[Show abstract][Hide abstract] ABSTRACT: In recent years, there was a surge in interest for biomarkers in ischemic stroke, with several purposes. In this chapter we will focus on biomarkers with potential use in ischemic stroke, namely, in diagnosis, grading of severity, identification of subtypes, and prediction of outcome or recurrence. A special emphasis will be placed on the role of inflammation in stroke, as it plays a key role in the cascade of events leading to progression of ischemic brain injury. However, the role of biomarkers in the clinical management of ischemic stroke is still limited. Therapeutic trials attempting to intervene on the inflammatory process are also briefly mentioned.
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
The efficacy of cerebrospinal fluid shunting to reduce intracranial hypertension and prevent fatal brain herniation in acute cerebral venous thrombosis (CVT) is unknown.
From the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) and a systematic literature review, we retrieved acute CVT patients treated only with shunting (external ventricular drain, ventriculoperitoneal or ventriculojugular shunt). Outcome was classified at 6 months and final follow-up by the modified Rankin Scale (mRS).
15 patients were collected (9 from the ISCVT and 6 from the review) who were treated with a shunt (external ventricular drain in 6 patients, a ventriculoperitoneal shunt in 8 patients or an unspecified type of shunt in another one). Eight patients (53.3%) regained independence (mRS 0-2), while 2 patients (13.3%) were left with a severe handicap (mRS 4-6) and 4 (26.7%) died despite treatment. Five patients with parenchymal lesions were shunted within 48 h from admission deterioration, 4 with an external ventricular drain: 2 (40%) recovered to independence, 2 (40%) had a severe handicap and 1 (20%) died. In contrast, all 3 patients with intracranial hypertension and no parenchymal lesions receiving a ventriculoperitoneal shunt later than 48 h regained independence.
Conclusion and implications:
A quarter of acute CVT patients treated with a shunt died, and only half regained independence. With the limitation of the small number of subjects, this review suggests that shunting does not appear to be effective in preventing death from brain herniation in acute CVT. We cannot exclude that shunting may benefit patients with sustained intracranial hypertension and no parenchymal lesions.
[Show abstract][Hide abstract] ABSTRACT: Background and purpose:
Lumbar puncture (LP) may precipitate cerebral venous thrombosis (CVT), but it is unclear if LP is deleterious in patients with CVT. We aimed to assess the safety of LP in the International Study on Cerebral Veins and Dural Sinus Thrombosis prospective cohort.
In 624 patients with CVT, we compared the prognosis of patients submitted or not to LP. The primary outcome was 'death or dependency at 6 months', as evaluated by the modified Rankin Scale (mRS; mRS = 3-6, with adjustment for variables associated with poor prognosis); secondary outcomes were: 'worsening after admission'; 'acute death'; and 'complete recovery at 6 months' (mRS = 0-1). We analyzed the same outcomes in subgroups of patients with brain lesions on the admission computer tomography/magnetic resonance imaging.
LP was performed in 224 patients (35.9%). There was no difference in frequency of 'death or dependency at 6 months' between patients with or without LP [13.4% vs. 14.4%; odds ratio (OR) = 0.9, 95% confidence interval (CI) 0.6-1.5; P = 0.739]. LP was not associated with 'worsening after hospitalization' [21.5% vs. 23.5%; OR = 0.9, 95% CI 0.6-1.3; P = 0.577], 'acute death' [3.6% vs. 3.3%; OR = 1.1, 95% CI 0.5-2.7; P = 0.844] or 'complete recovery' [79.9% vs. 76.6%; OR = 1.2, 95% CI 0.8-1.7; P = 0.484]. In the subgroups of patients with brain lesions, the prognoses were not different between patients submitted or not to LP.
LP was not associated with the functional outcome of patients with CVT, suggesting that LP was not harmful in these patients. These results should not be generalized to patients with large brain lesions and risk of herniation where LP is contraindicated.
European Journal of Neurology 03/2013; 20(7). DOI:10.1111/ene.12136 · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Studies suggest that N-terminal-pro-brain natriuretic peptide (NT-proBNP) can be a biomarker of cardioembolic stroke. However, the best time to measure it after stroke is unknown. We studied the time course of NT-proBNP in patients with ischemic stroke.
Consecutive acute ischemic stroke patients were admitted over 10 months to a Stroke Unit. Stroke type was classified according to TOAST. Blood samples were drawn within 24, 48, and 72 hours after stroke. Friedman test was used to compare NT-proBNP values across the 3 times in all, cardioembolic and non-cardioembolic stroke patients. Post hoc analysis with Wilcoxon signed-rank tests was conducted with a Bonferroni correction. Mann-Whitney test was used to compare median values of NT-proBNP between cardioembolic and non-cardioembolic stroke patients. ROC curves were drawn to determine NT-proBNP accuracy to diagnose cardioembolic stroke at 24, 48, and 72 hours after stroke onset.
One hundred and one patients were included (29 cardioembolic) with a mean age of 64.5±12.3 years. NT-proBNP values for cardioembolic stroke were significantly higher (P < 0.001) than for non-cardioembolic stroke in the 3 time points. NT-proBNP was highest in the first 24-48 h after ischemic stroke and decreased significantly 72 h after stroke onset. The area under the curve for the three time points was similar.
NT-proBNP levels were highest in the first 2 days after ischemic stroke and declined significantly thereafter. However, the area under the curve for the three time points was similar. The first 72 hours after ischemic stroke have a similar diagnostic accuracy to diagnose cardioembolic stroke.
[Show abstract][Hide abstract] ABSTRACT: To examine the independent contributions and combined interactions of medial temporal lobe atrophy (MTA), cortical and subcortical atrophy, and white matter lesion (WML) volume in longitudinal cognitive performance.
A total of 477 subjects with age-related WML were evaluated with brain MRI and annual neuropsychological examinations in 3-year follow-up. Baseline MRI determinants of cognitive decline were analyzed with linear mixed models controlling for multiple confounders.
MTA and subcortical atrophy predicted significantly steeper rate of decline in global cognitive measures as well as compound scores for psychomotor speed, executive functions, and memory after adjusting for age, gender, education, lacunes/infarcts, and WML volume. Cortical atrophy independently predicted decline in psychomotor speed. WML volume remained significantly associated with cognitive decline even after controlling for the atrophy scores. Moreover, significant synergistic interactions were found between WML and atrophy measures in overall cognitive performance across time and the rate of cognitive decline. Synergistic effects were also observed between baseline lacunar infarcts and all atrophy measures on change in psychomotor speed. The main results remained robust after exclusion of subjects with clinical stroke or incident dementia, and after additional adjustments for progression of WML and lacunes.
Brain atrophy and WML are independently related to longitudinal cognitive decline in small vessel disease. MTA, subcortical, and cortical atrophy seem to potentiate the effect of WML and lacunes on cognitive decline.
[Show abstract][Hide abstract] ABSTRACT: Quantitative measurement of circulating D-dimer, a product of fibrin degradation, has been shown to be a very useful diagnostic tool in the management of patients with suspected deep vein thrombosis and/or pulmonary embolism. Whether D-dimer can play a similar role in the diagnostic approach to patients with suspected cerebral vein thrombosis (CVT) remains controversial.
Studies evaluating the diagnostic accuracy of the D-dimer test in the diagnosis of CVT were systematically searched for in the MEDLINE and EMBASE databases (up to July 2011). Weighted mean sensitivity and specificity with 95% confidence intervals (CIs) were calculated with a bivariate random-effects regression approach.
Fourteen studies, for a total of 1134 patients, were included. D-dimer accuracy was good, with a resulting weighted mean sensitivity of 93.9% (95% CI 87.5-97.1) and weighted mean specificity of 89.7% (95% CI 86.5-92.2), calculated with a bivariate approach. Potential risk factors for false-negative D-dimer results included isolated headache, longer duration of symptoms, and limited sinus involvement. ConclusIONS: Our findings suggest that D-dimer may be a useful diagnostic tool in the management of patients with suspected CVT. Future prospective studies are warranted to confirm our preliminary findings.
Journal of Thrombosis and Haemostasis 01/2012; 10(4):582-9. DOI:10.1111/j.1538-7836.2012.04637.x · 5.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Growth factors are thought to modulate neurological function in stroke recovery through effects in angiogenesis, neurogenesis, and neuroprotection.
We tested the association of variants in the brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) genes, and epistatic interactions between them, with functional outcome in a sample of 546 stroke patients.
While none of the tested genes was independently associated with stroke outcome, two significant gene-gene interaction models were identified. One model combined one BDNF and three FGF2 markers, with a global odds ratio (OR) (95% confidence interval [CI]) of 4.15 [2.86-6.04]. The second model included one FGF2 and two VEGFA markers with a global OR [95% CI] = 2.54 [1.76-3.67].
The results provide evidence for gene interactions in stroke outcome, highlighting the complexity of the recovery mechanisms after a stroke event.
European Journal of Neurology 01/2012; 19(8):1151-3. DOI:10.1111/j.1468-1331.2011.03625.x · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Apathy is a frequent disturbance in stroke patients. The aim of this case-control study was to elucidate whether apathy: (i) was secondary to stroke or related to hospitalization, (ii) was related to thalamic and striatocapsular stroke lesions, (iii) was independent from cognitive impairment and depression in the acute phase of stroke, (iv) was associated with clinical and demographical variables and (v) was associated with a worse functional outcome at discharge.
We assessed a sample of 94 consecutive patients with an acute (≤4 days) stroke (22 intracerebral haemorrhages, 72 cerebral infarcts), and a control group of 50 patients with acute coronary syndrome, with the 10-item Apathy Evaluation Scale-Clinical. We related apathy with cognition (MMSE), depression (Montgomery Åsberg Depression Rating Scale) and with outcome (modified Rankin Scale).
Apathy was present in 36 (38.3%) acute stroke patients but was also frequent in patients with acute coronary syndrome (24%). Stroke patients were more inaccurate in understanding their problems than patients with acute coronary syndrome (P=0.005). Logistic regression identified cerebral haemorrhage (OR=3.5), low educational level (OR=4.7) and a trend of right hemispherical lesion (OR=3.0) as independent predictors for apathy (R(2)=32.3%). Cognitive impairment and depression were not associated to apathy. Apathy was associated with a worse outcome (P=0.03).
Apathy was frequent in acute stroke patients, and it was predicted by acute intracerebral haemorrhage and right hemispherical acute stroke lesion.
European Journal of Neurology 09/2011; 19(2):291-7. DOI:10.1111/j.1468-1331.2011.03508.x · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In cerebral small vessel disease, the core MRI findings include white matter lesions (WML) and lacunar infarcts. While the clinical significance of WML is better understood, the contribution of lacunes to the rate of cognitive decline has not been established. This study investigated whether incident lacunes on MRI determine longitudinal cognitive change in elderly subjects with WML.
Within the Leukoaraiosis and Disability Study (LADIS), 387 subjects were evaluated with repeated MRI and neuropsychological assessment at baseline and after 3 years. Predictors of change in global cognitive function and specific cognitive domains over time were analyzed with multivariate linear regression.
After controlling for demographic factors, baseline cognitive performance, baseline lacunar and WML lesion load, and WML progression, the number of new lacunes was related to subtle decrease in compound scores for executive functions (p = 0.021) and speed and motor control (p = 0.045), but not for memory or global cognitive function. Irrespective of lacunes, WML progression was associated with decrease in executive functions score (p = 0.016).
Incident lacunes on MRI parallel a steeper rate of decline in executive functions and psychomotor speed. Accordingly, in addition to WML, lacunes determine longitudinal cognitive impairment in small vessel disease. Although the individual contribution of lacunes on cognition was modest, they cannot be considered benign findings, but indicate a risk of progressive cognitive impairment.
[Show abstract][Hide abstract] ABSTRACT: The aim of this 3-year follow-up study was to investigate whether corpus callosum (CC) atrophy may predict future motor and cognitive impairment in an elderly population. On baseline MRI from 563 subjects with age-related white matter changes (ARWMC) from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented and subdivided into five anterior-posterior regions (CC1-CC5). Associations between the CC areas and decline in motor performance and cognitive functions over a 3-year period were analyzed. CC atrophy at baseline was significantly associated with impaired cognitive performance (p<0.01 for CC1, p<0.05 for CC5), motor function (p<0.05 for CC2 and CC5), and walking speed (p<0.01 for CC2 and CC5, p<0.05 for CC3 and total CC), and with development of dementia at 3 years (p<0.05 for CC1) after correction for appropriate confounders (ARWMC volume, atrophy, age, gender and handedness). In conclusion, CC atrophy, an indicator of reduced functional connectivity between cortical areas, seems to contribute, independently of ARWMC load, to future cognitive and motor decline in the elderly.
Journal of the neurological sciences 05/2011; 307(1-2):100-5. DOI:10.1016/j.jns.2011.05.002 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Behçet's disease (BD) is a chronic inflammatory multisystem disorder which can involve the central nervous system (CNS). Cerebral venous thrombosis (CVT) is one of its major neurological manifestations. We aimed to review the epidemiologic and clinical features of CVT in patients with BD, as well as the available data on therapeutic interventions and prognosis. Systematic review of all observational studies of BD patients was done. Search strategy included electronic searches of MEDLINE (1966-August 2009). Occurrence of CVT in BD and Neuro-Behçet patients, occurrence of CVT as the inaugural manifestation of BD, clinical and neuro-imaging characteristics of CVT, prothrombotic evaluation, treatment options and prognosis were extracted. A meta-analysis of available results was performed when feasible. Twenty-three studies were included, with 290 cases of CVT in patients with BD. The incidence of CVT per 1,000 person-years was 3 (95% CI: 1-8), being higher in retrospective studies (3.2, 95% CI: 1-10) than in prospective studies (2.7, 95% CI: 1-13). Among patients with neurologic involvement, the incidence rate was 15.1/1,000 person-years. The onset was progressive in 77% of the patients. Intracranial hypertension syndrome was a frequent presentation of CVT in BD. The most frequent sites of occlusion were the superior sagittal and the transverse sinus. Most of the studies did not evaluate the prevalence of prothrombotic disorders. Treated CVT was associated with a good prognosis. CVT is a frequent neurological manifestation of BD. When treated, BD-associated CVT bears a good prognosis. There is insufficient information regarding the role of concomitant prothrombotic disorders and specific treatments.
Journal of Neurology 05/2011; 258(5):719-27. DOI:10.1007/s00415-010-5885-9 · 3.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute and unexpected neuropsychiatric disturbances can herald subarachnoid haemorrhage (SAH). We investigated the risk factors for neuropsychiatric disturbances in acute SAH and analysed the relation between neuropsychiatric disturbances and location and amount of haematic densities and hydrocephalus.
We assessed a sample of 108 consecutive patients with an acute (≤ 4 days) SAH (61 aneurysmal, 47 non-aneurysmal SAH), before aneurysmal treatment, using DSM-IV-TR criteria and the Montgomery Åsberg Depression Rating Scale and Mania Rating Scale, the Denial of Illness Scale, the Catastrophic Reaction Scale and the Apathy Evaluation Scale, excluding patients with severe consciousness or language disturbance. Performance on each scale was related to (i) the total amount of haematic densities in 10 basal cisterns/fissures and in the four ventricles, using the Hijdra et al. rating scale, (ii) the haematic densities in the prepontine cistern and the convexity of the brain and (iii) hydrocephalus.
Depression (45%), apathy (42%), denial (21%) and catastrophic reaction (17%) were frequent in acute SAH patients. Mania was present in two patients. Denial was associated with higher haematic densities in the left and right basal sylvian fissure and in the 4th ventricle (P < 0.01) and with hydrocephalus (P = 0.05). Catastrophic reaction and depression were associated with previous mood disorder (P < 0.007). Apathy was associated with blood in the left or right lateral ventricles (P < 0.03).
In the first 4 days of SAH, depression, apathy, catastrophic reaction and denial were rather frequent. SAH haematic densities were associated with denial and apathy, but not with depression, mania or catastrophic reaction.
European Journal of Neurology 12/2010; 18(6):857-64. DOI:10.1111/j.1468-1331.2010.03271.x · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cerebral venous and sinus thrombosis (CVST) is a rather rare disease which accounts for <1% of all strokes. Diagnosis is still frequently overlooked or delayed as a result of the wide spectrum of clinical symptoms and the often subacute or lingering onset. Current therapeutic measures which are used in clinical practice include the use of anticoagulants such as dose-adjusted intravenous heparin or body weight-adjusted subcutaneous low-molecular-weight heparin (LMWH), the use of thrombolysis and symptomatic therapy including control of seizures and elevated intracranial pressure.
We searched MEDLINE (National Library of Medicine), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Library to review the strength of evidence to support these interventions and the preparation of recommendations on the therapy of CVST based on the best available evidence. Review articles and book chapters were also included. Recommendations were reached by consensus. Where there was a lack of evidence but consensus was clear we stated our opinion as good practice points.
Patients with CVST without contraindications for anticoagulation (AC) should be treated either with body weight-adjusted subcutaneous LMWH or with dose-adjusted intravenous heparin (level B recommendation). Concomitant intracranial haemorrhage (ICH) related to CVST is not a contraindication for heparin therapy. The optimal duration of oral anticoagulant therapy after the acute phase is unclear. Oral AC may be given for 3 months if CVST was secondary to a transient risk factor, for 6-12 months in patients with idiopathic CVST and in those with "mild" thrombophilia, such as heterozygous factor V Leiden or prothrombin G20210A mutation and high plasma levels of factor VIII. Indefinite AC should be considered in patients with recurrent episodes of CVST and in those with one episode of CVST and 'severe' thrombophilia, such as antithrombin, protein C or protein S deficiency, homozygous factor V Leiden or prothrombin G20210A mutation, antiphospholipid antibodies and combined abnormalities (good practice point). There is insufficient evidence to support the use of either systemic or local thrombolysis in patients with CVST. If patients deteriorate despite adequate AC and other causes of deterioration have been ruled out, thrombolysis may be a therapeutic option in selected cases, possibly in those without large ICH and threatening herniation (good practice point). There are no controlled data about the risks and benefits of certain therapeutic measures to reduce an elevated intracranial pressure (with brain displacement) in patients with severe CVST. However, in severe cases with impending herniation craniectomy can be used as a life-saving intervention (good practice point).
European Journal of Neurology 10/2010; 17(10):1229-35. DOI:10.1111/j.1468-1331.2010.03011.x · 4.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We aimed to study if age-related white matter changes (WMC) and vascular risk factors were predictors of cognitive decline in elderly subjects with WMC living independently.
The Leukoaraiosis and Disability prospective multinational European study (LADIS) evaluates the impact of WMC on the transition of independent elderly subjects into disability. Independent elderly were enrolled due to the presence of WMC. Subjects were evaluated yearly during 3 years with a comprehensive clinical protocol and a neuropsychological battery. Additionally, dementia, subtypes of dementia, and cognitive decline without dementia were classified according to usual clinical criteria. MRI was performed at entry and at the end of the study.
A total of 639 subjects were included (74.1 +/- 5 years, 55% women, 9.6 +/- 3.8 years of schooling). At end of follow-up, 90 patients had dementia and 147 had cognitive impairment no dementia. Using Cox regression analysis, WMC severity independently predicted cognitive decline (dementia and not dementia), independently of age, education, and medial temporal atrophy (MTA). Diabetes at baseline was the only vascular risk factor that independently predicted cognitive decline during follow-up, controlling for age, education, WMC severity, and temporal atrophy. Considering subtypes of dementia, Alzheimer disease (AD) was predicted only by MTA, while vascular dementia was predicted by previous stroke, WMC severity, and MTA.
WMC severity and diabetes are independent predictors of cognitive decline in an initially nondisabled elderly population. Vascular dementia is predicted by previous stroke and WMC, while AD is predicted only by MTA.