Abstract
Background
Neurologic manifestations are increasingly reported in patients with coronavirus disease 2019 (COVID-19). Yet, data on prevalence, predictors and relevance for outcome of ...neurological manifestations in patients requiring intensive care are scarce. We aimed to characterize prevalence, risk factors and impact on outcome of neurologic manifestations in critically ill COVID-19 patients.
Methods
In the prospective, multicenter, observational registry study PANDEMIC (Pooled Analysis of Neurologic DisordErs Manifesting in Intensive care of COVID-19), we enrolled COVID-19 patients with neurologic manifestations admitted to 19 German intensive care units (ICU) between April 2020 and September 2021. We performed descriptive and explorative statistical analyses. Multivariable models were used to investigate factors associated with disorder categories and their underlying diagnoses as well as to identify predictors of outcome.
Results
Of the 392 patients included in the analysis, 70.7% (277/392) were male and the mean age was 65.3 (SD ± 3.1) years. During the study period, a total of 2681 patients with COVID-19 were treated at the ICUs of 15 participating centers. New neurologic disorders were identified in 350 patients, reported by these centers, suggesting a prevalence of COVID-19-associated neurologic disorders of 12.7% among COVID-19 ICU patients. Encephalopathy (46.2%; 181/392), cerebrovascular (41.0%; 161/392) and neuromuscular disorders (20.4%; 80/392) were the most frequent categories identified. Out of 35 cerebrospinal fluid analyses with reverse transcriptase PCR for SARS-COV-2, only 3 were positive. In-hospital mortality was 36.0% (140/389), and functional outcome (mRS 3 to 5) of surviving patients was poor at hospital discharge in 70.9% (161/227). Intracerebral hemorrhage (OR 6.2, 95% CI 2.5–14.9,
p
< 0.001) and acute ischemic stroke (OR 3.9, 95% CI 1.9–8.2,
p
< 0.001) were the strongest predictors of poor outcome among the included patients.
Conclusions
Based on this well-characterized COVID-19 ICU cohort, that comprised 12.7% of all severe ill COVID-19 patients, neurologic manifestations increase mortality and morbidity. Since no reliable evidence of direct viral affection of the nervous system by COVID-19 could be found, these neurologic manifestations may for a great part be indirect para- or postinfectious sequelae of the infection or severe critical illness. Neurologic ICU complications should be actively searched for and treated.
Background:
After thrombectomy has shown to be effective in acute stroke patients with large vessel occlusion, the potential benefit of secondary referral for such an intervention needs to be ...validated.
Aims:
We aimed to compare consecutive stoke patients directly admitted and treated with thrombectomy at a neurointerventional centre with patients secondarily referred for such a procedure from hospitals with a stroke unit.
Methods:
Periprocedure times and mortality in 300 patients primarily treated in eight neurointerventional centres were compared with 343 patients referred from nine other hospitals in a prospective multicentre study of a German neurovascular network. Data on functional outcome at 3 months was available in 430 (76.4%) patients.
Results:
In-hospital mortality (14.8% versus 11.7%, p = 0.26) and 3 months mortality (21.9% versus 24.1%, p = 0.53) were not statistically different in both patient groups despite a significant shorter symptom to groin puncture time in directly admitted patients, which was mainly caused by a longer interfacility transfer time. We found a nonsignificant trend for better functional outcome at 3 months in directly admitted patients (modified Rankin Scale 0–2, 44.0% versus 35.7%, p = 0.08).
Conclusions:
Our results show that a drip-and-ship thrombectomy concept can be effectively organized in a metropolitan stroke network. Every effort should be made to speed up the emergency interfacility transfer to a neurointerventional centre in stroke patients eligible for thrombectomy after initial brain imaging.
IMPORTANCE: Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH). OBJECTIVE: To assess the ...association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption. EXPOSURES: Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment. MAIN OUTCOMES AND MEASURES: Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome. RESULTS: Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 19.8%) vs INR of ≥1.3 (264/636 41.5%; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 33.1%) vs ≥160 mm Hg (98/187 52.4%; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 18.1% vs 220/498 44.2% not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 13.5% vs 103/498 20.7%; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 5.2% vs no OAC: 82/547 15.0%; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 8.1% vs no OAC: 36/547 6.6%; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%). CONCLUSIONS AND RELEVANCE: Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01829581
IMPORTANCE: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. OBJECTIVE: To determine the ...association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. DESIGN, SETTING, AND PARTICIPANTS: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). EXPOSURE: Surgical hematoma evacuation vs conservative treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. RESULTS: Among 578 patients with cerebellar ICH, propensity score–matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio AOR, 0.94 95% CI, 0.81 to 1.09, P = .43; adjusted risk difference ARD, −3.7% 95% CI, −8.7% to 1.2%) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 95% CI, 1.07 to 1.45, P = .005; ARD, 18.5% 95% CI, 13.8% to 23.2%) and at 12 months (71.7% vs 57.2%; AOR, 1.21 95% CI, 1.03 to 1.42, P = .02; ARD, 17.0% 95% CI, 11.5% to 22.6%). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% P = .003; ARD, −34.7% −38.8% to −30.6%; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% P < .001; ARD, 28.2% 95% CI, 24.6% to 31.8%; P value for interaction, .02). CONCLUSIONS AND RELEVANCE: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.
Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features ...characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder at least one symptom present in 38% (20/53). At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients 28% (15/53) reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 55% (24/44) was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.
General anaesthesia (GA) during mechanical thrombectomy (MT) might lead to an inferior clinical outcome compared to conscious sedation (CS). It was hypothesised that using CS might avoid a critical ...drop in cerebral perfusion, shorten the time of the intervention and therefore might result in better clinical outcome. In this study, we compared the procedural and clinical results of patients who underwent MT under GA or CS at two tertiary neuro-vascular centres on the basis of a matched-pair analysis.
Using a matched-pair approach, we compared the data of 56 patients that were treated under CS at centre A (n = 28) with selected patients who were treated under GA at the centre B (n = 28). Patients were matched for age, sex, site of vessel occlusion, NIHSS at admission (±3 points), time from symptom onset to initial stroke imaging, intravenous-lysis and co-morbidities. All patients had an ASPECT-score of ≥8. To exclude the effect of technical failures, only patients with successful recanalization of the occluded vessel (TICI 2b and 3) were included into the study. The primary endpoint was the proportion of patients with early good clinical outcome after MT, defined by a modified Ranking Scale (mRS)-score ≤2 at discharge. Secondary endpoints were the time from symptom onset to the start of the procedure, the duration of the procedure and the rate of procedural complications.
There were no differences concerning gender, age, the site of vessel occlusion and the degree of stroke severity at baseline. The proportion of patients with an early good clinical outcome (mRS ≤2 at discharge) was 60.4% (17/28) in both groups. The time from symptom onset to the start of the procedure was shorter at centre B, while the duration of the procedure was significantly faster at A, resulting in an overall time from symptom onset to complete recanalization of 152.2 ± 68.0 min for patients treated at centre A and 171.1 ± 43.5 min for patients at centre B (ns).
Our study revealed no differences in the investigated clinical outcome for patients undergoing endovascular stroke treatment under GA versus CS.
Purpose: Endovascular treatment of acute stroke-patients with tandem lesions is challenging. We sought to evaluate the factors that influence the clinical outcome in these patients. Methods: We ...retrospectively evaluated the clinical, procedural and imaging data of 42 stroke-patients (mean age 65 years, 67% male, mean NIHSS on admission 11.8) with tandem lesions of the anterior circulation that received endovascular treatment at our institution from January 2012 to December 2017. All patients were treated under general anaesthesia; 34% of the patients received IV-lysis. Results: Recanalization and stenting of the ICA was successful in all patients; TICI 2b and 3 was achieved in 13 (35%) in 28 (65%) patients, respectively. Periprocedural complications including symptomatic intracranial haemorrhage occurred in 10% of the patients. At 90 days follow-up good clinical outcome at 90days (MRS less than or equal to 2) was 65%. A more favourable clinical outcome correlated with a lower NIHSS on admission, younger age, and good cerebral collaterals on CT-angiography (> Tan 2). Conclusion: Interventional treatment of acute stroke-patients with tandem lesions is technically feasible and safe. A favourable outcome can be achieved in more than 60% of the patients and is most probable in younger patients with lower NIHSS and good intracranial collaterals.
Abstract
Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe ...seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS.
We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls.
Our GWAS identified 16 genome-wide significant (P < 5 × 10−8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 P = 4.42 × 10−16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187–0.358, localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10−4, OR = 2.5, 95%CI = 1.499–4.157) and DRB1*04:01 allele (P = 8.3 × 10−5, OR = 2.4, 95%CI = 1.548–3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS.
These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles.
Strippel et al. report the results of a genome-wide association study in a German cohort of 167 patients with autoimmune neurological syndromes with anti-GAD65 autoantibodies. Sixteen associated loci were identified, primarily in genomic regions implicated in immunity and neural function.
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.
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).
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.
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.
PDF
