Validation of a prediction model for long-term outcome of aphasia after stroke.

BACKGROUND: About 30% of stroke patients suffer from aphasia. As aphasia strongly affects daily life, most patients request a prediction of outcome of their language function. Prognostic models provide predictions of outcome, but external validation is essential before models can be used in clinical practice. We aim to externally validate the prognostic model from the Sequential Prognostic Evaluation of Aphasia after stroKe (SPEAK-model) for predicting the long-term outcome of aphasia caused by stroke. METHODS: We used data from the Rotterdam Aphasia Therapy Study - 3 (RATS-3), a multicenter RCT with inclusion criteria similar to SPEAK, an observational prospective study. Baseline assessment in SPEAK was four days after stroke and in RATS-3 eight days. Outcome of the SPEAK-model was the Aphasia Severity Rating Scale (ASRS) at 1 year, dichotomized into good (ASRS-score of 4 or 5) and poor outcome (ASRS-score < 4). In RATS-3, ASRS-scores at one year were not available, but we could use six month ASRS-scores as outcome. Model performance was assessed with calibration and discrimination. RESULTS: We included 131 stroke patients with first-ever aphasia. At six months, 86 of 124 (68%) had a good outcome, whereas the model predicted 88%. Discrimination of the model was good with an area under the receiver operation characteristic curve of 0.87 (95%CI: 0.81-0.94), but calibration was unsatisfactory. The model overestimated the probability of good outcome (calibration-in-the-large α = - 1.98) and the effect of the predictors was weaker in the validation data than in the derivation data (calibration slope ß = 0.88). We therefore recalibrated the model to predict good outcome at six months. CONCLUSION: The original model, renamed SPEAK-12, has good discriminative properties, but needs further external validation. After additional external validation, the updated SPEAK-model, SPEAK-6, may be used in daily practice to discriminate between patients with good and patients with poor outcome of aphasia at six months after stroke. TRIAL REGISTRATION: RATS-3 was registered on January 13th 2012 in the Netherlands Trial Register: NTR3271 . SPEAK was not listed in a trial registry.

Screening tests for aphasia in patients with stroke: a systematic review.

Aphasia has a large impact on the quality of life and adds significantly to the costs of stroke care. Early recognition of aphasia in stroke patients is important for prognostication and well-timed treatment planning. We aimed to identify available screening tests for differentiating between aphasic and non-aphasic stroke patients, and to evaluate test accuracy, reliability, and feasibility. We searched PubMed, EMbase, Web of Science, and PsycINFO for published studies on screening tests aimed at assessing aphasia in stroke patients. The reference lists of the selected articles were scanned, and several experts were contacted to detect additional references. Of each screening test, we estimated the sensitivity, specificity, likelihood ratio of a positive test, likelihood ratio of a negative test, and diagnostic odds ratio (DOR), and rated the degree of bias of the validation method. We included ten studies evaluating eight screening tests. There was a large variation across studies regarding sample size, patient characteristics, and reference tests used for validation. Many papers failed to report on the consecutiveness of patient inclusion, time between aphasia onset and administration of the screening test, and blinding. Of the three studies that were rated as having an intermediate or low risk of bias, the DOR was highest for the Language Screening Test and ScreeLing. Several screening tools for aphasia in stroke are available, but many tests have not been verified properly. Methodologically sound validation studies of aphasia screening tests are needed to determine their usefulness in clinical practice.

Early effect of intra-arterial treatment in ischemic stroke on aphasia recovery in MR CLEAN.

OBJECTIVE: To investigate the effect of intra-arterial treatment (IAT) on early recovery from aphasia in acute ischemic stroke. We hypothesized that the early effect of IAT on aphasia is smaller than the effect on motor deficits. METHODS: We included patients with aphasia from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN), in which 500 patients with a proximal anterior circulation stroke were randomized to usual care plus IAT (<6 hours after stroke, mainly stent retrievers) or usual care alone. We estimated the effect of IAT on the shift on the NIH Stroke Scale (NIHSS) item language and the NIHSS item motor arm at 24 hours and 1 week after stroke with multivariable ordinal logistic regression as a common odds ratio, adjusted for prognostic variables (acOR). Differences between the effect of IAT on aphasia and on motor deficits were tested in a multilevel model with a multiplicative interaction term. RESULTS: Of the 288 patients with aphasia, 126 were assigned to IAT and 162 to usual care alone. The acOR for improvement of language score at 24 hours was 1.65 (95% confidence interval [CI] 1.05-2.60), and at 1 week 1.86 (95% CI 1.18-2.94). The acOR for improvement of motor deficit at 24 hours was 2.44 (95% CI 1.54-3.88), and at 1 week 2.32 (95% CI 1.43-3.77). The effect of IAT on language deficits was significantly different from the effect on motor deficits at 24 hours and 1 week (p = 0.005 and p = 0.011). CONCLUSIONS: IAT results in better early recovery from aphasia than usual care alone. The early effect of IAT on aphasia is smaller than the effect on motor deficits. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute ischemic stroke IAT increases early recovery from aphasia and that the early effect on aphasia, as measured by the NIHSS, is smaller than the effect on motor deficits.

Short Door-to-Needle Times in Acute Ischemic Stroke and Prospective Identification of Its Delaying Factors.

BACKGROUND: The clinical benefit of intravenous thrombolysis (IVT) in acute ischemic stroke is time dependent. Several studies report a short median door-to-needle time (DNT; 20 min), mainly in large tertiary referral hospitals equipped with a level 1 emergency department, a dedicated stroke team available 24/7, and on-site neuroimaging facilities. Meanwhile, in daily practice, the majority of stroke patients are admitted to secondary care hospitals, and in practice, even the generous benchmark of the American Heart Association (a DNT of 60 min in >80% of the cases) is met for a minority of patients treated with IVT. The first objective of our study was to investigate if, in a secondary care teaching hospital rather than a tertiary referral hospital, similar short DNTs can be accomplished with an optimized IVT protocol. Our second objective was to prospectively identify factors that delay the DNT in this setting. METHODS: A multicenter, consecutive cohort study of patients treated with IVT in one of two secondary care teaching hospitals. In both hospitals, data of consecutive stroke patients as well as median DNTs and factors delaying this were prospectively assessed for each patient. Multivariable logistic regression analysis was used to evaluate associations between patient-related and logistic factors with a delayed (i.e. exceeding 30 min) DNT. RESULTS: In total, 1,756 patients were admitted for ischemic stroke during the study period. Out of these, 334 (19.0%) patients were treated with IVT. The median DNT was 25 min (interquartile range: 20-35). A total of 71% (n = 238) had a DNT below 30 min. In 63% of the patients treated with IVT the DNT was delayed by at least one factor. Patients without any delaying factor had a 10 min shorter median DNT compared to patients with at least one delaying factor (p < 0.001). The following factors were independently associated with a delayed DNT: uncertainty about symptom onset, uncontrolled blood pressure, fluctuating neurological deficit, other treatment before IVT, uncertainty about (anti-)coagulation status, other patient-related factors, and incorrect triage. CONCLUSIONS: Short median DNTs can also be accomplished in secondary care. Despite the short DNTs, several delaying factors were identified that could direct future improvement measures. This study supports the view that as a performance measure, the current DNT targets are no longer ambitious enough and it adds to the knowledge of factors delaying the DNT.

Optimal timing of speech and language therapy for aphasia after stroke: more evidence needed.

Aphasia due to stroke affects communication and quality of life. Most stroke survivors with aphasia receive speech and language therapy. Although an early start of treatment is advocated in clinical practice, evidence for "The earlier, the better" in aphasia rehabilitation is weak. Hence, clinicians are faced with the dilemma of when to initiate intensive treatment: as early as possible, when most of the spontaneous recovery occurs but when patients are often ill, or later, when the patients' condition is more stabilized. Here we discuss whether aphasia outcome is affected by timing of treatment in relation to stroke onset and whether there is evidence for an optimal window of time during which language therapy should be provided. Findings from various rehabilitation research fields are discussed and combined to provide principles for future research.

[Chronic insomnia: not always psychophysiological]. / Chronische insomnie: niet altijd psychofysiologisch.

OBJECTIVE: To determine the sensitivity, specificity and the positive and negative predictive value of taking a detailed sleep history for making the diagnosis of psychophysiological insomnia. DESIGN: Retrospective case file study. METHOD: We examined 767 patients referred to the Amsterdam Centre for Sleep and Wake Disorders, and who underwent polysomnography for the first time between 1 January and 31 December 2010. We compared the probable diagnosis made following history-taking with the final diagnosis made after polysomnography. In this we differentiated between organic and non-organic insomnia. The sensitivity, specificity, positive and negative predictive values of the sleep history were calculated. RESULTS: In 24.8% of the 303 patients whose histories did not indicate organic insomnia, polysomnography showed there to be an organic cause. Primary causes were obstructive sleep apnoea (13.2%), upper airway resistance syndrome (5.4%), and periodic limb movement disorder (4.0%) or a combination of these. In the histories of 464 patients there were indications that the insomnia had an organic cause and in 325 of them this was confirmed by polysomnography. The sensitivity of detailed history taking to psychophysiological insomnia was 62.1%, the specificity 81.3%, the positive predictive value was 75.2% and the negative predictive value was 70.0%. In patients under the age of 40 with a score on the Epworth sleepiness scale < 10 (i.e. no hypersomnolence), a BMI < 25 kg/m2 and indications of psychophysiological insomnia, organic insomnia could not be demonstrated, with the exception of one parasomnia. CONCLUSION: History-taking only meant that the organic cause was missed in a substantial percentage of patients with insomnia, in particular in older patients with hypersomnolence and a high BMI.

Survival in Parkinson's disease. Relation with motor and non-motor features.

BACKGROUND: Survival in patients with Parkinson's disease is reduced as compared to the general population. We aimed to identify motor and non-motor features that predict mortality in Parkinson's disease. METHODS: A broad range of motor and non-motor features were assessed in a hospital-based cohort of 414 patients with Parkinson's disease, who underwent five annual follow-up examinations including vital status assessment. Multivariable Cox's proportional hazards regression analysis was used to evaluate the association between baseline characteristics and mortality risk. Stepwise regression with backward elimination was carried out to determine the best model to predict mortality in Parkinson's disease. RESULTS: After a mean follow-up period of 4.3 years, 49 (11.8%) patients had died. In the stepwise regression model, predictors of mortality in Parkinson's disease were higher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms. CONCLUSIONS: Higher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms are independent predictors of decreased survival in Parkinson's disease. Mortality in Parkinson's disease thus seems to be affected mainly by non-dopaminergic and non-motor features.

Relationship of Von Willebrand Factor with carotid artery and aortic arch calcification in ischemic stroke patients.

BACKGROUND: Large population studies have revealed that increased von Willebrand Factor (VWF) levels are associated with an increased risk of ischemic stroke. In previous studies VWF was associated with atherosclerosis in healthy individuals. However, it is yet unknown what the association is between atherosclerosis and VWF levels in patients with ischemic stroke. OBJECTIVES: The aim of our study was to determine the association of atherosclerosis, measured with recent developed techniques, and VWF levels in a large, well characterized, cohort of ischemic stroke patients and to determine the prognostic value. METHODS: We included 925 consecutive patients with transient ischemic attack (TIA) or ischemic stroke. Calcification volumes (mm(3)) were scored in the aortic arch and both carotid arteries using multidetector computed tomography (CT) angiography. VWF antigen (VWF:Ag) levels were measured using ELISA. RESULTS: Mean VWF:Ag levels were significantly higher in the presence of calcification in either the aortic arch (1.47 vs. 1.37 IU/ml [P = 0.039]) or the carotid arteries (1.49 vs. 1.34 IU/ml [P = 0.001]). Patients with a large artery atherosclerosis ischemic stroke had significantly higher VWF:Ag levels then the other TOAST subtypes (P < 0.0001). High VWF:Ag levels were associated with an unfavorable outcome (modified Rankin Scale >2 vs. ≤2; 1.64 vs. 1.41 IU/ml, [P < 0.0001]). CONCLUSION: Our study showed a strong association between the extent of atherosclerosis in both the aortic arch and the carotid arteries and VWF levels in patients with TIA or ischemic stroke. Higher VWF levels are found in large artery atherosclerosis and are associated with a poor outcome.

Rotterdam Aphasia Therapy Study (RATS)-3: "The efficacy of intensive cognitive-linguistic therapy in the acute stage of aphasia"; design of a randomised controlled trial.

BACKGROUND: Aphasia is a severely disabling condition occurring in 20 to 25% of stroke patients. Most patients with aphasia due to stroke receive speech and language therapy. Methodologically sound randomised controlled trials investigating the effect of specific interventions for patients with aphasia following stroke are scarce. The currently available evidence suggests that intensive speech and language therapy is beneficial for restoration of communication, but the optimal timing of treatment is as yet unclear.In the Rotterdam Aphasia Therapy Study-3 we aim to test the hypothesis that patients with aphasia due to stroke benefit more from early intensive cognitive-linguistic therapy than from deferred regular language therapy. METHODS/DESIGN: In a single blinded, multicentre, randomised controlled trial, 150 patients with first ever aphasia due to stroke will be randomised within two weeks after stroke to either early intensive cognitive-linguistic therapy (Group A) or deferred regular therapy (Group B). Group A will start as soon as possible, at the latest two weeks after stroke, with a four week period of one hour a day treatment with cognitive-linguistic therapy. In Group B professional speech and language therapy is deferred for four weeks. After this period, patients will follow the conventional procedure of speech and language therapy. Participants will be tested with an extensive linguistic test battery at four weeks, three months and six months after inclusion. Primary outcome measure is the difference in score between the two treatment groups on the Amsterdam-Nijmegen Everyday Language Test, a measure of everyday verbal communication, four weeks after randomisation. TRIAL REGISTRATION: This trial is registered in the Dutch Trial Register (http://www.trialregister.nl), NTR3271.

Association of two single nucleotide polymorphisms from genomewide association studies with clinical phenotypes of cerebral ischemia.

BACKGROUND: Recent genomewide association studies have revealed an association between two single nucleotide polymorphisms, rs11833579 and rs12425791, and ischemic stroke. AIM: To gain more insight in pathophysiological mechanisms underlying the found associations by exploring relationships between these single nucleotide polymorphisms and clinical and radiological characteristics of patients with cerebral ischemia. METHODS: Our cohort consisted of 660 Caucasian patients with cerebral ischemia; from all patients detailed clinical and radiological data were available. Etiologic subtype of cerebral ischemia was determined according to the TOAST classification and an alternative classification. We studied associations between risk alleles and etiologic subtype, duration of ischemia, occurrence of multiple events, functional outcome and findings on CT-angiography by means of logistic regression analysis. RESULTS: The risk allele of rs11833579 was associated with an atherothrombotic etiology of cerebral ischemia, but not with other etiologic subtypes. Risk alleles of both single nucleotide polymorphisms were related to events of shorter duration (<24 h), the risk allele of rs11833579 with occurrence of multiple events. There was no association between single nucleotide polymorphism and clinical outcome. Both single nucleotide polymorphismswere associated with presence of stenotic calcifications and stenosis >30% in a symptomatic artery on CT-angiography. CONCLUSIONS: This is the first study to show an association of rs11833579 with multiple episodes of cerebral ischemia of atherothrombotic origin, and of rs11833579 and rs12425791 with short duration of ischemia. Also, we found an association of both single nucleotide polymorphisms with atherosclerotic lesions in the extracranial vessels on CT-angiography. Together this suggests a relationship between the two single nucleotide polymorphisms and large artery pathology.

Catechol-O-methyltransferase Val158Met and the risk of dyskinesias in Parkinson's disease.

BACKGROUND: The A-allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability. METHODS: We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations. RESULTS: The A-allele of the COMT Val158Met polymorphism was related to an increased risk of developing dyskinesias during follow-up, in a dose-dependent manner (adjusted hazard ratios for the AG and AA genotypes [compared to GG]: 2.09 [95% confidence interval (CI), 1.07-4.06] and 2.81 [CI, 1.43-5.54], respectively). CONCLUSIONS: This finding suggests that genetic factors may affect susceptibility to dyskinesias in PD.

γ'/total fibrinogen ratio is associated with short-term outcome in ischaemic stroke.

Fibrinogen γ' (γ') is a natural isoform of fibrinogen, and alters the rate of formation and the properties of clots. It could therefore affect outcome after ischaemic stroke. The prognostic significance of γ' fibrinogen levels is, however, still unclear. It was the objective of this study to assess levels of γ' in ischaemic stroke, and its association with short-term outcome. We included 200 ischaemic stroke patients and 156 control persons. Total fibrinogen and γ' levels were measured; outcome at discharge was assessed by means of the modified Rankin Scale score (defined as unfavourable when >2). We compared levels between patients and controls using multiple linear regression analysis, and logistic regression analysis was used to assess the relationship between levels and outcome. All analyses were adjusted for age and sex. Mean γ' levels were significantly higher in patients with ischaemic stroke than in controls (0.37 vs. 0.32 g/l, p<0.001), and patients also had a higher γ'/total fibrinogen ratio (0.102 vs. 0.096, p=0.19). The γ'/total fibrinogen ratio is associated with unfavourable outcome in patients with ischaemic stroke (odds ratio per unit increase of γ'/total fibrinogen ratio 1.27, 95% confidence interval 1.09-1.47). Our study shows that patients with ischaemic stroke have increased levels of fibrinogen γ' and suggests a trend towards an increased γ'/total fibrinogen ratio in ischaemic stroke. Increased fibrinogen γ' relative to total fibrinogen levels are associated with unfavourable outcome in the early phase after stroke.

A review of hereditary and acquired coagulation disorders in the aetiology of ischaemic stroke.

The diagnostic workup in patients with ischaemic stroke often includes testing for prothrombotic conditions. However, the clinical relevance of coagulation abnormalities in ischaemic stroke is uncertain. Therefore, we reviewed what is presently known about the association between inherited and acquired coagulation disorders and ischaemic stroke, with a special emphasis on the methodological aspects. Good-quality data in this field are scarce, and most studies fall short on epidemiological criteria for causal inference. While inherited coagulation disorders are recognised risk factors for venous thrombosis, there is no substantial evidence for an association with arterial ischaemic stroke. Possible exceptions are the prothrombin G20210A mutation in adults and protein C deficiency in children. There is proof of an association between the antiphospholipid syndrome and ischaemic stroke, but the clinical significance of isolated mildly elevated antiphospholipid antibody titres is unclear. Evidence also suggests significant associations of increased homocysteine and fibrinogen concentrations with ischaemic stroke, but whether these associations are causal is still debated. Data on other acquired coagulation abnormalities are insufficient to allow conclusions regarding causality. For most coagulation disorders, a causal relation with ischaemic stroke has not been definitely established. Hence, at present, there is no valid indication for testing all patients with ischaemic stroke for these conditions. Large prospective population-based studies allowing the evaluation of interactive and subgroup effects are required to appreciate the role of coagulation disorders in the pathophysiology of arterial ischaemic stroke and to guide the management of individual patients.

Acute disseminating encephalomyelitis following legionnaires disease.

OBJECTIVE: To describe 2 patients presenting with severe neurological deficits and extensive lesions on brain magnetic resonance imaging after having experienced Legionella pneumonia. DESIGN: Case reports. SETTING: University hospital. PATIENTS: Two patients who developed severe neurological symptoms, including encephalopathic signs, following Legionella infection, with widespread lesions on magnetic resonance imaging compatible with demyelination. RESULTS: After extensive ancillary investigations, a diagnosis of acute disseminating encephalomyelitis was considered most likely. Steroid therapy was initiated in 1 of the patients, followed by plasmapheresis. In both patients, clinical and radiological signs gradually recovered, with only slight residual deficits. CONCLUSION: In patients presenting with neurological symptoms after an episode of pneumonia, Legionella infection and a subsequent immune-mediated process such as acute disseminating encephalomyelitis should be considered.

Genetic variation in homocysteine metabolism, cognition, and white matter lesions.

Several studies have shown an association between homocysteine concentration and cognitive performance or cerebral white matter lesions. However, variations in genes encoding for enzymes and other proteins that play a role in homocysteine metabolism have hardly been evaluated in relation to these outcome measures. In the population-based Rotterdam Scan Study, we examined the association of seven polymorphisms of genes involved in homocysteine metabolism (MTHFR 677C>T, MTHFR 1298A>C, RFC 80G>A, TC 776C>G, MTR 2756A>G, MTRR 66A>G, and CBS 844ins68) with plasma total homocysteine, cognitive performance, and cerebral white matter lesions among 1011 non-demented elderly participants. Of all the studied polymorphisms, only MTHFR 677C>T was associated with homocysteine concentration. No significant relationship was observed for any of the polymorphisms with cognitive performance or severity of cerebral white matter lesions.

Predicting and preventing stroke after transient ischemic attack.

The prognosis of transient ischemic attacks (TIAs) is not as favorable as previously thought. Given a risk of stroke of approximately 10% in the first week following a TIA, urgent evaluation and initiation of treatment are required. Recently developed scores to predict the early risk of subsequent stroke in individual patients may guide treatment decisions in the acute phase. Lately it has become clear that transient attacks with nonfocal symptoms are not benign either, as these were found to be associated with an increased risk of vascular disease. The significance of this finding and its implications for treatment are not yet clear. There is substantial evidence from a number of clinical trials that adequate secondary prevention therapies can reduce the risk of stroke after TIA. In addition to the conventional vascular risk factors, interest has grown in less strong but more prevalent lifestyle factors, but trials evaluating the effect of modifying these factors are as yet lacking.

Genomewide association studies of stroke.

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined. METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

Acute CNS white matter lesions in patients with inflammatory bowel disease.

BACKGROUND: Neurological manifestations in patients with inflammatory bowel disease supposedly are rare, although the exact frequency is not known. Most previous reports involve cerebral venous thrombosis, central nervous system vasculitis, or peripheral nerve inflammation. METHODS: Two cases of patients diagnosed with inflammatory bowel disease developing neurological symptoms with corresponding lesions in the white matter of the central nervous system led us to search a neurological database with clinical and radiological data for similar cases. RESULTS: We identified five patients who presented with acute neurological deficits preceding or following a diagnosis of inflammatory bowel disease with evidence of lesions in the central nervous system white matter on magnetic resonance imaging. Ancillary investigations did not provide evidence of systemic infetcion, coagulation disorders, or vasculitis. CONCLUSIONS: These cases, together with previous reports, suggest that white matter lesions may be another extraintestinal manifestation of inflammatory bowel disease.