Arteriolar Tortuosity Research Articles

Correlation and Reproducibility of Retinal Vascular Geometric Measurements for Stereoscopic Retinal Images of the Same Eyes

Purpose: To assess the correlation and reproducibility of retinal vascular geometric measurements obtained from two stereo-paired fundus images.Methods: Thirty stereoscopic pairs of color optic disc-centered photographs from the Blue Mountains Eye Study were analyzed. Side-by-side grading was performed by a single grader, using semi-automated computer software to quantify the following retinal geometric parameters: (1) retinal arteriolar/venular caliber (CRAE/CRVE); (2) arteriole-to-venule ratio (AVR); (3) branching angle; and (4) tortuosity. We used Pearson correlation (r), intra-class correlation coefficient (ICC), and Bland-Altman plots to assess within-pair correlation and reproducibility for each parameter measured.Results: Inter- and intra-grader r and ICC were high (all r > 0.90 and ICC > 0.90), except for branching angle (ICCs between 0.69–0.83). There was no significant difference between within-pair means of all retinal vascular geometric parameters, before and after excluding poor quality images. CRAE, CRVE, AVR, and arteriolar and venular tortuosity showed very high within-pair correlation and agreement (all r > 0.80 and all ICC > 0.90 respectively). Arteriolar and venular branching angles demonstrated moderate within-pair correlation (r = 0.65 and r = 0.62, respectively) and within-pair agreement (ICC = 0.76 and ICC = 0.77, respectively).Conclusions: Use of computer-assisted software to measure retinal vascular geometric parameters from paired fundus images was highly repeatable and is robust to differences in photographic angles of paired stereo images. Such measurements can be applied to evaluate temporal changes in longitudinal studies.

361 RETINAL MICROVASCULAR GEOMETRIC PARAMETERS IN STROKE

Background: Retinal vasculature can reflect microvascular damage from hypertension, and may be a marker of target end-organ damage. We studied the relationship of a range of retinal vascular structural parameters with stroke and its major subtypes. Methods: We conducted a case-control study of acute stroke cases recruited from a tertiary hospital in Singapore. Clinical assessment included neuroimaging and retinal photography, classifying strokes by TOAST criteria. Non-stroke healthy controls selected from the Singapore Epidemiology of Eye Disease program were matched by age, gender and race. Retinal vascular parameters (retinal vascular caliber, tortuosity, fractal dimension and branching angle) were assessed using a semi-automated computer-based program. Logistic regression models were constructed adjusting for age, gender, and race; and additionally for smoking, hypertension, diabetes and hypercholesterolemia status. Results: A total of 563 ischemic stroke cases and 576 controls were included in this analysis. Major subtypes of ischemic strokes included 264 lacunar, 186 large artery and 55 cardioembolic strokes. Narrower arteriolar caliber (multivariable-adjusted odds ratio (OR) per standard deviation (SD) decrease: 2.18; 95%CI: 1.83-2.61), decreased arteriolar fractal dimension (OR per SD decrease: 2.35; 95%CI: 1.95-2.82) and venular fractal dimension (OR per SD decrease: 1.73; 95%CI: 1.48-2.05), and increased arteriolar tortuosity (OR per SD increase: 1.57; 95%CI: 1.25-1.97) and venular tortuosity (OR per SD increase: 1.53; 95%CI: 1.29-1.80) were associated with stroke. Similar associations were found for lacunar, large artery and cardioembolic strokes. Conclusions: Stroke cases were more likely to have altered retinal microvasculature, reflecting microvascular changes that may be independent of hypertension and other traditional risk factors.

Serum Apolipoproteins Are Associated With Systemic and Retinal Microvascular Function in People With Diabetes

Serum apolipoprotein (apo)AI and -B have been shown to be associated with diabetic retinopathy, but the underlying mechanisms are unclear. We investigated whether apoAI and apoB levels are associated with measures of systemic and retinal microvascular function in patients with diabetes. We recruited 224 diabetic patients (85 type 1 and 139 type 2) and assessed serum lipids and lipoproteins from fasting blood, skin responses to sodium nitroprusside (endothelium independent) and acetylcholine (ACh) (endothelium dependent) iontophoresis, flicker-light–induced retinal vasodilatation, and retinal vascular tortuosity. After adjustment for age and sex, every SD increase in apoAI level was associated with ACh-induced skin perfusion (mean change 1.27%; P < 0.001 for apoAI) and flicker-light retinal arteriolar vasodilatation (0.33%; P = 0.003) and was associated inversely with arteriolar tortuosity (−2.83 × 10−5; P = 0.044). Each SD increase in apoB was associated with arteriolar tortuosity only (1.75 × 10−5; P = 0.050). These associations, except for apoB, remained in multivariate models. Serum apoAI was associated with increased vasomotor responsiveness to ACh and flickering light and inversely related to retinal vessel tortuosity—a characteristic that has both structural and functional dimensions. These findings provide additional insights into the potential mechanisms of apos in the pathogenesis of diabetic retinopathy and other diabetic microvascular complications.

Digital image analysis in retinopathy of prematurity: A comparison of vessel selection methods

To evaluate vessel selection methods to distinguish between eyes with and without retinopathy of prematurity (ROP) and between different stages of ROP when quantifying the associated vessel changes in width and tortuosity semiautomatically from digital retinal images. Color digital images from 75 infants screened for ROP were cropped to a standardized diameter of 240 pixels and evaluated by semiautomated vessel analysis software, Computer-Aided Image Analysis of the Retina (CAIAR), to measure retinal vessel width and tortuosity. Two methods of vessel selection were used: (1) clinical observer selecting the most prominent arteriole or venule in each retinal quadrant (4-vessel analysis) and then separately the 4 most prominent arterioles and venules from each quadrant (8-vessel analysis); (2) CAIAR selecting, regardless of retinal quadrant, the 4 widest or most tortuous arterioles or venules. Selected vessels were measured by CAIAR for tortuosity and width. When comparing ROP stages, whether observer or CAIAR selected and whether 4 or 8 vessels were analyzed, we found that arteriolar tortuosity was significantly greater with advancing ROP stage for stage 0 versus stage 2; stage 0 or 1 versus stage 3; stages 1+2 combined versus stage 3; and stage 0 versus 1+2+3 combined (P < 0.01). Venular tortuosity was significantly greater with advancing ROP stage for stage 0 versus stage 3 and stage 0 versus stages 1 and 2+3 combined (P < 0.01). Width parameters did not help us to distinguish between stages. Distinguishing between arterioles and venules is not necessary to differentiate stage 0 ROP from stage 2 or 3 ROP when one is using CAIAR. Tortuosity shows more promise than width at providing a reliable vessel parameter for distinguishing between eyes without and with ROP.

Abstract 507: Effects of Arteriole Tortuosity on Platelet Activation and Collision in Thrombosis

Introduction: Thrombosis and artery tortuosity are major contributors to cardiovascular disease. A fundamental gap exists in understanding how tortuosity regulates thrombosis through modification of blood flow. Accordingly, the objective of this research was to elucidate the physical mechanisms of artery tortuosity in thrombus formation. Hypothesis: An increase in arteriole tortuosity promotes platelet adhesion to the convex surface of the endothelium by increasing platelet collisions and shear-induced platelet activation. Methods: Platelet-mediated thrombosis was computationally simulated in 100-μm diameter vessels with sinusoidal shapes. The model used a discrete element algorithm for transport, collision, shear-induced activation, and receptor-ligand adhesion and aggregation of individual platelets. For a given simulation, platelets were set to be either (1) unactivated, (2) pre-activated, or (3) activated by shear stress. Tortuosity values (ratio of amplitude to wavelength) were set from 0 to 0.23, average velocity was 0.1 cm s -1 , and Reynolds number was 0.1. Results: For cases with platelets subject to shear-induced activation, increased tortuosity increased platelet activation, and platelets adhered to the convex endothelial wall, where shear stress was highest, while negligible numbers of platelets contacted the concave wall. For cases in which all platelets were previously activated, however, considerable platelet adhesion occurred on the concave wall. For cases with unactivated platelets in tortuous arterioles, as tortuosity increased, platelet contacts with the concave wall decreased until reaching the same value as the convex wall. Additionally, for cases with unactivated platelets, collisions between platelets was highest for the straight vessel, and collisions with walls throughout the entire arteriole were relatively negligible for straight and highly tortuous arterioles, but much larger for arterioles with intermediate tortuosity. Conclusions: Shear-induced activation due to tortuosity generates platelet adhesion to the convex wall of arterioles. Increased tortuosity increases platelet activation, though the relationship between tortuosity and platelet collisions is less evident.

Migraine and small vessel diseases

It is remarkable that migraine is a prominent part of the phenotype of several genetic vasculopathies affecting small cerebral vessels, including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy and hereditary infantile hemiparesis, retinal arteriolar tortuosity and leucoencephalopathy. Moreover, several studies have reported an association between migraine and white matter lesions or clinically silent infarct-like abnormalities in the posterior circulation. In this review, we focus on genetic vasculopathies associated with migraine and speculate about the pathophysiological mechanism that can explain this comorbidity.

Novel versus traditional risk markers for diabetic retinopathy

To explore the relative contribution of novel and traditional risk markers for diabetic retinopathy (DR). A clinic-based study of 224 diabetic patients (85 type 1, 139 type 2) from a diabetes clinic was performed. DR was graded from fundus photographs according to the Airlie House Classification system and classified as absent or present (at least ETDRS level 14). Novel risk markers assessed included serum apolipoprotein (Apo) AI and B, skin microvascular responses to acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) iontophoresis, flicker-light-induced retinal vasodilation and retinal vascular tortuosity. Relative contribution was determined by semi-partial correlation coefficient generated from a logistic regression model containing all traditional and novel risk markers simultaneously. There were 144 (64.3%) participants with DR. Of the novel markers, ApoAI, flicker-light-induced vasodilation and retinal arteriolar tortuosity were significantly associated with DR, independently of traditional measures (all p < 0.03). Diabetes duration contributed most (51%) to the risk of DR, followed by ApoAI (16%), systolic blood pressure (13%), retinal arteriolar tortuosity (8%) and flicker-light-induced venular and arteriolar dilation (3% and 0.5%, respectively). ApoAI and retinal arteriolar tortuosity made considerable contributions to DR risk, independently of traditional risk markers. Findings from this study suggest that serum ApoAI and retinal arteriolar tortuosity may be novel and independent risk markers of DR.

Retinal Arteriolar Tortuosity is Associated With Retinopathy and Early Kidney Dysfunction in Type 1 Diabetes

To examine the association of retinal vessel tortuosity with diabetic retinopathy and early nephropathy in type 1 diabetes. Cross-sectional. A total of 1159 participants with type 1 diabetes aged 12 to 20 years, attending diabetes clinics in Children's Hospital at Westmead, Sydney, Australia between 1990 and 2002, were included. Retinal photography and clinical examinations were performed during the baseline visit to assess diabetic retinopathy and albumin excretion rate (AER). Retinal vessel tortuosity was measured from digitized retinal photographs using a semi-automated computer program by a single grader masked to participants' characteristics. Diabetic retinopathy was defined as ETDRS level ≥21 (mild nonproliferative retinopathy) and early kidney dysfunction was defined as AER ≥7.5 μg/min. Of 944 patients (81.4%), 85 (9.0%) had signs of retinopathy only, 250 (26.5%) had early kidney dysfunction only, and 85 (9.0%) had both retinopathy and early kidney dysfunction. In multivariate analysis, higher arteriolar tortuosity was associated with retinopathy (odds ratio [OR] 2.01, 95% confidence interval [CI] 1.23-3.29, the highest quartile vs the remaining 3 quartiles), early kidney dysfunction (OR 1.56, 95% CI 1.06-2.28, per standard deviation [SD] increase), or coexistence of both complications (OR 1.96, 95% CI 1.21-3.24, the highest quartile vs the remaining 3 quartiles). Greater retinal arteriolar tortuosity was independently associated with retinopathy and early stage of nephropathy in type 1 diabetes. These findings may offer the potential of quantitative measurement of retinal vessel tortuosity for diabetic complication risk assessment.

Computer-assisted image analysis of temporal retinal vessel width and tortuosity in retinopathy of prematurity for the assessment of disease severity and treatment outcome

To quantify the severity of retinopathy of prematurity (ROP) through temporal retinal vessel diameter and tortuosity by the use semiautomated analysis and to evaluate the effects of laser treatment on retinal vessel measurements. A total of 176 RetCam digital fundus images from 63 infants diagnosed with ROP between January 2005 and December 2008 were retrospectively analyzed with Retinal Vessel Measurement V5.8 software. Patients were classified into 1 of 3 groups: stage 1 and 2 (Group 1), stage 3 not requiring treatment (Group 2), and stage 3 requiring treatment (Group 3). Diameter and tortuosity of the 4 major temporal retinal arteries and veins close to the optic disk were quantified. Tortuosity was measured as central (within 2 disk diameters from the center of the optic disk) and paracentral (from 2 to 4 disk diameters). For Group 3, measurements of vessels immediately before treatment and all follow-up post-treatment measurements of vessels were analyzed. Differences in central and paracentral arteriolar tortuosity were pronounced. The average central arteriolar tortuosities were 1.12 ± 0.018 for Group 1, 1.13 ± 0.018 for Group 2, and 1.32 ± for Group 3; the paracentral arteriolar tortuosities were 1.11 ± 0.019 for Group 1, 1.12 ± 0.019 for Group 2, and 1.31 ± 0.02 for Group 3. In the post-treatment analysis of Group 3 patients, significant reductions in all vascular measurements were observed compared to pre-treatment, except for central and paracentral vein tortuosity. Computerized systems can be used to objectively assess differences in vascular parameters between ROP stages.

Quantitative and qualitative retinal microvascular characteristics and blood pressure

The present study examined the effects of blood pressure on a spectrum of quantitative and qualitative retinal microvascular signs. Retinal photographs from the Singapore Malay Eye Study, a population-based cross-sectional study of 3280 (78.7% response) persons aged 40-80 years, were analyzed. Quantitative changes in the retinal vasculature (branching angle, vascular tortuosity, fractal dimension, and vascular caliber) were measured using a semi-automated computer-based program. Qualitative signs, including focal arteriolar narrowing (FAN), arteriovenous nicking (AVN), opacification of the arteriolar wall (OAW), and retinopathy (e.g., microaneurysms, retinal hemorrhages), were assessed from photographs by trained technicians. After excluding persons with diabetes and ungradable photographs, 1913 persons provided data for this analysis. In multivariable linear regression models controlling for age, sex, BMI, use of antihypertensive medication, and other factors, retinal arteriolar branching asymmetry ratio, arteriolar tortuosity, venular tortuosity, fractal dimension, arteriolar caliber, venular caliber, FAN, AVN, and retinopathy were independently associated with mean arterial blood pressure. In contrast, arteriolar/venular branching angle, venular branching asymmetry ratio and OAW were not related to blood pressure. Retinal arteriolar caliber (sβ = -0.277) and FAN (sβ = 0.170) had the strongest associations with mean arterial blood pressure, and higher blood pressure levels were associated with increasing number of both quantitative and qualitative retinal vascular signs (P trend <0.001). Elevated blood pressure is associated with a spectrum of quantitative and qualitative retinal vascular signs, with the number of signs increasing with higher blood pressure levels.

Retinal Arteriolar Tortuosity and Cardiovascular Risk Factors in a Multi-Ethnic Population Study of 10-Year-Old Children; the Child Heart and Health Study in England (CHASE)

To examine the association between cardiovascular risk factors and retinal arteriolar tortuosity in a multi-ethnic child population. Cross sectional study of 986 UK primary school children of South Asian, black African Caribbean, and white European origin aged 10 to 11 years. Anthropometric measurements and retinal imaging were carried out and a fasting blood sample collected. Digital images of retinal arterioles were analyzed using a validated semiautomated measure of tortuosity. Associations between tortuosity and cardiometabolic risk factors were analyzed using multi-level linear regression, adjusted for gender, age, ethnicity, arteriole branch status, month, and school. Levels of arteriolar tortuosity were similar in boys and girls and in different ethnic groups. Retinal arteriolar tortuosity was positively associated with levels of triglyceride, total and LDL cholesterol, and systolic and diastolic blood pressure. One standard deviation increases in these risk factors were associated with 3.7% (95% CI: 1.2%, 6.4%), 3.3% (0.9%, 5.8%), 3.1% (0.6%, 5.6%), 2.0% (-0.3%, 4.2%), and 2.3% (0.1%, 4.6%) increases in tortuosity, respectively. Adiposity, insulin resistance, and blood glucose showed no associations with tortuosity. Established cardiovascular risk factors, strongly linked to coronary heart disease in adulthood, may influence retinal arteriolar tortuosity at the end of the first decade of life.

Retinal vascular tortuosity in persons with diabetes and diabetic retinopathy

The aim of this hypothesis was to examine the association of retinal vessel tortuosity with diabetes and diabetic retinopathy (DR). A clinic-based study of 327 participants (224 with diabetes and 103 non-diabetic controls) aged ≥ 18 years. DR was graded from fundus photographs according to the modified Airlie House Classification system and categorised into mild non-proliferative DR (NPDR), moderate NPDR and vision-threatening DR (VTDR). Retinal vessel tortuosity was measured from disc-centred retinal photographs. Measurements were taken, using a semi-automated computer program by a single grader, of arterioles and venules within 0.5 to 2 disc diameters away from the optic disc. There were 114 (44%) participants with DR. In the multivariate analysis, retinal arteriolar and venular tortuosity were increased in participants with diabetes without DR (mean difference 12.4 × 10(-5) and 13.3 × 10(-5), respectively; both p < 0.05) and in those with DR (mean difference 15.4 × 10(-5) and 15.0 × 10(-5), respectively; both p < 0.01) compared with non-diabetic participants. Among participants with diabetes, increased arteriolar tortuosity was significantly associated with mild NPDR (OR 1.53, 95% CI 1.03-2.05, per SD increase in arteriolar tortuosity) and moderate NPDR (OR 1.67, 95% CI 1.10-2.55) but not VTDR (OR 0.91, 95% CI 0.54-1.54). No association with DR was found for venular tortuosity. Persons with diabetes had more tortuous retinal vasculature than persons without diabetes. In persons with diabetes, increased arteriolar tortuosity was associated with mild and moderate stages of DR. This suggests that retinal vascular tortuosity might be an early indicator of microvascular damage in diabetes; thus, further investigation is indicated.

Retinal vessel analysis in familial retinal arteriolar tortuosity

BACKGROUND: Familial retinal arteriolar tortuosity (fRAT) is an autosomal dominant disorder characterized by marked tortuosity of second- and third-order retinal arteries with normal first-order arteries and venous system. In most reported cases of this rare disease no other vascular malformations or associated systemic diseases have been found. It can be complicated by retinal hemorrhages after minor stress or trauma, but prognosis is usually excellent. MATERIAL AND METHODS: To assess function of retinal vessels in this disorder we performed a complete ophthalmological examination including fluorescein and indocyanin green angiography in a patient with fRAT. For static and dynamic retinal vessel analysis we used the Dynamic Vessel Analyzer both in the patient with fRAT and in an age-matched control group of 10 healthy male subjects. RESULTS: Ophthalmologic examination showed an extremely corkscrew-shaped tortuosity of small second- and third-order arterioles on both eyes and a small preretinal hemorrhage in the left eye. In the patient with fRAT, the arteriolar-to-venular ratio was similar to that of the control group and flicker-induced change of vessel diameter did not differ from the controls in both retinal arterioles and venules. CONCLUSIONS: Results from retinal vessel analysis suggest that patients with fRAT have normal endothelial function and regulation of vessel diameter.

Computer-Based Image Analysis for Plus Disease Diagnosis in Retinopathy of Prematurity

Presence of plus disease in retinopathy of prematurity (ROP) is an important criterion for identifying ROP requiring treatment. Plus disease is defined by a standard published photograph selected more than 20 years ago by expert consensus. However, diagnosis of plus disease has been shown to be subjective and qualitative. Computer-based image analysis using quantitative methods has potential to improve the objectivity of plus disease diagnosis. The objective was to review the published literature involving computer-based image analysis for ROP diagnosis. The PubMed and Cochrane library databases were searched for the keywords "retinopathy of prematurity" AND "image analysis" AND/OR "plus disease." Reference lists of retrieved articles were searched to identify additional relevant studies. All relevant English-language studies were reviewed. There are four main computer-based systems-ROPtool (area under the receiver operating characteristic curve [AUROC], plus tortuosity 0.95, plus dilation 0.87), RISA (AUROC, arteriolar TI 0.71, venular diameter 0.82), Vessel Map (AUROC, arteriolar dilation 0.75, venular dilation 0.96), and CAIAR (AUROC, arteriole tortuosity 0.92, venular dilation 0.91)-attempting to objectively analyze vessel tortuosity and dilation in plus disease in ROP. Some show promise for identification of plus disease using quantitative methods. This has potential to improve the diagnosis of plus disease and may contribute to the management of ROP using both traditional binocular indirect ophthalmoscopy and image-based telemedicine approaches.

Comparison of expert graders to computer-assisted image analysis of the retina in retinopathy of prematurity

AimsTo determine correlation of width and tortuosity between expert graders and computer-assisted image analysis of the retina in narrow-field images of eyes with retinopathy of prematurity.Methods11 digital images were selected...

Familial retinal arteriolar tortuosity associated with retinal and vitreous hemorrhages.

The purpose of this study was to report a patient with familial retinal arteriolar tortuosity who presented with both retinal and vitreous hemorrhages. This was a single case report. A young woman affected by severe spina bifida with myelomeningocele and hydrocephalus presented with a 4-month history of blurred vision in both eyes. The patient had a history of severe constipation. Fundus examination of both eyes showed tortuosity of the retinal arterioles and multiple hemorrhages throughout the fundus at the sub-, intraretinal, subhyaloid, and intravitreal levels. The bleeding was likely because of a Valsalva effect. Familial retinal arteriolar tortuosity is a rare disease characterized by the selective tortuosity of the second- and third-order retinal arterioles in the macula and peripapillary area. Patients may experience episodes of vision loss secondary to retinal hemorrhages. To our knowledge, this is the first report of vitreous hemorrhage in a patient with familial retinal arteriolar tortuosity.

Retinal Vascular Tortuosity, Blood Pressure, and Cardiovascular Risk Factors

To examine the relationship of retinal vascular tortuosity to age, blood pressure, and other cardiovascular risk factors. Population-based, cross-sectional study. A total of 3280 participants aged 40 to 80 years from the Singapore Malay Eye Study (78.7% response rate). Retinal arteriolar and venular (vascular) tortuosity were quantitatively measured from fundus images using a computer-assisted program. Retinal vascular tortuosity was defined as the integral of the curvature square along the path of the vessel, normalized by the total path length. Data on blood pressure and major cardiovascular disease (CVD) risk factors were collected from all participants. Retinal arteriolar and venular tortuosity. A total of 2915 participants contributed data to this study. The mean (standard deviation) and median were 2.99 (1.40) and 2.73 for retinal arteriolar tortuosity (×10(4)), and 4.64 (2.39) and 4.19 for retinal venular tortuosity (×10(4)), respectively. Retinal venules were significantly more tortuous than retinal arterioles (P<0.001). In multivariable-adjusted linear regression models, less arteriolar tortuosity was independently associated with older age, higher blood pressure, higher body mass index (BMI), and narrower retinal arteriolar caliber (all P<0.05); greater venular tortuosity was independently associated with younger age, higher blood pressure, lower high-density lipoprotein (HDL) cholesterol level, and wider retinal venular caliber (all P<0.05). Retinal arteriolar tortuosity was associated with older age and higher levels of blood pressure and BMI, whereas venular tortuosity was also associated with lower HDL level. The quantitative assessment of retinal vascular tortuosity from retinal images may provide further information regarding effects of cardiovascular risk factors on the retinal vasculature.

ACUTE URINARY RETENTION DUE TO A NOVEL COLLAGEN COL4A1 MUTATION

The gene COL4A1 encodes the α1 chain of type IV collagen, a basement-membrane protein implying vascular parietal strength. Mutations in the gene COL4A1 have been described in families with diffuse small-vessel disease of the brain, resulting in perinatal stroke, congenital porencephaly, extensive leukoencephalopathy, intracerebral hemorrhage, and retinal arteriolar tortuosity.1–4 Our observation extends the clinical and magnetic resonance (MR) phenotype of COL4A1 mutation. ### Case reports. A 21-year-old man without neurologic medical history presented with acute urinary retention. He had a right amblyopia due to a congenital strabismus surgically treated in childhood. Clinical examination showed brisk lower limb reflexes and a left Babinski sign. Blood pressure was normal. The Mini-Mental State Examination score was strictly normal. The patient declined further neuropsychological testing. Brain CT showed diffuse leukoencephalopathy and multiple supratentorial microcalcifications (figure, A). Brain MRI revealed widespread white matter hyperintensities on T2 and fluid-attenuated inversion recovery sequences, dilated perivascular spaces, and lacunar infarctions. Leukoencephalopathy involved the cerebral periventricular and cerebellar deep white matter (figure, B). Multiple microbleeds were seen on gradient echo sequences, involving brainstem and supratentorial white matter (figure, C). MR angiography of cervical and intracranial arteries was normal, as was spinal …

More on Clinical Renal Genetics

The clinical heterogeneity of genetic diseases characterized by well identified mutations is a striking feature. The diseases related to COL4A1 mutations are a new example of this statement. The COL4A1 gene codes for the α1 chain of type IV collagen (α1(IV)), a major ubiquitous component of basement membranes. Mutations in this gene were first reported by neurologists in families with autosomal dominant forms of porencephaly. The porencephalic cavity is caused by cerebral hemorrhage that occurred during the intrauterine or neonatal period. A broad range of neurologic features have been reported, including infantile hemiplegia, mental retardation, and hemorrhagic strokes in children or in adults that are triggered by trauma or anticoagulation. In another group of patients, cerebral small vessel disease (CSVD) predominates, with leukoencephalopathy, lacunar infarcts, and micro- or macrobleeds without porencephaly. Various eye abnormalities may be found, including retinal arteriolar tortuosity, cataract, or anterior segment dysgenesis of the eye (Axenfeld–Rieger anomaly). This CSVD is reminiscent of the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) because of mutations in the NOTCH 3 receptor. Rare cases of CADASIL syndrome associated with renal involvement have been reported. Electron microscopic analysis showed pathognomonic granular osmiophilic material in cerebral, cutaneous, and intrarenal arteries. Immunohistochemistry using an antibody specific for the NOTCH 3 ectodomain showed positive granular staining in the same vessels, whereas no staining was found in a patient with common nephroangiosclerosis (1). In addition, hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS) was reported in 1997 and is caused by mutations in the TREX1 transcription factor (2). This represents a distinctive subtype of retinal vasculopathy with cerebral leukodystrophy. The third mode of presentation of COL4A1 mutations has been described by Plaisier et al., and the patients first presented with renal disease (3). This autosomal dominant entity has been named HANAC syndrome, or hereditary angiopathy with nephropathy, aneurysm, and muscle cramps (3). Mutations affect glycine residues in close proximity in exons 24 and 25 within the triple-helix domain of the protein. The main phenotypic features encompass a nephropathy with hematuria or bilateral renal cysts, a muscular disease with cramps, and retinal arterial tortuosity. Skin and kidney biopsies show by electron microscopy abnormal thickening, multilamination, and/or focal disruption of the basement membranes. In their recent study, Alamovitch et al. collected data on the neurologic condition of 14 HANAC patients (ranging from 22 to 57 years of age) belonging to three unrelated families. Nine were interviewed and examined. For the four deceased subjects (ages at death ranging from 60 to 69 years), the causes of death were not neurologic. One patient declined to participate in this study. No patient had infantile hemiparesia, mental retardation, history of stroke, or spontaneous subarachnoid or intracerebral hemorrhage. Only two patients had a history of cerebrovascular injury: acute cerebellar ataxia in one and posttraumatic cerebromeningeal hemorrhage in the other. In nine patients, brain magnetic resonance imaging (MRI) was performed and all showed at least one abnormality. No porencephaly was observed. Multiple intracranial aneurysms (ICAs) were found in three patients; these ICAs were small, asymptomatic, and localized on the intracranial carotid at the level of the carotid siphon. Seven patients had MRI abnormalities consistent with CSVD dominated by leukoencephalopathy. No cortical involvement was detected. HANAC syndrome therefore constitutes a new monogenic cause of familial ICAs. Of interest, two other inherited diseases with syndromic ICAs have been identified: autosomal dominant polycystic kidney disease and Ehlers–Danlos syndrome type IV with mutations in COL3A1. Regarding diagnosis, skin vessels changes have been described in three autosomal dominant angiopathies: CADASIL, HERNS, and HANAC. Skin biopsy analysis may provide a cost-effective guide before practicing an expensive and time-consuming gene screening. These entities such as HANAC or CADASIL syndromes can be considered as “systemic basalopathies.” They also reopened the field of renal angiopathies/nephrosclerosis/nephroangiosclerosis by using new tools of investigation and by suggesting more pathophysiological heterogeneity than previously thought.

Alterations in Retinal Microvascular Geometry in Young Type 1 Diabetes

OBJECTIVETo describe retinal microvascular geometric parameters in young patients with type 1 diabetes.RESEARCH DESIGN AND METHODSPatients with type 1 diabetes (aged 12–20 years) had clinical assessments and retinal photography following standardized protocol at a tertiary-care hospital in Sydney. Retinal microvascular geometry, including arteriolar and venular tortuosity, branching angles, optimality deviation, and length-to-diameter ratio (LDR), were measured from digitized photographs. Associations of these geometric characteristics with diabetes duration, A1C level, systolic blood pressure (SBP), and other risk factors were assessed.RESULTSOf 1,159 patients enrolled, 944 (81.4%) had gradable photographs and 170 (14.7%) had retinopathy. Older age was associated with decreased arteriolar (P = 0.024) and venular (P = 0.002) tortuosity, and female subjects had larger arteriolar branching angle than male subjects (P = 0.03). After adjusting for age and sex, longer diabetes duration was associated with larger arteriolar branching angle (P ≤ 0.001) and increased arteriolar optimality deviation (P = 0.018), higher A1C was associated with increased arteriolar tortuosity (>8.5 vs. ≤8.5%, P = 0.008), higher SBP was associated with decreased arteriolar LDR (P = 0.002), and higher total cholesterol levels were associated with increased arteriolar LDR (P = 0.044) and decreased venular optimality deviation (P = 0.044). These associations remained after controlling for A1C, retinal vessel caliber, and retinopathy status and were seen in subjects without retinopathy.CONCLUSIONSKey diabetes-related factors affect retinal microvascular geometry in young type 1 diabetes, even in those without evidence of retinopathy. These early retinal alterations may be markers of diabetes microvascular complications.