Causative Subtypes Research Articles

Effects of Carotid Artery Stiffness on Cerebral Small-Vessel Disease and Cognition.

Background Carotid artery stiffness is associated with cognitive impairment and dementia, but the underlying mechanisms remain unknown. We examined the associations of carotid artery stiffness with cerebral small-vessel disease markers, cognition, and dementia subtypes in a memory clinic cohort. Methods and Results A total of 272 participants underwent carotid ultrasonography, 3 Tesla brain magnetic resonance imaging, and neuropsychological assessment. Carotid ultrasonography was used to assess β-index, pressure-strain elastic modulus, and pulse-wave velocity-β. Brain magnetic resonance images were graded for cerebral small-vessel disease markers, including white matter hyperintensities, lacunes, and cerebral microbleeds. Participants were classified as having no cognitive impairment, cognitive impairment and no dementia, or dementia subtyped as Alzheimer disease and vascular dementia. Cognition was assessed using National Institute of Neurological Disorders and Stroke-Canadian Stroke Network harmonization battery. After adjusting for age, sex, cardiovascular risk factors, and diseases, multivariable models showed that β-index (β=0.69; P=0.002), elastic modulus (β=0.78; P<0.001), and pulse-wave velocity-β (β=0.80; P<0.001) were associated with white matter hyperintensities, and elastic modulus (odds ratio [OR], 1.39 [95% CI, 1.04-1.85]) and pulse-wave velocity-β (OR, 1.47 [95% CI, 1.10-1.98]) were independently associated with lacunes. Similarly, β-index (OR, 2.04 [95% CI, 1.14-4.13]), elastic modulus (OR, 2.22 [95% CI, 1.25-4.42]), and pulse-wave velocity-β (OR, 2.50 [95% CI, 1.36-5.18]) were independently associated with vascular dementia. Carotid stiffness measures were independently associated with worse performance in global cognition, visuomotor speed, visuospatial function, and executive function. These associations became largely nonsignificant after further adjusting for cerebral small-vessel disease markers. Conclusions In memory clinic patients, carotid artery stiffness was associated with white matter hyperintensities and lacunes, impairment in global and domain-specific cognition, and causative subtypes of dementia, particularly vascular. The effects of carotid stiffness on cognition were not independent of, and were partially mediated by, cerebral small-vessel disease.

Characteristics and prognosis of patients with embolic stroke of undetermined source in China.

We aimed to explore the frequencies, risk factors, and natural history of embolic stroke of undetermined source (ESUS) through a national prospective registry in China. Between August 2015 and March 2018, the Third China National Stroke Registry recruited consecutive patients with ischemic stroke or transient ischemic attack in China. The baseline characteristics, risks of stroke, and prognosis in patients with embolic stroke of undetermined source were described and compared with that in patients with other causative subtypes. A total of 15,166 transient ischemic attack and ischemic stroke patients were enrolled in the Third China National Stroke Registry. Among 8528 ischemic stroke with standard diagnostic work-up, 2415 (28.3%) patients were diagnosed with embolic stroke of undetermined source. The mean age was 61 years and 70% of them were male. Compared to patients with cardioembolic strokes and small vessel disease, patients with embolic stroke of undetermined source had higher prevalence of nonstenosing large artery atherosclerosis (37.93% vs. 31.26%, P = 0.008 and 37.93% vs. 34.40%, P = 0.044 respectively). The cumulative probability of stroke recurrence in patients with embolic stroke of undetermined source at three months and one year was 5.59% and 8.74%. Compared with embolic stroke of undetermined source patients (0.70% and 1.99%), patients with the large artery atherosclerosis and cardioembolic strokes had higher cumulative probability of death at three months (1.94% and 3.22%) and one year (4.17% and 7.39%). Embolic stroke of undetermined source is a common cause of ischemic stroke in Chinese population with a higher stroke recurrence than previously reported. It was more likely to have nonstenosing large artery atherosclerosis in patients with embolic stroke of undetermined source than with cardioembolic strokes and small vessel disease.

Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study

SummaryBackgroundA third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. If these events are due to occult atheroma, the risk-factor profile and coronary prognosis should resemble that of overt large artery events. If they have a cardioembolic cause, the risk of future cardioembolic events should be increased. We aimed to assess the burden, outcome, risk factors, and long-term prognosis of cryptogenic TIA and stroke.MethodsIn a population-based study in Oxfordshire, UK, among patients with a first TIA or ischaemic stroke from April 1, 2002, to March 31, 2014, we compared cryptogenic events versus other causative subtypes according to the TOAST classification. We compared markers of atherosclerosis (ie, risk factors, coronary and peripheral arterial disease, asymptomatic carotid stenosis, and 10-year risk of acute coronary events) and of cardioembolism (ie, risk of cardioembolic stroke, systemic emboli, and new atrial fibrillation [AF] during follow-up, and minor-risk echocardiographic abnormalities and subclinical paroxysmal AF at baseline in patients with index events between 2010 and 2014).FindingsAmong 2555 patients, 812 (32%) had cryptogenic events (incidence of cryptogenic stroke 0·36 per 1000 population per year, 95% CI 0·23–0·49). Death or dependency at 6 months was similar after cryptogenic stroke compared with non-cardioembolic stroke (23% vs 27% for large artery and small vessel subtypes combined; p=0·26) as was the 10-year risk of recurrence (32% vs 27%; p=0·91). However, the cryptogenic group had fewer atherosclerotic risk factors than the large artery disease (p<0·0001), small vessel disease (p=0·001), and cardioembolic (p=0·008) groups. Compared with patients with large artery events, those with cryptogenic events had less hypertension (adjusted odds ratio [OR] 0·41, 95% CI 0·30–0·56; p<0·0001), diabetes (0·62, 0·43–0·90; p=0·01), peripheral vascular disease (0·27, 0·17–0·45; p<0·0001), hypercholesterolaemia (0·53, 0·40–0·70; p<0·0001), and history of smoking (0·68, 0·51–0·92; p=0·01), and compared with small vessel and cardioembolic subtypes, they had no excess risk of asymptomatic carotid disease (adjusted OR 0·64, 95% CI 0·37–1·11; p=0·11) or acute coronary events (adjusted hazard ratio [HR] 0·76, 95% CI 0·49–1·18; p=0·22) during follow-up. Compared with large artery and small vessel subtypes combined, patients with cryptogenic events also had no excess of minor-risk echocardiographic abnormalities (cryptogenic 37% vs 45%; p=0·18) or paroxysmal AF (6% vs 10%; p=0·17) at baseline or of new AF (adjusted HR 1·23, 0·78–1·95; p=0·37) or presumed cardioembolic events (1·16, 0·62–2·17; p=0·64) during follow-up.InterpretationThe clinical burden of cryptogenic TIA and stroke is substantial. Although stroke recurrence rates are comparable with other subtypes, cryptogenic events have the fewest atherosclerotic markers and no excess of cardioembolic markers.FundingWellcome Trust, Wolfson Foundation, UK Stroke Association, British Heart Foundation, Dunhill Medical Trust, National Institute for Health Research, Medical Research Council, and the NIHR Oxford Biomedical Research Centre.

Abstract 205: Etiologic Ischemic Stroke Phenotypes in the NINDS Stroke Genetics Network

Background and Purpose: NINDS Stroke Genetics Network (SiGN) is an international consortium of ischemic stroke studies that aims to generate high quality phenotype data to identify the genetic basis of ischemic stroke subtypes. The goal of this analysis is to characterize the etiopathogenetic basis of ischemic stroke in the consortium. Methods: This analysis included 16,954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries. 52 trained and certified adjudicators used the web-based Causative Classification of Stroke System for etiologic stroke classification through chart reviews to determine both phenotypic (abnormal test findings categorized in major etiologic groups without weighting towards the most likely cause in the presence of multiple etiologies) and causative subtypes in each subject. Classification reliability was assessed with blinded re-adjudication of 1509 randomly selected cases. Findings: The figure shows the distribution of etiologic categories. Overall, only 40% to 54% of cases with a given major ischemic stroke etiology (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (kappa 0·72, 95%CI:0·69-0·75) and phenotypic classifications (kappa 0·73, 95%CI:0·70-0·75). Conclusions: This study provides high quality data on etiologic stroke subtypes and demonstrates that etiologic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes suggests that the presence of an abnormality in a stroke patient does not necessarily mean that it is the cause of stroke.

Screening, confirming, and treating amblyopia based on binocularity.

Screening, confirming, and treating amblyopia based on binocularity.

Epidermodysplasia verruciformis associated with HPV 10

Epidermodysplasia verruciformis (EV) is a rare, inherited dermatologic condition demonstrating an increased susceptibility to specific HPV genotypes, resulting in both benign and malignant skin lesions. Epidermodysplasia verruciformis lesions are frequently described as pityriasis versicolor-like scaly macules, flat wart-like papules, or verrucous and seborrhic keratosis-like papules and plaques. Acquired EV has been described in patients with HIV and in those who are on immunosuppressive therapy. We discuss a patient with congenital EV who presents with skin lesions associated with HPV 10, a less frequently cited causative subtype, and histological findings that are not classic for EV.

Abstract 11: The Utility of Causative Classification System: Correlation between Causative and Phenotypic Stroke Subtypes

Background: Causative Classification of Stroke (CCS) system is a novel, web-based, and fully-computerized algorithm that integrates clinical, diagnostic, and etiologic stroke characteristics in an evidence-based manner (available at http://ccs.mgh.harvard.edu ) and provides in a given patient both phenotypic subtypes where abnormal evaluation findings are simply organized in major etiologic categories and causative subtypes where abnormal evaluation findings are filtered through a decision making process to identify the most likely cause of stroke. In this study, we sought to identify the concordance between phenotypic and causative CCS subtypes in the NINDS Stroke Genetics Network (SiGN). Methods: A total of 24 adjudicators from 15 US and European sites certified in CCS retrospectively determined CCS subtypes through chart review in 7134 patients. The CCS software provided causative subtypes in 3 confidence levels as “evident”, “probable” or “possible” based on the weight of causal evidence. We estimated how often CCS classified a given major abnormal evaluation finding as the causative stroke mechanism. Results: CCS assigned 55% of patients with the phenotype of moderate-to-severe atherosclerotic stenosis into the causative category of “evident large artery atherosclerosis”. Likewise, 50% of patients with a major cardiac source (such as atrial fibrillation) were classified into “evident cardio-aortic embolism”, and 74% of those with imaging evidence of a typical lacunar infarct into “evident small artery occlusion”. In 20% to 30% of patients, phenotypic and causative categories were the same but the causative subtype was assigned with a lower level of confidence. Six to 20% of patients with a given phenotypic feature were classified into a different causative category. Failure to investigate for other subtypes in the presence of a positive test finding and the presence of multiple competing etiologies were key contributors to the observed disconcordance between phenotypic and causative subtypes. Conclusions: Our findings show that the presence of a major abnormality in stroke evaluation does not necessarily mean that it is always the cause. The ability of CCS system to discriminate between phenotypic and causative characteristics of stroke etiology provides the opportunity to refine stroke phenotypes for use in research studies.

Advances in the Diagnosis of Etiologic Subtypes of Ischemic Stroke

A fundamental goal of etiologic stroke classification is to generate subgroups with discrete phenotypic, therapeutic, and prognostic features. Accurate stroke classification requires integration of multiple aspects of diagnostic stroke evaluation in a standardized manner. Diagnostic test findings can be simply organized into major etiologic groups to create a phenotypic subtype, or they can be reduced to a single causative subtype through a decision-making process. It is essential for a classification system to provide consistent results across different raters in different clinical settings. Comparability of subtype assignments is the key to valid communication of research results across the field. This article highlights important theoretical aspects of etiologic stroke classification and reviews major etiologic classification systems that have benefited from recent advances in etiologic stroke evaluation.

Correlates of hippocampal neuron number in Alzheimer's disease and ischemic vascular dementia

The cornu ammonis 1 region of the hippocampus (CA1) sector of hippocampus is vulnerable to both Alzheimer's disease (AD)-type neurofibrillary degeneration and anoxia-ischemia. The objective of this article is to compare number and size of neurons in CA1 in AD versus ischemic vascular dementia. Unbiased stereological methods were used to estimate the number and volume of neurons in 28 autopsy-derived brain samples. For each case, the entire hippocampus from one cerebral hemisphere was sliced into 5mm slabs (5-7 slabs/case), cut into 50 microm sections, and stained with gallocyanine. Using the optical dissector, we systematically sampled the number and size of neurons throughout the extent of CA1 and CA2. The total number of neurons was significantly less in AD compared with ischemic vascular dementia (p < 0.02), but there was no significant difference in neuron size. The greatest loss of neurons was observed in two cases with combined AD and hippocampal sclerosis. Regardless of causative diagnosis, the number of CA1 neurons correlates with magnetic resonance imaging-derived hippocampal volume (r = 0.72; p < 0.001) and memory score (r = 0.62; p < 0.01). We conclude that although CA1 neuron loss is more consistently observed in AD than ischemic vascular dementia, severity of loss shows the expected correlation with structure and function across causative subtype. Reductions in magnetic resonance imaging-derived hippocampal volume reflect loss, rather than shrinkage, of CA1 neurons.

Trend of neonatal group B streptococcal infection during the last 15 years.

The survey was designed to determine the trend of group B streptococcal (GBS) infection during the last 15 years, as well as update the reality of this disease. Questionnaires were administered every 5 years towards neonatal intensive care unit-equipped hospitals. The first survey was made from 1983 to 1987, the second one from 1988 to 1992 and the third one from 1993 to 1997. The 15-year questionnaire survey included a total of 831 patients. The changes in number of patients, the ages at onset, the diagnosis, the serotypes of causative agents, the presence or absence of complicated delivery and the prognosis were analyzed. It seems that the increasing trend of the number of patients has stopped in the period from 1993 to 1997 (third survey). The most common causative subtype was type III GBS, regardless of early onset type or late onset type. As to perinatal abnormality, approximately 40% of the early onset cases were free from risk factors. Concerning the prognosis, 22.6% of early onset cases and 38.7% of late onset cases died or had sequelae. The number of GBS-infected cases has stopped increasing, but it is still necessary to carry out screenings of pregnant women for the purpose of decreasing the onset of the disease.

Salted food doesn’t eat

Non-agentive sentences of the type : these shirts do not iron ; the bicycle sells well this year..., are held to be relatable to active sentence patterns of the most common type. Yet very few English verbs can be used in this way. It has been noted that whereas the transitive use is primary, the intransitive use requires a negative or an adverbial of some sort, thus imparting to the construction an appreciative value that distinguishes it from the causative subtype represented by a much larger class of verbs like : move, open, or grow... By contrast, such generic statements as : glass breaks or ice melts in the sun, seem purely descriptive in nature. Also the referent of the grammatical subject is variously affected according to the verbal subtype. The purpose of this article is to find out more about the specificity of non-agentive sentences from an enunciative point of view, and to assess the role of a «quantitative / qualitative» component in the establishment of appropriate subtypes.

Enzyme immunoassay, complement fixation and hemagglutination inhibition tests in the diagnosis of influenza A and B virus infections. Purified hemagglutinin in subtype-specific diagnosis

The efficacy of enzyme immunoassay (EIA) in detecting diagnostic antibody rises to influenza A and B viruses was compared with complement fixation (CF) and hemagglutination inhibition (HI) tests in 455 patients with an acute respiratory infection. EIA and HI detected significantly more diagnostic antibody rises against influenza A than the CF method (96 and 87 vs. 47, respectively). In the case of influenza B significantly more diagnostic influenza B antibody rises were observed by EIA than by CF or HI (59 vs. 37 and 40, respectively). In most of the cases antibody rises in EIA were found in both IgG and IgA isotypes whereas increases in IgM antibodies were seen less frequently. Purified hemagglutinins (HA) were prepared from influenza A HI- and H3-subtypes and from influenza B viruses and used as antigens in EIA and the results were compared with those of HI. Infections caused by influenza A HI-subtype showed good homologous antibody responses in EIA but heterologous antibody responses to H3-subtype and influenza B HAs were frequently observed. Heterologous responses were clearly less frequent in patients with infections caused by the H3-subtype. Influenza B infections occasionally raised HA antibodies against influenza A H1-subtype but not to the H3-subtype. Interestingly, HI detected these heterologous responses at least as frequently as EIA. When whole viruses were used as antigens in EIA, subtype specificity was not observed and cross-reactions between influenza A and B virus antibodies were found. These observations suggest that, although EIA can show greater diagnostic efficacy over HI and CF methods, HI is still the serological method of choice in determining the causative subtype of influenza A virus infection.