Therapeutic Advances in Neurological Disorders最新文献

Background: The role of gut microbiota in multiple sclerosis (MS) has become increasingly important, intestinal dysbiosis with reduced production of short-chain fatty acids (SCFA) being the prevailing paradigm. However, the direction of causality, that is, whether intestinal changes are cause or consequence of chronic central nervous system inflammation, remains to be elucidated. Previous studies have focused on long-term MS patients. Alteration in fecal SCFA concentrations in early MS, particularly during relapses, remains to be extensively studied.

Objectives: To compare fecal SCFA concentrations in patients with a first diagnosis of MS with those in patients with long-term MS and in healthy controls (HCs).

Design: Prospective cohort study.

Methods: The prospective case-control study was conducted on relapsing-remitting MS (RRMS) patients at the time of first, acute relapse without ongoing immunotherapy (Early-RRMS). Clinical and demographic parameters, as well as fecal SCFA concentrations (measured by gas chromatography) were collected. The parameters were compared with those of matched RRMS patients under different, long-term immunotherapy (Late-RRMS) and HCs.

Results: SCFA concentrations of propionate, butyrate, isobutyrate, valerate, and isovalerate were not significantly different between the early-RRMS cohort and HCs, but were lower in the late-RRMS cohort.

Conclusion: The findings indicate that reduction in SCFA levels is exclusively observed in patients with RRMS during the further course of the disease and not at the onset. Decrease in SCFA concentration may be rather consequence or related to neurodegeneration than linked to the first demyelinating event. Further investigation related to disease trajectories of immunomodulatory or neuroprotective treatments are required.

Background: With the development of highly effective disease-modifying treatments, vaccinations are becoming increasingly important in people with neurological autoimmune diseases. However, questions regarding the safety and efficacy of vaccinations under immunotherapy remain.

Objective: To provide recommendations on types and timing of vaccinations for people with neuroimmunological diseases under different immunotherapies.

Design: Our study presents a German evidence-based expert consensus on vaccination under immunotherapies in neurological autoimmune diseases.

Methods: Based on literature research, a consortium of experts evaluated the quality of evidence, integrated clinical experience, and responded to a questionnaire determining an agreement (>75%) on statements concerning vaccination upon immune therapies in neuroimmunological diseases.

Results: The specific humoral and cellular response to vaccination can be compromised under alemtuzumab, azathioprine, cladribine, cyclophosphamide, CD19/CD20 antibodies (inebilizumab, ocrelizumab, ofatumumab, rituximab, ublituximab), dimethyl fumarate/diroximel fumarate, FcRn inhibitors (efgartigimod, rozanolixizumab), complement C5 inhibitors (eculizumab, ravulizumab, zilucoplan), interleukin-6 receptor antibodies (tocilizumab, satralizumab), intravenous immunoglobulins, long-term steroid administration, methotrexate, mitoxantrone, mycophenolate mofetil, tacrolimus, teriflunomide, tumor necrosis factor-α blockers, and sphingosine-1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, siponimod), as well as after autologous stem cell transplantation. The lymphocyte count can have an influence here. Overall, it is generally advisable to complete vaccination before starting immunotherapy. However, in the case of an active inflammatory disease course with possible irreversible neurological deficits, a delay in therapy initiation until immunization has been completed cannot be justified. The application of live vaccines is contraindicated for most therapies and is only recommended after a strict risk-benefit assessment.

Conclusion: Vaccinations are necessary for individuals on immunotherapy to reduce the risk of infections and the associated risk of worsening neurological autoimmune diseases. However, the humoral and cellular vaccination response may be impaired under immunotherapy necessitating close monitoring. Here, we provide applicable recommendations to optimize immunization for individuals receiving immunotherapy due to a neurological autoimmune disease.

The development and successful clinical application of engineered T cells expressing synthetic chimeric antigen receptors (CARs) represents a milestone in cancer therapy. This approach optimizes physiological in vivo T-cell activation against specific target antigens expressed on defined cell subsets with the goal of their deep and sustained depletion. Significant progress has been made in redesigning CAR T-cell constructs to improve patient safety, therapeutic efficacy, and accessibility. Efforts have also focused on streamlining manufacturing to improve availability and reduce costs, two critical challenges to widespread adoption. Beyond hematologic malignancies, CAR T-cell therapies are now increasingly being repurposed to tackle B-cell-mediated autoimmune diseases (AIDs). This is primarily achieved through broad B-cell depletion, but more targeted approaches-such as the selective elimination of autoantibody-producing B-cell subpopulations-are also being explored. Important considerations in their implementation are identifying the most pertinent patient groups, tailoring their treatment up to the point of CAR-infusion, and following up on their unique toxicity-profile. In the context of neurological AIDs-including refractory myasthenia gravis, Lambert-Eaton syndrome, multiple sclerosis, and stiff-person syndrome-early clinical experience suggests promising efficacy and tolerability, leading to a growing number of registered clinical trials. In this review, we provide an overview of the mechanism and evolution of CAR T-cell therapy, highlighting why its application in AIDs, particularly in neurology, represents a highly promising therapeutic strategy.

Background: There is no standardized treatment for acquired amyloid polyneuropathy (AAP) in domino liver transplant (DLT) recipients.

Objectives: Our objective is to analyze the efficacy and safety of patisiran for the treatment of AAP in DLT recipients.

Design: We performed a postauthorization prospective longitudinal study of DLT recipients with AAP who received patisiran treatment for 22 months.

Methods: The primary endpoint was change in the Neuropathy Impairment Scale (NIS) from baseline. Other assessments included neurophysiologic study, quantitative sensory testing, 10 m walking test, and quality of life and disability questionnaires. As safety parameters we analyzed evidence of graft rejection, immunosuppression levels, and renal and cardiac adverse effects.

Results: Four patients were recruited. The mean NIS at baseline was 8.5 ± 2.08. All patients presented clinical improvement after 22 months of treatment, with a mean NIS of 4.75 ± 2.27 points. The mean change from baseline in the NIS was -3.75 ± 0.71 (95% CI: -0.47 to 7.97). The use of patisiran was not associated with cardiovascular or renal side effects. No patient presented relevant changes in immunosuppression levels or graft rejection.

Conclusion: Our study suggests that patisiran may improve neurological manifestations in DLT recipients with AAP, producing no relevant adverse effects.

Background: Although migraine is the second most prevalent form of headache, its preventive treatment has some contraindications and complications. It has been postulated that lacosamide reacts with collapsin response mediator protein 2 and prevents its phosphorylation, inhibiting calcitonin gene-related peptide release in the trigeminal system, which might have a role in migraine management.

Objective: Our study aimed mainly to evaluate the efficacy and safety of lacosamide as an alternative medication to topiramate for the prevention of migraine, especially in patients who had contraindications to topiramate and other approved antiseizure medications used for migraine prevention.

Design: Our study included two parallel groups: the lacosamide and the topiramate groups.

Methods: We recruited episodic migraine patients between the ages of 18 and 65; the lacosamide group received lacosamide 50 mg once daily for 1 week, then twice daily from the 8th day till the 90th day); while the topiramate group received topiramate 50 mg once daily for 1 week, then 50 mg twice daily from the 8th day till the 90th day.

Results: There was not a statistically significant difference between the lacosamide and topiramate in the absolute change in monthly migraine days (MMD) at 90 days with p-value 0.34, there was no significant difference between lacosamide and topiramate groups regarding the percentage of patients with ⩾50% reduction in the baseline migraine days frequency in the last 4 weeks of the treatment period with a p-value 0.11. In total, 14.0 (4.7%) patients in the lacosamide group and 24.0 (8.0%) in the topiramate group stopped treatment prematurely due to intolerance to drug-related adverse effects, hazard ratio 2.83, 95% confidence interval (1.34-4.72), p-value 0.03.

Conclusion: In episodic migraine patients, the regular use of lacosamide 50 mg Bid for 3 months yielded reductions in the MMD, migraine days that required acute medications, and Headache Impact Test-6 score comparable to those achieved using topiramate 50 mg Bid. Lacosamide was more tolerable than topiramate in episodic migraine patients.

Trial registration: Prospectively registered on clinicaltrials.gov, NCT06243692-January 29, 2024; https://clinicaltrials.gov/study/NCT06243692.

Background: Magnetic resonance imaging (MRI) is often used to evaluate disease-related brain changes in patients with aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD).

Objectives: To use a meta-analysis for assessment of quantitative volumetric brain and spinal cord changes in patients with AQP4-IgG+ NMOSD and healthy participants.

Design: We analyzed volume estimates of the brain, gray matter, white matter, thalamus, T2/FLAIR-brain lesions, as well as mean upper cervical cord area (MUCCA). Inclusion criteria included patients with AQP4-IgG+ NMOSD, MRI-based segmentation data, and matched healthy participants. Data from NMOSD patients with mixed/unknown serostatus or significant comorbidities were excluded.

Data sources: We searched MEDLINE through Pubmed for peer-reviewed articles published between 05/2006 (revised NMOSD diagnostic criteria) and 01/2025.

Methods: Standardized mean differences and pooled effect sizes (Hedges' g) were determined with random-effects models, adjusting for duplicate reporting, outliers, and small study effects. Metaregressions were used to determine clinical associations.

Results: Evidence of pooled data showed that whole brain volume (g = -0.61, 95% confidence interval (CI): -0.91 to -0.32, p < 0.001, N _pat/con = 385/325, k = 11) and gray matter volume (g = -0.40, 95% CI: -0.72 to -0.09, p = 0.018, N _pat/con = 259/267, k = 9) were significantly different between patients and healthy participants. Heterogeneity was moderate (τ² = 0.08 and τ² = 0.09, respectively). Moreover, we found a large effect for reduced MUCCA (g = -0.99, 95% CI: -1.59 to -0.39, p = 0.007, N _pat/con = 189/162, k = 7) with moderate heterogeneity (τ² = 0.31). No conclusive evidence emerged for changes in thalamic or white matter volume. Bias analysis did not indicate that smaller studies affected effect sizes. A systematic review of voxel-based morphometry revealed that reduced gray matter volume was most likely in the bilateral thalamus (⩽69%) and occipital (44%), frontal (27%), and temporal cortices (27%).

Conclusion: AQP4-IgG+ NMOSD patients have specific global and local central nervous system volume reductions, potentially induced by astrocytic damage and demyelination. Volumetric outcomes may therefore inform MRI-guided disease monitoring and endpoints in clinical studies.

Trial registration: PROSPERO (CRD42024493121). This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines.

Background: Over recent decades, several high-efficacy disease-modifying therapies (DMTs) have been approved for multiple sclerosis (MS), prompting a shift from an escalation strategy toward early high-efficacy treatment. Yet, DMT initiation patterns and safety profiles remain unexplored in research relying solely on patient self-reports and have not been examined in Switzerland.

Objectives: To investigate (1) time from MS diagnosis to first DMT, (2) temporal trends in initial DMT use, (3) number of suspected adverse drug reactions (sADRs) following the first DMT, and (4) occurrence of any severe sADR.

Design: Retrospective cohort study using longitudinal, patient-reported data from the Swiss MS Registry (SMSR) between 1995 and 2024.

Methods: We analyzed data from SMSR participants with relapsing-remitting MS or clinically isolated syndrome diagnosed after 1995. Time from diagnosis to first DMT was analyzed using Kaplan-Meier analysis. Temporal trends were assessed through annual distributions of first DMTs. sADR burden was modeled with a two-part zero-inflated negative-binomial model, and severe sADRs (⩾1 severe sADR) were assessed with logistic regression. All models were adjusted for sex and age at DMT initiation.

Results: Median time from diagnosis to first DMT decreased from 4.5 months (95% confidence interval (CI): 2-6) in the 1995-2004 diagnosis group to 2 months (95% CI: 1-2) in more recent groups (⩾2010). First DMT use shifted from predominantly low-efficacy to moderate (2013-2020) and, since 2020, to high-efficacy DMTs. Compared to low-efficacy DMTs, moderate (incidence risk ratio (IRR) = 0.63, 95% CI: 0.48-0.84) and high-efficacy DMTs (IRR = 0.55, 95% CI: 0.31-0.98) were associated with fewer sADRs, and high-efficacy DMTs had higher odds of reporting zero sADRs (OR = 8.61, 95% CI: 2.34-31.76). We observed signals of a higher likelihood of severe sADRs in high-efficacy DMTs (OR = 1.41, 95% CI: 0.55-3.24) compared to low-efficacy DMTs, although this was not statistically significant.

Conclusion: Patient self-reports can reliably capture trends in DMT use. In Switzerland, the first DMT use has evolved, with patients starting DMTs earlier and more frequently with higher-efficacy DMTs. While moderate and high-efficacy DMTs were associated with fewer sADRs, they may also carry a higher risk of severe sADRs, underscoring the need to balance personal preferences, efficacy, and safety in first-line MS treatment.

Background: Drug-resistant epilepsy (DRE) imposes a heavy disease burden and urgently requires new, effective, and safe treatment options.

Objective: To evaluate the efficacy and safety of transcutaneous auricular vagus nerve stimulation (ta-VNS) in patients with DRE.

Design: Ongoing, single-center, prospective real-world study.

Data sources and methods: Patients diagnosed with DRE and undergoing ta-VNS treatment at Beijing Tiantan Hospital, affiliated with Capital Medical University, were prospectively enrolled in this study between January 2023 and December 2024. The follow-up period lasted 1-2 years. The frequency of seizure reduction was assessed using seizure diaries, with a 50% decrease in seizure frequency deemed indicative of efficacy. Adverse reactions and comorbidities were recorded concurrently. All patients were maintained on stable anti-seizure medications during this study.

Results: Ninety-nine patients were enrolled, among whom 16 were lost to follow-up and 18 refused follow-up. Ultimately, 65 patients were successfully followed up for analysis. The overall efficacy rate was 61.54%. Specifically, 15 patients experienced seizure reductions >90%, 8 achieved a reduction between 75% and 90%, 17 demonstrated a reduction ranging from 50% to 75%, and 1 exhibited a reduction of <50%. There were no severe adverse events, although 10 patients reported mild side effects (e.g., ear tingling and tinnitus). The efficacy rate was found to be independent of variables such as age, sex, treatment frequency, and type of epilepsy. However, it demonstrated an association with baseline seizure frequency prior to treatment and the etiology of epilepsy. Patients exhibiting a higher baseline frequency of seizures (>30 episodes per month) demonstrated significantly improved response rates, with an efficacy rate of 90.9%. Etiologies, including posttumor surgery, congenital brain dysplasia, and genetic mutations, demonstrated efficacy rates >90%.

Conclusion: The efficacy of ta-VNS was 61.54% in patients with DRE. Patients with high baseline seizure frequency or identifiable etiologies tended to experience greater therapeutic benefits. Owing to its noninvasive nature and favorable safety profile, it presents a promising alternative for the management of DRE.

[This corrects the article DOI: 10.1177/17562864251313914.].