Multicenter Randomized Controlled Trial of Vitamin K Antagonist Replacement by Rivaroxaban with or without Vitamin K2 in Hemodialysis Patients with Atrial Fibrillation: the Valkyrie Study.

BACKGROUND: Vitamin K antagonists (VKAs), although commonly used to reduce thromboembolic risk in atrial fibrillation, have been incriminated as probable cause of accelerated vascular calcification (VC) in patients on hemodialysis. Functional vitamin K deficiency may further contribute to their susceptibility for VC. We investigated the effect of vitamin K status on VC progression in 132 patients on hemodialysis with atrial fibrillation treated with VKAs or qualifying for anticoagulation. METHODS: Patients were randomized to VKAs with target INR 2-3, rivaroxaban 10 mg daily, or rivaroxaban 10 mg daily plus vitamin K2 2000 µg thrice weekly during 18 months. Systemic dp-ucMGP levels were quantified to assess vascular vitamin K status. Cardiac and thoracic aorta calcium scores and pulse wave velocity were measured to evaluate VC progression. RESULTS: Baseline dp-ucMGP was severely elevated in all groups. Initiation or continuation of VKAs further increased dp-ucMGP, whereas levels decreased in the rivaroxaban group and to a larger extent in the rivaroxaban+vitamin K2 group, but remained nevertheless elevated. Changes in coronary artery, thoracic aorta, and cardiac valve calcium scores and pulse wave velocity were not significantly different among the treatment arms. All cause death, stroke, and cardiovascular event rates were similar between the groups. Bleeding outcomes were not significantly different, except for a lower number of life-threatening and major bleeding episodes in the rivaroxaban arms versus the VKA arm. CONCLUSIONS: Withdrawal of VKAs and high-dose vitamin K2 improve vitamin K status in patients on hemodialysis, but have no significant favorable effect on VC progression. Severe bleeding complications may be lower with rivaroxaban than with VKAs.

C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer's disease.

INTRODUCTION: Biomarkers monitoring synaptic degeneration/loss would be valuable for Alzheimer's disease (AD) diagnosis. Postsynaptic protein neurogranin may be a promising cerebrospinal fluid (CSF) biomarker but has not yet been evaluated as a plasma biomarker. METHODS: Using an in-house designed prototype enzyme-linked immunosorbent assay (ELISA) targeting neurogranin C-terminally, we studied neurogranin in paired CSF/plasma samples of controls (n = 29) versus patients experiencing MCI, or dementia, due to AD (in total n = 59). RESULTS: CSF neurogranin was increased in AD and positively correlated with CSF tau, whereas there was a negative relationship between CSF neurogranin (and tau) and CSF Aß1-42/Aß1-40. No differences were detected in plasma neurogranin between controls and AD. Also, there was no correlation between CSF and plasma neurogranin, excluding confounding effects of the latter. DISCUSSION: This study strengthens the potential of neurogranin as an AD CSF biomarker, which now needs validation in larger studies. As tools, straightforward immunoassays can be used, as demonstrated by the described ELISA.

Mastication dyspraxia: a neurodevelopmental disorder reflecting disruption of the cerebellocerebral network involved in planned actions.

This paper reports the longitudinal clinical, neurocognitive, and neuroradiological findings in an adolescent patient with nonprogressive motor and cognitive disturbances consistent with a diagnosis of developmental coordination disorder (DCD). In addition to prototypical DCD, the development of mastication was severely impaired, while no evidence of swallowing apraxia, dysphagia, sensorimotor disturbances, abnormal tone, or impaired general cognition was found. He suffered from bronchopulmonary dysplasia and was ventilated as a newborn for 1.5 months. At the age of 3 months, a ventriculoperitoneal shunt was surgically installed because of obstructive hydrocephalus secondary to perinatal intraventricular bleeding. At the age of 5 years, the patient's attempts to masticate were characterized by rough, effortful, and laborious biting movements confined to the vertical plane. Solid food particles had a tendency to get struck in his mouth and there was constant spillage. As a substitute for mastication, he moved the unground food with his fingers in a lateral direction to the mandibular and maxillary vestibule to externally manipulate and squeeze the food between cheek and teeth with the palm of his hand. Once the food was sufficiently soft, the bolus was correctly transported by the tongue in posterior direction and normal deglutition took place. Repeat magnetic resonance imaging (MRI) during follow-up disclosed mild structural abnormalities as the sequelae of the perinatal intraventricular bleeding, but this could not explain impaired mastication behavior. Quantified Tc-99m-ethylcysteinate dimer single-photon emission computed tomography (Tc-99m-ECD SPECT), however, revealed decreased perfusion in the left cerebellar hemisphere, as well as in both inferior lateral frontal regions, both motor cortices, and the right anterior and lateral temporal areas. Anatomoclinical findings in this patient with DCD not only indicate that the functional integrity of the cerebellocerebral network is crucially important in the planning and execution of skilled actions, but also seem to show for the first time that mastication deficits may be of true apraxic origin. As a result, it is hypothesized that "mastication dyspraxia" may have to be considered as a distinct nosological entity within the group of the developmental dyspraxias following a disruption of the cerebellocerebral network involved in planned actions.

Biochemical markers for blood-brain barrier dysfunction in acute ischemic stroke correlate with evolution and outcome.

BACKGROUND/AIMS: We evaluated the cerebrospinal fluid/serum albumin ratio (AR) and kinetics of matrix metalloproteinase-9 (MMP-9) in blood as markers for blood-brain barrier (BBB) disruption after acute ischemic stroke. METHODS: The AR was determined in 88 patients with acute ischemic stroke or transient ischemic attack. MMP-9 was measured on admission, 24, 72 h and 7 days after stroke onset. RESULTS: The AR was related to stroke severity, the occurrence of stroke progression and the modified Rankin Scale score at month 3. MMP-9 levels on admission were significantly elevated compared to controls and dropped in the first 72 h after stroke, except in patients with stroke progression and larger infarcts in the subacute phase. CONCLUSIONS: We demonstrate that the extent of BBB breakdown in hyperacute stroke relates to initial stroke severity, stroke evolution and long-term outcome. The kinetics of MMP-9 confirm its pivotal role in secondary brain damage after ischemic stroke.

Comparison between the ATS/ERS/JRS/ALAT criteria of 2011 and 2018 for Usual Interstitial Pneumonia on HRCT: a cross-sectional study.

OBJECTIVES: To determine whether the revised 2018 ATS/ERS/JRS/ALAT radiological criteria for usual interstitial pneumonia (UIP) provide better diagnostic agreement compared to the 2011 guidelines. METHODS: Cohort for this cross-sectional study (single center, nonacademic) was recruited from a multidisciplinary team discussion (MDD) from July 2010 until November 2018, with clinical suspicion of fibrosing interstitial lung disease (n= 325). Exclusion criteria were technical HRCT issues, known connective tissue disease (rheumatoid arthritis, systemic sclerosis, poly-or dermatomyositis), exposure to pulmonary toxins or lack of working diagnosis after MDD. Four readers with varying degrees in HRCT interpretation independently categorized 192 HRCTs, according to both the previous and current ATS/ERS/JRS/ALAT radiological criteria. An inter-rater variability analysis (Gwet's second-order agreement coefficient, AC2) was performed. RESULTS: The resulting Gwet's AC2 for the 2011 and 2018 ATS/ERS/JRS/ALAT radiological criteria is 0.62 (±0.05) and 0.65 (±0.05), respectively. We report only minor differences in agreement level among the readers. Distribution according to the 2011 guidelines is as follows: 57.3% 'UIP pattern', 24% 'possible UIP pattern', 18.8% 'inconsistent with UIP pattern' and for the 2018 guidelines: 59.6% 'UIP', 14.5% 'probable UIP', 15.9% 'indeterminate for UIP' and 10% 'alternative diagnosis'. CONCLUSIONS: No statistically significant higher degree of diagnostic agreement is observed when applying the revised 2018 ATS/ERS/JRS/ALAT radiological criteria for UIP compared to those of 2011. The inter-rater variability for categorizing the HRCT patterns is moderate for both classification systems, independent of experience in HRCT interpretation. The major advantage of the current guidelines is the better subdivision in the categories with a lower diagnostic certainty for UIP. ADVANCES IN KNOWLEDGE: - In 2018, a revision of the 2011 ATS/ERS/JRS/ALAT radiological criteria for UIP was published, part of diagnostic guidelines for idiopathic pulmonary fibrosis.- The inter-rater agreement among radiologist is moderate for both classification systems, without a significantly higher degree of agreement when applying the revised radiological criteria.

Neurobiochemical markers of brain damage in cerebrospinal fluid of acute ischemic stroke patients.

BACKGROUND: Ischemic injury to the central nervous system causes cellular activation and disintegration, leading to release of cell-type-specific proteins into the cerebrospinal fluid (CSF). We investigated CSF concentrations of myelin basic protein (MBP), glial fibrillary astrocytic protein (GFAP), the calcium-binding protein S100B, and neuron-specific enolase (NSE) in acute ischemic stroke patients and their relation to initial stroke severity, stroke location, and long-term stroke outcome. METHODS: CSF concentrations of MBP, GFAP, S100B, and NSE were assessed in 89 stroke patients on admission (mean 8.7 h after stroke onset) and in 35 controls. We evaluated the relation between CSF concentrations and (a) stroke severity (NIH Stroke Scale [NIHSS] score on admission, infarct volume), (b) stroke location, and (c) stroke outcome (modified Rankin Scale [mRS] score at month 3). RESULTS: MBP concentration was significantly higher in subcortical than in cortical infarcts (median MBP, 1.18 vs 0.66 microg/L, P < 0.001). GFAP and S100B concentrations correlated with the NIHSS score on admission (GFAP, R = 0.35, P = 0.001; S100B, R = 0.29, P = 0.006), infarct volume (GFAP, R = 0.34, P = 0.001; S100B, R = 0.28, P = 0.008), and mRS score at month 3 (R = 0.42, P < 0.001 and R = 0.28, P = 0.007). Concentrations of NSE did not correlate with stroke characteristics. CONCLUSIONS: MBP, GFAP, S100B, and NSE display relevant differences in cellular and subcellular origins, which are reflected in their relation to stroke characteristics. MBP is a marker for infarct location. GFAP and S100B correlate with stroke severity and outcome.

Developmental coordination disorder: disruption of the cerebello-cerebral network evidenced by SPECT.

Little is known about the neurobiological substrate of developmental coordination disorder (DCD), a neuro-developmental syndrome with significant, negative impact on the motor, cognitive and affective level throughout lifespan. This paper reports the clinical, neurocognitive and neuroradiological findings of a 19-year-old patient with typical DCD. As demonstrated by mild ataxia and a close semiological correspondence with the recently acknowledged 'cerebellar cognitive affective syndrome', clinical and neurocognitive investigations unambiguously indicated functional disruption of the cerebellum. Structural MRI of the brain confirmed cerebellar involvement revealing a slight anterior/superior asymmetry of vermal fissures consistent with rostral vermisdysplasia. Although this abnormality of vermal fissuration is generally considered an incidental neuroradiological finding without any clinical relevance, a potentially subtle impact on the developmental level has never been formally excluded. In addition to a generally decreased perfusion of the cerebellum, a quantified Tc-99m-ECD SPECT disclosed functional suppression of the anatomoclinically suspected supratentorial regions involved in the execution of planned actions, visuo-spatial processing and affective regulation. Based on these findings, it is hypothesised that the cerebellum is crucially implicated in the pathophysiologcial mechanisms of DCD, reflecting disruption of the cerebello-cerebral network involved in the execution of planned actions, visuo-spatial cognition and affective regulation.

The role of tryptophan catabolism along the kynurenine pathway in acute ischemic stroke.

Post-stroke inflammation may induce upregulation of the kynurenine (KYN) pathway for tryptophan (TRP) oxidation, resulting in neuroprotective (kynurenic acid, KA) and neurotoxic metabolites (3-hydroxyanthranillic acid, 3-HAA). We investigated whether activity of the kynurenine pathway in acute ischemic stroke is related to initial stroke severity, long-term stroke outcome and the ischemia-induced inflammatory response. Plasma concentrations of TRP and its metabolites were measured in 149 stroke patients at admission, at 24 h, at 72 h and at day 7 after stroke onset. We evaluated the relation between the KYN/TRP ratio, the KA/3-HAA ratio and stroke severity, outcome and inflammatory parameters (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and neutrophil/lymphocyte ratio (NLR)). KYN/TRP but not KA/3-HAA correlated with the NIHSS score and with the infarct volume. Patients with poor outcome had higher mean KYN/TRP ratios than patients with more favourable outcome. The KYN/TRP ratio at admission correlated with CRP levels, ESR and NLR. The activity of the kynurenine pathway for tryptophan degradation in acute ischemic stroke correlates with stroke severity and long-term stroke outcome. Tryptophan oxidation is related to the stroke-induced inflammatory response.

Decrease in uric acid in acute ischemic stroke correlates with stroke severity, evolution and outcome.

BACKGROUND: Although uric acid (UA) is one of the most important antioxidants in plasma and appears to be neuroprotective in animal models, results from human studies are controversial. In this study, we investigated the kinetics of serum UA concentrations in the acute, subacute and chronic phase of ischemic stroke and its relation with initial stroke severity, stroke evolution in the subacute phase and long-term stroke outcome. METHODS: Serum concentrations of UA were measured in 199 stroke patients at admission (median, 2.8 h after stroke onset), at 24 h, 72 h, day 7, month 1 and month 3 after onset of stroke. We evaluated the relationship between changes in UA concentrations and (a) stroke severity [patients with transient ischemic attack (TIA) vs. stroke patients, National Institutes of Health Stroke Scale (NIHSS) score at admission], (b) stroke evolution (stroke progression, infarct volume at 72 h), and (c) stroke outcome [modified Rankin scale (mRS) score at month 3, mortality]. RESULTS: UA concentrations decreased significantly during the first 7 days after stroke onset before returning to baseline (p < 0.001). Mean plasma UA concentrations decreased from 336.66 +/- 113.01 micromol/L at admission to 300.37 +/- 110.04 micromol/L at day 7 (p < 0.001) in patients with stroke, but did not change significantly in patients with TIA. Changes in UA concentrations from admission to day 7 (DeltaUA(day 7)) correlated with the NIHSS score (rho = 0.32; p < 0.001), stroke progression (rho = 0.29; p = 0.001), infarct volume (rho = 0.37; p < 0.001), mRS score (rho = 0.28; p = 0.001) and mortality (p = 0.010). CONCLUSIONS: Decreases in UA during the first week after onset of stroke correlates with more severe stroke, unfavorable stroke evolution, and poor long-term stroke outcome.

18F-Florbetapir PET in Primary Cerebral Amyloidoma.

Amyloid deposition can lead to Alzheimer disease and cerebral amyloid angiopathy. Rarely, it presents as a solitary focal deposition, primary cerebral amyloidoma, which can be misinterpreted as a neoplasm because of the "tumor-like" appearances. We present the case of a 54-year-old woman where MRI revealed a T2-hyperintense mass periventricular in the white matter with moderate contrast enhancement. Pathological investigation revealed AL (lambda) amyloidoma. F-florbetapir PET/CT was used to support the diagnosis and in follow-up. This case highlights that F-florbetapir PET/CT might play a role in the diagnostic workup of patients suggestive of cerebral amyloidoma, especially in cases where biopsy is not feasible.

Clinical, biochemical and neuroimaging parameters after thrombolytic therapy predict long-term stroke outcome.

INTRODUCTION: We investigated the predictive value of standard neurological evaluation, a commercially available biomarker assay and neuroimaging in the subacute phase for outcome after thrombolytic therapy in ischemic stroke. METHODS: Thirty-four consecutive ischemic stroke patients were evaluated by means of the NIH Stroke Scale (NIHSS(72)), the Triage(R) Stroke Panel (MMX(72)) and standardized infarct volumetry at 72 h after treatment with intravenous recombinant tissue plasminogen activator or intra-arterial urokinase. Outcome was assessed by the modified Rankin Scale (mRS) at 3 months after the stroke. RESULTS: NIHSS(72), MMX(72) and infarct volume correlated significantly with the mRS score at month 3 and emerged as independent outcome predictors from logistic regression analysis. NIHSS(72) is the best predictor for outcome, but its accuracy increases by 9 and 6% when combined with MMX(72) and infarct volumetry, respectively. The combined use of NIHSS(72) and MMX(72) allows long-term outcome prediction with 97% accuracy, which is not further improved by infarct volumetry. CONCLUSIONS: Routine clinical evaluation, bedside testing of biochemical markers by the Triage Stroke Panel and infarct volumetry on neuroimaging at 72 h after thrombolytic therapy are predictors for long-term outcome of ischemic stroke patients. Clinical assessment is the most reliable parameter for outcome prediction, but its predictive value is substantially improved when combined with the biomarker panel.

Evaluation of lactate as a marker of metabolic stress and cause of secondary damage in acute ischemic stroke or TIA.

BACKGROUND: Accumulation of lactate in ischemic regions has been documented in acute stroke. We evaluated the relation between lactate levels in blood and cerebrospinal fluid (CSF) and ischemic stroke evolution and outcome. METHODS: Lactate was measured in blood of 187 acute ischemic stroke and TIA patients at admission, 24 h, 72 h and 7 days after stroke onset. In a subpopulation of 85 stroke patients and in 51 controls, lactate was measured in CSF. Stroke evolution was evaluated by change in the NIHSS score within the first 72 h and by occurrence of progressing stroke. At 3 months after stroke, outcome was assessed on the basis of mortality rate and the modified Rankin Scale. RESULTS: We found no relation between lactate levels in blood and stroke evolution or outcome. Lactate in CSF was higher in stroke patients than in controls and correlated with stroke evolution and outcome. Multivariate regression analyses showed that CSF lactate levels, age and stroke severity are independent predictors for stroke evolution and outcome. CONCLUSIONS: Lactate levels in CSF, but not in blood, are a reliable marker for metabolic crisis in acute ischemic stroke and correlate with the stroke evolution in the subacute phase and with long-term outcome.

Predominant dendriform pulmonary ossification in a usual interstitial pneumonia-like distribution: to be distinguished from idiopathic pulmonary fibrosis.

Idiopathic dendriform diffuse pulmonary ossification (DPO) is a rare disorder. High resolution CT (HRCT) with appropriate osteoporosis window setting reveals the diagnosis. We report the features of eight patients, of whom two brothers, with HRCT findings compatible with predominant DPO in a bibasal subpleural distribution (usual interstitial pneumonia (UIP)-like distribution) and review the literature for DPO in this UIP-like distribution. DPO in a UIP-like distribution seems to be a disorder of the very old (age 75-87 (mean 83.6) male (8 out of 8), with familial occurrence, with associated cardiovascular disease and frequent use of anticoagulants as common findings, and with a slowly progressive nature and the absence of radiological honeycombing despite long lasting disease contrasting with idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis (IPF) should be differentiated from predominant DPO in a UIP-like distibution. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 251-256).

Atypical cerebral language dominance in a right-handed patient: An anatomoclinical study.

OBJECTIVE: Approximately 97% of the right-handers has left hemisphere language dominance. Within the language dominant hemisphere Broca's area is of crucial importance for a variety of linguistic functions. As a result, tumour resection in and around Broca's area is controversial. However, studies showed that by means of Direct Electrical Stimulation (DES) tumour resection in this region can be safely performed. We report unexpected anatomoclinical findings in a right-handed patient who underwent tumour resection in the left prefrontal lobe. METHODS: Language functions in this right-handed patient were extensively examined in the pre-, intra-, and postoperative phase by means of a standardised battery of neurolinguistic and neurocognitive tests. Results obtained in the pre- and postoperative phase are compared. In addition, intraoperative DES findings and postoperative functional Magnetic Resonance Imaging (fMRI) and Diffusion Tensor Imaging (DTI) results are reported. RESULTS: Tumour resection near Broca's area was safely performed since no positive language sites were found during intraoperative DES. Since no linguistic deficits occurred in the pre-, intra-, or postoperative phase, atypical language dominance was suspected. Neuropsychological investigations, however, disclosed permanent executive dysfunction. Postoperative fMRI and DTI confirmed right cerebral language dominance as well as a crossed cerebro-cerebellar functional link with the left cerebellar hemisphere. DISCUSSION: Atypical right hemisphere language dominance in this right-handed patient is reflected by: (1) the total absence of language problems in the pre-, intra- and postoperative phase, (2) absence of positive stimulation sites during DES, (3) a clearly more pronounced arcuate fasciculus in the right cerebral hemisphere (DTI), (4) a crossed functional connection between the right cerebrum and the left cerebellum (fMRI). Two hypothetical explanations for the pattern of crossed cerebral language dominance are put forward: (1) preoperative brain plasticity mechanisms inducing a shift of language functions to the right hemisphere or (2) right hemisphere language dominance as a maturational variant. This case with atypical cerebral language dominance shows that although DES is the 'gold standard' to identify eloquent language regions and their pathways, fMRI and DTI are important adjuncts to guide surgery, to identify language lateralisation and to study anatomoclinical correlations.

Excitatory amino acids and monoaminergic neurotransmitters in cerebrospinal fluid of acute ischemic stroke patients.

BACKGROUND AND PURPOSE: Improved insight in the role of neurotransmitters in acute cerebral ischemic injury may be fundamental for the successful development of novel therapeutic approaches. We investigated excitatory amino acids and monoaminergic neurotransmitters in cerebrospinal fluid (CSF) of acute ischemic stroke patients and their relation to stroke characteristics. METHODS: CSF concentrations of glutamate, aspartate, glutamine, glycine, proline, taurine, norepinephrine, 5-hydroxyindoleacetic acid, homovanillic acid and 3,4-dihydroxyphenylacetic acid were assessed in 89 stroke patients at admission (median 6.3h after stroke onset) and in 31 controls. We evaluated the relation between CSF concentrations and (a) stroke severity (NIHSS score at admission, lesion volume), (b) stroke evolution in the subacute phase, (c) long-term stroke outcome, (d) lesion location, and (e) stroke etiology. RESULTS: Neurotransmitter systems display relevant interrelations, however, no significant associations between neurotransmitter concentrations in CSF and stroke characteristics were found, with the exception of higher 5-hydroxyindoleacetic acid levels in CSF of patients with progressing stroke and poor long-term outcome. CONCLUSIONS: The study results question the added value of neurotransmitter assessment in CSF for research on ischemic cerebral injury.

Additional value of quantitative EEG in acute anterior circulation syndrome of presumed ischemic origin.

OBJECTIVE: The clinical course of acute stroke can be highly variable and for effective management outcome prediction needs to be refined. We investigated whether EEG parameters are of additional diagnostic and prognostic value in the early phase of acute ischemic anterior circulation stroke. METHODS: Ninety-four patients presenting with acute anterior circulation syndrome (ACS) of presumed ischemic origin were incrementally included. Clinical characteristics were correlated with volume of ischemia and EEG parameters. Predictive values for definite stroke, early neurological deterioration, spontaneous early neurological improvement and death within 1 week after ACS were calculated using ROC curves and logistic regression modelling. RESULTS: In patients with normal or near normal NIHSS score of 0 or 1, the pairwise derived brain symmetry index (pdBSI) was an independent predictor for definite stroke displaying an overall accuracy of 80%. Early neurological deterioration was independently predicted by pdBSI with a correct classification rate of 95%. In ROC analysis, death was predicted by pdBSI with overall accuracy of 97%. Spontaneous neurological improvement was independently predicted by the delta+theta/alpha+beta - ratio with overall accuracy of 75%. Small-vessel stroke was independently predicted by pdBSI with a correct classification rate of 92%. CONCLUSIONS: EEG may be of prognostic value for spontaneous neurological improvement, early neurological deterioration and death in the acute setting of acute anterior circulation syndrome of presumed ischemic origin. SIGNIFICANCE: These findings may have an impact on stroke care.

Clinical and biochemical diagnosis of small-vessel disease in acute ischemic stroke.

BACKGROUND AND PURPOSE: Both from clinical and research standpoints, it may be highly relevant to differentiate between small-artery and large-artery infarction in the acute phase of ischemic stroke. We conducted a study on the added value of two D-dimer assays over clinical assessment for diagnosis of lacunar infarction. METHODS: Clinical evaluation using the Oxfordshire Community Stroke Project (OCSP) classification and measurement of plasma D-dimer levels by the VIDAS D-dimer test (VIDAS) and the Triage Stroke Panel (TSP) were performed in 128 patients with ischemic stroke presenting within 9 h after onset of symptoms. The stroke subtype was defined as small-artery or large-artery infarction based on the TOAST classification. RESULTS: The overall accuracy for diagnosing of acute lacunar stroke using the OCSP classification, VIDAS (cut point for D-dimer 445 ng/mL) or TSP (cut point 300 ng/mL) was 89%, 88% and 87% respectively (P<0.001). The conjunctive use of the OCSP classification and VIDAS or TSP improved the accuracy to 97% and 98% respectively (P<0.001). The kappa coefficient for agreement between the two assays was acceptable (kappa, 0.64). These results were reproducible in subgroups of patients presenting within 4.5 h and within 6 h after onset of stroke symptoms. CONCLUSIONS: Diagnosis of acute lacunar infarction can reliably be made, based on the conjunctive use of clinical evaluation and measurement of D-dimer levels either by a standard assay or by a bedside testing kit.

Carboxypeptidase U (TAFIa) decreases the efficacy of thrombolytic therapy in ischemic stroke patients.

INTRODUCTION: Thrombolytic therapy improves clinical outcome in patients with acute ischemic stroke but is compromised by symptomatic intracranial hemorrhage and an unpredictable therapeutic response. In vitro and in vivo data suggest that activation of procarboxypeptidase U (proCPU) inhibits fibrinolysis. AIMS: To investigate whether the extent of proCPU activation is related to efficacy and safety of thrombolytic therapy in ischemic stroke patients. METHODS: In twelve patients with ischemic stroke who were treated with intravenous (n=7) or intra-arterial (n=5) thrombolysis, venous blood samples were taken at different time points before, during and after thrombolytic therapy. ProCPU and carboxypeptidase U (CPU, TAFIa) plasma concentrations were determined by HPLC. The maximal CPU activity (CPU(max)) and the percentage of proCPU consumption during thrombolytic therapy were calculated. The efficacy and safety of the thrombolytic therapy were assessed by evolution of the clinical deficit, recanalisation, final infarct volume, thrombolysis-induced intracranial hemorrhage and mortality. RESULTS: No correlations between CPU(max) or proCPU consumption and patient or stroke characteristics were found. However, CPU(max) is associated with evolution of the clinical deficit and achieved recanalisation. ProCPU consumption is related to the risk of intracranial hemorrhage, mortality and final infarct volume. CONCLUSIONS: Irrespective of patient and stroke characteristics, CPU(max) and proCPU consumption during thrombolytic treatment for ischemic stroke are parameters for therapeutic efficacy and safety. Further evaluation of the clinical applicability of these parameters and further investigation of the potential role for CPU inhibitors as adjunctive therapeutics during thrombolytic treatment may be of value.