Corneal confocal microscopy : a novel noninvasive means to diagnose neuropathy in patients with Fabry disease

ABSTRACT: Neuropathy is a cause of significant disability in patients with Fabry disease, yet its diagnosis is difficult. In this study we compared the novel noninvasive techniques of corneal confocal microscopy (CCM) to quantify small-fiber pathology, and non-contact corneal esthesiometry (NCCA) to quantify loss of corneal sensation, with established tests of neuropathy in patients with Fabry disease. Ten heterozygous females with Fabry disease not on enzyme replacement therapy (ERT), 6 heterozygous females, 6 hemizygous males on ERT, and 14 age-matched, healthy volunteers underwent detailed quantification of neuropathic symptoms, neurological deficits, neurophysiology, quantitative sensory testing (QST), NCCA, and CCM. All patients with Fabry disease had significant neuropathic symptoms and an elevated Mainz score. Peroneal nerve amplitude was reduced in all patients and vibration perception threshold was elevated in both male and female patients on ERT. Cold sensation (CS) threshold was significantly reduced in both male and female patients on ERT (P < 0.02), but warm sensation (WS)and heat-induced pain (HIP) were only significantly increased in males onERT (P<0.01). However, corneal sensation assessed withNCCAwas significantly reduced in female (P < 0.02) and male (P < 0.04) patients on ERT compared with control subjects. According to CCM, corneal nerve fiber and branch density was significantly reduced in female (P < 0.03) and male (P < 0.02) patients on ERT compared with control subjects. Furthermore, the severity of neuropathic symptoms and the neurological component of the Mainz Severity Score Index correlated significantly with QSTand CCM. This study shows that CCM and NCCA provide a novel means to detect early nerve fiber damage and dysfunction, respectively, in patients with Fabry disease.

Technical note : modelling a complex micro-multileaf collimator using the standard BEAMnrc distribution

Purpose: The component modules in the standard BEAMnrc distribution may appear to be insufficient to model micro-multileaf collimators that have tri-faceted leaf ends and complex leaf profiles. This note indicates, however, that accurate Monte Carlo simulations of radiotherapy beams defined by a complex collimation device can be completed using BEAMnrc's standard VARMLC component module.---------- Methods: That this simple collimator model can produce spatially and dosimetrically accurate micro-collimated fields is illustrated using comparisons with ion chamber and film measurements of the dose deposited by square and irregular fields incident on planar, homogeneous water phantoms.---------- Results: Monte Carlo dose calculations for on- and off-axis fields are shown to produce good agreement with experimental values, even upon close examination of the penumbrae.--------- Conclusions: The use of a VARMLC model of the micro-multileaf collimator, along with a commissioned model of the associated linear accelerator, is therefore recommended as an alternative to the development or use of in-house or third-party component modules for simulating stereotactic radiotherapy and radiosurgery treatments. Simulation parameters for the VARMLC model are provided which should allow other researchers to adapt and use this model to study clinical stereotactic radiotherapy treatments.

Theory of radar imaging using time-frequency distribution

The concept of radar was developed for the estimation of the distance (range) and velocity of a target from a receiver. The distance measurement is obtained by measuring the time taken for the transmitted signal to propagate to the target and return to the receiver. The target's velocity is determined by measuring the Doppler induced frequency shift of the returned signal caused by the rate of change of the time- delay from the target. As researchers further developed conventional radar systems it become apparent that additional information was contained in the backscattered signal and that this information could in fact be used to describe the shape of the target itself. It is due to the fact that a target can be considered to be a collection of individual point scatterers, each of which has its own velocity and time- delay. DelayDoppler parameter estimation of each of these point scatterers thus corresponds to a mapping of the target's range and cross range, thus producing an image of the target. Much research has been done in this area since the early radar imaging work of the 1960s. At present there are two main categories into which radar imaging falls. The first of these is related to the case where the backscattered signal is considered to be deterministic. The second is related to the case where the backscattered signal is of a stochastic nature. In both cases the information which describes the target's scattering function is extracted by the use of the ambiguity function, a function which correlates the backscattered signal in time and frequency with the transmitted signal. In practical situations, it is often necessary to have the transmitter and the receiver of the radar system sited at different locations. The problem in these situations is 'that a reference signal must then be present in order to calculate the ambiguity function. This causes an additional problem in that detailed phase information about the transmitted signal is then required at the receiver. It is this latter problem which has led to the investigation of radar imaging using time- frequency distributions. As will be shown in this thesis, the phase information about the transmitted signal can be extracted from the backscattered signal using time- frequency distributions. The principle aim of this thesis was in the development, and subsequent discussion into the theory of radar imaging, using time- frequency distributions. Consideration is first given to the case where the target is diffuse, ie. where the backscattered signal has temporal stationarity and a spatially white power spectral density. The complementary situation is also investigated, ie. where the target is no longer diffuse, but some degree of correlation exists between the time- frequency points. Computer simulations are presented to demonstrate the concepts and theories developed in the thesis. For the proposed radar system to be practically realisable, both the time- frequency distributions and the associated algorithms developed must be able to be implemented in a timely manner. For this reason an optical architecture is proposed. This architecture is specifically designed to obtain the required time and frequency resolution when using laser radar imaging. The complex light amplitude distributions produced by this architecture have been computer simulated using an optical compiler.

Adapting a generic BEAMnrc model of the BrainLAB m3 micro-multileaf collimator to simulate a local collimation device

This work is focussed on developing a commissioning procedure so that a Monte Carlo model, which uses BEAMnrc’s standard VARMLC component module, can be adapted to match a specific BrainLAB m3 micro-multileaf collimator (μMLC). A set of measurements are recommended, for use as a reference against which the model can be tested and optimised. These include radiochromic film measurements of dose from small and offset fields, as well as measurements of μMLC transmission and interleaf leakage. Simulations and measurements to obtain μMLC scatter factors are shown to be insensitive to relevant model parameters and are therefore not recommended, unless the output of the linear accelerator model is in doubt. Ultimately, this note provides detailed instructions for those intending to optimise a VARMLC model to match the dose delivered by their local BrainLAB m3 μMLC device.

Examination of pencil beam predictions of small-field dose using dosimetry film and Monte Carlo simulations

The iPlan treatment planning sys-tem uses a pencil beam algorithm, with density cor-rections, to predict the doses delivered by very small (stereotactic) radiotherapy fields. This study tests the accuracy of dose predictions made by iPlan, for small-field treatments delivered to a planar solid wa-ter phantom and to heterogeneous human tissue using the BrainLAB m3 micro-multileaf collimator.

Validation and automation of the DYNJAWS component module of the BEAMnrc Monte Carlo code

The purpose of this work is to validate and automate the use of DYNJAWS; a new component module (CM) in the BEAMnrc Monte Carlo (MC) user code. The DYNJAWS CM simulates dynamic wedges and can be used in three modes; dynamic, step-and-shoot and static. The step-and-shoot and dynamic modes require an additional input file defining the positions of the jaw that constitutes the dynamic wedge, at regular intervals during its motion. A method for automating the generation of the input file is presented which will allow for the more efficient use of the DYNJAWS CM. Wedged profiles have been measured and simulated for 6 and 10 MV photons at three field sizes (5 cm x 5 cm , 10 cm x10 cm and 20 cm x 20 cm), four wedge angles (15, 30, 45 and 60 degrees), at dmax and at 10 cm depth. Results of this study show agreement between the measured and the MC profiles to within 3% of absolute dose or 3 mm distance to agreement for all wedge angles at both energies and depths. The gamma analysis suggests that dynamic mode is more accurate than the step-and-shoot mode. The DYNJAWS CM is an important addition to the BEAMnrc code and will enable the MC verification of patient treatments involving dynamic wedges.

The Kinaesthetic Fusion Effect : mechanisms and extensions

This study investigated the Kinaesthetic Fusion Effect (KFE) that was first described by Craske and Kenny in 1981. It was reported that when, without vision, participants pressed a button that resulted in a probe simultaneously touching the contralateral limb at a displaced location, they perceived an apparent change in limb length. The current study did not fully replicate these earlier findings. Participants did not perceive any reduction in the sagittal separation of the button and probe following repeated exposure to the tactile stimuli that was present on both arms. However, a localised and partial medio-lateral fusion was observed, with the touched positions seeming closer together. In addition, tactile acuity was found to decrease progressively for distal positions of the upper limb and a foreshortening effect was found which may result from a line-of-sight judgment and represent a feature of the reporting method used. A number of years have elapsed since the description of the original KFE. Although frequently cited in the literature, there has been no further investigation into the mechanisms of action. The results of the current study are considered in light of more recent literature concerning intersensory integration. Future research should focus on further clarification for the specific conditions that must be present for a fusion effect to occur. Finally, this thesis will benefit future studies that require participants to report the perceived locations of the unseen limbs.

A quasi four dimensional radiation detector

Techniques for the accurate measurement of ionising radiation have been evolving since Roentgen first discovered x-rays in 1895; until now experimental measurements of radiation fields in the three spatial dimensions plus time have not been successfully demonstrated. In this work, we embed an organic plastic scintillator in a polymer gel dosimeter to obtain the first quasi-4D experimental measurement of a radiation field.

A hybrid radiation detector for simultaneous spatial and temporal dosimetry

In this feasibility study an organic plastic scintillator is calibrated against ionisation chamber measurements and then embedded in a polymer gel dosimeter to obtain a quasi-4D experimental measurement of a radiation field. This hybrid dosimeter was irradiated with a linear accelerator, with temporal measurements of the dose rate being acquired by the scintillator and spatial measurements acquired with the gel dosimeter. The detectors employed in this work are radiologically equivalent; and we show that neither detector perturbs the intensity of the radiation field of the other. By employing these detectors in concert, spatial and temporal variations in the radiation intensity can now be detected and gel dosimeters can be calibrated for absolute dose from a single irradiation.

Investigation of stereotactic radiotherapy dose using dosimetry film and Monte Carlo simulations

This study uses dosimetry film measurements and Monte Carlo simulations to investigate the accuracy of type-a (pencil-beam) dose calculations for predicting the radiation doses delivered during stereotactic radiotherapy treatments of the brain. It is shown that when evaluating doses in a water phantom, the type-a algorithm provides dose predictions which are accurate to within clinically relevant criteria, gamma(3%,3mm), but these predictions are nonetheless subtly different from the results of evaluating doses from the same fields using radiochromic film and Monte Carlo simulations. An analysis of a clinical meningioma treatment suggests that when predicting stereotactic radiotherapy doses to the brain, the inaccuracies of the type-a algorithm can be exacerbated by inadequate evaluation of the effects of nearby bone or air, resulting in dose differences of up to 10% for individual fields. The results of this study indicate the possible advantage of using Monte Carlo calculations, as well as measurements with high-spatial resolution media, to verify type-a predictions of dose delivered in cranial treatments.

An indication that non-informative vision eliminates the Kinaesthetic Fusion Effect

This study investigated the Kinaesthetic Fusion Effect (KFE) first described by Craske and Kenny in 1981. The current study did not replicate these findings. Participants did not perceive any reduction in the sagittal separation of a button pressed by the index finger of one arm and a probe touching the other, following repeated exposure to the tactile stimuli present on both unseen arms. This study’s failure to replicate the widely-cited KFE as described by Craske et al. (1984) suggests that it may be contingent on several aspects of visual information, especially the availability of a specific visual reference, the role of instructions regarding gaze direction, and the potential use of a line of sight strategy when referring felt positions to an interposed surface. In addition, a foreshortening effect was found; this may result from a line-of-sight judgment and represent a feature of the reporting method used. The transformed line of sight data were regressed against the participant reported values, resulting in a slope of 1.14 (right arm) and 1.11 (left arm), and r > 0.997 for each. The study also provides additional evidence that mis-perceptions of the mediolateral position of the limbs specifically their separation and consistent with notions of Gestalt grouping, is somewhat labile and can be influenced by active motions causing touch of one limb by the other. Finally, this research will benefit future studies that require participants to report the perceived locations of the unseen limbs.

Improved image quality for x-ray CT imaging of gel dosimeters

Purpose: This study provides a simple method for improving precision of x-ray computed tomography (CT) scans of irradiated polymer gel dosimetry. The noise affecting CT scans of irradiated gels has been an impediment to the use of clinical CT scanners for gel dosimetry studies. Method: In this study, it is shown that multiple scans of a single PAGAT gel dosimeter can be used to extrapolate a ‘zero-scan’ image which displays a similar level of precision to an image obtained by averaging multiple CT images, without the compromised dose measurement resulting from the exposure of the gel to radiation from the CT scanner. Results: When extrapolating the zero-scan image, it is shown that exponential and simple linear fits to the relationship between Hounsfield unit and scan number, for each pixel in the image, provides an accurate indication of gel density. Conclusions: It is expected that this work will be utilised in the analysis of three-dimensional gel volumes irradiated using complex radiotherapy treatments.