) expansion. Cell-based therapies utilizing ex vivo-expanded Tregs or regulatory B cells (Bregs) have shown promise in preclinical models but face challenges in clinical translation due to scalability and safety concerns. Gene-editing technologies such as CRISPR/Cas9 present opportunities to modulate immune pathways and restore tolerance, although delivery and off-target effects remain obstacles. Additionally, strategies addressing double-seronegative NMOSD, which lacks detectable autoantibodies, emphasize broad immune modulation rather than antigen specificity. While significant progress has been achieved, the transition to clinical application requires overcoming hurdles such as optimizing antigen delivery, ensuring long-term efficacy, and identifying reliable biomarkers. Advances in personalized medicine hold promise for achieving sustained remission, reducing dependency on immunosuppression, and improving patient outcomes in NMOSD and MOGAD. This review explores advancements in tolerance strategies, highlighting their potential in NMOSD and MOGAD.

Background: Cladribine, an oral prodrug, penetrates the blood-brain barrier, impacting biomarkers of disease progression within the central nervous system.

Objectives: Describe disease activity in cladribine tablets (CladT)-treated people with highly active relapsing multiple sclerosis (pwRMS) using clinical outcomes and biomarkers.

Design: MAGNIFY-MS was an open-label, single-arm, phase IV trial with four sub-studies. Participants were grouped by previous treatment (Tx); Tx-naïve versus Tx-experienced; those with previous exposure to second-line therapies were excluded. This analysis describes cerebrospinal fluid (CSF) and optical coherence tomography (OCT) sub-studies. CSF sub-study participants were stratified by the number of oligoclonal bands (OCBs) at baseline (≥2/≥4).

Methods: Logistic regression analysis is reported for no evidence of disease activity (NEDA)-3 and no evidence of progression or active disease (NEPAD) at Year (Y)1 and Y2, and annualized relapse rate (ARR) at Y2. Changes in intrathecal (OCBs, kappa free light chain [KFLC], immunoglobulin [Ig]G and IgM indices), OCT measures, and neuroaxonal degeneration (neurofilament light chain [NfL]) biomarkers are reported at baseline, month (M)12, and M24.

Results: MAGNIFY-MS included 270 pwRMS; 28 and 36 were included in the CSF and OCT sub-studies, respectively. In Y2, estimated rates of NEDA-3 were 64.1% overall and 69.1% in the Tx-naïve group. The estimated rate of NEPAD overall was 60.2% in Y2. The estimated ARR was 0.09 from baseline to M24 (Tx-naïve participants, 0.04). In participants with ≥2 OCBs at baseline (n = 17), 76.5% had OCB reduction or disappearance at least once in the study. KFLC and IgG indices were reduced at M24 versus baseline. Sustained reductions were observed in median NfL, while IgG and IgM remained within normal ranges for most participants. Mean OCT measurements showed no retinal nerve fiber thinning.

Conclusion: For CladT-treated pwRMS, disease activity and biomarkers of intrathecal inflammation and neuroaxonal damage were reduced versus baseline.

Trial registration: ClinicalTrials.gov identifier, NCT03364036. Date registered: June 12, 2017. Date first patient enrolled: May 28, 2018. https://clinicaltrials.gov/study/NCT03364036. Extension study ClinicalTrials.gov Identifier: NCT04783935. Date registered: March 05, 2021. Date first patient enrolled: March 10, 2021. https://clinicaltrials.gov/study/NCT04783935.

Neuropsychiatric symptoms, such as depression, anxiety, cognitive changes, apathy or hallucinations are common in patients with Parkinson's disease (PD). They can appear at any stage of the disease and some symptoms may even be a harbinger of PD. These neuropsychiatric complications often become more pronounced as PD progresses and may worsen particularly during 'off-periods'. Moreover, neuropsychiatric symptoms are also frequently seen in patients with addictive behaviours, collectively called impulse control disorders, where insight is particularly low. In this narrative review, non-pharmacological as well as experimental and pragmatic pharmacological approaches are outlined to provide a deeper understanding of the best treatment strategy for these patients. Early detection as well as a tailored multidisciplinary approach is necessary to improve symptoms and ultimately the quality of life for patients and their family members.

Background: Serum glial fibrillary acidic protein (sGFAP) is a promising biomarker for multiple sclerosis (MS) disease progression. Elevated sGFAP levels are considered to reflect ongoing astrocyte-related pathology in the central nervous system.

Objectives: To study whether sGFAP levels associate with 18 kDa translocator protein (TSPO) availability in MS brain. TSPO is a mitochondrial molecule that is expressed by activated microglia and astrocytes.

Design: Cross-sectional multimodal biomarker correlation study.

Methods: We included 80 people with MS (66 relapsing-remitting and 14 progressive MS, 69% women), and 11 healthy control participants (73% women). sGFAP was measured using single molecule array (Simoa®) technology in combination with 3T magnetic resonance imaging and positron emission tomography (PET) using a TSPO-binding [¹¹C]PK11195 radioligand.

Results: sGFAP was higher among people with progressive MS (median 122 pg/ml) compared to healthy controls (median 59 pg/ml, p = 0.0002) or participants with relapsing-remitting MS (median 77 pg/ml, p = 0.0056). Among people with MS, higher sGFAP associated with higher volume of chronic lesions with increased TSPO activity (r = 0.36, p = 0.0011) and with thalamic TSPO activity (r = 0.30, p = 0.0069), as well as with T1 and T2 lesion loads (r = 0.38, 0.41, p = 0.0005, 0.0002, respectively). Smaller normal-appearing white matter (r = -0.36, p = 0.0009), cortical gray matter, and thalamus volumes (r = -0.39, p = 0.0003 for both) correlated with higher sGFAP. In regression analyses, the volume of TSPO-expressing lesions, together with age and MS disease-modifying treatment status, explained 27% of the variation in sGFAP.

Conclusion: sGFAP associates with adverse magnetic resonance imaging and PET imaging outcomes. The association between a high prevalence of TSPO-expressing white matter lesions and high sGFAP suggests that lesion-associated glial activity promotes MS progression partially via astrocyte-driven mechanisms. A combination of various soluble biomarkers and PET ligands for specific cell types may add to the understanding of progression-promoting cellular mechanisms in the brain.

Trial registration: ClinicalTrials.gov NCT03134716, NCT03368677, NCT04126772, NCT04239820, https://clinicaltrials.gov.

Background: Branch atheromatous disease (BAD) is a subtype of ischemic stroke associated with early neurological deterioration (END) and poor outcomes. Although BAD shares features with large artery atherosclerosis, optimal treatment strategies remain undefined.

Objectives: To assess the efficacy and safety of early dual antiplatelet therapy (DAPT) and high-intensity statins in reducing END and improving outcomes in BAD.

Design: A prospective, single-arm study with a historical control group.

Methods: This study reports the results of the Statin and Dual Antiplatelet Therapy in Preventing Early Neurological Deterioration in Branch Atheromatous Disease trial. Patients with BAD-related ischemic stroke were treated with aspirin, clopidogrel, and high-intensity statins within 24 h of symptom onset. Outcomes were compared with a historical control cohort treated with single antiplatelet therapy and moderate- or low-intensity statins. The primary outcome was the composite of END (defined as an National Institutes of Health Stroke Scale score increase ⩾2 points within 7 days) or recurrent stroke within 30 days. Secondary outcomes included severe END, functional outcomes at 90 days, and safety events.

Results: A total of 91 patients received intensive therapy and 285 received standard treatment. The primary endpoint occurred less frequently in the intensive group (34.1% vs 48.1%; adjusted risk ratio (aRR), 0.71; 95% confidence interval (CI), 0.52-0.98; p = 0.034). Intensive therapy significantly reduced END at 7 days (34.1% vs 47.0%; aRR, 0.73; 95% CI, 0.54-1.00; p = 0.049) but not recurrent stroke at 30 days (2.2% vs 1.8%; aRR, 1.16; 95% CI, 0.25-5.43). Good outcomes at 90 days (modified Rankin Scale ⩽2) were more common with intensive therapy (73.6% vs 57.2%; aRR, 1.27; 95% CI, 1.09-1.48; p = 0.002). Major bleeding and mortality did not differ between groups.

Conclusion: Early intensive therapy with DAPT and high-intensity statins significantly reduced END and improved recovery in BAD without compromising safety. Further studies are warranted to validate these findings.

Trial registration: ClinicalTrials.gov; Identifier: NCT04824911 (https://clinicaltrials.gov/study/NCT04824911).