Creating new guidelines on how best to treat foot symptoms in people with EB.

Epidermolysis bullosa (EB) is a complex rare condition that affects the skin and many parts of the body. Those born with EB have skin so fragile they are called 'butterfly children', their skin is quite simply as fragile as the wing of a butterfly. In the UK it is estimated that there are more than 5,000 people living with EB and 500,000 worldwide. Little clinical guidance for care existed until DEBRA International started a programme to develop clinical practice guidelines (CPGs). There were no previous guidelines and few published studies on foot care in EB so treatment decisions were largely based on individual opinion and experience. The panel - made up of clinical experts and people living with EB representing Australia, the UK, and the USA - aimed to describe foot problems in people of all ages with EB, and summarise current evidence and management. The authors used a logical podiatric (foot) care literature review focussed on patients with EB. The authors found that the evidence in this area was limited but several interventions (treatments) currently practised by podiatrists show positive outcomes. The study allowed the group to make recommendations on how to treat foot and nail disorders in patients with EB. Furthermore, the authors concluded that further research is needed. This is a summary of the study: Foot care in epidermolysis bullosa: evidence-based guideline.

Foot care in epidermolysis bullosa: evidence-based guideline.

This guideline was designed to provide service providers and users with an evidence-based set of current best practice guidelines for people and their families and carers, living with epidermolysis bullosa (EB). A systematic literature review relating to the podiatric care of patients with EB was undertaken. Search terms were used, for which the most recent articles relating to podiatric treatment were identified from as early as 1979 to the present day, across seven electronic search engines: MEDLINE, Wiley Online Library, Google Scholar, Athens, ResearchGate, Net and PubFacts.com. The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used. The first guideline draft was analysed and discussed by clinical experts, methodologists and patients and their representatives at four panel meetings. The resulting document went through an external review process by a panel of experts, other healthcare professionals, patient representatives and lay reviewers. The final document will be piloted in three different centres in the U.K. and Australia. Following an EB community international survey the outcomes indicated six main areas that the community indicated as a priority to foot management. These include blistering and wound management, exploring the most suitable footwear and hosiery for EB, management of dystrophic nails, hyperkeratosis (callus), maintaining mobility and fusion of toes (pseudosyndactyly). The evidence here is limited but several interventions currently practised by podiatrists show positive outcomes.

Variation associated with measurement of retinal vessel diameters at different points in the pulse cycle.

BACKGROUND/AIMS: To assess the variability in retinal vessel measurements at different points in the pulse cycle. METHODS: A healthy white male aged 19 years had 30 digitised images taken at three distinct points in the pulse cycle over a one hour period. A pulse synchronised ear clip trigger device was used to capture images at the desired point in the pulse cycle. Two trained graders measured the retinal vessel diameter of one large arteriole, one large venule, one small arteriole, and one small venule 10 times in each of these 30 images. RESULTS: Within an image, variability was similar between graders, pulse point, and vessel type. Across images taken at the same point in the pulse period, the change from the minimum to maximum measurement was between 6% and 17% for arterioles and between 2% and 11% for venules. In addition, measurements of small vessels had greater changes than large vessels and no point in the pulse period was more variable than another. Ignoring pulse cycle increased variability across images in the large venule, but not in the other vessel types. Mixed effect models were fit for each of the vessel types to determine the greatest source of variability. Controlling for pulse point and grader, the largest source of variability for all four vessels measured was across images, accounting for more than 50% of the total variability. CONCLUSION: Measurements of large retinal venules is generally less variable than measurements of other retinal vessels. After controlling for pulse point and grader, the largest source of variation is across images. Understanding the components of variability in measuring retinal vessels is important as these techniques are applied in epidemiological studies.

Retinal microvascular changes and MRI signs of cerebral atrophy in healthy, middle-aged people.

OBJECTIVE: To examine the relation of retinal microvascular abnormalities and MRI signs of cerebral atrophy in healthy middle-aged people. METHODS: A population-based, cross-sectional study involved 1,684 persons aged 51 to 72 years who had cerebral MRI and retinal photography in 1993 to 1995. Sulcal and ventricular size were quantified from the MRI scans and coded as grades 0 to 9, with sulcal widening (SW) and ventricular enlargement (VE) defined as grades 3 or higher. The presence or absence of retinopathy, microaneurysms, hemorrhages, and other characteristics were defined from retinal photographs using a standardized protocol. Generalized arteriolar narrowing was defined from a computer-assisted measurement of arteriolar diameters from digitized photographs. RESULTS: Persons with retinopathy had higher sulcal (p = 0.001) and ventricular (p = 0.03) grades than persons without retinopathy. After adjusting for age, gender, race, mean arterial blood pressure, diabetes, cigarette smoking, common carotid artery intima-media thickness, and other vascular risk factors, retinopathy was significantly associated with SW (odds ratio [OR], 1.9; 95% CI, 1.2, 3.0) and VE (OR, 1.5; 95% CI, 1.0, 2.3). These associations persisted even in people without diabetes or hypertension (OR 1.9, 95% CI, 0.8, 4.4 for SW; OR 2.7, 95% CI, 1.2, 6.5 for VE). Other retinal arteriolar characteristics (arteriovenous nicking, focal and generalized arteriolar narrowing) were not related to sulcal or ventricular grade. CONCLUSIONS: In healthy, middle-aged people, retinopathy is independently associated with sulcal and ventricular enlargement on MRI. This finding is compatible with the hypothesis that microvascular characteristics may influence the development of cerebral atrophic changes.

Retinal microvascular abnormalities and blood pressure in older people: the Cardiovascular Health Study.

AIM: To examine the relation between blood pressure and retinal microvascular abnormalities in older people. METHODS: The Cardiovascular Health Study is a prospective cohort study conducted in four US communities initiated in 1989 to 1990. Blood pressure was measured according to standardised protocols at each examination. During the 1997-8 examination, retinal photographs were taken of 2405 people aged 69-97 years (2056 without diabetes and 349 with diabetes). Signs of focal microvascular abnormalities (focal arteriolar narrowing, arteriovenous nicking, and retinopathy) were evaluated from photographs according to standardised methods. To quantify generalised arteriolar narrowing, the photographs were digitised and diameters of individual arterioles were measured and summarised. RESULTS: In non-diabetic people, elevated concurrent blood pressure taken at the time of retinal photography was strongly associated with presence of all retinal microvascular lesions. The multivariable adjusted odds ratios, comparing the highest to lowest quintile of concurrent systolic blood pressure, were 4.0 (95% confidence intervals (CI): 2.4 to 6.9, p test of trend<0.001) for focal arteriolar narrowing, 2.9 (95% CI: 1.6 to 5.3, p<0.001) for arteriovenous nicking, 2.8 (95% CI: 1.5 to 5.2, p<0.001) for retinopathy, and 2.1 (95% CI: 1.4 to 3.1, p<0.001) for generalised arteriolar narrowing. Generalised arteriolar narrowing and possibly arteriovenous nicking were also significantly associated with past blood pressure measured up to 8 years before retinal photography, even after adjustment for concurrent blood pressure. These associations were somewhat weaker in people with diabetes. CONCLUSIONS: Retinal microvascular abnormalities are related to elevated concurrent blood pressure in older people. Additionally, generalised retinal arteriolar narrowing and possibly arteriovenous nicking are related to previously elevated blood pressure, independent of concurrent blood pressure. These data suggest that retinal microvascular changes reflect severity and duration of hypertension.

Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study.

BACKGROUND: Retinal microvascular abnormalities reflect damage from hypertension and other vascular processes. We examined the relation of such abnormalities to incident stroke. METHODS: A cohort of 10358 men and women (aged 51 to 72 years) living in four US communities underwent retinal photography and standard grading for retinal microvascular abnormalities. The calibres of all retinal arterioles and venules were measured after digital conversion of the photographs, and a summary arteriole-to-venule ratio (AVR) was calculated as an index of arteriolar narrowing (smaller AVR indicates greater narrowing). Cases of incident stroke admitted to hospital were identified and validated by case record reviews. FINDINGS: Over an average of 3.5 years, 110 participants had incident strokes. After adjustment for age, sex, race, 6-year mean arterial blood pressure, diabetes, and other stroke risk factors, most retinal microvascular characteristics were predictive of incident stroke, with adjusted relative risks of 2.58 (1.59-4.20) for any retinopathy, 3.11 (1.71-5.65) for microaneurysms, 3.08 (1.42-6.68) for soft exudates, 2.55 (1.27-5.14) for blot haemorrhages, 2.26 (1.00-5.12) for flame-shaped haemorrhages, and 1.60 (1.03-2.47) for arteriovenous nicking. The relative risk of stroke increased with decreasing AVR (p=0.03). The associations were similar for ischaemic strokes specifically, and for strokes in individuals with hypertension, either with or without diabetes. INTERPRETATION: Retinal microvascular abnormalities are related to incident stroke. The findings support a microvascular role in the pathogenesis of stroke. They suggest that retinal photography may be useful for cerebrovascular-risk stratification in appropriate populations.

Risk factors for advancement of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome. Studies of Ocular Complications of AIDS Research Group.

OBJECTIVE: To identify ocular and systemic factors that predict advancement of cytomegalovirus (CMV) retinitis during treatment. METHODS: Patients with acquired immunodeficiency syndrome were enrolled in a multicenter clinical trial designed to evaluate foscarnet sodium and ganciclovir sodium as therapy for newly diagnosed CMV retinitis. Ocular characteristics at baseline and measurements of retinitis were assessed from fundus photographs by graders at a fundus photograph reading center. The following measures of advancement were assessed: (1) lesion border movement of at least 750 microm or development of a new lesion in involved eyes; (2) rate of increase in retinal area with CMV in involved eyes; and (3) development of retinitis in uninvolved eyes of patients with unilateral disease at baseline. RESULTS: In eyes with retinitis, risk factors at baseline for advancement while receiving treatment included smaller area involved, active margins of retinitis, and posterior location. Risk factors for development of retinitis in uninvolved fellow eyes included blood and urine cultures positive for CMV and lower CD8(+) T-lymphocyte count. CONCLUSIONS: Lesion characteristics can be used to predict advancement of preexisting disease, whereas only systemic factors are associated with development of bilateral disease. These analyses describe retinitis activity before the introduction of potent antiretroviral therapies but provide an important reference point for patients in whom CMV retinitis develops after failure or intolerance of antiretroviral agents. Arch Ophthalmol. 2000;118:1196-1204

Are retinal arteriolar abnormalities related to atherosclerosis?: The Atherosclerosis Risk in Communities Study.

The objective of this study was to describe associations of retinal arteriolar abnormalities with clinical and subclinical manifestations of atherosclerosis and a broad group of risk factors for vascular disease. A biracial population of 8772 adults (aged 48 to 72 years) living in 4 communities was examined from 1993 to 1995 were studied for that purpose. Retinal arteriovenous nicking and focal arteriolar narrowing were determined by light-box grading of a 45 degrees fundus photograph by use of a standardized protocol. Diameters of arterioles and venules were measured in digitized photographs, and a summary arteriolar-to-venular ratio was derived as an index of generalized arteriolar narrowing. Focal arteriolar narrowing was associated only with hypertension. Generalized arteriolar narrowing was associated with carotid plaque but not with any other evidence of atherosclerosis, either clinical (cardiovascular disease or stroke) or subclinical (carotid or popliteal artery thickness or lower limb obstructive disease), or with plasma cholesterol. It was also associated with smoking, with inflammatory markers (white blood cell count, fibrinogen, and reduced albumin), and with the triglyceride and high density lipoprotein cholesterol changes associated with inflammation. Arteriovenous nicking was inconsistently associated with subclinical atherosclerosis. It was not associated with cardiovascular disease, stroke, or plasma cholesterol. Arteriovenous nicking was associated with markers of inflammation and vascular endothelial dysfunction (von Willebrand factor and factor VIII). Arteriolar narrowing and nicking appear to be related to hypertension and inflammatory factors. Nicking may also be related to endothelial dysfunction. Results suggest that these arteriolar changes are pathologically distinct from atherosclerosis. Including their measurement in population studies may permit evaluation of the independent contribution of arteriolar disease to various ischemic diseases of the heart, brain, and other organs.

Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study.

OBJECTIVE: To develop protocols to photograph and evaluate retinal vascular abnormalities in the Atherosclerosis Risk in Communities (ARIC) Study; to test reproducibility of the grading system; and to explore the relationship of these microvascular changes with blood pressure. DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Among 4 examination centers, 11,114 participants (48-73 years of age) at their third triennial examination, after excluding persons with diabetes from this analysis. METHODS: One eye of each participant was photographed by technicians with nonmydriatic fundus cameras. Reading center graders evaluated focal arteriolar narrowing, arteriovenous (AV) nicking, and retinopathy by examining slides on a light box and measured diameters of all vessels in a zone surrounding the optic disc on enhanced digitized images. To gauge generalized narrowing, vessel diameters were combined into central arteriolar and venular equivalents with formulas adjusting for branching, and the ratio of equivalents (A/V ratio) was calculated. MAIN OUTCOME MEASURES: Retinal vascular abnormalities, mean arteriolar blood pressure (MABP). RESULTS: Among 11,114 participants, photographs were obtained of 99%, with quality sufficient to perform retinal evaluations in 81%. In the 9040 subjects with usable photographs, A/V ratio (lower values indicate generalized arteriolar narrowing) ranged from 0.57 to 1.22 (median = 0.84, interquartile range = 0.10), focal arteriolar narrowing was found in 7%, AV nicking in 6%, and retinopathy in 4%. Because of attrition of subjects and limitation of methods, prevalence of abnormality was likely underestimated. Controlling for gender, race, age, and smoking status, these retinal changes were associated with higher blood pressure. For every 10-mmHg increase in MABP, A/V ratio decreased by 0.02 unit (P < 0.0001), focal arteriolar narrowing had an odds ratio (OR) of 2.00 (95% confidence interval [CI] = 1.87-2.14), AV nicking had an OR of 1.25 (95% CI = 1.16-1.34), and retinopathy had an OR of 1.25 (95% CI = 1.15-1.37). For any degree of generalized narrowing, individuals with focal narrowing had MABP approximately 8 mmHg higher than those without (P < 0.0001). Masked replicate assessment of a sample found the following reproducibility: for A/V ratio, correlation coefficient = 0.79 and median absolute difference = 0.03; for focal arteriolar narrowing, kappa = 0.45; for AV nicking, kappa = 0.61; and for retinopathy, kappa = 0.89. CONCLUSION: Protocols have been developed for nonmydriatic fundus photography and for evaluation of retinal vascular abnormalities. Several microvascular changes were significantly associated with higher blood pressure; follow-up will show whether these are predictive of later cerebrovascular or cardiovascular disease independently of other known risk factors.

Prevalence of age-related maculopathy in the Atherosclerosis Risk in Communities Study.

OBJECTIVE: To describe the prevalence of age-related maculopathy (ARM) in blacks and whites and its relation to macrovascular disease and risk factors thereof in a population studied for cardiovascular disease risk factors and outcomes. POPULATION: A biracial population of 11532 adults (ranging from 48-72 years of age; 8984 whites and 2548 blacks) living in 4 US communities (Forsyth County, North Carolina; the city of Jackson, Miss; selected suburbs of Minneapolis, Minn; and Washington County, Maryland) were examined during the interval from 1993 to 1995. METHODS: Drusen and other lesions typical of ARM were identified by examining a 45 degrees color fundus photograph of 1 eye of each participant and classified by means of a modification of the Wisconsin Age-Related Maculopathy Grading System. RESULTS: The overall prevalence of any ARM was lower in blacks (3.7%) than whites (5.6%). After controlling for age and sex, the odds ratio for any ARM in blacks compared with whites was 0.73 (95% confidence interval, 0.58-0.91; P = .006). Few associations between atherosclerosis and its risk factors and the presence of early ARM or its component lesions were found. After adjusting for age, race, and sex, carotid artery plaque (odds ratio, 1.77; 95% confidence interval, 1.18-2.65) and focal retinal arteriolar narrowing (odds ratio, 1.79; 95% confidence interval, 1.07-2.98) were associated with retinal pigment epithelial depigmentation. CONCLUSIONS: This population-based study documents the higher prevalence of early ARM in whites compared with blacks. Measures of atherosclerosis and its risk factors were generally unrelated to ARM and do not explain these racial differences.

Retinal arteriolar diameters and elevated blood pressure: the Atherosclerosis Risk in Communities Study.

Narrowing and other changes in retinal arterioles may reflect damage due to hypertension, which may predict stroke and other cardiovascular diseases independently of blood pressure level. Newly developed quantitative methods of assessing retinal narrowing are used to determine whether this sign is related only to current blood pressure or whether it also independently reflects the effects of previous blood pressure. Retinal photography was performed at the third examination of Atherosclerosis Risk in Communities (ARIC) Study in 1993-1995, and results are presented for the 9,300 nondiabetic participants aged 50-71 years. Generalized narrowing of smaller arterioles was strongly and monotonically related to current blood pressure in men and women, whether they were taking antihypertensive medications or not, and, independent of current blood pressure, was consistently and monotonically related to blood pressure levels measured 3 and 6 years before the retinal assessment. Arteriovenous nicking was also independently related to both current and previous blood pressures. The patterns of association suggested that these signs reflect both transient and persisting structural effects of elevated blood pressure, in agreement with the scant pathologic literature available. The findings suggest that retinal assessment may be useful for research on the microvascular contributions to clinical cardiovascular diseases.

Subretinal fibrosis in diabetic macular edema. ETDRS report 23. Early Treatment Diabetic Retinopathy Study Research Group.

OBJECTIVE: To describe the characteristics of and risk factors for subretinal fibrosis (SRF) in patients with diabetic macular edema. PATIENTS AND METHODS: A total of 109 eyes (in 96 persons) with SRF, defined as a mound or sheet of gray to white tissue beneath the retina at or near the center of the macula, were identified during the Early Treatment Diabetic Retinopathy Study, which is a randomized clinical trial of photocoagulation and aspirin treatment in patients with mild to severe nonproliferative or early proliferative diabetic retinopathy. The patients and the ocular characteristics of these 109 eyes, all of which had clinically significant macular edema, were compared with those of 5653 eyes in which clinically significant macular edema, but not SRF, was observed during the trial. RESULTS: In 9 of 109 eyes, the development of SRF may have been directly related to focal photocoagulation. Seventy-four percent of the eyes in which SRF developed had very severe hard exudates in the macula prior to the development of SRF, while this level of hard exudates was seen in only 2.5% of the eyes with clinically significant macular edema in which SRF did not develop (P < .001). Of the 264 eyes with this level of hard exudates at baseline (n = 29) or during follow-up (n = 235), SRF developed in 30.7% of the eyes, while this complication developed in only 0.05% of 5498 eyes with clinically significant macular edema without this level of hard exudates. CONCLUSIONS: Subretinal fibrosis is an infrequent complication of diabetic macular edema. Although it has been reported to be associated with photocoagulation burn intensity, in only 9 of 109 eyes in which SRF developed was it located adjacent to a photocoagulation-related scar (among 4823 eyes that received focal photocoagulation for treatment of macular edema). The strongest risk factor for the development of SRF is very severe hard exudate.

Serum copper and zinc concentrations in patients with burns in relation to burn surface area.

Serum zinc and copper concentrations were measured by flame atomic absorption spectroscopy in 34 patients between 1 and 3 weeks after thermal injury. Mean (range) admission burn surface area was 29.8% (10% to 79%), and mean (range) serum zinc and copper concentrations within the first postburn week were 0.59 (0.2 to 1.5) and 0.74 (0.1 to 1.6) mg/L, respectively. Serum copper concentration was inversely correlated with burn surface area (r = -0.611, p < 0.01), whereas serum zinc concentration showed no such association. In the first postburn week hypocupremia (< 0.7 mg/L) was found in 15 of 32 (48%) of patients and hypozincemia (< 0.7 mg/L) in 21 of 32 (68%). Serum copper concentrations in patients with less than 15% burns remained within normal limits throughout the study period, but hypozincemia was found in patients irrespective of burn surface area. Long-term monitoring of two patients with 79% and 70% burns showed initial hypocupremia and hypozincemia. Hypocupremia only resolved in the patient with 79% burns when skin healing was almost complete 75 days after burns. Postburn hypozincemia was found to be very variable and not associated with either serum albumin concentration or periods of clinical sepsis. Because major burn injuries are associated with hypocupremia, serial monitoring is recommended with appropriate copper supplementation.

Are seven standard photographic fields necessary for classification of diabetic retinopathy?

Stereoscopic fundus photography of seven fields has become standard procedure for detecting diabetic retinopathy. However, the question has arisen as to whether adequate detection of retinopathy can be achieved with fewer fields. This question was investigated in a population-based study of 2694 diabetic persons. Retinopathy levels derived from the detailed grading of all seven fields were compared with those derived from combinations of two, three or four fields, the data for these being selected from the grading of the full seven fields. For eight retinopathy levels, the rate of agreement with seven fields ranges from 80% for two fields to 91% for four fields. For four retinopathy levels, agreement increases to 85 to 95%. The rate of agreement also varies with the specific retinopathy level, with level 65 being especially sensitive to the number of fields. The sensitivity of two to four fields compared to seven fields for detecting any retinopathy varies from 87 to 95%. For detecting proliferative retinopathy, sensitivity varies from 74 to 90%, and for Diabetic Retinopathy Study high-risk characteristics, it varies from 81 to 91%. Analysis of two groups of 50 eyes in which the combinations of fields were graded independently shows a small but nonsignificant effect of field overlap. These results indicate that in some situations, fewer fields may be adequate.

Optic disk neovascularization and retinal vessel diameter in diabetic retinopathy.

We measured retinal vessel diameter before and after panretinal photocoagulation in 59 eyes with diabetic retinopathy and moderate to severe optic disk neovascularization. Treatment significantly reduced mean arteriolar and venular diameter. The diameter of the retinal arterioles after treatment correlated significantly with the amount of regression in disk neovascularization. Eyes with large diameter vessels after treatment usually had little or no regression of proliferative retinopathy, whereas regression was more frequently seen in eyes with smaller diameter vessels after treatment.

Conference on insulin pump therapy in diabetes. Multicenter study effect on microvascular disease. Studies of retinopathy. Methodology for assessment and classification with fundus photographs.

A major goal of the study was to assess the methodologies available for the quantification of retinal lesions suitable for application in trials of metabolic management. We describe the methods used for grading stereoscopic color fundus photographs. Overall retinopathy severity level for each eye ranging from normal (level 10) to high-risk category (level 70) was assigned on the basis of gradings of individual lesions. Change in retinopathy severity level over the 8-mo period was detected in 3-62% of patients, depending on the method used and the definition of change. Lesions responsible for change in level were mainly retinal infarcts (soft exudates) and intraretinal microvascular abnormalities.

Diabetic retinopathy as detected using ophthalmoscopy, a nonmydriatic camera and a standard fundus camera.

The study was performed to evaluate whether the severity of diabetic retinopathy as assessed by three alternative methods was concordant with the severity of retinopathy as determined from 30 degrees stereoscopic photographs. The three methods were direct ophthalmoscopy through an undilated pupil, nonstereoscopic 45 degrees retinal photography through a pharmacologically undilated pupil and nonstereoscopic 45 degrees photography through a dilated pupil. A single 45 degrees photograph centered between the disc and fovea was taken and direct ophthalmoscopy was performed on 99 persons prior to pharmacological dilation of the pupil. After dilation, another 45 degrees photograph was taken of the same field, as well as 30 degrees stereoscopic color photographs of DRS fields 1, 2 and 4 (modified). Corresponding photographic fields were graded by masked, trained graders for the severity of retinopathy and for the presence of specified diabetic lesions using the Modified Airlie House Classification scheme. For three levels of severity of retinopathy (none, nonproliferative or proliferative) exact agreement between direct ophthalmoscopy and grading of retinopathy from stereoscopic photographs taken with the standard 30 degrees camera was 54.3% (n = 94). For four levels of severity of retinopathy (none, microaneurysms only, all other nonproliferative retinopathy and proliferative retinopathy), exact agreement between gradings of retinopathy of the 45 degrees photographs taken through undilated pupils and 30 degrees photographs taken through dilated pupils was 82.5% (n = 63); and for 45 degrees photographs and 30 degrees photographs taken through dilated pupils it was 86.5% (n = 74). These data suggest that 45 degrees nonstereoscopic fundus photographs, when graded according to a standard classification scheme, provide reasonably reliable photographic representation of the severity of retinopathy when broad overall categories are used.