Neurological research and practice最新文献

Background: The decision to discontinue disease-modifying therapies (DMTs) in patients with multiple sclerosis (PwMS) is a critical clinical challenge. Historically, DMTs were discontinued due to side effects, treatment limitations, or progression to secondary progressive MS. However, advancements in MS therapies, particularly high-efficacy DMTs (HE-DMTs) and the increased knowledge on disease courses and phenotypes have resulted in more personalized treatment approaches and introduced discussion on scheduled DMT discontinuation. This review explores the current evidence on DMT discontinuation, focusing on its implications for aging populations and the interplay between cardiovascular diseases (CVD) and MS.

Current evidence and interplay with cvd: Randomized trials such as DISCOMS and DOT-MS have provided insights into discontinuing DMTs in stable patients. In summary, both randomized clinical trials highlight the risk of disease reactivation following treatment discontinuation. Due to the limited sample size, neither study was able to conduct subgroup analyses based on age groups. Additionally, DOT-MS was terminated prematurely, direct comparisons with other studies should be avoided. While older studies and observational data (e.g., OFSEP) have shown relapse risks associated with discontinuation, particularly for drugs like natalizumab and fingolimod, there is limited data on HE-DMT discontinuation outcomes. Comorbidities, particularly CVDs, further complicate decisions regarding the continuation of DMTs in older adults. MS patients bear a higher burden of CVD, which is also associated with unfavorable disease courses. While optimizing cardiovascular risk profiles appears advisable, it remains unclear whether DMTs themselves have a positive impact on CVDs.

Conclusion: Given the complexities associated with discontinuing DMTs in MS patients, it is essential to balance the avoidance of polypharmacy with the potential risks of disease reactivation and the impact of comorbidities, especially CVDs, on disease progression. The interplay between MS and CVD highlights the importance of a holistic risk assessment when considering DMT discontinuation.

Background: Atrial fibrillation (AF) is a common cause of cardioembolic stroke and can lead to severe and recurrent cerebrovascular events. Thus, identifying patients suffering from cardioembolic events caused by undetected AF is crucial. Previously, we found an association between increasing stroke severity and a decreasing left atrial appendage (LAA) blood flow velocity below 60 cm/s.

Methods: This was a prospective single-center cohort study including hospitalized patients who underwent a transesophageal echocardiography (TEE) in sinus rhythm. The participants were divided into two groups (≥ 60 cm/s;<60 cm/s) based on their maximum LAA blood flow velocity. The results of the cardiovascular risk assessment and 24- to 72-hour ECG Holter were recorded. Follow-up appointments were scheduled at 3, 6, 12, 24 and 36 months. The primary endpoint was new-onset AF. The statistics included a Cox-proportional-hazard-model and a binary logistic regression. Numerical data or categorical data were analyzed with the Mann-Whitney U test or chi-square test.

Results: A total of 166 patients were recruited. The median LAA blood flow velocity was 64 cm/s. New-onset AF was diagnosed in 22.9% of the patients. An LAA blood flow velocity ≤ 60 cm/s was associated with a threefold increased risk of new-onset AF (35.8% vs. 11.5%; HR3.56; CI95%1.70-7.46; p < 0.001), independently according to a multivariate analysis (p = 0.035). Furthermore, a decreasing LAA blood flow velocity was associated with an increased risk of new-onset AF (OR1.043; CI95%1.021-1.069; p < 0.001).

Conclusion: A low LAA blood flow velocity (≤ 60 cm/s) in sinus rhythm is prospectively associated with an increased risk of new-onset AF. Additional simple LAA-TEE examinations could help to identify patients who benefit from more accurate cardiac rhythm monitoring.

Background: Pharyngeal electrical stimulation (PES) is a neurostimulation intervention that can improve swallowing and facilitate decannulation in tracheotomised stroke patients with dysphagia. The PHAryngeal electrical stimulation for treatment of neurogenic Dysphagia European Registry (PHADER) study found that PES can reduce dysphagia severity in patients with neurogenic (non-stroke) dysphagia who required mechanical ventilation and tracheotomy. However, the predictive factors for treatment success among these patients remain unclear.

Methods: We conducted a subgroup analysis using data from PHADER, with a focus on non-stroke participants who had required mechanical ventilation and tracheotomy. Multiple linear regression was performed to predict treatment success, as measured in improvement in dysphagia severity rating scale (DSRS) total score, accounting for age, sex, time from diagnosis to PES, PES perceptual threshold and PES stimulation intensity at the first session.

Results: Fifty-seven participants (mean[standard deviation] age: 63.6[15.5] years; male: 70.2%) were included in the analysis. These comprised traumatic brain injury (22[38.6%]), critical illness polyneuropathy (15[26.4%]), and other neurological conditions that caused dysphagia (20[35.0%]). Regression analyses identified that a lower PES perceptual threshold at the first session (p = 0.027) and early intervention (p = 0.004) were significant predictors associated with treatment success at Day 9 and 3 months post PES respectively.

Conclusions: We identified two predictive factors associated with successful PES treatment in patients with neurogenic (non-stroke) dysphagia requiring mechanical ventilation and tracheotomy: a lower PES perceptual threshold at the first session and early intervention. These predictors provide critical guidance for optimizing clinical decision-making in managing non-stroke neurogenic dysphagia patients in critical care settings.

Background: Congenital anomalies and neurodevelopmental disorders are complex conditions often requiring comprehensive diagnostic approaches. Next-generation sequencing (NGS), particularly whole-exome sequencing (WES), has greatly improved the detection of pathogenic variants, including copy number variations (CNVs), which account for up to 35% of genetic causes in neurological patients. Combining CNV and single nucleotide variant (SNV) analysis through WES enhances diagnostic accuracy, especially in cases with unclassified congenital anomalies.

Case presentation and literature review: This study reports a 14-year-old male patient with multiple congenital anomalies, including hypospadias, complete cleft palate, and recurrent pneumonia. His clinical presentation includes significant physical and intellectual developmental delays, autism-like symptoms, and spastic diplegia. Whole-exome sequencing (WES) was performed due to these complex symptoms, revealing a novel heterozygous deletion on chromosome 10q24.31-q24.33. Laboratory findings indicated agammaglobulinemia, leading to prophylactic antibiotic therapy and immunoglobulin replacement. Additional imaging studies showed cystic malformation of the middle lobe of the right lung, sliding hiatal hernia with prolapse of the gastric mucosa, and brain anomalies consistent with Joubert syndrome.

Conclusions: This case underscores the importance of genetic analysis in understanding the etiology of congenital anomalies and neurodevelopmental disorders, providing critical insights into the molecular mechanisms driving complex phenotypes. The identified chromosomal deletion contributes to the existing literature on genomic imbalances associated with similar phenotypes.

Background: Intracranial haemorrhage (ICH) is one of the most serious complications of anticoagulant therapy with oral factor Xa inhibitors (FXai). To meet an urgent medical need of optimising treatment pathways, we assessed the frequency of ICH during oral FXai treatment, as well as the associated burden on the German healthcare system.

Methods: Our study was based on a claims database comprising over 4 million people with statutory health insurance in Germany. The study included people initiating oral FXai treatment for the first time between 2016 and 2021, and who experienced ICH during a three-year treatment period. For a balanced comparison of hospitalisations, costs, and mortality, propensity score matching between patients with and without ICH was performed.

Results: During the study period, 78,086 patients had started oral FXai therapy, of which 530 experienced ICH during the therapy. The incidence rate of ICH was highest within the first 90 days after the start of oral FXai therapy during follow-up with 0.64 events per 100 patient-years (PY; 95% CI: 0.52-0.77%). Three-month mortality rates were significantly higher among patients who had experienced an ICH event (39.4%; 95% CI: 35.4-43.8%), as opposed to patients without ICH (5.9%; 95% CI: 4.2-8.3%). This difference prevailed during follow-up, while mortality increased at roughly equal rates in both patient groups. Patients with ICH were on average hospitalised for 40.4 days/PY (95% CI: 35.7 days - 45.2 days) in the first year after the event; comparable patients without ICH were hospitalised for 10.8 days/PY (95% CI: 8.3 days - 13.2 days). Annual total costs per patient were €37,328 (95% CI: €32,243-€42,412) for patients with ICH, and €10,564 (95% CI: €9,298-€11,831) for patients without ICH. Hospitalisation costs were the main driver with 86.1% versus 50.8%, respectively.

Conclusions: Incidence rates of ICH during oral FXai therapy were within the range of other published real-world data. Duration of hospitalisations, associated costs, and mortality were high and significantly higher for patients with ICH than for comparable patients without ICH. The high burden on the healthcare system highlights the need for preventive measures and more efficient treatment pathways for patients with ICH under oral FXai therapy.

Objective: Immunomodulatory treatment options for multiple sclerosis show an inverse risk‒benefit ratio of side effects and treatment efficacy. Although rare, anti-B-cell therapies can cause acute or late-onset neutropenia.

Methods: We report a case of severe recurrent fluctuating neutropenia after ofatumumab treatment.

Results: We observed four recurrences even after pausing with ofatumumab and repeated granulocyte stimulating factor (G-CSF) treatment. In total, neutropenia occurred five times and was associated with recurrent pulmonary, urinary tract, and skin infections. Bone marrow investigation revealed no signs of lymphoma or leukemia. Interestingly, routine molecular testing revealed two gene variants of unknown significance for BCORL1 and ASXL1, both of which play a role in hematopoiesis. The neutrophil count recovered spontaneously six months after the cessation of treatment with ofatumumab.

Discussion: This case highlights the necessity of identifying patients at risk and monitoring white blood cell counts regularly for up to 6 months after initial neutropenia.

Background: Decannulation in tracheotomized neurological patients is often complicated by severe dysphagia, which compromises airway safety and delays weaning. Additional challenges, including reduced cough strength, excessive bronchial secretions, and altered airway anatomy exacerbate weaning issues, thereby increasing morbidity and mortality. This review summarizes diagnostic procedures and therapeutic options crucial for the rehabilitation of tracheotomized patients.

Main body: Key diagnostic strategies for assessing decannulation readiness focus on airway protection, airway patency, bronchial secretion management, and cough function. These are collectively introduced as the A²BC criteria in this review. Advanced tools such as flexible endoscopic evaluation of swallowing, endoscopic assessment of airway anatomy, measurement of cough strength, and intrathoracic pressure are essential components of a systematic evaluation. Therapeutic interventions encompass restoring physiological airflow, behavioral swallowing treatment, secretion management, and pharyngeal electrical stimulation. The proposed decannulation algorithm integrates two pathways: the "fast-track" pathway, which facilitates rapid decannulation based on relevant predictors of decannulation-success, and the "standard-track" pathway, which progressively increases cuff deflation intervals to build tolerance over time.

Conclusion: Successful decannulation in neurological patients demands a multidisciplinary, patient-centered approach that combines advanced diagnostics, targeted therapies, and structured management pathways. The proposed algorithm integrates fast-track and standard-track pathways, balancing rapid diagnostics with gradual weaning strategies. This framework promotes flexibility, enabling clinicians to tailor interventions to individual patient needs while maintaining safety and optimizing outcomes.

Background: There is an emerging understanding of the increased risk of stroke in patients with immune thrombocytopenic purpura (ITP) and immune thrombotic thrombocytopenic purpura (iTTP). We aimed to determine the prevalence and characteristics of acute ischemic stroke (AIS) and intracranial hemorrhage (ICH) in patients with ITP and iTTP in a systematic review and meta-analysis.

Methods: We used PubMed, Embase, Cochrane, Web of Science, and Scopus using text related to ITP, iTTP, stroke, AIS, and ICH from inception to 11/3/2023. Our primary outcome was to determine prevalence of AIS and/or ICH in a cohort of ITP or iTTP patients (age > 18). Our secondary outcomes were to determine stroke type associated with thrombopoietin receptor agonists (TPO-RAs) in ITP patients, as well as risk factors associated with stroke in ITP and iTTP patients.

Results: We included 42 studies with 118,019 patients (mean age = 50 years, 45% female). Of those, 27 studies (n = 116,334) investigated stroke in ITP patients, and 15 studies (n = 1,685) investigated stroke in iTTP patients. In all ITP patients, the prevalence of AIS and ICH was 2.1% [95% Confidence Interval (CI) 0.8-4.0%] and 1.5% (95% CI 0.9%-2.1%), respectively. ITP patients who experienced stroke as an adverse event (AE) from TPO-RAs had an AIS prevalence of 1.8% (95% CI 0.6%-3.4%) and an ICH prevalence of 2.0% (95% CI 0.2%-5.3%). Prevalence of stroke did not significantly differ between all ITP patients and those treated with TPO-RAs. iTTP patients had a prevalence of AIS and ICH of 13.9% (95% CI 10.2%-18.1%) and 3.9% (95% CI 0.2%-10.4%), respectively. Subgroup analysis revealed the prevalence of AIS and ICH was greater in iTTP patients vs. all ITP patients (p < 0.01 and p = 0.02, respectively). Meta-regression analysis revealed none of the collected variables (age, sex, history of diabetes or hypertension) were risk factors for stroke in all ITP patients, although there were high levels of data missingness.

Conclusions: Prevalence of different stroke types was lower in all ITP patients vs. iTTP patients. Additionally, ITP patients experienced a similar prevalence of stroke regardless of if they were specifically denoted to have been treated with TPO-RAs or not, supporting the continued use of TPO-RAs in management. Risk factors for stroke remain unclear, and future studies should continue to investigate this relationship.

Background: The majority of randomised controlled trials in acute stroke and many for prevention are neutral, i.e. they failed to reach statistical significance. However, many of these will find apparent benefit in a component of a subgroup, findings which may be 'chased' in a follow-up trial. The evidence to date is that these follow-on trials are very likely to be neutral.

Findings: We discuss the issue of chasing subgroups in neutral trials and illustrate the challenges in five pairs of exemplar acute stroke trials. Problems in the exemplar trials include failing to define the subgroup in advance or even changing its definition, failing to show that both the interaction test and the primary outcome in the component were statistically significant, failing to publish additional information on the positive subgroup component, having too many subgroups, failing to make the follow-on trial large enough and failing to report the findings of the follow-on trial.

Conclusion: When chasing a positive component in a subgroup, it is vital that the subgroup: should be plausible biologically, defined a priori and have a significant interaction test. Further the number of subgroups should be limited and the component of interest should be statistically significant. Explanations should be given as to why the component is positive and other components of the subgroup are negative. Other outcomes should also show potential benefit. Unless this guidance is followed, it is highly likely that follow-on trials will be neutral as has occurred previously.

Background: Animal studies suggest that high-density lipoprotein cholesterol (HDL-C) attenuates reperfusion injury. We aimed to assess whether higher serum HDL-C levels modulate the risk of intracranial haemorrhage (ICH) after thrombectomy in human stroke survivors.

Methods: We included consecutive patients from our prospective anterior circulation large vessel occlusion (acLVO) registry who underwent thrombectomy between 01/2017 and 01/2023 at the tertiary stroke centre of the University Hospital Carl Gustav Carus in Dresden, Germany in a propensity score-matched analysis. We assessed the association between serum HDL-C levels and post-interventional ICH as well as 90-day functional outcome quantified by the modified Rankin Scale (mRS). For sensitivity analysis, we used multivariable lasso logistic regression. Analyses were adjusted for demographics, cardiovascular risk profiles, stroke characteristics, and procedural times.

Results: Of 1702 patients screened, 807 (420 women, median age 77 years [66-84, IQR]) were included. Post-interventional ICH reduced the probability of a favourable functional outcome (90-day mRS 0-2) by 14.8% (ß = 0.15; 95% CI [0.06;0.24]; p = 0.001. An HDL-C level above the median (1.15 mmol/L) decreased the probability of ICH by 13.6% (ß = - 0.14; 95CI% [- 0.22; - 0.05]; p = 0.002) and increased the probability of favourable functional outcome by 13.2% (ß = - 0.13; 95CI% [- 0.22; - 0.05]; p = 0.003). In sensitivity analyses, higher HDL-C levels were independently associated with lower odds of ICH (adjusted OR 0.62; 95% CI [0.43;0.88]; p = 0.008) and higher odds of favourable functional outcome (adjusted OR 0.60; 95% CI [0.40; 0.90]; p = 0.015).

Conclusions: In patients undergoing thrombectomy for acLVO, higher HDL-C levels were associated with a reduced probability of post-interventional ICH and a favourable functional outcome. These observations could not be explained by conventional vascular risk profiles.