Intravenous Thrombolysis Before Thrombectomy Improves Functional Outcome After Stroke Independent of Reperfusion Grade.

BACKGROUND: We studied the association of bridging intravenous thrombolysis (IVT) before thrombectomy for anterior circulation large-vessel occlusion and functional outcome and scrutinized its dependence on grade of reperfusion and distal thrombus migration. METHODS AND RESULTS: We included consecutive patients with anterior circulation large-vessel occlusion from our prospective registry of thrombectomy-eligible patients treated from January 1, 2017 to January 1, 2023 at a tertiary stroke center in Germany in this retrospective cohort study. To evaluate the association of bridging IVT and functional outcome quantified via modified Rankin Scale score at 90 days we used multivariable logistic and lasso regression including interaction terms with grade of reperfusion quantified via modified Thrombolysis in Cerebral Infarction (mTICI) scale and distal thrombus migration adjusted for demographic and cardiovascular risk profiles, clinical and imaging stroke characteristics, onset-to-recanalization time and distal thrombus migration. We performed sensitivity analysis using propensity score matching. In our study population of 1000 thrombectomy-eligible patients (513 women; median age, 77 years [interquartile range, 67-84]), IVT emerged as a predictor of favorable functional outcome (modified Rankin Scale score, 0-2) independent of modified mTICI score (adjusted odds ratio, 0.49 [95% CI, 0.32-0.75]; P=0.001). In those who underwent thrombectomy (n=812), the association of IVT and favorable functional outcome was reproduced (adjusted odds ratio, 0.49 [95% CI, 0.31-0.74]; P=0.001) and was further confirmed on propensity score analysis, where IVT led to a 0.35-point decrease in 90-day modified Rankin Scale score (ß=-0.35 [95 CI%, -0.68 to 0.01]; P=0.04). The additive benefit of IVT remained independent of modified mTICI score (ß=-1.79 [95% CI, -3.43 to -0.15]; P=0.03) and distal thrombus migration (ß=-0.41 [95% CI, -0.69 to -0.13]; P=0.004) on interaction analysis. Consequently, IVT showed an additive association with functional outcome in the subpopulation of patients undergoing thrombectomy who achieved successful reperfusion (mTICI ≥2b; ß=-0.46 [95% CI, -0.74 to -0.17]; P=0.002) and remained beneficial in those with unsuccessful reperfusion (mTICI ≤2a; ß=-0.47 [95% CI, -0.96 to 0.01]; P=0.05). CONCLUSIONS: In thrombectomy-eligible patients with anterior circulation large-vessel occlusion, IVT improves functional outcome independent of grade of reperfusion and distal thrombus migration.

Validation of the Distress Thermometer as a Screening Tool for Psychosocial Distress and Resilience in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is associated with psychosocial distress that affects patients' quality of life. The distress thermometer (DT) is an 11-point visual analogue scale that is used as a screening tool for the assessment of psychosocial distress, originally developed for oncological diseases. OBJECTIVES: To validate the DT for PD and to explore contributing factors. METHODS: The DT scale was administered to 105 people with Parkinson's Disease (PwPD). Along with it, we assessed motor symptoms (Unified Parkinson's Disease Rating Scale part III [UPDRS III], Hoehn and Yahr-stage [H&Y]), non-motor symptoms (Non-motor Symptom Questionnaire [NMSQ]), anxiety and depression (Hospital Anxiety and Depression Scale [HADS], Fear of Progression-Questionnaire Short Form [FOP-Q-SF], Generalized Anxiety Disorder Scale-7 [GAD-7], 9-question Patient Health Questionnaire [PHQ-9]), the feeling of hope (Herth Hope Index [HHI]) and quality of life (Schedule for the Evaluation of Individual Quality of Life [SEIQoL]). RESULTS: With a cut-off of 4, the DT identified PwPD with distress with a sensitivity of 97% and a specificity of 38%. With this cut-off, the DT will yield false negative results in 1 out of 100 cases. Factor analyses and a random forest regression of the dataset revealed that distress can be predicted by two factors, which we termed "anxiety" and "depression/resilience/motor symptoms". CONCLUSION: The DT is an ultra-short and reliable screening tool for distress in PwPD. DT values below 4 rule out distress with a high degree of certainty. Anxiety and depression are important factors in distress but are counterbalanced by the individuals' psychological resilience.

Serum neurofilament indicates accelerated neurodegeneration and predicts mortality in late-stage Parkinson's disease.

Different stages of Parkinson's disease (PD) are defined by clinical criteria, while late-stage PD is marked by the onset of morbidity milestones and rapid clinical deterioration. Based on neuropathological evidence, degeneration in the dopaminergic system occurs primarily in the early stage of PD, raising the question of what drives disease progression in late-stage PD. This study aimed to investigate whether late-stage PD is associated with increased neurodegeneration dynamics rather than functional decompensation using the blood-based biomarker serum neurofilament light chain (sNfL) as a proxy for the rate of neurodegeneration. The study included 118 patients with PD in the transition and late-stage (minimum disease duration 5 years, mean (SD) disease duration 15 (±7) years). The presence of clinical milestones (hallucinations, dementia, recurrent falls, and admission to a nursing home) and mortality were determined based on chart review. We found that sNfL was higher in patients who presented with at least one clinical milestone and increased with a higher number of milestones (Spearman's ρ = 0.66, p < 0.001). Above a cutoff value of 26.9 pg/ml, death was 13.6 times more likely during the follow-up period (95% CI: 3.53-52.3, p < 0.001), corresponding to a sensitivity of 85.0% and a specificity of 85.7% (AUC 0.91, 95% CI: 0.85-0.97). Similar values were obtained when using an age-adjusted cutoff percentile of 90% for sNfL. Our findings suggest that the rate of ongoing neurodegeneration is higher in advanced PD (as defined by the presence of morbidity milestones) than in earlier disease stages. A better understanding of the biological basis of stage-dependent neurodegeneration may facilitate the development of neuroprotective means.

Weaning and extubation failure in myasthenic crisis: a multicenter analysis.

Myasthenic crisis (MC) requiring mechanical ventilation is a serious complication of myasthenia gravis (MG). Here we analyze the frequency and risk factors of weaning- and extubation failure as well as its impact on the clinical course in a large cohort. We performed a retrospective chart review on patients treated for MC in 12 German neurological departments between 2006 and 2015. Weaning failure (WF) was defined as negative spontaneous breathing trial, primary tracheostomy, or extubation failure (EF) (reintubation or death). WF occurred in 138 episodes (64.2%). Older Age (p = 0.039), multiple comorbidities (≥ 3) (p = 0.007, OR = 4.04), late-onset MG (p = 0.004, OR = 2.84), complications like atelectasis (p = 0.008, OR = 3.40), pneumonia (p < 0.0001, OR = 3.45), cardio-pulmonary resuscitation (p = 0.005, OR = 5.00) and sepsis (p = 0.02, OR = 2.57) were associated with WF. WF occurred often in patients treated with intravenous immungloblins (IVIG) (p = 0.002, OR = 2.53), whereas WF was less often under first-line therapy with plasma exchange or immunoadsorption (p = 0.07, OR = 0.57). EF was observed in 58 of 135 episodes (43.0%) after first extubation attempt and was related with prolonged mechanical ventilation, intensive care unit stay and hospital stay (p ≤ 0.0001 for all). Extubation success was most likely in a time window for extubation between day 7 and 12 after intubation (p = 0.06, OR = 2.12). We conclude that WF and EF occur very often in MC and are associated with poor outcome. Older age, multiple comorbidities and development of cardiac and pulmonary complications are associated with a higher risk of WF and EF. Our data suggest that WF occurs less frequently under first-line plasma exchange/immunoadsorption compared with first-line use of IVIG.

A Paradigm Shift in the Management of Patients with Parkinson's Disease.

BACKGROUND: Technological evolution leads to the constant enhancement of monitoring systems and recording symptoms of diverse disorders. SUMMARY: For Parkinson's disease, wearable devices empowered with machine learning analysis are the main modules for objective measurements. Software and hardware improvements have led to the development of reliable systems that can detect symptoms accurately and be implicated in the follow-up and treatment decisions. KEY MESSAGES: Among many different devices developed so far, the most promising ones are those that can record symptoms from all extremities and the trunk, in the home environment during the activities of daily living, assess gait impairment accurately, and be suitable for a long-term follow-up of the patients. Such wearable systems pave the way for a paradigm shift in the management of patients with Parkinson's disease.

Olfactory dysfunction after autoimmune encephalitis depending on the antibody type and limbic MRI pathologies.

Objective: Patients' olfactory function after autoimmune encephalitis (AE) involving limbic structures may be impaired. This study aimed to characterize olfactory function in patients after autoimmune encephalitides. Methods: A case-control study was performed including 11 AE patients with antibodies against NMDAR (n = 4), GAD (n = 3), VGKC (n = 3) and antibody-negative AE (n = 1) and a control group of 12 patients with pneumococcal meningo-encephalitis (PC). In subgroup analyses, AE patients with and without NMDAR-antibodies were compared. Olfactory function was assessed using the Sniffin Sticks test and the resulting TDI-score (threshold, discrimination, identification). Involvement of limbic structures was evaluated on imaging data (MRI). Statistical analyses were performed to test for correlations of TDI-score and MRI results. Results: The overall olfactory function of the AE-group and the PC-group was comparable (mean TDI 32.0 [CI 27.3-36.7], 32.3 [CI 28.5-36.0)]. The proportions of hyposmic patients were similar compared to the general population. However, AE patients of the non-NMDAR group had significantly lower TDI-scores (28.9 ± 6,8) than NMDAR patients (37.4 ± 3.5) (p = 0.046) and a significantly lower discrimination capability than the NMDAR patients (9.9 ± 2.0 vs. 14.5 ± 0.6) (p = 0.002). The non-NMDAR patients had significantly more limbic MRI pathologies (6/7) compared to the NMDAR patients (0/4) (p = 0.015). Furthermore, a correlation between limbic MRI pathologies and worse capability of smelling discrimination was found (p = 0.016, r = -0.704, n = 11). Conclusion: Our results indicate that patients with NMDAR autoimmune encephalitis have normal long term olfactory function. However, patients with non-NMDAR autoimmune encephalitis appear to have a persistently impaired olfactory function, probably mediated by encephalitic damage to limbic structures.

Real-world considerations regarding the use of the combination of levodopa, carbidopa, and entacapone (Stalevo® ) in Parkinson's disease.

An important aim in long-term levodopa therapy is to prolong the duration of symptomatic efficacy of each dose without increasing peak plasma concentrations above the threshold for the emergence of dyskinesias. One strategy is to enhance levodopa delivery to the brain by co-administering it with inhibitors of peripheral dopa-decarboxylase and catechol-O-methyltransferase (COMT). Levodopa, carbidopa and entacapone (LCE), available in a range of fixed-dose combinations as the branded formulation Stalevo® (Orion Pharma), has been developed to address this requirement and has been in general use for 20 years, having first been evaluated in randomized controlled trials. Experience with LCE has established that improved levodopa pharmacokinetics achieved with dual-enzyme inhibition are translated into improved clinical efficacy, including the possibility of reducing total levodopa dosage with no loss of therapeutic effect. The ease and tolerability of switching to LCE has been affirmed in the SIMCOM trial and by personal experience detailed in this review. Some 300,000 patient-years of safety data are available for LCE, including trial data for up to 5 years. Most adverse effects associated with LCE are attributable to the levodopa component rather than the enzyme inhibitors. The hepatotoxicity observed with the class comparator tolcapone has not been observed with entacapone, the COMT inhibitor in LCE, and there is no formal requirement to monitor liver function during LCE therapy. Other common side effects include diarrhoea, which is one of the more prominent non-dopaminergic adverse events, and urine discolouration, which is harmless but about which patients may require reassurance.

Toward objective monitoring of Parkinson's disease motor symptoms using a wearable device: wearability and performance evaluation of PDMonitor®.

Parkinson's disease (PD) is characterized by a variety of motor and non-motor symptoms. As disease progresses, fluctuations in the response to levodopa treatment may develop, along with emergence of freezing of gait (FoG) and levodopa induced dyskinesia (LiD). The optimal management of the motor symptoms and their complications, depends, principally, on the consistent detection of their course, leading to improved treatment decisions. During the last few years, wearable devices have started to be used in the clinical practice for monitoring patients' PD-related motor symptoms, during their daily activities. This work describes the results of 2 multi-site clinical studies (PDNST001 and PDNST002) designed to validate the performance and the wearability of a new wearable monitoring device, the PDMonitor®, in the detection of PD-related motor symptoms. For the studies, 65 patients with Parkinson's disease and 28 healthy individuals (controls) were recruited. Specifically, during the Phase I of the first study, participants used the monitoring device for 2-6 h in a clinic while neurologists assessed the exhibited parkinsonian symptoms every half hour using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III, as well as the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia severity assessment. The goal of Phase I was data gathering. On the other hand, during the Phase II of the first study, as well as during the second study (PDNST002), day-to-day variability was evaluated, with patients in the former and with control subjects in the latter. In both cases, the device was used for a number of days, with the subjects being unsupervised and free to perform any kind of daily activities. The monitoring device produced estimations of the severity of the majority of PD-related motor symptoms and their fluctuations. Statistical analysis demonstrated that the accuracy in the detection of symptoms and the correlation between their severity and the expert evaluations were high. As a result, the studies confirmed the effectiveness of the system as a continuous telemonitoring solution, easy to be used to facilitate decision-making for the treatment of patients with Parkinson's disease.

Morbidity Milestones Demonstrate Long Disability-Free Survival in Parkinson's Disease Patients with Deep Brain Stimulation of the Subthalamic Nucleus.

Background: Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an effective treatment for Parkinson's disease (PD). The long-term benefit in PD patients with STN-DBS in comparison to medical treatment (MT) alone has not yet been demonstrated conclusively. Objectives: To judge the long-term outcome of patients with STN-DBS. Methods: To assess the evolution of PD symptoms and health-related quality of life (HRQoL) after deep brain stimulation (DBS) surgery, we conducted a cross-sectional analysis of 115 patients with STN-DBS with rater-based scales and self-reported questionnaires. In addition, we screened records of all our STN-DBS patients (2001-2019, n = 162 patients) for the onset of the morbidity milestones (falls, hallucinations, dementia, and nursing home placement) to assess disability-free life expectancy. Results: In the first year of STN-DBS, levodopa equivalent dose was reduced and motor function improved. Nonmotor symptoms and cognition remained stable. These effects were similar to previous studies. Morbidity milestones occurred 13 ± 7 years after diagnosis. Motor function, cognition, and HRQoL significantly worsened after the occurrence of any milestone, confirming the clinical relevance of these milestones. After onset of the first milestone, mean survival time was limited to 5 ± 0.8 years, which is comparable with patients with PD but without STN-DBS. Conclusions: On average, PD patients with STN-DBS live with their disease for a longer time, and morbidity milestones occur later in the disease course than in PD patients with MT. As judged by morbidity milestones, morbidity remains compressed into the final 5 years of life in PD patients with STN-DBS.

The Gut Dysmotility Questionnaire for Parkinson's disease: Insights into development and pretest studies.

Objective: A total of 48% of patients with Parkinson's disease (PD) present symptoms of gastrointestinal dysfunction, particularly constipation. Furthermore, gastrointestinal tract (GIT)-related non-motor symptoms (NMSs) appear at all stages of PD, can be prodromal by many years and have a relevant impact on the quality of life. There is a lack of GIT-focused validated tools specific to PD to assess their occurrence, progress, and response to treatment. The aim of this study was to develop and evaluate a novel, disease- and symptom-specific, self-completed questionnaire, titled Gut Dysmotility Questionnaire (GDQ), for screening and monitoring gastrointestinal dysmotility of the lower GIT in patients with PD. Methods: In phase 1, a systematic literature review and multidisciplinary expert discussions were conducted. In phase 2, cognitive pretest studies comprising standard pretests, interviews, and evaluation questionnaires were performed in patients with PD (n = 21), age- and sex-matched healthy controls (HC) (n = 30), and neurologists (n = 11). Incorporating these results, a second round of cognitive pretests was performed investigating further patients with PD (n = 10), age- and sex-matched HC (n = 10), and neurologists (n = 5). The questionnaire was adapted resulting in the final GDQ, which underwent cross-cultural adaptation to the English language. Results: We report significantly higher GDQ total scores and higher scores in five out of eight domains indicating a higher prevalence of gastrointestinal dysmotility in patients with PD than in HC (p < 0.05). Cognitive pretesting improved the preliminary GDQ so that the final GDQ was rated as relevant (100/100%), comprehensive (100/90%), easy to understand concerning questions and answer options (100/90%), and of appropriate length (80/100%) by neurologists and patients with PD, respectively. The GDQ demonstrated excellent internal consistency (Cronbach's alpha value of 0.94). Evidence for good construct validity is given by moderate to high correlations of the GDQ total score and its domains by intercorrelations (r s = 0.67-0.91; p < 0.001) and with validated general NMS measures as well as with specific items that assess gastrointestinal symptoms. Interpretation: The GDQ is a novel, easy, and quick 18-item self-assessment questionnaire to screen for and monitor gastrointestinal dysmotility with a focus on constipation in patients with PD. It has shown high acceptance and efficacy as well as good construct validity in cognitive pretests.

Two-Year observational study of autonomic skin function in patients with Parkinson's disease compared to healthy individuals.

BACKGROUND AND PURPOSE: We characterized autonomic pilomotor and sudomotor skin function in early Parkinson's disease (PD) longitudinally. METHODS: We enrolled PD patients (Hoehn and Yahr 1-2) and healthy controls from movement disorder centers in Germany, Hungary, and the United States. We evaluated axon-reflex responses in adrenergic sympathetic pilomotor nerves and in cholinergic sudomotor nerves and assessed sympathetic skin response (SSR), predominantly parasympathetic neurocardiac function via heart rate variability, and disease-related symptoms at baseline, after 2 weeks, and after 1 and 2 years. CLINICALTRIALS: gov: NCT03043768. RESULTS: We included 38 participants: 26 PD (60% females, aged 62.4 ± 7.4 years, mean ± SD) and 12 controls (75% females, aged 59.5 ± 5.8 years). Pilomotor function was reduced in PD compared to controls at baseline when quantified via spatial axon-reflex spread (78 [43-143], median [interquartile range] mm2 vs. 175 [68-200] mm2 , p = 0.01) or erect hair follicle count in the axon-reflex region (8 [6-10] vs. 11 [6-16], p = 0.008) and showed reliability absent any changes from baseline to Week 2 (p = not significant [ns]). Between-group differences increased over the course of 2 years (p < 0.05), although no decline was observed within groups (p = ns). Pilomotor impairment in PD correlated with motor symptoms (rho = -0.59, p = 0.017) and was not lateralized (p = ns). Sudomotor axon-reflex and neurocardiac function did not differ between groups (p = ns), but SSR was reduced in PD (p = 0.0001). CONCLUSIONS: Impairment of adrenergic sympathetic pilomotor function and SSR in evolving PD is not paralleled by changes to cholinergic sudomotor function and parasympathetic neurocardiac function, suggesting a sympathetic pathophysiology. A pilomotor axon-reflex test might be useful to monitor PD-related pathology.

The use of wearables for the diagnosis and treatment of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, with increasing numbers of affected patients. Many patients lack adequate care due to insufficient specialist neurologists/geriatricians, and older patients experience difficulties traveling far distances to reach their treating physicians. A new option for these obstacles would be telemedicine and wearables. During the last decade, the development of wearable sensors has allowed for the continuous monitoring of bradykinesia and dyskinesia. Meanwhile, other systems can also detect tremors, freezing of gait, and gait problems. The most recently developed systems cover both sides of the body and include smartphone apps where the patients have to register their medication intake and well-being. In turn, the physicians receive advice on changing the patient's medication and recommendations for additional supportive therapies such as physiotherapy. The use of smartphone apps may also be adapted to detect PD symptoms such as bradykinesia, tremor, voice abnormalities, or changes in facial expression. Such tools can be used for the general population to detect PD early or for known PD patients to detect deterioration. It is noteworthy that most PD patients can use these digital tools. In modern times, wearable sensors and telemedicine open a new window of opportunity for patients with PD that are easy to use and accessible to most of the population.

[Caffeine, Chocolate and Adenosine A2A Receptor Antagonists in the Treatment of Parkinson's Disease]. / Koffein, Schokolade und Adenosin A2A Rezeptorantagonisten in der Behandlung des Parkinson Syndroms.

BACKGROUND: Patients with Parkinson's disease can apparently benefit from caffeine consumption, as a number of experimental and clinical studies have already shown. METHODS: The review examined the available literature on caffeine and Parkinson's disease. RESULTS: Caffeine can penetrate the blood-brain barrier and exerts its biological effects mainly by antagonizing adenosine receptors. Numerous studies indicate that caffeine and its derivatives theobromine and theophylline are associated with a reduced risk of Parkinson's disease. Caffeine and adenosine antagonists reduce the excitotoxicity caused by glutamate. Evidence from animal models supports the potential of A2A receptor antagonism as an innovative disease-modifying target in Parkinson's disease CONCLUSION: The present review shows that the investigation and synthesis of xanthine derivatives as well as their analysis in clinical studies could be a promising approach in the therapy of neurodegenerative diseases.

Measuring the Usability of eHealth Solutions for Patients With Parkinson Disease: Observational Study.

BACKGROUND: Parkinson disease (PD) is a neurodegenerative disorder with a variety of motor and nonmotor symptoms. Many of these symptoms can be monitored by eHealth solutions, including smartphone apps, wearable sensors, and camera systems. The usability of such systems is a key factor in long-term use, but not much is known about the predictors of successful use and preferable methods to assess usability in patients with PD. OBJECTIVE: This study tested methods to assess usability and determined prerequisites for successful use in patients with PD. METHODS: We performed comprehensive usability assessments with 18 patients with PD using a mixed methods usability battery containing the System Usability Scale, a rater-based evaluation of device-specific tasks, and qualitative interviews. Each patient performed the usability battery with 2 of 3 randomly assigned devices: a tablet app, wearable sensors, and a camera system. The usability battery was administered at the beginning and at the end of a 4-day testing period. Between usability batteries, the systems were used by the patients during 3 sessions of motor assessments (wearable sensors and camera system) and at the movement disorder ward (tablet app). RESULTS: In this study, the rater-based evaluation of tasks discriminated the best between the 3 eHealth solutions, whereas subjective modalities such as the System Usability Scale were not able to distinguish between the systems. Successful use was associated with different clinical characteristics for each system: eHealth literacy and cognitive function predicted successful use of the tablet app, and better motor function and lower age correlated with the independent use of the camera system. The successful use of the wearable sensors was independent of clinical characteristics. Unfortunately, patients who were not able to use the devices well provided few improvement suggestions in qualitative interviews. CONCLUSIONS: eHealth solutions should be developed with a specific set of patients in mind and subsequently tested in this cohort. For a complete picture, usability assessments should include a rater-based evaluation of task performance, and there is a need to develop strategies to circumvent the underrepresentation of poorly performing patients in qualitative usability research.

Development and Validation of a Fall Questionnaire for Patients with Parkinson's Disease.

Background: In Parkinson's disease, postural instability and falls are of particular socioeconomic relevance. Although effective fall prevention and the prophylaxis of fall-related injuries depend on low-threshold symptom monitoring, validated instruments are lacking. Objectives: To develop a self-report questionnaire for the assessment of falls, near falls, fear of falling, fall-related injuries, and causes of falls for patients with Parkinson's disease (PwPD). Methods: A pool of potential items was generated from a literature review and by discussion in an expert panel. The first version of the Dresden Fall Questionnaire (DREFAQ) was tested in a group of German-speaking movement disorder specialists as well as PwPD. The resulting 5-item questionnaire was assessed in a validation cohort of 36 PwPD who documented fall events and near-fall events in a calendar for 3 months and completed the DREFAQ at the end of the study. The questionnaire was subsequently used in a separate cohort of 46 PwPD to determine test-retest reliability and confirm the factor structure. Results: The DREFAQ showed good internal consistency (Cronbach's α = 0.84) and good test-retest reliability (intraclass correlation coefficient, 0.76; 95% confidence interval, 0.60-0.86). The total DREFAQ score showed good concurrent validity with fall events (Spearman's ρ = 0.82) and near-fall events (Spearman's ρ = 0.78) as determined by fall and near-fall diaries. Factor analysis revealed a 2-factor structure composed of near falls with fear of falling and severe falls with injuries. Conclusions: The DREFAQ is a reliable and valid 5-item questionnaire for determining the incidence of falls, near falls, fear of falling, fall-related injuries, and causes of falls in PwPD.

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. METHODS: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). RESULTS: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome. CONCLUSIONS: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.