Inter-Rater Reliability of the CASCADE Criteria: Challenges in Classifying Arteriopathies.

BACKGROUND AND PURPOSE: There are limited data about the reliability of subtype classification in childhood arterial ischemic stroke, an issue that prompted the IPSS (International Pediatric Stroke Study) to develop the CASCADE criteria (Childhood AIS Standardized Classification and Diagnostic Evaluation). Our purpose was to determine the CASCADE criteria's reliability in a population of children with stroke. METHODS: Eight raters from the IPSS reviewed neuroimaging and clinical records of 64 cases (16 cases each) randomly selected from a prospectively collected cohort of 113 children with arterial ischemic stroke and classified them using the CASCADE criteria. Clinical data abstracted included history of present illness, risk factors, and acute imaging. Agreement among raters was measured by unweighted κ statistic. RESULTS: The CASCADE criteria demonstrated a moderate inter-rater reliability, with an overall κ statistic of 0.53 (95% confidence interval [CI]=0.39-0.67). Cardioembolic and bilateral cerebral arteriopathy subtypes had much higher agreement (κ=0.84; 95% CI=0.70-0.99; and κ=0.90; 95% CI=0.71-1.00, respectively) than cases of aortic/cervical arteriopathy (κ=0.36; 95% CI=0.01-0.71), unilateral focal cerebral arteriopathy of childhood (FCA; κ=0.49; 95% CI=0.23-0.76), and small vessel arteriopathy of childhood (κ=-0.012; 95% CI=-0.04 to 0.01). CONCLUSIONS: The CASCADE criteria have moderate reliability when used by trained and experienced raters, which suggests that it can be used for classification in multicenter pediatric stroke studies. However, the moderate reliability of the arteriopathic subtypes suggests that further refinement is needed for defining subtypes. Such revisions may reduce the variability in the literature describing risk factors, recurrence, and outcomes associated with childhood arteriopathy.

Identification of a genetic variant common to moyamoya disease and intracranial major artery stenosis/occlusion.

BACKGROUND AND PURPOSE: The c.14576G>A variant in ring finger protein 213 (RNF213) was recently identified as a susceptibility gene variant for moyamoya disease (MMD). The occurrence of c.14576G>A variant was evaluated in patients with intracranial major artery stenosis/occlusion (ICASO) without signs of MMD (non-MMD ICASO), as well as in patients with MMD and other cerebrovascular diseases as controls. METHODS: This single-hospital-based case-control study was completed in 7 months (from October 2011-April 2012) at Department of Neurosurgery, The University of Tokyo Hospital. The occurrence of c.14576G>A variant was analyzed in 41 patients with non-MMD ICASO, in 48 with MMD, in 21 with cervical disease, in 61 with cerebral aneurysm, and in 25 normal subjects. RESULTS: Nine of 41 patients (21.9%) with non-MMD ICASO and 41 of 48 (85.4%) with MMD had the c.14576G>A variant. One of 61 patients (1.6%) with cerebral aneurysm and no patients with cervical disease or normal subjects had the variant. Comparison of each phenotype group with the normal subjects showed that presence of c.14576G>A variant had significant associations with MMD (odds ratio [OR], 292.8; 95% confidence interval [CI], 15.4-5153.0; P<0.0001) and with non-MMD ICASO (OR, 14.9; 95% CI, 0.82-268.4; P=0.01), but no association with either cerebral aneurysm (OR, 1.2; 95% CI, 0.04-32.0; P=1.00) or cervical disease (OR, 1.1; 95% CI, 0.02-62.3; P=1.00). CONCLUSIONS: The present study indicates that a particular subset of Japanese patients with non-MMD ICASO has a genetic variant associated with MMD. Therefore, we propose the existence of a new entity of ICASO caused by the c.14576G>A variant in RNF213.

Towards a consensus-based classification of childhood arterial ischemic stroke.

BACKGROUND AND PURPOSE: The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS. METHODS: Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinician's current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted κ-statistic. RESULTS: In Group 1 (with training), IRR was improved using CASCADE criteria (κ=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (κ=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (κ=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (κ=0.23, 95% CI=[0.03, 0.36]). CONCLUSIONS: A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.

Diabetes increases large artery diseases, but not small artery diseases in the brain.

BACKGROUND: It is established that diabetes causes various systemic micro- and macro-vascular complications. Little has been, however, studied on the differential effects of diabetes on the large artery diseases (LAD) or small artery disease (SAD) in the brain. The purpose of this study was to examine an association of diabetes on the incidence of underlying LAD versus SAD in ischemic stroke patients. METHODS: We prospectively collected 523 acute ischemic stroke patients without cardioembolic causes or other determined causes of stroke. Using brain MRI, the cerebral LAD (extracranial and intracranial arterial stenosis of 50 % or more) and the cerebral SAD (old lacunar infarction, microbleeds and leukoaraiosis) findings were assessed. Information regarding vascular risk factor was also collected. RESULTS: Among the patients (male, n = 342; diabetes, n = 200), diabetes was not associated with the presence of LADs or SADs in female subjects, but strongly with the presence of intracranial LAD in male subjects (p < 0.01). The association remained significant (OR 2.09, 95 %CI 1.25-3.51) after adjusting for major confounders. A similar association was also found in intracranial LAD and insulin resistance. There was, however, no significant association of diabetes with SAD in male nor in female patients. CONCLUSIONS: Our results showed that diabetes is associated with the frequency of intracranial LAD, especially in males. Out study may be regarded as evidence of differential biological effects of diabetes on cerebral vasculature.

Dissections of brain-supplying arteries.

Arterial dissections involving arteries in the neck and head are being identified increasingly readily because of growing awareness of their clinical features, along with advances in imaging technologies. Dissections are caused mostly by stretching and tearing of arteries, which leads to bleeding within the arterial wall. Dissections of brain-supplying arteries are invariably accompanied by headache and other forms of pain. Subintimal dissections cause mostly brain and eye ischemia, whereas subadventitial dissections lead to formation of aneurysms and pseudoaneurysms and, if the dissection is intracranial, subarachnoid hemorrhage. Dissections are most effectively visualized by conventional angiography, but they can also be imaged by CT or magnetic resonance angiography, fat-saturated MRI cross sections, and ultrasound. Treatment for arterial dissections has not been studied with randomized trial methodology, but most clinicians prescribe antithrombotic medications as prophylaxis. The recurrence rate of infarction or arterial dissections is very low.

Evolution of cerebral arteriopathies in childhood arterial ischemic stroke.

OBJECTIVE: To investigate evolution of cerebral arteriopathy in children with arterial ischemic stroke (AIS) and its influence on recurrence. METHODS: Arteriopathy severity was graded on serial magnetic resonance angiograms from 50 children with first AIS; diagnostic categories were assigned. RESULTS: Arteriopathy affected 72 arteries in 43 of 50 children. Five had clinical recurrence, with reinfarction in four; another had clinically silent reinfarction. Twelve children (24%; 4 with recurrence) had progressive arteriopathy. Arteriopathy improved in 24 patients (including 1 with recurrent transient ischemic attacks) and was stable in 7 patients. Magnetic resonance angiograms remained normal in seven patients; one had recurrent stroke. Diagnoses were transient cerebral arteriopathy (n = 24), chronic cerebral arteriopathy (n = 11), arterial dissection (n = 3), possible moyamoya (n = 2), primary moyamoya (n = 1), dysplastic arteriopathy (n = 1), and cerebral vasculitis (n = 1). Some of the first two categories could represent thromboembolic arterial occlusion with recanalization. The hazard of recurrence was three times higher when arterial disease had progressed (Cox regression hazard ratio, 3.2; 95% confidence intervals, 0.5-20.3; p = 0.22). After adjustment for age and number of AIS risk factors, the hazard ratio was 3.1 (95% confidence interval, 0.4-22.2; p = 0.27). INTERPRETATION: Arteriopathy frequently progresses after childhood AIS. Further studies are needed to examine the relationship between progressive arteriopathy and recurrence.

Transcranial Doppler sonography evaluation of anterior cerebral artery hypoplasia or aplasia.

BACKGROUND AND PURPOSE: Transcranial Doppler (TCD) sonography is useful to evaluate intracranial arteries, however, interpretation of the TCD results in anterior cerebral artery (ACA) is difficult because of hypoplasia or aplasia. We try to define useful TCD indices and cut-off values to determine the variations of ACA. METHODS: Consecutive patients who underwent TCD and magnetic resonance angiography (MRA) were included. Patients with cerebrovascular abnormality or inadequate temporal windows were excluded. ACA status was classified as normal (NL), hypoplasia (HP), and aplasia (AP) according to MRA. TCD indices of mean flow velocity (MFV), pulsatility index (PI), ACA/middle cerebral artery (MCA) flow velocity ratio (ACA/MCA FVR), and asymmetry index (AI) of ACA were blindly compared with MRA between three groups. RESULTS: Two hundred and forty-one patients were included, and 193 patients (80%) were classified as NL, 34 (14%) as HP and 14 (6%) as AP. MFV was significantly lower in HP and AP (p<0.001), however, PI and ACA/MCA FVR were not different. AI was significantly different between NL and HP (21.5% vs. 50.4%), NL and AP (21.5% vs. 105.2%) (p<0.001). CONCLUSIONS: MFV of ACA should be interpreted with caution for its frequent anatomical variations. AI is useful to differentiate hypoplasia and aplasia from normal ACA with optimal criteria.

Association of lacunar infarcts with small artery and large artery disease: a comparative study.

OBJECTIVES: Patients with lacunar infarcts (LI) and ipsilateral large artery disease (LAD) greater than 50% must be classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria as strokes of undetermined etiology. The purpose of this study was to compare the vascular risk factors, clinical symptoms, and outcome characteristics of LI associated with LAD with those patients with LI who fulfilled the TOAST criteria of small artery disease (SAD). METHODS: Among 1754 consecutive first ever stroke patients admitted to our department, we analyzed age, gender, vascular risk factors (hypertension, diabetes, ischemic heart disease, arterial peripheral disease, hypercholesterolemia, smoking, alcohol, or illicit drug use), clinical data (motor or sensitive deficit and presence of dysarthria), and outcome (hospitalization length, in-hospital medical complications rate, need of rehabilitation, treatment at discharge, in-hospital mortality, and modified Rankin Scale at discharge) of those patients classified as LI associated with LAD as compared with those with SAD. RESULTS: After a strict application of the TOAST criteria, we found 144 patients with LI associated with SAD and 73 patients with LI associated with LAD. Univariate analysis showed statistical differences in gender (OR: 0.46; 95% CI: 0.23-0.89; P = 0.014), past history of ischemic heart disease (OR: 0.32; 95% CI: 0.13-0.78; P = 0.004), and smoking (OR: 0.56; 95% CI: 0.31-1.04; P = 0.048). After logistic regression analysis only ischemic heart disease (OR: 0.31; 95% CI: 0.11-0.78; P = 0.013), and gender (OR: 0.51; 95% CI: 0.28-0.98; P = 0.05) showed statistical differences. During the follow-up, six patients (all with LI associated with LAD) experienced stroke recurrences (OR: 0.32; 95% CI: 0.26-0.39; P < 0.001). CONCLUSIONS: 1) There are no differences in clinical presentation and in-hospital outcome between patients with LI associated with SAD and patients with LI associated with LAD. 2) Risk factors are very similar in both groups, and the only differences observed (gender and ischemic heart disease) are related to the atherosclerotic factor. 3) Stroke recurrence seems to be more frequent in LI associated with LAD than in LI associated with SAD, but large follow-up studies are needed to be able to decide whether clinical recurrence of stroke allows to differentiate both clinical entities.

[Symptomatic intracranial artery stenosis: angiographic classifications and stent-assisted angioplasty].

OBJECTIVE: To assess the safety and efficacy of stent-assisted angioplasty (SAA) for symptomatic intracranial artery stenosis, and to evaluate preliminarily the significance of classification of location, morphology and access (LMA classification) of intracranial artery stenosis in SAA. METHODS: Forty-two patients with symptomatic intracranial artery stenosis (diameter reduction: 50% - 74%, n = 15; >or= 75%, n = 27), located in middle cerebral artery (n = 27), intracranial internal carotid artery (n = 4), intracranial vertebral artery (n = 7) and basilar artery (n = 4) respectively, refractory to medical therapy were enrolled in this study. RESULTS: LMA classification: 23 of the forty-two lesions (54.8%) located at the site of bifurcation, which were classified according to the location into type A (n = 8), B (n = 11), C (n = 2), D (n = 1) and F (n = 1) respectively. Type A, B and C lesions were 19, 19 and 4 respectively in the light of morphologic classification. Type I, II and III accesses were 15, 23 and 4 respectively in the light of access classification. TECHNIQUE: The technical successful rate of SAA was 95.2% (40/42) for the group overall, and 100% (15/15), 94.7% (22/23), and 75% (3/4) for type I, II, III accesses, respectively. The rate of periprocedural complication and death was 9.5% (4/42), including acute occlusion (n = 1) and high perfusion syndrome (n = 3). After emergency measures, 3 patients were cured completely, and the remaining one with severe MCA trunk stenosis of type C lesion died of subarachnoid hemorrhage (2.4%). During a clinical follow-up period ranging from 1 to 18 months (median 8 months), 39 patients receiving SAA have been still free from ischemic events. There was no restenosisfound angiographically 6 months (n = 7) and 12 months (n = 4) after SAA. CONCLUSIONS: Our results suggest that under rigorous control of procedural and periprocedural measures, SAA appears to be a safe and effective therapy for symptomatic intracranial stenoses of type A and B lesions, but it is not risk-free for type C lesions. The LMA classification is helpful for predicting the results of SAA and to design the procedure. However, further study is needed.

Neurovascular territory involved in different etiological subtypes of ischemic stroke in the Perugia Stroke Registry.

UNLABELLED: We studied the correlation between the potential causes of stroke (TOAST etiological groups) and the involvement of different vascular territories seen on computed tomography (CT) scans in patients with ischemic stroke. Information from consecutive patients with a first-ever stroke have been prospectively coded and entered into a computerized data bank (Perugia Stroke Registry). A population of 1,719 patients were evaluated: 1,284 patients (74.7%) had ischemic stroke. Large artery disease was the main cause of entire middle cerebral artery (MCA) territory infarcts (40.9%), superficial MCA territory infarcts (35.7%), and watershed infarcts (68.2%). The highest presence of emboligenic heart disease was found in the entire MCA territory infarcts (28.8%) or superficial (29.4%) supratentorial infarcts and in cerebellar infarcts (36.8%). Small artery disease was the most common presumed cause of deep MCA infarcts (75.0%) and posterior cerebral artery (PCA) territory infarcts (52.1%). IN CONCLUSION: stroke location could depend on its etiology. Lacunar infarcts are the most prevalent (36.7%), being mostly localized in the deep MCA territory; large artery disease includes more than two-thirds of watershed infarcts; the most prevalent territories involved in cardioembolic stroke are the entire MCA and posterior fossa.

Inaccuracy of the International Classification of Diseases (ICD-9-CM) in identifying the diagnosis of ischemic cerebrovascular disease.

In administrative databases the International Classification of Diseases, Version 9, Clinical Modification (ICD-9-CM) is often used to identify patients with specific diagnoses. However, certain conditions may not be accurately reflected by the ICD-9 codes. We assessed the accuracy of ICD-9 coding for cerebrovascular disease by comparing ICD-9 codes in an administrative database with clinical findings ascertained from medical record abstractions. We selected patients with ICD-9 diagnostic codes of 433 through 436 (in either the primary or secondary positions) from an administrative database of patients hospitalized in five academic medical centers in 1992. Medical records of the selected patients were reviewed by trained medical abstractors, and the patients' clinical conditions during the admission (stroke, TIA, asymptomatic) were recorded, as well as any history of cerebrovascular symptoms. Results of the medical record review were compared with the ICD-9 codes from the administrative database. More than 85% of those patients with the ICD-9 code 433 were asymptomatic for the index admission. More than one-third of these asymptomatic patients did not undergo either cerebral angiography or carotid endarterectomy. For ICD-9 code 434, 85% of patients were classified as having a stroke and for ICD-9 code 435, 77% had TIAs. For code 436, 77% of patients were classified as having strokes. Limiting the identifying ICD-9 code to the primary position increased the likelihood of agreement with the medical record review. The ICD-9 coding scheme may be inaccurate in the classification of patients with ischemic cerebrovascular disease. Its limitations must be recognized in the analyses of administrative databases selected by using ICD-9 codes 433 through 436.

Proximal intracranial territory posterior circulation infarcts in the New England Medical Center Posterior Circulation Registry.

We studied 91 patients with proximal intracranial territory posterior circulation ischemia from the New England Medical Center Posterior Circulation Registry to learn their distribution, underlying cardiovascular causes and longterm outcome. All patients had imaging and vascular studies. Six patients had proximal territory TIAs. Among 85 stroke patients, 52% had infarcts limited to the proximal territory, while 48% also had infarcts in other intracranial posterior circulation territories. Eighty-five percent of proximal territory infarcts were posterior inferior cerebellar artery (PICA) territory cerebellar infarcts and 30% were lateral medullary infarcts. One patient had a hemimedullary syndrome. Six patients had PICA territory cerebellar and lateral medullary infarcts. The most common vascular lesion in lateral medullary infarct patients was ipsilateral intracranial vertebral artery (ICVA) disease (38% isolated ICVA disease) and in PICA territory cerebellar infarcts, extracranial vertebral artery (ECVA) disease (29% isolated ECVA disease). Half of all lateral medullary infarcts were due to a hemodynamic mechanism, most often in situ thrombosis of an ICVA occlusive lesion. Half of all PICA territory cerebellar infarcts were due to intra-arterial embolism and one-fifth to cardiac origin embolism. Embolism was a more frequent cause of proximal territory posterior circulation infarcts than intrinsic ICVA disease. The etiological profiles of lateral medullary and PICA cerebellar infarcts were different. Seventeen percent of all patients died during follow-up (41 months) but mortality related to the acute stroke or new strokes was only 6 percent. The outcome was favorable in the surviving patients; 89% had no or only slight disability.

Cerebral dural arteriovenous fistulas: clinical and angiographic correlation with a revised classification of venous drainage.

PURPOSE: To review the symptoms and progression of dural arteriovenous fistulas (AVFs) and correlate the findings with various angiographic patterns. MATERIALS AND METHODS: Patterns of venous drainage allowed classification of dural AVFs into five types: type I, located in the main sinus, with antegrade flow; type II, in the main sinus, with reflux into the sinus (IIa), cortical veins (IIb), or both (IIa + b); type III, with direct cortical venous drainage without venous ectasia; type IV, with direct cortical venous drainage with venous ectasia; and type V, with spinal venous drainage. RESULTS: Type I dural AVFs had a benign course. In type II, reflux into the sinus induced intracranial hypertension in 20% of cases, and reflux into cortical veins induced hemorrhage in 10%. Hemorrhage was present in 40% of cases of type III dural AVFs and 65% of type IV. Type V produced progressive myelopathy in 50% of cases. CONCLUSION: This classification provides useful data for determination of the risk with each dural AVF and enables decision-making about the appropriate therapy.

Systemic and cerebral amyloidosis.

Two types of familial cerebral amyloid angiopathy or hereditary cerebral hemorrhage with amyloidosis (HCHWA) have been described: the Icelandic type (HCHWA-I), and the Dutch type (HCHWA-D). Both are autosomal-dominant forms of amyloidosis restricted to the small vasculature of the brain and clinically characterized by recurrent strokes leading to an early death. In spite of their clinico-pathological similarities, the amyloid fibrils are structurally different. In the case of HCHWA-I, the amyloid protein is a degradation product of Cystatin C variant (gamma trace), a normal serum protein and an inhibitor of cysteine proteases. The amyloid protein is the expression of a genetic aberration, since it has been demonstrated that a point mutation occurred in the Cystatin C gene. On the other hand the amyloid protein in HCHWA-D type has very recently been shown to be related to Alzheimer's disease (AD) and Down's syndrome (DS) beta-protein. However, the complete sequence of HCHWA-D beta-protein obtained from leptomeninges was three residues shorter (39 instead of 42) than that reported for the insoluble plaque amyloid of AD. The distinct enzymatic cleavage at the carboxyl end of the beta protein is consistent with the concept that the amyloid fibrils derive from a larger precursor by specific and partial degradation. The difference may reflect a particular type of proteolysis that occurs in the vessel wall and not in the brain parenchyma.(ABSTRACT TRUNCATED AT 250 WORDS)

Three phases of cerebral arteriopathy in meningitis: vasospasm and vasodilatation followed by organic stenosis.

A systematic radiological and pathological study of the cerebral arteries was made in an autopsy case of meningitis associated with three phases of cerebral arteriopathy. The latter consisted of vasospasm, vasodilatation, and organic stenosis. A marked change in the caliber of the cerebral arteries was demonstrated 3 times. Vasospasm, the stimulus phenomenon, was produced by the surrounding purulent material. Vasodilatation, the paralytic phenomenon, was presumably due to decreased contractile energy in association with myonecrosis. Organic stenosis, the repair process, was due to the organization of subendothelial edema with resultant intimal thickening. Evidence of increased endothelial permeability, subendothelial proliferation of smooth muscle cells, and necrosis of the latter in the media is presented in both light and electron micrographs.