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. Author manuscript; available in PMC: 2022 Jul 1.
Published in final edited form as: Stroke. 2021 May 13;52(7):2311–2318. doi: 10.1161/STROKEAHA.120.032225

Prevalence and Clinical Correlates of Intracranial Dolichoectasia in Individuals with Ischemic Stroke.

Victor J Del Brutto 1, Jose Gutierrez 2, Mohammed Z Goryawala 3, Ralph L Sacco 1, Tatjana Rundek 1, Jose G Romano 1
PMCID: PMC8238812  NIHMSID: NIHMS1696049  PMID: 33980042

Abstract

Background and Purpose:

Acute ischemic stroke (AIS) is a known complication of intracranial dolichoectasia (IDE). However, the frequency of IDE causing brain infarction is unknown. We aim to determine the prevalence and clinical correlates of IDE in AIS by employing an objective IDE definition for major intracranial arteries of the anterior and posterior circulation.

Methods:

Consecutive AIS patients admitted to a tertiary-care hospital during a 4-month period were analyzed. Intracranial arterial diameter, length, and tortuosity were determined by semi-automatic vessel segmentation and considered abnormal if ≥2 standard deviations from the study population mean. Either ectasia (increased diameter) or dolichosis (increased length or tortuosity) of at least one proximal intracranial artery defined IDE. Symptomatic IDE was considered when the infarct was located in the territory supplied by an affected artery in the absence of any alternative pathogenic explanation. Multivariate models were fitted to determine IDE clinical correlates.

Results:

Among 211 cases screened, 200 patients (mean age 67 ±14 years, 47.5% men) with available intracranial vessel imaging were included. IDE was identified in 24% cases (5% with isolated ectasia, 9.5% with isolated dolichosis, and 9.5% with both ectasia and dolichosis). IDE was considered the most likely pathogenic mechanism in 12 cases (6% of the entire cohort), which represented 23.5% of strokes initially categorized as undetermined etiology. In addition, 21% of small-artery occlusion strokes had the infarct territory supplied by a dolichoectatic vessel (3% of the entire cohort). IDE was independently associated with male sex (OR=4.2; 95% C.I. 1.7-10.6) and its component of ectasia was associated with advanced age (OR=3.5; 95%C.I. 1.3-9.5). Vascular risk profile was similar across stroke patients with and without IDE.

Conclusions:

Our findings suggest that IDE is an arteriopathy frequently found in patients with AIS and is likely responsible for a sizable fraction of strokes initially categorized as of undetermined etiology and perhaps also in those with small-artery occlusion.

Keywords: Dolichoectasia, ectasia, dolichosis, ischemic stroke

Introduction

Intracranial Dolichoectasia (IDE) is a well-recognized arteriopathy characterized by dilation (ectasia) and increased length or tortuosity (dolichosis) of the intracranial arteries.1 IDE may manifest clinically with brain infarction, intracerebral hemorrhage, or compression of surrounding structures. IDE has been mainly studied in the posterior circulation where the prevalence of vertebrobasilar dolichoectasia ranges from 7.6 to 18.8% in stroke patients, 2–7 and 1.3 to 4.4% in unselected populations. 8,9 It has been proposed that IDE originates from injury to the tunica media resulting in the disruption of the internal elastic lamina and subsequent disturbance of the normal vessel architecture.10,11 Several inherited,12–15 inflammatory,16,17and infectious18–20 conditions have been associated with IDE. However, this arteriopathy is frequently found in the absence of an apparent cause.

A lack of validated criteria to identify this arteriopathy in all major intracranial vessels is a key limitation to study IDE. Smoker and co-workers21 recommended a basilar artery diameter cutoff of 4.5mm to define ectasia and demarcated anatomical landmarks to identify dolichosis. However, these criteria have shortcomings, which include the exclusion of evaluation for anterior circulation IDE and the use of a fixed diameter cutoff in a population with a broad age range.21 Larger studies have relied on subjective criteria based on visual impression to evaluate the presence of IDE.22,23 Other investigators have proposed an IDE definition relevant to arteries of the anterior and posterior circulation based on total cranial volume-adjusted diameters.24 The majority of studies that have used objective definitions of IDE have relied on arterial diameters (ectasia), but the component of dolichosis has not been systematically studied.

IDE may result in cerebral ischemia either by abnormal, non-laminar anterograde blood flow causing thrombi formation and embolism, or alternatively, by stretching and occlusion of small penetrating vessels arising from a dolichoectatic artery.25 However, IDE is often overlooked as a mechanism of ischemic stroke. In this study, we aim to determine the prevalence and clinical correlates of IDE in patients with acute ischemic stroke (AIS) using objective diagnostic parameters for proximal intracranial vessels of the anterior and posterior circulation, and to identify the role of IDE in causing acute ischemic stroke.

Methods

Data supporting the findings of this study are available from the corresponding author upon reasonable request.

Study population

We analyzed consecutive adult patients admitted with AIS to a large comprehensive stroke center from October 2017 to January 2018. As part of the standard protocol, patients with AIS undergo etiologic diagnostic evaluation including intracranial and extracranial vessel imaging, transthoracic echocardiogram, and continuous cardiac monitoring during the length of hospitalization. Additional diagnostic studies including transesophageal echocardiogram and hypercoagulable tests are done on a case-by-case basis. For this analysis, we excluded patients that did not undergo intracranial vessel examination with either CT-angiogram or MR-angiogram. The Institutional Review Board of the University of Miami approved the protocol. No informed consent was required.

Assessment of IDE

Semi-automatic vessel segmentation of both intracranial internal carotid arteries (ICA), middle cerebral arteries (MCA) M1 segment, intracranial vertebral arteries (VA), and the basilar artery (BA) was performed using TeraRecon software (Foster City, CA), and used to calculate the arterial diameter, length, and tortuosity index (TI) of each vessel. The software generated a centerline path along each vessel course and the average diameter was calculated on the cross-sectional area perpendicular to the long axis at prespecified landmarks. Vessel length was measured by dragging the cursor along two points of the virtual axis (from origin to terminus). TI was calculated by the ratio between the true vessel length and a straight-line distance between origin and terminus (Figure1). Among 200 patients included in the study, 1306 arterial segments were analyzed (ICA=385, MCA=375, VA=353, and BA=193). Values ≥2 standard deviations from the study population mean were considered abnormal. IDE was defined as at least one vessel with abnormally increased diameter (ectasia), or abnormally increased length or tortuosity (dolichosis). In addition, 3D-reconstruction of intracranial vessels was used to classify the circle of Willis (CoW) variants as a potential confounding variable. CoW type O (ordinary type) was defined if both A1 segments were visualized and both posterior cerebral arteries originated from the BA. Incomplete types of CoW were named as type A when one A1 segment was not visualized, and type P when one posterior cerebral artery was continuously delineated from the ICA through the posterior communicating artery. Combinations of incomplete CoW types included type AP, type PP, and type APP.26

Figure 1.

Figure 1.

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Three-dimensional models of the internal carotid artery, middle cerebral artery, vertebral artery, and basilar artery indicating where target measurements took place to establish the presence of intracranial dolichoectasia and its components of ectasia and dolichosis.

Clinical data

Baseline clinical features were collected at admission by neurologists’ physicians. Demographic information included age, sex, and self-reported race/ethnic group. Anthropometric data comprised height and weight at presentation. History of arterial hypertension, diabetes, hyperlipidemia, tobacco use, stroke or transient ischemic attack (TIA) prior to the index event, coronary artery disease, chronic kidney disease, and cancer were recorded. Obesity was defined as a body mass index ≥30 kg/m2. In addition, a comprehensive chart review was conducted to determine the presence of inflammatory, inherited and infectious conditions previously associated with IDE (Supplemental Table I).

Assessment of symptomatic IDE

Clinical data and diagnostic tests were reviewed independently by two vascular neurologists to classify stroke patients into etiologic subtypes based on the TOAST criteria.27 In case of discrepancies, stroke subtype was classified by consensus. IDE was considered the most likely pathogenic mechanism when the infarct was located in the territory supplied by an affected artery in the absence of any alternative pathogenic explanation, including the absence of definitive cardioembolic source, extracranial or intracranial atherosclerosis causing ≥50% stenosis in the arteries supplying the affected territory, and any other specific known cause. Infarcts categorized as small-artery occlusion within the territory of a dolichoectatic vessel were reported separately due to the uncertainty whether the mechanism of injury was directly related to the IDE or was due to small-vessel disease.

Statistical analysis

Data analysis was carried out by SAS v9.4 (SAS Institute, Cary, NC). Descriptive statistics were used to report arterial dimensions and the prevalence of IDE, ectasia, and dolichosis among the studied population. A random sample of 25 cases were analyzed by two raters (V.J.D. and M.Z.G.) to estimate the inter-reader reliability. We calculated the intraclass correlation coefficients for arterial diameters, lengths, and TIs, as well as the Cohen’s kappa for the diagnosis of IDE. To test whether baseline clinical features and vascular risk factors were associated with IDE and its components of ectasia and dolichosis, we used linear models for continuous variables and Chi-square or the Fisher exact test for categorical variables, as appropriate. In the multivariable analysis, binary logistic regression models were fitted using the presence of IDE, ectasia, and dolichosis as dependent variables after adjustment for demographics, weight, height, CoW variants, and vascular risk factors. A p-value of <0.05 was considered statistically significant.

Results

Out of 211 consecutive AIS admissions during the 4-month study period, 200 patients with available intracranial vessel imaging (83% CT-angiogram and 17% MR-angiogram) were included in the analysis. Nine individuals without vessel imaging performed during hospitalization and two readmissions were excluded. The mean age of the studied population was 67 ±14 years (range 29-97) and 47.5% were men. Overall, IDE was identified in 24% patients (5% with isolated ectasia, 9.5% with isolated dolichosis, and 9.5% with both ectasia and dolichosis). IDE affecting a single vessel was found in 14 (7%) cases, two vessels in 15 (7.5%), and three or more vessels in 19 (9.5%). Anterior and posterior circulation were equally involved (18% and 16%, respectively), and the BA was the single most common affected artery (11%) (Table 1). Cohen’s kappa for the diagnosis IDE was 0.857 and intraclass correlation coefficients ranged from 0.872-0.967, 0.818-0.888 and 0.939-0.982 for arterial diameters, lengths and TIs, respectively.

Table 1.

Prevalence of ectasia, dolichosis, and dolichoectasia according to arterial segments among 200 patients admitted with acute ischemic stroke.

Mean ± SD Cutoff Ectasia Dolichosis IDE
Left Right Left Right Left Right
Internal Carotid Artery (n=385)*
 Cavernous ICA diameter 5.0 ± 0.8 mm ≥ 6.6 mm
 Terminal ICA diameter 3.5 ± 0.7 mm ≥ 4.9 mm 15 (7.5%) 9(4.5%) 13 (6.5%) 13 (6.5%) 17 (8.5%) 19 (9.5%)
 ICA length 36.2 ± 6.8 mm ≥ 49.7 mm
 ICA tortuosity index 2.3 ± 0.5 ≥ 3.4
Middle Cerebral Artery (n=375)*
 M1 diameter 2.9 ± 0.5 mm ≥ 3.9 mm
 M2 diameter 2.2 ± 0.5 mm ≥ 3.2 mm 7(3.5%) 9(4.5%) 9(4.5%) 11(5.5%) 13(6.5%) 15(7.5%)
 MCA length 26.2 ± 6.8 ≥ 39.8 mm
 MCA tortuosity index 1.2 ± 0.2 ≥ 1.6
Vertebral Artery (n=353)*
 Proximal VA diameter 3.6 ± 0.8 mm ≥ 5.2 mm
 Distal VA diameter 2.5 ± 0.8 mm ≥4.1 mm 8(4.0%) 2(1.0%) 10(5.0%) 7(3.5) 17(8.5%) 8(4.0%)
 VA length 40.7 ± 6.8 ≥54.3 mm
 VA tortuosity index 1.1 ± 0.1 ≥ 1.3
Basilar Artery (n=193)*
 Proximal BA diameter 3.4 ± 0.8 mm ≥ 5.0 mm
 Distal BA diameter 2.8 ± 0.7 mm ≥ 4.1 mm 16
 BA length 31.0 ± 5.4 mm ≥ 41.7 mm 9 (4.5%) (8.0%) 22 (11.0%)
 BA tortuosity index 1.1 ± 0.1 ≥1.3
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*

Missing values due to arterial hypoplasia or occlusion

Abbreviations: BA basilar artery; IDE intracranial dolichoectasia; ICA internal carotid artery; MCA middle cerebral artery; SD standard deviation; VA vertebral artery

Overall, 84.5% of patients had arterial hypertension, 51.5% had diabetes mellitus, 32.5% had hyperlipidemia, 36.5% were current smokers, 32.5% were obese, 31% had a stroke or TIA prior to the index event, and 15.5%, 13%, and 7.5% had history of coronary artery disease, chronic kidney disease, and cancer, respectively. Vascular risk factors prevalence was similar in AIS patients with and without IDE. A greater prevalence of IDE was observed among men (Table 2). Multivariate analyses adjusted for relevant confounders showed an independent association between male sex and IDE (OR=4.2; 95% C.I. 1.7-10.6). Ectasia was associated with older age (OR=3.5; 95%C.I. 1.3-9.5) and male sex (OR=3.7; 95%C.I. 1.2-11.4), and dolichosis, similar to IDE, was more frequent among men (OR=6.4; 95%C.I. 2.3-17.9). Only three IDE cases were associated with an underlying infectious disorder including one patient with acquired immunodeficiency syndrome and two patients with syphilis.

Table 2.

Demographics and prevalence of vascular risk factors in ischemic stroke patients with and without intracranial dolichoectasia, ectasia, and dolichosis.

IDE(−) IDE(+) P-value Ectasia(−) Ectasia(+) P-value Dolichosis(−) Dolichosis(+) P-value
n=152 n=48 n=171 n=29 n=162 n=38
Age, mean ± SD 67.1 ± 14.1 69.6 ± 13.7 0.27 66.6 ± 14.2 73.8 ± 11.4 0.01 67.6 ± 13.9 67.8 ± 14.4 0.94
Male, n (%) 64 (43.1) 31 (64.9) 0.01 76 (44.4) 19 (65.5) 0.04 68 (42.0) 27 (71.1) <0.01
Height, mean ± SD 168.1 ± 8.4 168.9 ± 8.3 0.57 168.0 ± 8.3 169.7 ± 8.4 0.32 168.1 ± 8.6 169.0 ± 7.2 0.55
Weight, mean ± SD 79.1 ± 16.7 81.8 ± 20.1 0.37 79.5 ± 17.1 81.5 ± 20.2 0.58 79.1 ± 17.0 82.53 ± 20.0 0.28
Race/ethnicity,
n (%)
 Caucasian 26 (17.1) 8 (16.7) 0.08 28 (16.4) 6 (20.7) 0.13 28 (17.3) 6 (15.8) 0.36
 Black 47 (30.9) 23 (47.9) 56 (32.8) 14 (48.3) 53 (32.7) 17 (44.7)
 Hispanic 79 (52.0) 17 (35.2) 87 (50.9) 9 (31.0) 81 (50.0) 15 (39.5)
Hypertension, n (%) 127 (83.6) 42 (87.5) 0.51 142 (83.0) 27 (93.1) 0.27 136 (84.0) 33 (86.8) 0.66
Diabetes Mellitus, n (%) 76 (50.0) 27 (56.3) 0.45 85 (49.7) 18 (62.1) 0.22 83 (51.2) 20 (52.6) 0.88
Hyperlipidemia, n (%) 49 (32.2) 16 (33.3) 0.89 56 (32.8) 9 (31.0) 0.86 52 (32.1) 13 (34.2) 0.80
Tobacco use, n (%) 55 (36.2) 18 (37.5) 0.87 62 (36.3) 11 (37.9) 0.86 58 (35.8) 15 (39.5) 0.67
Obesity, n (%) 49 (32.2) 16 (33.3) 0.89 56 (32.8) 9 (31.0) 0.86 50 (30.9) 15 (39.5) 0.31
Previous stroke or TIA, n (%) 48 (31.6) 14 (29.2) 0.75 53 (30.1) 9 (31.0) 1.00 50 (30.9) 12 (31.6) 0.93
History of cancer, n (%) 11 (7.2) 4 (8.3) 0.76 14 (8.2) 1 (3.5) 0.70 12 (7.4) 3 (7.9) 1.00
Coronary artery disease, n (%) 22 (14.5) 10 (20.8) 0.29 23 (13.5) 9 (31.0) 0.03 24 (14.8) 8 (21.1) 0.34
Chronic kidney disease, n (%) 19 (12.5) 7 (14.6) 0.71 19 (11.1) 7 (24.1) 0.07 21 (13.0) 5 (13.2) 1.00
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Abbreviations: IDE intracranial dolichoectasia; SD standard deviation; TIA transient ischemic attack

Etiologic diagnostic evaluation was complete in 197 (98.5%) cases. Cardiac monitoring length median was 6 days (IQR 4-13.3) and 15.5% underwent transesophageal echocardiogram. Stroke etiology was determined in 149 (74.5%) cases: cardioembolism in 51 (25.5%), large-artery atherosclerosis in 59 (29.5%), small-artery occlusion in 29 (14.5%), and other determined etiologies in 10 (5%). Stroke was classified as undetermined in 51 (25.5%) cases, including three patients with competing etiologies and three patients with incomplete evaluation. Using cardioembolic strokes as reference, IDE prevalence was significantly higher across strokes of undetermined etiology (37.3% vs. 17.6%; OR=2.8, 95%C.I. 1.1-6.9) and there was a trend towards higher IDE prevalence in those with small-artery occlusion (27.6% vs. 17.6%; OR=1.8, 95%C.I. 0.6-5.3) (Figure 2).

Figure 2.

Figure 2.

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Presence of intracranial dolichoectasia (IDE) among patients with acute ischemic stroke according to the stroke subtype.

IDE was considered to play a direct role in the pathogenic mechanism of 12 cases initially categorized as of undetermined etiology (6% of the entire cohort). The latter did not include cases with competing mechanisms on injury. Also, the median length of cardiac monitoring was 9.5 days (IQR 5-15.3) and two cases (16.7%) underwent transesophageal echocardiogram without remarkable findings. The median age of symptomatic IDE cases was 72.5 years (range 56-86), men-to-women ratio was 1:1, and invariably had history of arterial hypertension, as well as two or more vascular risk factors. Infarcts topography and proposed mechanisms of injury are summarized in table 3. Of note, three cases (patients 1, 5, and 11) had occlusive thrombus in the IDE culprit vessel, and two out of six cases (patients 4 and 10) with suspected artery-to-artery embolism had filling defects within the IDE vessel suggestive of subocclusive intraluminal thrombi. In addition, six out of eight cases with coexisting IDE and small-artery occlusion had the infarct in the territory supplied by a dolichoectatic artery. The latter represented 21% of all small-artery occlusion strokes and 3% of the study population. Finally, five out of 12 cases with IDE and large-artery atherosclerosis had intracranial stenosis in association of either ectasia or dolichosis of the culprit vessel.

Table 3.

Demographics, vascular risk factors, and infarct characteristics of patients with acute ischemic stroke likely secondary to intracranial dolichoectasia.

Case Age (years) Sex Vascular risk factors Anatomical location Vessel affected Proposed mechanism of injury
1 82 female Hypertension, chronic kidney disease. Entire pons, caudal midbrain, and bilateral cerebellar hemispheres • BA ectasia Thrombosis-in-situ
2 56 male Hypertension, diabetes mellitus. Right middle cerebellar peduncle • Left VA ectasia and dolichosis
• BA ectasia		 Branch artery occlusion
3 78 male Hypertension, diabetes mellitus, hyperlipidemia, obesity, coronary artery disease. Right insular cortex • Right ICA dolichosis Artery-to-artery embolism
4 56 female Hypertension, diabetes mellitus, hyperlipidemia, obesity, previous ischemic stroke. Left frontal cortex • Left ICA dolichosis Artery-to-artery embolism
5 74 male Hypertension, diabetes mellitus, obesity. Right paramedian pons and bilateral cerebellar hemispheres • Right VA ectasia
• BA ectasia		 Thrombosis-in-situ
6 71 female Hypertension, diabetes mellitus, syphilis. Left paramedian pons • Left VA ectasia Artery-to-artery embolism
7 74 female Hypertension, diabetes mellitus, hyperlipidemia, obesity, previous ischemic stroke. Left medial medulla • Left VA dolichosis Branch artery occlusion
8 71 male Hypertension, diabetes mellitus, hyperlipidemia, obesity, coronary artery disease. Left PCA territory • BA ectasia Artery-to-artery embolism
9 70 male Hypertension, diabetes mellitus, previous ischemic stroke, chronic kidney disease. Watershed zone between left MCA and center PCA. • Left ICA dolichosis and ectasia
• Left MCA ectasia		 Hypoperfusion
10 86 female Hypertension, diabetes mellitus, underlying malignancy (colon cancer) Right MCA territory • Right MCA dolichosis Artery-to-artery embolism
11 67 male Hypertension, diabetes mellitus, hyperlipidemia, smoker, obesity, coronary artery disease. Entire pons • Left VA dolichosis and ectasia
• BA dolichosis and ectasia		 Thrombosis-in-situ
12 79 female Hypertension, diabetes mellitus, hyperlipidemia, previous stroke. Left parasagittal frontal cortex • Left ICA ectasia Artery-to-artery embolism
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Abbreviation BA basilar artery; ICA internal carotid artery, MCA middle cerebral artery, PCA posterior cerebral artery, VA vertebral artery

Discussion

The current study reports the IDE prevalence of 24% among AIS patients. Additionally, 6% of AIS cases had IDE affecting the culprit vessel without an alternative pathogenic cause, thus indicating IDE likely played a key role in the mechanism of ischemia. Although the prevalence of vascular risk factors was high across IDE patients, no particular factor was associated with IDE. Intracranial ectasia was independently associated with advanced age, whereas IDE and its individual components (ectasia and dolichosis) were associated with male sex.

Prevalence of IDE varies according to the characteristics of the study population and the diagnostic criteria applied to define dolichoectasia. The GENIC study reported an IDE prevalence of 12% among 510 Caucasians patients with MRI-proven ischemic stroke on the basis of visual impression.23 Other series focused on vertebrobasilar dolichoectasia found a prevalence of 7.6 to 13.2% in stroke patients,2–5 and up to 17 to 18.8% in series confined to patients with posterior circulation stroke.6,7 In the Northern Manhattan Study, 19% of stroke-free participants had at least one abnormally dilated artery based on total cranial volume-adjusted diameters.24 Our series coincides with the aforementioned studies in that IDE is more common condition than previously proposed.28 The higher IDE prevalence in our series is likely attributed to the systematic approach used to define the components of ectasia and dolichosis, as well as the high-risk vascular profile of the studied population.

Ischemic stroke is the most common clinical manifestation and cause of death in individuals with IDE.29,30 However, the role of IDE as a mechanism of cerebral ischemia have been scantily investigated and to date, no large-scale stroke registry has determined the fraction of stroke cases directly related to IDE. In our study, IDE was responsible for a sizable proportion of patients with stroke of undetermined etiology, thus suggesting IDE is a relative common cause of stroke often overlooked during etiologic work-up. In addition, IDE was particularly common in patients with small-artery occlusion and was directly related to the infarct territory in 21% of these cases. The link between IDE and small-vessel disease has been previously reported,31–33 and suggested a common pathogenic mechanism attributed to the abnormal upregulation of metalloproteinase activity.34 Nevertheless, the majority of individuals with IDE and small-artery occlusion in our series had the infarct territory supplied by a dolichoectatic artery, and therefore, a direct mechanistic association such as artery-to-artery embolism or stretching of the small branch vessels is possible. Finally, we found five AIS cases secondary to intracranial stenosis in which IDE was affecting the target vessel. Although IDE has been traditionally considered an atherosclerotic variant, some authors have proposed that atherosclerosis is a consequential effect of abnormal wall shear stress caused by primary vascular dilation and tortuosity,11,35 or rather coincidental.36,37 To date, the association between intracranial atherosclerosis and IDE continues to be a matter of debate.

Individuals with vertebrobasilar dolichoectasia and ischemic stroke have shown to have decreased cerebral blood flow velocities on transcranial Doppler,25,38 FLAIR vascular hyperintensities as a marker of slow arterial flow on brain MRI,39 and lower time to peak on perfusion-weighted imaging,40 therefore indicating that blood stagnation may play an important pathophysiological role leading to the development of cerebral ischemia in these patients. In our series, infarct characteristics among IDE patients suggested that thrombosis-in-situ and artery-to-artery embolism were predominant mechanisms of injury. The latter may have important clinical implications in regards to the appropriate preventive strategies for stroke recurrence among IDE patients. No randomized clinical trial has assessed the optimal preventive strategy for ischemic stroke in IDE patients.

The etiology of IDE is uncertain. Early stages of the disease may involve internal elastic lamina fragmentation followed by intima hyperplasia and neovascularization. The latter may lead to the formation of intramural hematoma with subsequent thrombi recanalization and abnormal vessel growth.10 Recognizing risk factors associated with IDE is essential to understanding the initial trigger of this pathological process. Similar to previous studies,2,23,32,33 our study has shown a relationship between IDE and advanced age suggesting that IDE is the result of an arterial aging. The association between IDE and male sex has also been previously identified,2,23,32 and explained by the privation of estrogen protection on the cerebral vasculature including an anti-inflammatory action and reduction of oxidative stress.41 Other modifiable vascular risk factors such as arterial hypertension, diabetes, smoking, and hyperlipidemia have shown inconsistent results, 2–5,22 thus providing poor insights in IDE physiopathology. In addition, a variety of mechanisms related to underlying disorders such as vacuolization of vascular smooth muscle (i.e. Fabry’s disease and late-onset Pompe’s disease)12,13 and direct injury to the elastic fibers by medial fibrosis (i.e. HIV infection and meningovascular syphilis)17,18 have been described. In our series, only three cases were infection-related, indicating that IDE mainly originates as a spontaneous arteriopathy.

The current study is novel as it established the presence of both ectasia and dolichosis by employing objective parameters inclusive of proximal intracranial arteries of the anterior and posterior circulation. Moreover, the use of semi-automatic vessel analysis resulted in excellent inter-reader reliability for the estimation of arterial dimensions. We used two standard deviations above the population mean to identify the most extreme phenotypes of IDE. However, due to the empirical rule of normal distributions, a predictable fraction of arteries is foreseen to be classified as abnormal when definitions based on measures of spread are applied. Moreover, cutoff values were dependent of the study population characteristics and generalizability of our IDE definition should be taken with caution. In addition, we were unable to adjust arterial diameters to head size, a variable that has shown to directly relates to vessel dimensions.24 Ideally, cutoffs to define pathological intracranial vessel enlargement should rely on hemodynamically significant effects on cerebral blood flow or, alternatively, on established increased risk of stroke. Future studies that correlate arterial dimensions with such outcomes are warranted to reach a reliable definition of IDE.

Limitations of our study are related to its retrospective design and a relatively small sample size. Data collection was restricted by the accuracy of chart documentation. Although every patient underwent basic etiologic stroke work up, additional diagnostic evaluations such as transesophageal echocardiogram or prolonged cardiac monitoring beyond hospitalization were not performed systematically. Similarly, we performed a comprehensive chart review to identify underlying conditions associated with IDE. However, not all patients were screened for conditions previously associated with IDE, and detailed medical history other than vascular risk factors was not always available. Furthermore, we lack a control group representative of the general population that could contribute to the identification of risk factors associated with IDE.

In conclusion, we report that IDE is common among patients with AIS and likely plays a direct pathogenic role in a noteworthy fraction of AIS cases. Future studies should focus on determining the mechanisms by which IDE affects cerebral hemodynamics and causes stroke, as well as on factors that can be modified to prevent ischemia in patients with IDE. Prospective IDE studies are needed to determine arteriopathy progression in order to identify disease-specific strategies for stroke treatment and prevention.

Supplementary Material

Supplemental Publication Material

Acknowledgments

We want to thank Jonathan Amodio, BS and Viviana Jimenez, BS for their help in data collection.

Source of Funding

None

Disclosures

Dr. Del Brutto has salary support from the Florida Regional Coordinating Center for the NINDS Stroke Trials Network; Dr. Gutierrez is funded by grants from the National Institute of Aging. Dr. Goryawala have no disclosures; Dr. Sacco has institutional grant support from NIH, National Center for Advancing Translational Sciences, National Institute on Minority Health and Health Disparities, and The Florida Department of Health; Dr. Rundek is funded by grants from NIH and the National Center for Advancing Translational Sciences; Dr. Romano has research salary support from NIH/NINDS for the MyRIAD study.

Abbreviations

AIS

acute ischemic stroke

CoW

Circle of Willis

IDE

intracranial dolichoectasia

TI

tortuosity index

TIA

transient ischemic attack

TOAST

Trial of Org 10172 in Acute Stroke Treatment

Footnotes

Supplemental Materials

Expanded Materials & Methods

Online Supplemental Table I

References

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