Serum C-reactive protein adds predictive information for post-stroke delirium: The PROPOLIS study.

OBJECTIVE: Delirium is common and serious complication after stroke. Accurate prediction of delirium is important for prevention and monitoring of high-risk patients. Our study aimed to determine if addition of C-reactive protein (CRP) to a model based on easy-to-access clinical predictors improves accuracy of delirium prediction in acute stroke patients. METHODS: We analyzed data of patients participating in the Prospective Observational Polish Study on post-stroke delirium. We included patients admitted within 24 h after stroke or transient ischemic attack (TIA) in whom serum CRP was measured on admission. We examined core features of delirium during first 7 days of hospitalization. We assessed if addition of CRP to two clinical models improved metrics of discrimination and reclassification. Model A included age and stroke severity and Model B included stroke severity, atrial fibrillation, diabetes mellitus, pre-stroke dependency, and hemorrhagic stroke. RESULTS: We included 459 patients. We diagnosed delirium in 29.2% of them. Patients who developed delirium had higher CRP level than those without delirium (median: 13.2 vs. 4.4 mg/L, p < 0.001). CRP >7.09 mg/L was associated with an increased risk of delirium (adjusted OR: 2.98, 95%CI: 1.71-5.19, p < 0.001). After adding CRP to clinical models, an area under receiver operator curve increased from 0.77 to 0.80 (p = 0.038) for Model A and from 0.81 to 0.84 (p = 0.016) for Model B. There was also improvement in reclassification. CONCLUSIONS: Addition of CRP to clinical predictors moderately improved prediction of post-stroke delirium. CRP could be considered as a potential biomarker to stratify risk of delirium after stroke.

Relapsing antibody-negative patients with features of neuromyelitis optica spectrum disorders: Differences in N-acetylaspartate level in the cervical spinal cord indicate distinct underlying processes.

BACKGROUND: Due to lack of biomarkers, antibody-negative patients with features of neuromyelitis optica spectrum disorders (NMOSD) are among the most challenging to diagnose and treat. Using unsupervised clustering, we recently identified 'MS-like', 'spinal MS-like', 'classic NMOSD-like' and 'NMOSD-like with brain involvement' subgroups in this cohort. OBJECTIVE: We used magnetic resonance spectroscopy (MRS) to examine differences in the level of key metabolites in the spinal cord between the four identified subgroups. METHODS: Twenty-five relapsing antibody-negative patients with NMOSD features classified by the unsupervised algorithm to one of the subgroups underwent a prospective cervical spinal cord MRS. Spectra from 16 patients fulfilled quality criteria and were included in the analysis. RESULTS: Total N-acetylaspartate (tNAA), but not total choline (tCho) or myo-inositol (Ins), was significantly different between the four subgroups (p = 0.03). In particular, tNAA was 47.8% lower in the 'MS-like' subgroup as compared with the 'classic NMOSD-like' subgroup (p = 0.02). While we found a negative overall correlation between tNAA and disability score (r = -0.514, p = 0.04) in the whole cohort, the disability score did not differ significantly between the subgroups to explain subgroup differences in tNAA level. CONCLUSIONS: Significant differences in the cervical spinal cord tNAA measurements confirm that the previously identified clinico-radiologic subgroups contain patients with distinct underlying disease processes.

Delirium and subsyndromal delirium are associated with the long-term risk of death after ischaemic stroke.

BACKGROUND: Post-stroke delirium has a negative impact on functional outcome. We explored if there is any association between delirium, subsyndromal delirium and long-term mortality after ischaemic stroke and transient ischaemic attack. METHODS: We included 564 patients with ischaemic stroke or transient ischaemic attack. We assessed symptoms of delirium during the first 7 days after admission. We used Cox proportional hazards models to analyse all-cause mortality during the first 5 years after stroke. RESULTS: We diagnosed delirium in 23.4% and subsyndromal delirium in 10.3% of patients. During the follow-up, 72.7% of patients with delirium, 51.7% of patients with subsyndromal delirium and 22.7% of patients without delirious symptoms died (P < 0.001). Patients with subsyndromal delirium and delirium had higher risk of death in the multivariate analysis (HR 1.72, 95% CI 1.11-2.68, P = 0.016 and HR 3.30, 95% CI 2.29-4.76, P < 0.001, respectively). CONCLUSIONS: Post-stroke delirium is associated with long-term mortality. Patients with subsyndromal delirium are at the intermediate risk of death.

Elucidating distinct clinico-radiologic signatures in the borderland between neuromyelitis optica and multiple sclerosis.

BACKGROUND: Separating antibody-negative neuromyelitis optica spectrum disorders (NMOSD) from multiple sclerosis (MS) in borderline cases is extremely challenging due to lack of biomarkers. Elucidating different pathologies within the likely heterogenous antibody-negative NMOSD/MS overlap syndrome is, therefore, a major unmet need which would help avoid disability from inappropriate treatment. OBJECTIVE: In this study we aimed to identify distinct subgroups within the antibody-negative NMOSD/MS overlap syndrome. METHODS: Twenty-five relapsing antibody-negative patients with NMOSD features underwent a prospective brain and spinal cord MRI. Subgroups were identified by an unsupervised algorithm based on pre-selected NMOSD/MS discriminators. RESULTS: Four subgroups were identified. Patients from Group 1 termed "MS-like" (n = 6) often had central vein sign and cortical lesions (83% and 67%, respectively). All patients from Group 2 ("spinal MS-like", 8) had short-segment myelitis and no MS-like brain lesions. Group 3 ("classic NMO-like", 6) had high percentage of bilateral optic neuritis and longitudinally extensive transverse myelitis (LETM, 80% and 60%, respectively) and normal brain appearance (100%). Group 4 ("NMO-like with brain involvement", 5) typically had a history of NMOSD-like brain lesions and LETM. When compared with other groups, Group 4 had significantly decreased fractional anisotropy in non-lesioned tracts (0.46 vs. 0.49, p = 0.003) and decreased thalamus volume (0.84 vs. 0.98, p = 0.04). CONCLUSIONS: NMOSD/MS cohort contains distinct subgroups likely corresponding to different pathologies and requiring tailored treatment. We propose that non-conventional MRI might help optimise diagnosis in these challenging patients.

Subtypes of delirium after ischaemic stroke-predisposing factors and outcomes: a prospective observational study (PROPOLIS).

BACKGROUND AND PURPOSE: Delirium is a serious complication after stroke. It remains unclear whether different motor subtypes of delirium are associated with diverse risk factors and outcomes. The aim was to investigate if delirium subtypes differ in predisposing factors, clinical characteristics and outcomes. METHODS: In all, 698 patients with ischaemic stroke or transient ischaemic attack (median age 73 years; 53.7% female) were prospectively included. Core features of delirium during the first 7 days after admission were examined. The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for delirium were used. Pre-stroke characteristics were compared between different delirium subtypes and logistic regression and Cox proportional hazard models were used to explore the association between delirium, functional outcome and death. RESULTS: Hyperactive, hypoactive and mixed delirium were diagnosed in 28, 75 and 66 patients, respectively. Patients with hyperactive delirium had less severe neurological deficit on admission and more often had transient ischaemic attack compared with patients with hypoactive and mixed delirium. Compared with patients with hypoactive delirium, those with hyperactive delirium more often suffered from irritability/lability prior to stroke. Hyperactive and hypoactive delirium did not differ in age, sex, comorbidities, pre-stroke dependency, cognitive decline and severity of delirium. Hyperactive, hypoactive and mixed delirium were associated with an increased risk of poor 3- and 12-month functional outcome compared with patients without delirium. Moreover, patients with hypoactive and mixed delirium had an elevated risk of death. CONCLUSIONS: Hyperactive delirium is associated with less severe stroke and higher scores of pre-existing irritability/lability. All three motor subtypes of delirium are associated with poor outcome, although hyperactive delirium seems to have a less unfavourable prognosis.

Comorbidities in older patients with myasthenia gravis - Comparison between early- and late-onset disease.

BACKGROUND: Multimorbidity is an emerging challenge in older myasthenia gravis patients, which can have even greater impact on quality of life and outcome than symptoms of myasthenia. AIMS OF THE STUDY: We aimed to investigate comorbidities in older population and compare early-onset (EOMG) and late-onset (LOMG) myasthenia patients. METHODS: We investigated clinical information of patients from Oxford Myasthenia Centre age 50 or older. Data on 60 chronic disorders were extracted. RESULTS: We included 327 myasthenia patients (30.9% EOMG and 69.1% LOMG) with a median age of 70 years. Comorbidities were present in 94.5% of patients and accumulated with age. Hypertension (58.4% vs. 31.7%), hypercholesterolemia (41.2% vs. 23.8%), diabetes (24.8% vs. 11.9%), cataract (15.5% vs. 5.0%) and prostate disorders (15.0% vs. 2.0%) were more common in LOMG than EOMG, but there were no differences between 70 EOMG and 70 LOMG patients matched according to age and sex. CONCLUSIONS: Comorbidities in older patients with myasthenia are very common, increase with age, and do not differ between early- and late-onset disease.

Elevated plasma levels of galectin-3 binding protein are associated with post-stroke delirium - A pilot study.

To explore the role of systemic inflammation in post-stroke delirium, we investigated the level of two inflammatory mediators: high mobility group box 1 (HMGB1) and galectin-3 binding protein (Gal-3BP). Of 571 stroke patients, we compared plasma levels of HMGB1 and Gal-3BP in 79 delirious patients with 81 non-delirious patients matched for age and stroke severity. Delirious patients had higher Gal-3BP level (median: 1440 vs 1053 ng/mL, P < 0.01). An elevated level of Gal-3BP was associated with an increased risk of delirium. HMGB1 levels did not differ between groups. Our results suggest that pro-inflammatory monocytes and macrophages might be involved in delirium pathophysiology.

Lipopolysaccharide binding protein and sCD14 as risk markers of stroke-associated pneumonia.

To determine the utility of lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14) as risk markers of stroke-associated pneumonia (SAP). We included 331 stroke patients. The plasma levels of LBP (median: 19.4 vs 15.3 µg/mL, P < 0.01) and sCD14 (median: 1.5 vs 1.4 µg/mL, P = 0.04) were elevated in SAP. In multivariate analysis, a higher level of LBP (OR: 1.09, 95%CI: 1.05-1.13), but not sCD14 (OR: 2.16, 0.94-4.97), was associated with SAP. The addition of LBP or sCD14 to the clinical model did not improve its discriminatory ability. Our results suggest the modest value of studied biomarkers for SAP prediction.

Magnetisation transfer imaging revealed microstructural changes related to apathy symptoms after ischaemic stroke.

OBJECTIVES: Apathy after stroke is common and has a negative impact on functional recovery. Neuroimaging correlates of poststroke apathy remain unclear. We aimed to investigate microstructural changes associated with the severity of poststroke apathy symptoms. METHODS: We assessed 67 patients with cerebral ischaemia who underwent magnetisation transfer brain imaging 12-15 months after stroke. We used magnetisation transfer ratio (MTR) to represent microstructural integrity. We performed whole-brain voxel-based analysis and subsequent region of interest analysis to investigate the association between MTR and symptoms of poststroke apathy. To assess apathy symptoms, we used clinician-reported version of the Apathy Evaluation Scale. RESULTS: Voxel-based analysis showed the association between symptoms of apathy and decreased MTR in areas overlapping with structures located in both hemispheres: left thalamus, bilateral hippocampus, bilateral fornix/stria terminalis, right amygdala, splenium of the corpus callosum, the retrolenticular part of left internal capsule and left sagittal stratum. In the region of interest analysis, only lower MTR in right fornix/stria terminalis was associated with greater poststroke apathy symptoms in a multivariate logistic model (odds ratio: 1.25, 95% CI: 1.09-1.46, p = 0.003). These associations were independent of depressive symptoms. CONCLUSION: Magnetisation transfer brain imaging 12-15 months after stroke revealed changes in microstructural integrity associated with apathy symptoms in brain areas related to processing emotional information and reward valuation.

The specific ex vivo released cytokine profile is associated with ischemic stroke outcome and improves its prediction.

BACKGROUND: Inflammation is associated with poor outcome after stroke. A relationship between ex vivo cytokine synthesis and stroke outcome remains unclear. We explored an association between ex vivo cytokine release, circulating interleukin (IL)-6 as a marker of systemic inflammation, and stroke prognosis. We assessed the utility of ex vivo synthesized cytokines for predicting stroke outcome. METHODS: We collected blood from 248 ischemic stroke patients and stimulated it ex vivo with lipopolysaccharide. We measured concentration of synthesized cytokines (TNFα, IP-10, IL-1ß, IL-6, IL-8, IL-10, and IL-12) and plasma IL-6. We assessed functional outcome 3 months after stroke using the modified Rankin Scale. To assess the prognostic ability of cytokines, we applied multivariate logistic regression, cluster analysis, and construction of multimarker score. RESULTS: Decreased release of IP-10, TNFα, IL-1ß, and IL-12; increased release of IL-10 and IL-8; and higher plasma IL-6 level were associated with poor outcome. Cluster analysis identified three groups of patients with distinct cytokine profiles. The group with the worst outcome demonstrated high synthesis of IL-10, IL-8, IL-1ß, and IL-6 and low synthesis of IL-12, IP-10, and TNFα accompanied by high circulating IL-6 level. The group with the best prognosis showed high synthesis of TNFα, IP-10, IL-12, IL-1ß, and IL-6; low synthesis of IL-10 and IL-8; and low plasma IL-6. Patients with intermediate outcome had low synthesis of all cytokines accompanied by low circulating IL-6. We constructed a multimarker score composed of ex vivo released IL-12, IL-10, TNFα, and plasma IL-6. Addition of this score to clinical variables led to significant increase in c-statistic (0.81 vs 0.73, p = 0.02) and net reclassification improvement. CONCLUSION: The decreased ex vivo release of pro-inflammatory cytokines and increased release of IL-10 and IL-8 are related to poor outcome after stroke. Cytokine-based multimarker score adds prognostic value to clinical model for predicting stroke outcome.

C-reactive protein and post-stroke depressive symptoms.

Our study aimed to explore the association between serum C-reactive protein (CRP) and post-stroke depressive symptoms. We prospectively recruited 572 patients with ischemic stroke or transient ischemic attack in whom serum CRP level was measured within 48 h after stroke onset. Depressive symptoms were assessed at day 8 and 3 months after stroke in 405 and 306 patients, respectively. Patients with greater depressive symptoms at day 8 and patients with greater depressive symptoms 3 months after stroke had higher CRP level (median: 7.9 vs 4.3 mg/L, P < 0.01 and 6.7 vs 3.4 mg/L, P = 0.01, respectively). In the univariate analysis, CRP > 9.2 mg/L was associated with depressive symptoms at day 8 (OR: 2.06, 95%CI: 1.30-3.28, P < 0.01) and CRP > 4.3 mg/L was associated with depressive symptoms 3 months after stroke (OR: 1.79, 95%CI: 1.06-3.02, P = 0.03). In the multivariate analysis, higher CRP level was related to depressive symptoms at day 8 (OR: 2.23, 95%CI: 1.28-3.90, P < 0.01), but not depressive symptoms 3 months after stroke (OR: 1.13, 95%CI: 0.59-2.17, P = 0.71). In conclusion, higher levels of CRP are associated with greater depressive symptoms at day 8 after stroke, but their effects on depressive symptoms 3 months after stroke are less significant.