Clinical and neuroanatomical predictors of post-stroke fatigue.

INTRODUCTION: Post-stroke fatigue (PSF) has been described as early exhaustion with tiredness that develops during physical or mental activity and generally does not improve with rest. There are inconsistent findings on the relationship between the characteristics of the ischemic brain lesion and PSF. However, some studies suggest that specific neuroanatomical and neuroplastic changes could explain post-stroke fatigue. The aim was to evaluate the severity of PSF in relation to the location and the size of the ischemic lesion in acute stroke patients to establish possible predictors of PSF. PATIENTS AND METHODS: We performed a prospective observational study to establish potential early predictors of long-term PSF, which was assessed using the Fatigue Assessment Scale six months after ischemic stroke. After segmenting brain infarcts on Diffusion-Weighted Imaging (DWI) images, we studied the association with PSF using Voxel-Based Lesion-Symptom Mapping (VLSM). RESULTS: Out of 104 patients, 61 (59 %) reported PSF. Female sex and history of diabetes mellitus were associated with a greater risk of developing PSF. The association of PSF with female sex was confirmed in a replication cohort of 50 patients. The ischemic lesion volume was not associated with PSF, and VBLSM analysis did not identify any specific brain area significantly associated with PSF. CONCLUSIONS: PSF is frequent in stroke patients, especially women, even after six months. The absence of neuroanatomical correlates of PSF suggests that it is a multifactorial process with biological, psychological, and social risk factors that require further study.

Optimizing the Definition of Ischemic Core in CT Perfusion: Influence of Infarct Growth and Tissue-Specific Thresholds.

BACKGROUND AND PURPOSE: CTP allows estimating ischemic core in patients with acute stroke. However, these estimations have limited accuracy compared with MR imaging. We studied the effect of applying WM- and GM-specific thresholds and analyzed the infarct growth from baseline imaging to reperfusion. MATERIALS AND METHODS: This was a single-center cohort of consecutive patients (n = 113) with witnessed strokes due to proximal carotid territory occlusions with baseline CT perfusion, complete reperfusion, and follow-up DWI. We segmented GM and WM, coregistered CTP with DWI, and compared the accuracy of the different predictions for each voxel on DWI through receiver operating characteristic analysis. We assessed the yield of different relative CBF thresholds to predict the final infarct volume and an estimated infarct growth-corrected volume (subtracting the infarct growth from baseline imaging to complete reperfusion) for a single relative CBF threshold and GM- and WM-specific thresholds. RESULTS: The fixed threshold underestimated lesions in GM and overestimated them in WM. Double GM- and WM-specific thresholds of relative CBF were superior to fixed thresholds in predicting infarcted voxels. The closest estimations of the infarct on DWI were based on a relative CBF of 25% for a single threshold, 35% for GM, and 20% for WM, and they decreased when correcting for infarct growth: 20% for a single threshold, 25% for GM, and 15% for WM. The combination of 25% for GM and 15% for WM yielded the best prediction. CONCLUSIONS: GM- and WM-specific thresholds result in different estimations of ischemic core in CTP and increase the global accuracy. More restrictive thresholds better estimate the actual extent of the infarcted tissue.

Leukoaraiosis May Confound the Interpretation of CT Perfusion in Patients Treated with Mechanical Thrombectomy for Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Leukoaraiosis frequently coexists in patients with acute stroke. We studied whether leukoaraiosis could confound the interpretation of CTP findings in patients treated with mechanical thrombectomy. MATERIALS AND METHODS: We analyzed 236 patients with stroke treated with mechanical thrombectomy and studied with CTP, of whom 127 (53.8%) achieved complete reperfusion. Periventricular white matter hyperintensities on MR imaging and hypodensities on NCCT were assessed through the Fazekas score. CTP-predicted nonviable tissue was defined as relative CBF <30%, and final infarct volume was quantified in DWI. We estimated mean MTT, CBV, and CBF in the asymptomatic hemisphere. In patients achieving complete reperfusion, we assessed the accuracy of nonviable tissue to predict final infarct volume using the intraclass correlation coefficient across periventricular hyperintensity/hypodensity Fazekas scores and variable relative CBF cutoffs. RESULTS: MTT was longer (Spearman ρ = 0.279, P < .001) and CBF was lower (ρ = -0.263, P < .001) as the periventricular hyperintensity Fazekas score increased, while CBV was similar across groups (ρ = -0.043, P = .513). In the subgroup of patients achieving complete reperfusion, nonviable tissue-final infarct volume reliability was excellent in patients with periventricular hyperintensity Fazekas score grade 0 (intraclass correlation coefficient, 0.900; 95% CI, 0.805-0.950), fair in patients with periventricular hyperintensity Fazekas scores 1 (intraclass correlation coefficient, 0.569; 95% CI, 0.327-0.741) and 2 (intraclass correlation coefficient, 0.444; 95% CI, 0.165-0.657), and poor in patients with periventricular hyperintensity Fazekas score 3 (intraclass correlation coefficient, 0.310; 95% CI, -0.359-0.769). The most accurate cutoffs were relative CBF <30% for periventricular hyperintensity Fazekas score grades 0 and 1, relative CBF <25% for periventricular hyperintensity Fazekas score 2, and relative CBF <20% for periventricular hyperintensity Fazekas score 3. The reliability analysis according to periventricular hypodensity Fazekas score grades on NCCT was similar to that in follow-up MR imaging. CONCLUSIONS: In patients with stroke, the presence of leukoaraiosis confounds the interpretation of CTP despite proper adjustment of CBF thresholds.

Frequency and outcome of total anterior circulation strokes without intracranial large-vessel occlusion.

BACKGROUND AND PURPOSE: The percentage of patients with clinical total anterior circulation infarct (TACI) syndrome treated with reperfusion therapies in the absence of intracranial large-vessel occlusion (ILVO) was determined and their characteristics and outcome are described. METHODS: Data from a population-based, prospective, externally audited registry of all stroke patients treated with intravenous thrombolysis (IVT) and endovascular therapies in Catalonia from January 2011 to December 2013 were used. Patients with a baseline TACI and initial stroke severity measured by the National Institute of Health Stroke Scale (NIHSS) ≥ 8, evaluated less than 4.5 h post-onset, for whom a vascular study prior to treatment was available (n = 1070) were selected. Clinical characteristics, outcome and radiological data for patients treated with IVT alone (n = 605) were compared between those with detected ILVO (n = 474) and non-ILVO patients (n = 131). RESULTS: A total of 1070 patients met study criteria; non-ILVO was found in 131 (12.2%). Analysing the 605 patients treated only with IVT, no significant differences were found between non-ILVO and ILVO patients in age, sex, risk factors, time-to-treatment and type of radiological studies performed. Although non-ILVO patients had lower initial stroke severity (P < 0.001) and a better prognosis (P = 0.001), 51.3% had a poor outcome and 16% were deceased at 90 days. In 66.4% of patients without ILVO, a recent anterior territorial infarct was detected. CONCLUSIONS: Intracranial artery patency was observed in 12.2% of TACI patients evaluated within 4.5 h. Although absence of ILVO was associated with slightly better prognosis, more than half had a poor outcome at 3 months.

Perfusion Deficits and Mismatch in Patients with Acute Lacunar Infarcts Studied with Whole-Brain CT Perfusion.

BACKGROUND AND PURPOSE: The incidence and significance of perfusion abnormalities on brain imaging in patients with lacunar infarct are controversial. We studied the diagnostic yield of CTP and the type of perfusion abnormalities in patients presenting with a lacunar syndrome and in those with MR imaging-confirmed lacunar infarcts. MATERIALS AND METHODS: A cohort of 33 patients with lacunar syndrome underwent whole-brain CTP on admission. Twenty-eight patients had an acute ischemic lesion at follow-up MR imaging; 16 were classified as lacunar infarcts. Two independent readers evaluated NCCT and CTP to compare their diagnostic yield. In patients with DWI-confirmed lacunar infarcts and visible deficits on CTP, the presence of mismatch tissue was measured by using different perfusion thresholds. RESULTS: The symptomatic acute lesion was seen on CTP in 50% of patients presenting with a lacunar syndrome compared with only 17% on NCCT, and in 62% on CTP compared with 19% on NCCT, respectively, in patients with DWI-confirmed lacunar infarcts. CTP was more sensitive in supratentorial than in infratentorial lesions. In the nonblinded analysis, a perfusion deficit was observed in 12/16 patients with DWI-confirmed lacunar infarcts. The proportion of mismatch tissue was similar in patients with lacunar infarcts or nonlacunar strokes (32% versus 36%, P = .734). CONCLUSIONS: Whole-brain CTP is superior to NCCT in identifying small ischemic lesions, including lacunar infarcts, in patients presenting with a lacunar syndrome. Perfusion deficits and mismatch are frequent in lacunar infarcts, but larger studies are warranted to elucidate the clinical significance of these CTP findings.

Harms and benefits of lymphocyte subpopulations in patients with acute stroke.

UNLABELLED: Lymphocytes are major players in the development of innate and adaptive immune responses but their behavior in patients with acute stroke has received little attention. EXPERIMENTAL PROCEDURES: Using flow cytometry we identified total lymphocytes, T cells, helper T (Th) cells, cytotoxic T lymphocytes (CTL), natural killer (NK) cells, B cells, and regulatory T (Treg) cells in 46 consecutive patients with acute stroke within a median of 180 min of clinical onset, and at days 2, 7, and 90. Daily neurological score (National Institutes of Health Stroke Scale), diffusion-weighted imaging on brain magnetic resonance imaging, functional impairment, and stroke-associated infection (SAI) at day 7 were assessed. Apoptosis in lymphocyte subsets, tumor necrosis factor (TNF) -alpha/interleukin (IL) -4 production in stimulated Th and CTL, cluster of differentiation 86 (CD86) (B7-2) expression in B cells, cortisol and metanephrine in serum were measured. Multivariate analyses were used to evaluate SAI, and stroke outcome. RESULTS: Increased apoptosis and a fall of T, Th, CTL, B, and Treg cells were observed after stroke. Severer stroke on admission and SAI disclosed a greater decline of T, Th, and CTL cells. Increased cortisol and metanephrine was associated with severe stroke and SAI, and inversely correlated with T, and CTL. T cells, and CTL were correlated with infarct growth. Stroke but not SAI resulted in lower TNF-alpha production in Th cells. SAI showed the greatest fall of lymphocytes, T, Th, and CTL, but not B cells, or Treg. Poor outcome was associated with reduced levels of B cells, and increased expression of CD86 in B cells, but not with SAI. CONCLUSION: Lymphopenia and increased apoptosis of T, Th, CTL, Treg and B cells are early signatures after human stroke. A decreased cellular response after stroke is a marker of ongoing brain damage, the stress response, and a higher risk of infection. A lower humoral response is predictor of poorer long-term outcome.

The response to IV rt-PA in very old stroke patients.

The use of rtPA in stroke patients aged >80 years remains controversial and it is debated whether there are sex-based differences in the response to rtPA. We assessed the clinical value of thrombolytic therapy in patients aged >80 years (elderly group) in comparison with a non-elderly group, and evaluated the existence of sex differences in the response to rtPA. All consecutive patients (n = 157) treated with rtPA were prospectively assessed since July 2001, including 49 elderly patients who fulfilled the National Institute of Neurological Disorders and Stroke (NINDS) criteria. Changes of the National Institute of Health Stroke Scale (NIHSS) score at 1 h, 24 h, and 7 days after rtPA administration, favourable outcome at day 90 [(modified Rankin Scale) mRS 0-1, or 2 if mRS = 2 before the stroke], symptomatic bleedings, and death rates were compared between elderly and non-elderly patients. Using logistic regression, baseline NIHSS score [odds ratio (OR) 0.59, 95% confidence interval (CI) 0.41-0.84] was an independent predictor of favourable outcome, but not sex (OR 0.72, 95% CI 0.33-1.56), or age >80 years (OR 0.74, 95% CI 0.32-1.70). The rates of clinical improvement, mortality, or symptomatic CNS bleeding were also unrelated to age and sex. In conclusion, the response to IV rtPA is not impaired in elderly stroke patients and male and female are equally responsive.

Complex brain circuits studied via simultaneous and permanent detection of three transported neuroanatomical tracers in the same histological section.

Experimental neuroanatomical tracing methods lie at the basis of the study of the nervous system. When the scientific question is relatively straightforward, it may be sufficient to derive satisfactory answers from experiments in which a single neuroanatomical tracing method is applied. In various scientific paradigms however, for instance when the degree of convergence of two different projections on a particular cortical area or subcortical nucleus is the subject of study, the application of single tracing methods can be either insufficient or uneconomical to solve the questions asked. In cases where chains of projections are the subjects of study, the simultaneous application of two tracing methods or even more may be compulsory. The present contribution focuses on combinations of several neuroanatomical tract-tracing strategies, enabling in the end the simultaneous, unambiguous and permanent detection of three transported markers according to a three-color paradigm. A number of combinations of three tracers or of two tracers plus the immunocytochemical detection of a neuroactive substance can be conceived; we describe several of these combinations implemented by us using the present multitracer protocol.