A pilot randomized controlled trial comparing effectiveness of prism glasses, visual search training and standard care in hemianopia.

OBJECTIVE: Pilot trial to compare prism therapy and visual search training, for homonymous hemianopia, to standard care (information only). METHODS: Prospective, multicentre, parallel, single-blind, three-arm RCT across fifteen UK acute stroke units. PARTICIPANTS: Stroke survivors with homonymous hemianopia. INTERVENTIONS: Arm a (Fresnel prisms) for minimum 2 hours, 5 days per week over 6 weeks. Arm b (visual search training) for minimum 30 minutes, 5 days per week over 6 weeks. Arm c (standard care-information only). INCLUSION CRITERIA: Adult stroke survivors (>18 years), stable hemianopia, visual acuity better than 0.5 logMAR, refractive error within ±5 dioptres, ability to read/understand English and provide consent. OUTCOMES: Primary outcomes were change in visual field area from baseline to 26 weeks and calculation of sample size for a definitive trial. Secondary measures included Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual, Short Form-12 questionnaires and Radner reading ability. Measures were post-randomization at baseline and 6, 12 and 26 weeks. RANDOMIZATION: Randomization block lists stratified by site and partial/complete hemianopia. BLINDING: Allocations disclosed to patients. Primary outcome assessor blind to treatment allocation. RESULTS: Eighty-seven patients were recruited: 27-Fresnel prisms, 30-visual search training and 30-standard care; 69% male; mean age 69 years (SD 12). At 26 weeks, full results for 24, 24 and 22 patients, respectively, were compared to baseline. Sample size calculation for a definitive trial determined as 269 participants per arm for a 200 degree2 visual field area change at 90% power. Non-significant relative change in area of visual field was 5%, 8% and 3.5%, respectively, for the three groups. Visual Function Questionnaire responses improved significantly from baseline to 26 weeks with visual search training (60 [SD 19] to 68.4 [SD 20]) compared to Fresnel prisms (68.5 [SD 16.4] to 68.2 [18.4]: 7% difference) and standard care (63.7 [SD 19.4] to 59.8 [SD 22.7]: 10% difference), P=.05. Related adverse events were common with Fresnel prisms (69.2%; typically headaches). CONCLUSIONS: No significant change occurred for area of visual field area across arms over follow-up. Visual search training had significant improvement in vision-related quality of life. Prism therapy produced adverse events in 69%. Visual search training results warrant further investigation.

A randomised controlled trial to compare the clinical and cost-effectiveness of prism glasses, visual search training and standard care in patients with hemianopia following stroke: a protocol.

INTRODUCTION: Homonymous hemianopia is a common and disabling visual problem after stroke. Currently, prism glasses and visual scanning training are proposed to improve it. The aim of this trial is to determine the effectiveness of these interventions compared to standard care. METHODS AND ANALYSIS: The trial will be a multicentre three arm individually randomised controlled trial with independent assessment at 6 week, 12 week and 26 week post-randomisation. Recruitment will occur in hospital, outpatient and primary care settings in UK hospital trusts. A total of 105 patients with homonymous hemianopia and without ocular motility impairment, visual inattention or pre-existent visual field impairment will be randomised to one of three balanced groups. Randomisation lists will be stratified by site and hemianopia level (partial or complete) and created using simple block randomisation by an independent statistician. Allocations will be disclosed to patients by the treating clinician, maintaining blinding for outcome assessment. The primary outcome will be change in visual field assessment from baseline to 26 weeks. Secondary measures will include the Rivermead Mobility Index, Visual Function Questionnaire 25/10, Nottingham Extended Activities of Daily Living, Euro Qual-5D and Short Form-12 questionnaires. Analysis will be by intention to treat. ETHICS AND DISSEMINATION: This study has been developed and supported by the UK Stroke Research Network Clinical Studies Group working with service users. Multicentre ethical approval was obtained through the North West 6 Research ethics committee (Reference 10/H1003/119). The trial is funded by the UK Stroke Association. Trial Registration: Current Controlled Trials ISRCTN05956042. Dissemination will consider usual scholarly options of conference presentation and journal publication in addition to patient and public dissemination with lay summaries and articles. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05956042.

High prevalence in Malawi of sight-threatening retinopathy and visual impairment caused by diabetes: identification of population-specific targets for intervention.

AIMS: To report the prevalence of all grades of diabetic retinopathy and associations with demographic, clinical and biochemical variables in people with diabetes in Southern Malawi. METHODS: We report baseline data from a 24-month prospective cohort study. Subjects were systematically sampled from two hospital-based, primary care diabetes clinics. Visual acuity, glycaemic control, systolic blood pressure, HIV status, urine albumin-creatinine ratio, and haemoglobin and serum lipid levels were assessed. Retinopathy was graded at an accredited reading centre using modified Wisconsin grading of four-field mydriatic photographs. RESULTS: A total of 357 subjects were studied. Of these, 13.4% subjects were HIV-positive and 15.1% had anaemia. The overall prevalence rates of any retinopathy, sight-threatening diabetic retinopathy and proliferative retinopathy were 50.1% (95% CI 44.9-55.3), 29.4% (95% CI 24.7-34.1) and 7.3% (95% CI 4.6-10.0), respectively. In multivariate logistic analysis the presence of sight-threatening retinopathy was associated with duration of diabetes (odds ratio 1.11, 95% CI 1.05-1.17), HbA1c (odds ratio 1.31, 95% CI 1.13-1.50), systolic blood pressure (odds ratio 1.03, 95% CI 1.01-1.04), haemoglobin (odds ratio 0.98, 95% CI 0.96-0.99) and LDL cholesterol (odds ratio 1.63, 95% CI 1.18-2.25). No significant association with HIV status was observed. In all, 3.6 and 1.4% of people in our study cohort had visual acuity worse than 6/18 and 6/60 in the better eye, respectively. CONCLUSIONS: The present study found a prevalence of sight-threatening retinopathy in diabetes clinics in one Sub-Saharan African country of approximately four times that reported in recent European studies and a prevalence of proliferative retinopathy approximately 10 times higher. The association of sight-threatening retinopathy with lower haemoglobin level is a new finding. Our results highlight the urgent need for provision of services for retinopathy detection and management to avoid a large burden of vision loss.

In utero exposure to levetiracetam vs valproate: development and language at 3 years of age.

OBJECTIVE: To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy. METHODS: The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled. RESULTS: After controlling for confounding variables, children exposed to LEV in utero (n = 53) did not differ from unexposed control children (n = 131) on any scale administered. Children exposed to VPA (n = 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] -24.5 to -7.1, p < 0.001), 6.4 points below on comprehension language abilities (95% CI -11.0 to -1.8, p = 0.005), and 9.5 points below on expressive language abilities (95% CI -14.7 to -4.4, p < 0.001). CONCLUSION: The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on women's preferred choice of antiepileptic drug.

The effect of sex and handedness on white matter anisotropy: a diffusion tensor magnetic resonance imaging study.

Diffusion tensor magnetic resonance imaging provides a way of assessing the asymmetry of white matter (WM) connectivity, the degree of anisotropic diffusion within a given voxel being a marker of coherently bundled myelinated fibers. Voxel-based statistical analysis was performed on fractional anisotropy (FA) images of 42 right- and 40 left-handers, to assess differences in underlying WM anisotropy and FA asymmetry across the whole brain. Right-handers show greater anisotropy than left-handers in the uncinate fasciculus (UF) within the limbic lobe, and WM underlying prefrontal cortex, medial and inferior frontal gyri. Significantly greater leftward FA asymmetry in cerebellum posterior lobe is seen in left- than right-handers, and males show significantly greater rightward (right-greater-than-left) FA asymmetry in regions of middle occipital lobe, medial temporal gyrus, and a region of the superior longitudinal fasciculus underlying the supramarginal gyrus. Leftward (left-greater-than-right) anisotropy is found in regions of the arcuate fasciculus (AF), UF, and WM underlying pars triangularis in both handedness groups, with right-handers alone showing additional leftward FA asymmetry along the length of the superior temporal gyrus. Overall results indicate that although both handedness groups show anisotropy in similar WM regions, greater anisotropy is observed in right-handers compared with left-handers. The largest differences in FA asymmetry are found between males and females, suggesting a greater effect of sex than handedness on FA asymmetry.

Baseline clinical measures and early response predict success in verteporfin photodynamic therapy for neovascular age-related macular degeneration.

PURPOSE: To analyse the influence of baseline clinical characteristics on the outcome of verteporfin photodynamic therapy (VPDT) for neovascular age-related macular degeneration (nAMD). METHODS: A total of 1008 patients commencing VPDT for nAMD in a single UK centre entered a prospective observational study between 1999 and 2006 and were followed for 2 years. Longitudinal linear mixed-effects modelling was applied to assess the influence of baseline covariates, such as best corrected visual acuity (BCVA), contrast sensitivity (CS), age, lesion size, and lesion type, on changes of BCVA over time in patients after VPDT. A logistic regression analysis was used to analyse clinical features significantly associated with treatment failure. RESULTS: Study eye BCVA was significantly better on average throughout the course of treatment in patients with better baseline BCVA and CS in the study eye (P<0.001 and P<0.01, respectively) and lower age (P=0.01). Mean BCVA showed a significant reduction over time with a significant quadratic relationship between 0 and 6 months and with stabilisation between 6 and 9 months. Patients with better BCVA and worse CS at baseline, and those in whom BCVA dropped during the first 3 months of follow-up, were more likely to lose >/=15 letters after 12 months. CONCLUSIONS: Findings from our large longitudinal data set provide estimates of likely outcome based on baseline features and response at 3 months in patients commencing a course of VPDT for nAMD. Statistical modelling built up for this large data set can be applicable to other studies in ophthalmology research.

Observational prospective study of the effectiveness in routine clinical practice of verteporfin photodynamic therapy in patients with neovascular age-related macular degeneration.

AIMS: To investigate effectiveness in routine clinical practice of verteporfin photodynamic therapy (PDT) for neovascular age-related macular degeneration (nAMD). PATIENTS AND METHODS: Patients commencing PDT for nAMD in a single UK centre entered a prospective observational 7-year study and were followed for 2 years. Best-corrected visual acuity (BCVA) and contrast sensitivity (CS) were measured at each visit by accredited technicians after full protocol refraction on standardised charts. Reasons for failure to complete the course of therapy were documented. RESULTS: 1008 patients entered the study between 1999 and 2006. 81% and 52% completed 12 and 24 months' follow-up respectively (excluding administrative censoring). Results at 12 and 24 months respectively were: maintenance of BCVA 62%, 63%; drop in mean BCVA (letters) 10.1, 9.4; numbers of treatments 2.9, 3.5. The mean CS remained stable. No correlation of change in BCVA outcome between first and second treated eyes in 82 bilateral cases was detected. Loss to follow-up was significantly associated with age, CS and distance from the treating centre. CONCLUSIONS: PDT delivered in clinical practice is at least as effective as that reported in randomised clinical trials and uses fewer treatments.

Effect of ultra-high molecular weight polyethylene thickness on contact mechanics in total knee replacement.

One of the important design parameters in current knee joint replacements is the thickness of the ultra-high molecular weight polyethylene (UHMWPE) tibial insert, yet there is no clear definition of the upper limit of the 'thick' polyethylene insert. Using one design knee implant and subjecting it to the physiological loads encountered throughout the gait cycle, measurements of the lengths of contact imprints generated were compared with the corresponding theoretical predictions for different insert thicknesses under the same applied load. Multiple regression analysis was applied to test whether the dimensions of contact imprints are influenced by UHMWPE thickness. Good agreement was obtained between the theoretical predictions and the experimental measurements of the dimensions of contact imprints when the knee was at 60 degrees flexion. Therefore, it was possible to estimate the contact pressure at the articulating surface using the theoretical model. Contact imprint dimensions increased with increasing applied load. Statistical analysis of the experimental data revealed that, at 0 degree flexion, the overall imprint dimensions increased as the UHMWPE thickness increased from 8 to 20 mm. However, the increment was not significant when the thickness subinterval 10-15 mm was considered. Furthermore, at 60 degrees flexion, thickness was not a significant factor for the overall imprint dimensions. No evidence was found from the data to suggest that an increment in polyethylene thickness over 10 mm would significantly reduce the contact imprint dimensions. These findings suggest that thicker inserts can be avoided, as they require unnecessary bone resection.

Confidence intervals in Cavalieri sampling.

The aim of this study is to derive a formula that allows the prediction, from a Cavalieri data sample, of an appropriate confidence interval for a parameter Q. Two different approaches are used to address the problem. The first approach is to investigate whether the asymptotic distribution of the Cavalieri estimator exists when the sampling period T tends to zero. In particular, the distribution of the standardized version of the Cavalieri estimator z(T) is analysed for a measurement function f whose smoothness constant is an integer number m. The analysis reveals that when the first noncontinuous derivative of f, f((m)), exhibits a unique discontinuity, the asymptotic distribution of z(T) exists and it has a bounded support. An analytical expression of the distribution is derived for the cases m = 0 and 1. However, when f((m)) has two or more discontinuities, the asymptotic distribution of z(T) does not exist and its support may be unbounded. In the second approach, a generalized version of the refined Euler Mac-Laurin summation formula, valid for measurement functions with a fractional, rather than just an integer, smoothness constant, is applied to the Cavalieri estimator. As a result, a formula that predicts a lower and upper bound for the true parameter is derived for small T. This bound prediction formula is applied to Cavalieri data samples of human cerebral cortex. In particular, for sample sizes n = 8, 12 and 16, the true volume of cerebral cortex is bounded by relative distances 8%, 4% and 2% of the Cavalieri estimate, respectively.

Degree of hippocampal atrophy is related to side of seizure onset in temporal lobe epilepsy.

BACKGROUND AND PURPOSE: Temporal lobe epilepsy (TLE) is associated with pathologic changes in hippocampal physiology and morphology. Our aim was to quantify volume reduction of the right and left hippocampus in patients with TLE and to investigate whether the degree of hippocampal atrophy is related to the side of seizure onset. METHODS: The volume of the right and left hippocampus was estimated for 50 controls and 101 patients with TLE, by applying the unbiased Cavalieri method on MR images. RESULTS: Pairwise comparisons, within a multivariate analysis of variance and adjusted by using the Bonferroni correction, revealed that both right and left hippocampal volumes were, on average, significantly smaller in patients with right-sided seizure onset (R-patients) relative to those of controls (P < .001 and P = .04, respectively). Furthermore, left hippocampal volume was significantly smaller in patients with left-sided seizure onset (L-patients) compared with controls (P < .001), but the right-sided hippocampal volume was not significantly smaller (P = .71). Moreover, a correlation analysis revealed that the strong linear association between the right and left hippocampal volumes existing in the control population (r = 0.73) is partially lost in patients with TLE (r < or = 0.48), and this loss in correlation appears to be more pronounced in L-patients than in R-patients. CONCLUSION: Our MR imaging results suggest that although the major damage in patients with TLE is located in the hippocampus ipsilateral to the side of seizure onset, R-patients are more likely to have bilateral hippocampal volume reduction. These findings support the hypothesis that cerebral hemispheres may not only differ in their functionality organization but also in their vulnerability to a neurologic insult.

Quantification of tumour response to radiotherapy.

In 1979, the World Health Organization (WHO) established criteria based on tumour volume change for classifying response to therapy as (i) progressive disease (PD), (ii) partial recovery (PR), and (iii) no change (NC). Typically, the tumour volume is reported from diameter measurements, using the calliper method. Alternatively, the Cavalieri method provides unbiased volume estimates of any structure without assumptions about its shape. In this study, we applied the Cavalieri method in combination with point counting to investigate the changes in tumour volume in four patients with high grade glioma, using 3D MRI. In particular, the volume of tumour within the enhancement boundary, the enhancing abnormality (EA), was estimated from T(1) weighted images, and the volume of the non-enhancing abnormality, (NEA) enhancing abnormality, was estimated from T(2) relaxation time and magnetic transfer ratio tissue characterization maps. We compared changes in tumour volume estimated by the Cavalieri method with those obtained using the calliper method. Absolute tumour volume differed significantly between the two methods. Analysis of relative change in tumour volume, based on the WHO criteria, provided a different classification using the calliper and Cavalieri methods. The benefit of the Cavalieri method over the calliper method in the estimation of tumour volume is justified by the following factors. First, Cavalieri volume estimates are mathematically unbiased. Second, the Cavalieri method is highly efficient under an appropriate sampling density (i.e. EA volume estimates can be obtained with a coefficient of error no higher than 5% in 2-3 min). Third, the source of variation of the volume estimates due to disagreements between observers, and within observer, is much greater in the positioning of the calliper diameters than in the identification of the tumour boundaries when applying the Cavalieri method. Additionally, the error prediction formula, available to estimate the coefficient of error of Cavalieri volume estimates from the data, allows us to establish more precise classification criteria against which to identify potentially clinical significant changes in tumour volume.

New approximations for the variance in cavalieri sampling

The theory of Cavalieri sampling - or systematic sampling along an axis - has received a recent impetus. The error variance may be represented by the sum of three components, namely the extension term, the 'Zitterbewegung', and higher order terms. The extension term can be estimated from the data, and it constitutes the standard variance approximation used so far. The Zitterbewegung oscillates about zero, and neither this nor higher order terms have hitherto been considered to predict the variance. The extension term is always a good approximation of the variance when the number of observations is very large, but not necessarily when this number is small. In this paper we propose a more general representation of the variance, and from it we construct a flexible extension term which approximates the variance satisfactorily for an arbitrary number of observations. Furthermore, we generalize the current connection between the smoothness properties of the measurement function (e.g. the section area function of an object when the target is the volume) and the corresponding properties of its covariogram to facilitate the computation of the new variance approximations; this enables us to interpret the behaviour of the variance from the 'overall shape' of the measurement function. Our approach applies mainly to measurement functions whose form is known analytically, but it helps also to understand the behaviour of the variance when the measurement function is known at sufficiently many points; in fact, we illustrate the concepts with both synthetic and real data.

Estimation of body composition in muscular dystrophy by MRI and stereology.

We have applied the Cavalieri method of modern design stereology with magnetic resonance imaging for estimating the volume of whole-body muscle and fat compartments in four patients with muscular dystrophy, a patient with myopathy, five controls, an anorexic subject, and a body builder. Detailed systematic series (ie, 50) of axial MR images (T1-weighted, TR/TE 400/10 msec) were obtained throughout the whole body of each subject. The results showed that 15, 20, and 35 axial sections through the body are sufficient to secure coefficients of error (CEs) on the estimates of total muscle and fat volume of around 10%, 5%, and 3% respectively in muscular dystrophy patients and controls. The mean normalized volumes of muscle in four muscular dystrophy patients were decreased by 27% (t-test: P < 0.05), and those of total fat were increased by 12% (t-test: P > 0.05) relative to controls. The Cavalieri method provides a direct, efficient, and mathematically unbiased approach for studying human body compartments and may have application in assessing treatment efficacy in patients with muscular dystrophy. J. Magn. Reson. Imaging 2000;12:467-475.

Estimation of breast volume and its variation during the menstrual cycle using MRI and stereology.

Unbiased estimates of breast volume may be obtained in vivo from systematic series of MR images acquired in accordance with the Cavalieri method of modern design-based stereology. The method does not require any assumptions to be made regarding breast shape. If point counting techniques are used to obtain the required breast section areas estimates, 10-15 min analysis (i.e. counting about 250 points on 12 to 16 images) ensures that the contribution of sectioning and point counting to the coefficient of error (CE) on the volume estimate is less than 3%. The methods were applied to measure breast volume in 15 healthy females aged between 22 and 44 years (mean 31.7 years; SD 8.2 years). One subject was studied on every fourth day during two consecutive cycles. The other 14 subjects were studied on three occasions corresponding to menses, ovulation and pre-menses during a single menstrual cycle. Repeat imaging after repositioning on three occasions within a period of 30 min and also at three different times of day for a single subject, both yielded a coefficient of variation (CV) of less than 3% in the estimation of breast volume. ANOVA indicates that there is no significant difference between the mean volume of the left and the right breast (p = 0.294). The mean volume of the left breast is 561 ml (95% confidence interval (CI): 553 ml, 569 ml) and the mean volume of the right breast is 567 ml (95% CI: 559 ml, 576 ml). There are highly significant differences between the three named stages of the menstrual cycle (p < 0.0005), whereby the mean volume at ovulation is 5.5% less than the mean volume at menses (95% CI: 3.0%, 7.9%) and the mean volume pre-menses is 8.1% greater than the mean volume at menses (95% CI: 5.3%, 10.9%). Overall, the volume of each breast varies by an average of 76 ml (95% CI: 61 ml, 92 ml) during the menstrual cycle, which corresponds to 13.6% of the volume at menses (95% CI: 13.3%, 13.8%). No significant interaction was found between the relative volumes of the left and right breast and the stage of the menstrual cycle (p = 0.277), nor between subjects and stages of cycle (p = 0.296). However, a significant interaction was observed between the volume of the left and right breasts in different subjects (p < 0.005). The average difference in the volume of the left and right breasts of all 15 subjects is 39.7 ml (95% CI: 21.3 ml, 58.1 ml), which is 7% of average breast volume and approximately 50% of the average variation in the volume of the breast during the menstrual cycle.