Abnormal systemic and ocular vascular response to temperature provocation in primary open-angle glaucoma patients:a case for autonomic failure?

PURPOSE. To assess systemic and ocular vascular reactivity in response to warm and cold provocation in untreated patients with primary open-angle glaucoma and normal control subjects. METHODS. Twenty-four patients with primary open-angle glaucoma and 22 normal control subjects were subjected to a modified cold pressor test involving immersion of the right hand in 40°C warm water followed by 4°C cold water exposure, and finger and ocular blood flow were assessed by means of peripheral laser Doppler flowmetry and retinal flowmetry, respectively. Finger and body temperature as well as intraocular pressure, systemic blood pressure, systemic pulse pressure, heart rate, and ocular perfusion pressure were also monitored. RESULTS. The patients with glaucoma demonstrated an increase in diastolic blood pressure (P = 0.023), heart rate (P = 0.010), and mean ocular perfusion pressure (P = 0.039) during immersion of the tested hand in 40°C water. During cold provocation, the patients demonstrated a significant decrease in finger (P = 0.0003) and ocular blood flow (the parameter velocity measured at the temporal neuroretinal rim area; P = 0.021). Normal subjects did not demonstrate any blood flow or finger temperature changes during immersion of the tested hand in 40°C water (P > 0.05); however, they exhibited increases in systolic blood pressure (P = 0.034) and pulse pressure (P = 0.0009) and a decrease in finger blood flow (P = 0.0001) during cold provocation. In normal subjects, the ocular blood flow was unchanged during high- and low-temperature challenge. CONCLUSIONS. Cold provocation elicits a different blood pressure, and ocular blood flow response in patients with primary open-angle glaucoma compared with control subjects. These findings suggest a systemic autonomic failure and ocular vascular dysregulation in POAG patients.

Analysis of the intraocular pressure pulse

This thesis was concerned with investigating methods of improving the IOP pulse’s potential as a measure of clinical utility. There were three principal sections to the work. 1. Optimisation of measurement and analysis of the IOP pulse. A literature review, covering the years 1960 – 2002 and other relevant scientific publications, provided a knowledge base on the IOP pulse. Initial studies investigated suitable instrumentation and measurement techniques. Fourier transformation was identified as a promising method of analysing the IOP pulse and this technique was developed. 2. Investigation of ocular and systemic variables that affect IOP pulse measurements In order to recognise clinically important changes in IOP pulse measurement, studies were performed to identify influencing factors. Fourier analysis was tested against traditional parameters in order to assess its ability to detect differences in IOP pulse. In addition, it had been speculated that the waveform components of the IOP pulse contained vascular characteristic analogous to those components found in arterial pulse waves. Validation studies to test this hypothesis were attempted. 3. The nature of the intraocular pressure pulse in health and disease and its relation to systemic cardiovascular variables. Fourier analysis and traditional parameters were applied to the IOP pulse measurements taken on diseased and healthy eyes. Only the derived parameter, pulsatile ocular blood flow (POBF) detected differences in diseased groups. The use of an ocular pressure-volume relationship may have improved the POBF measure’s variance in comparison to the measurement of the pulse’s amplitude or Fourier components. Finally, the importance of the driving force of pulsatile blood flow, the arterial pressure pulse, is highlighted. A method of combining the measurements of pulsatile blood flow and pulsatile blood pressure to create a measure of ocular vascular impedance is described along with its advantages for future studies.

Accommodation and intraocular pressure

The relationship between accommodation and intraocular pressure (lOP) has not been addressed as a research question for over 20 years, when measurement of both of these parameters was less advanced than today. Hence the central aim of this thesis was to evaluate the effects of accommodation on lOP. The instrument of choice throughout this thesis was the Pulsair EasyEye non-contact tonometer (NCT) due principally to its slim-line design which allowed the measurement of lOP in one eye and simultaneous stimulation of accommodation in the other eye. A second reason for using the Pulsair EasyEye NCT was that through collaboration with the manufacturers (Keeler, UK) the instrument's operational technology was made accessible. Hence, the principle components underpinning non-contact lOP measures of 0.1mmHg resolution (an order of magnitude greater than other methods) were made available. The relationship between the pressure-output and corneal response has been termed the pressure-response relationship, aspects of which have been shown to be related to ocular biometric parameters. Further, analysis of the components of the pressure-response relationship together with high-speed photography of the cornea during tonometry has enhanced our understanding of the derivation of an lOP measure with the Pulsair EasyEye NCT. The NCT samples the corneal response to the pressure pulse over a 19 ms cycle photoelectronically, but computes the subject's lOP using the data collected in the first 2.34 ms. The relatively instantaneous nature of the lOP measurement renders the measures susceptible to variations in the steady-state lOP caused by the respiratory and cardiac cycles. As such, the variance associated with these cycles was minimised by synchronising the lOP measures with the cardiac trace and maintaining a constant pace respiratory cycle at 15 breathes/minute. It is apparent that synchronising the lOP measures with the peak, middle or trough of the cardiac trace significantly reduced the spread of consecutive measures. Of the 3 locations investigated, synchronisation with the middle location demonstrated the least variance (coeflicient of variation = 9.1%) and a strong correlation (r = 0.90, p = <0.001) with lOP values obtained with Goldmann contact tonometry (n = 50). Accordingly lOP measures synchronised with the middle location of the cardiac cycle were taken in the RE while the LE fixated low (L; zero D), intermediate (I; 1.50 D) and high (H; 4 D) accommodation targets, Quasi-continuous measures of accommodation responses were obtained during the lOP measurement period using the portable infrared Grand Seiko FR-5000 autorefractor. The lOP reduced between L and I accommodative levels by approximately 0.61 mmHg (p <0.00 I). No significant reduction in IOP between L and H accommodation levels was elicited (p = 0.65) (n = 40). The relationship between accommodation and lOP was characterised by substantial inter-subject variations. Myopes demonstrated a tendency to show a reduction in IOP with accommodation which was significant only with I accommodation levels when measured with the NCT (r = 0.50, p = 0.01). However, the relationship between myopia and lOP change with accommodation reached significance for both I (r = 0.61, p= 0.003) and H (r = 0.531, p= 0.0 1) accommodation levels when measured with the Ocular blood Flow Analyser (OBFA). Investigation of the effects of accommodation on the parameters measured by the OBFA demonstrated that with H accommodation levels the pulse amplitude (PA) and pulse rate (PR) responses differed between myopes and emmetropes (PA: p = 0.03; PR: p = 0.004). As thc axial length increased there was a tendency for the pulsatile ocular blood flow (POBF) to reduce with accommodation, which was significant only with H accommodation levels (r = 0.38, p = 0.02). It is proposed that emmetropes arc able to regulate the POBF responses to changes in ocular perfusion pressure caused by changes in lOP with I (r = 0.77, p <0.001) and H (r = 0.73, p = 0.001) accommodation levels. However, thc relationship between lOP and POBF changes in the myopes was not correlated for both I (r = 0.33, p = 0.20) and H (r = 0.05, p = 0.85) accommodation levels. The thesis presents new data on the relationships between accommodation, lOP and parameters of the OBFA,: and provides evidence for possible lOP and choroidal blood flow regulatory mechanisms. Further the data highlight possible deficits in the vascular regulation of the myopic eye during accommodation, which may play a putative role in the aetiology of myopia development.

The missing ingredient:inter-municipal cooperation and central-local relations in the UK

The thrust of the argument presented in this chapter is that inter-municipal cooperation (IMC) in the United Kingdom reflects local government's constitutional position and its exposure to the exigencies of Westminster (elected central government) and Whitehall (centre of the professional civil service that services central government). For the most part councils are without general powers of competence and are restricted in what they can do by Parliament. This suggests that the capacity for locally driven IMC is restricted and operates principally within a framework constructed by central government's policy objectives and legislation and the political expediencies of the governing political party. In practice, however, recent examples of IMC demonstrate that the practices are more complex than this initial analysis suggests. Central government may exert top-down pressures and impose hierarchical directives, but there are important countervailing forces. Constitutional changes in Scotland and Wales have shifted the locus of central- local relations away from Westminster and Whitehall. In England, the seeding of English government regional offices in 1994 has evolved into an important structural arrangement that encourages councils to work together. Within the local government community there is now widespread acknowledgement that to achieve the ambitious targets set by central government, councils are, by necessity, bound to cooperate and work with other agencies. In recent years, the fragmentation of public service delivery has affected the scope of IMC. Elected local government in the UK is now only one piece of a complex jigsaw of agencies that provides services to the public; whether it is with non-elected bodies, such as health authorities, public protection authorities (police and fire), voluntary nonprofit organisations or for-profit bodies, councils are expected to cooperate widely with agencies in their localities. Indeed, for projects such as regeneration and community renewal, councils may act as the coordinating agency but the success of such projects is measured by collaboration and partnership working (Davies 2002). To place these developments in context, IMC is an example of how, in spite of the fragmentation of traditional forms of government, councils work with other public service agencies and other councils through the medium of interagency partnerships, collaboration between organisations and a mixed economy of service providers. Such an analysis suggests that, following changes to the system of local government, contemporary forms of IMC are less dependent on vertical arrangements (top-down direction from central government) as they are replaced by horizontal modes (expansion of networks and partnership arrangements). Evidence suggests, however that central government continues to steer local authorities through the agency of inspectorates and regulatory bodies, and through policy initiatives, such as local strategic partnerships and local area agreements (Kelly 2006), thus questioning whether, in the case of UK local government, the shift from hierarchy to network and market solutions is less differentiated and transformation less complete than some literature suggests. Vertical or horizontal pressures may promote IMC, yet similar drivers may deter collaboration between local authorities. An example of negative vertical pressure was central government's change of the systems of local taxation during the 1980s. The new taxation regime replaced a tax on property with a tax on individual residency. Although the community charge lasted only a few years, it was a highpoint of the then Conservative government policy that encouraged councils to compete with each other on the basis of the level of local taxation. In practice, however, the complexity of local government funding in the UK rendered worthless any meaningful ambition of councils competing with each other, especially as central government granting to local authorities is predicated (however imperfectly) on at least notional equalisation between those areas with lower tax yields and the more prosperous locations. Horizontal pressures comprise factors such as planning decisions. Over the last quarter century, councils have competed on the granting of permission to out-of-town retail and leisure complexes, now recognised as detrimental to neighbouring authorities because economic forces prevail and local, independent shops are unable to compete with multiple companies. These examples illustrate tensions at the core of the UK polity of whether IMC is feasible when competition between local authorities heightened by local differences reduces opportunities for collaboration. An alternative perspective on IMC is to explore whether specific purposes or functions promote or restrict it. Whether in the principle areas of local government responsibilities relating to social welfare, development and maintenance of the local infrastructure or environmental matters, there are examples of IMC. But opportunities have diminished considerably as councils lost responsibility for services provision as a result of privatisation and transfer of powers to new government agencies or to central government. Over the last twenty years councils have lost their role in the provision of further-or higher-education, public transport and water/sewage. Councils have commissioning power but only a limited presence in providing housing needs, social care and waste management. In other words, as a result of central government policy, there are, in practice, currently far fewer opportunities for councils to cooperate. Since 1997, the New Labour government has promoted IMC through vertical drivers and the development; the operation of these policy initiatives is discussed following the framework of the editors. Current examples of IMC are notable for being driven by higher tiers of government, working with subordinate authorities in principal-agent relations. Collaboration between local authorities and intra-interand cross-sectoral partnerships are initiated by central government. In other words, IMC is shaped by hierarchical drivers from higher levels of government but, in practice, is locally varied and determined less by formula than by necessity and function. © 2007 Springer.

Ocular blood flow measurements in healthy human myopic eyes

Background. To evaluate the haemodynamic features of young healthy myopes and emmetropes, in order to ascertain the perfusion profile of human myopia and its relationship with axial length prior to reaching a degenerative state. Methods The retrobulbar, microretinal and pulsatile ocular blood flow (POBF) of one eye of each of twenty-two high myopes (N=22, mean spherical equivalent (MSE) =-5.00D), low myopes (N=22, MSE-1.00 to-4.50D) and emmetropes (N=22, MSE±0.50D) was analyzed using color Doppler Imaging, Heidelberg retinal flowmetry and ocular blood flow analyser (OBF) respectively. Intraocular pressure, axial length (AL), systemic blood pressure, and body mass index were measured. Results. When compared to the emmetropes and low myopes, the AL was greater in high myopia (p<0.0001). High myopes showed higher central retinal artery resistance index (CRA RI) (p=0.004), higher peak systolic to end diastolic velocities ratio (CRA ratio) and lower end diastolic velocity (CRA EDv) compared to low myopes (p=0.014, p=0.037). Compared to emmetropes, high myopes showed lower OBFamplitude (OBFa) (p=0.016). The POBF correlated significantly with the systolic and diastolic blood velocities of the CRA (p=0.016, p=0.036). MSE and AL correlated negatively with OBFa (p=0.03, p=0.003), OBF volume (p=0.02, p<0.001), POBF (p=0.01, p<0.001) and positively with CRA RI (p=0.007, p=0.05). Conclusion. High myopes exhibited significantly reduced pulse amplitude and CRA blood velocity, the first of which may be due to an OBF measurement artefact or real decreased ocular blood flow pulsatility. Axial length and refractive error correlated moderately with the ocular pulse and with the resistance index of the CRA, which in turn correlated amongst themselves. It is hypothesized that the compromised pulsatile and CRA haemodynamics observed in young healthy myopes is an early feature of the decrease in ocular blood flow reported in pathological myopia. Such vascular features would increase the susceptibility for vascular and age-related eye diseases.

Characterising the central mechanisms of sensory modulation in human swallowing motor cortex

Objective: Pharyngeal stimulation can induce remarkable increases in the excitability of swallowing motor cortex, which is associated with short-term improvements in swallowing behaviour in dysphagic stroke patients. However, the mechanism by which this input induces cortical change remains unclear. Our aims were to explore the stimulus-induced facilitation of the cortico-bulbar projections to swallowing musculature and examine how input from the pharynx interacts with swallowing motor cortex. Methods: In 8 healthy subjects, a transcranial magnetic stimulation (TMS) paired-pulse investigation was performed comprising a single conditioning electrical pharyngeal stimulus (pulse width 0.2 ms, 240 V) followed by cortical TMS at inter-stimulus intervals (ISI) of 10-100 ms. Pharyngeal sensory evoked potentials (PSEP) were also measured over the vertex. In 6 subjects whole-brain magnetoencephalography (MEG) was further acquired following pharyngeal stimulation. Results: TMS evoked pharyngeal motor evoked potentials were facilitated by the pharyngeal stimulus at ISI between 50 and 80 ms (Δ mean increase: 47±6%, P<0.05). This correlated with the peak latency of the P1 component of the PSEP (mean 79.6±8.5 ms). MEG confirmed that the equivalent P1 peak activities were localised to caudolateral sensory and motor cortices (BA 4, 1, 2). Conclusions: Facilitation of the cortico-bulbar pathway to pharyngeal stimulation relates to coincident afferent input to sensorimotor cortex. Significance: These findings have mechanistic importance on how pharyngeal stimulation may increase motor excitability and provide guidance on temporal windows for future manipulations of swallowing motor cortex. © 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The effect of corneal thickness and corneal curvature on pneumatonometer measurements

Purpose. The purpose of this study was to investigate the influence of corneal topography and thickness on intraocular pressure (IOP) and pulse amplitude (PA) as measured using the Ocular Blood Flow Analyzer (OBFA) pneumatonometer (Paradigm Medical Industries, Utah, USA). Methods. 47 university students volunteered for this cross-sectional study: mean age 20.4 yrs, range 18 to 28 yrs; 23 male, 24 female. Only the measurements from the right eye of each participant were used. Central corneal thickness and mean corneal radius were measured using Scheimpflug biometry and corneal topographic imaging respectively. IOP and PA measurements were made with the OBFA pneumatonometer. Axial length was measured using A-scan ultrasound, due to its known correlation with these corneal parameters. Stepwise multiple regression analysis was used to identify those components that contributed significant variance to the independent variables of IOP and PA. Results. The mean IOP and PA measurements were 13.1 (SD 3.3) mmHg and 3.0 (SD 1.2) mmHg respectively. IOP measurements made with the OBFA pneumatonometer correlated significantly with central corneal thickness (r = +0.374, p = 0.010), such that a 10 mm change in CCT was equivalent to a 0.30 mmHg change in measured IOP. PA measurements correlated significantly with axial length (part correlate = -0.651, p < 0.001) and mean corneal radius (part correlate = +0.459, p < 0.001) but not corneal thickness. Conclusions. IOP measurements taken with the OBFA pneumatonometer are correlated with corneal thickness, but not axial length or corneal curvature. Conversely, PA measurements are unaffected by corneal thickness, but correlated with axial length and corneal radius. These parameters should be taken into consideration when interpreting IOP and PA measurements made with the OBFA pneumatonometer.

Relationship between ocular perfusion pressure and retrobulbar blood flow in patients with glaucoma with progressive damage

PURPOSE: To evaluate the relationship between ocular perfusion pressure and color Doppler measurements in patients with glaucoma. MATERIALS AND METHODS: Twenty patients with primary open-angle glaucoma with visual field deterioration in spite of an intraocular pressure lowered below 21 mm Hg, 20 age-matched patients with glaucoma with stable visual fields, and 20 age-matched healthy controls were recruited. After a 20-minute rest in a supine position, intraocular pressure and color Doppler measurements parameters of the ophthalmic artery and the central retinal artery were obtained. Correlations between mean ocular perfusion pressure and color Doppler measurements parameters were determined. RESULTS: Patients with glaucoma showed a higher intraocular pressure (P <.0008) and a lower mean ocular perfusion pressure (P <.0045) compared with healthy subjects. Patients with deteriorating glaucoma showed a lower mean blood pressure (P =.033) and a lower end diastolic velocity in the central retinal artery (P =.0093) compared with normals. Mean ocular perfusion pressure correlated positively with end diastolic velocity in the ophthalmic artery (R = 0.66, P =.002) and central retinal artery (R = 0.74, P <.0001) and negatively with resistivity index in the ophthalmic artery (R = -0.70, P =.001) and central retinal artery (R = -0.62, P =.003) in patients with deteriorating glaucoma. Such correlations did not occur in patients with glaucoma with stable visual fields or in normal subjects. The correlations were statistically significantly different between the study groups (parallelism of regression lines in an analysis of covariance model) for end diastolic velocity (P =.001) and resistivity index (P =.0001) in the ophthalmic artery, as well as for end diastolic velocity (P =.0009) and resistivity index (P =. 001) in the central retinal artery. CONCLUSIONS: The present findings suggest that alterations in ocular blood flow regulation may contribute to the progression in glaucomatous damage.

Flow and pressure drop on the shellside of cylindrical heat exchangers

This work presents pressure distributions and fluid flow patterns on the shellside of a cylindrical shell-and-tube heat exchanger. The apparatus used was constructed from glass enabling direct observation of the flow using a dye release technique and had ten traversable pressure instrumented tubes permitting detailed pressure distributions to be obtained. The `exchanger' had a large tube bundle (278 tubes) and main flow areas typical of practical designs. Six geometries were studied: three baffle spacings both with and without baffle leakage. Results are also presented of three-dimensional modelling of shellside flows using the Harwell Laboratory's FLOW3D code. Flow visualisation provided flow patterns in the central plane of the bundle and adjacent to the shell wall. Comparison of these high-lighted significant radial flow variations. In particular, separated regions, originating from the baffle tips, were observed. The size of these regions was small in the bundle central plane but large adjacent to the shell wall and extended into the bypass lane. This appeared to reduce the bypass flow area and hence the bypass flow fraction. The three-dimensional flow modelling results were presented as velocity vector and isobar maps. The vector maps illustrated regions of high and low velocity which could be prone to tube vibration and fouling. Separated regions were also in evidence. A non-uniform crossflow was discovered with, in general, higher velocities in the central plane of the bundle than near the shell wall._The form of the isobar maps calculated by FLOW3D was in good agreement with experimental results. In particular, larger pressure drops occurred across the inlet than outlet of a crossflow region and were higher near the upstream than downstream baffle face. The effect of baffle spacing and baffle leakage on crossflow and window pressure drop measurements was identified. Agreement between the current measurements, previously obtained data and commonly used design correlations/models was, in general, poor. This was explained in terms of the increased understanding of shellside flow. The bulk of previous data, which dervies from small-scale rigs with few tubes, have been shown to be unrepresentative of typical commerical units. The Heat Transfer and Fluid Flow Service design program TASC provided the best predictions of the current pressure drop results. However, a number of simple one-dimensional models in TASC are, individually, questionable. Some revised models have been proposed.

The relationship between measurement method and corneal structure on apparent intraocular pressure in glaucoma and ocular hypertension

Purpose: To analyse the relationship between measured intraocular pressure (IOP) and central corneal thickness (CCT), corneal hysteresis (CH) and corneal resistance factor (CRF) in ocular hypertension (OHT), primary open-angle (POAG) and normal tension glaucoma (NTG) eyes using multiple tonometry devices. Methods: Right eyes of patients diagnosed with OHT (n=47), normal tension glaucoma (n=17) and POAG (n=50) were assessed, IOP was measured in random order with four devices: Goldmann applanation tonometry (GAT); Pascal(R) dynamic contour tonometer (DCT); Reichert(R) ocular response analyser (ORA); and Tono-Pen(R) XL. CCT was then measured using a hand-held ultrasonic pachymeter. CH and CRF were derived from the air pressure to corneal reflectance relationship of the ORA data. Results: Compared to the GAT, the Tonopen and ORA Goldmann equivalent (IOPg) and corneal compensated (IOPcc) measured higher IOP readings (F=19.351, p<0.001), particularly in NTG (F=12.604, p<0.001). DCT was closest to Goldmann IOP and had the lowest variance. CCT was significantly different (F=8.305, p<0.001) between the 3 conditions as was CH (F=6.854, p=0.002) and CRF (F=19.653, p<0.001). IOPcc measures were not affected by CCT. The DCT was generally not affected by corneal biomechanical factors. Conclusion: This study suggests that as the true pressure of the eye cannot be determined non-invasively, measurements from any tonometer should be interpreted with care, particularly when alterations in the corneal tissue are suspected.

Does rebound tonometry probe misalignment modify intraocular pressure measurements in human eyes?

Purpose. To examine the influence of positional misalignments on intraocular pressure (IOP) measurement with a rebound tonometer. Methods. Using the iCare rebound tonometer, IOP readings were taken from the right eye of 36 healthy subjects at the central corneal apex (CC) and compared to IOP measures using the Goldmann applanation tonometer (GAT). Using a bespoke rig, iCare IOP readings were also taken 2 mm laterally from CC, both nasally and temporally, along with angular deviations of 5 and 10 degrees, both nasally and temporally to the visual axis. Results. Mean IOP ± SD, as measured by GAT, was 14.7±2.5 mmHg versus iCare tonometer readings of 17.4±3.6 mmHg at CC, representing an iCare IOP overestimation of 2.7±2.8 mmHg (P<0.001), which increased at higher average IOPs. IOP at CC using the iCare tonometer was not significantly different to values at lateral displacements. IOP was marginally underestimated with angular deviation of the probe but only reaching significance at 10 degrees nasally. Conclusions. As shown previously, the iCare tonometer overestimates IOP compared to GAT. However, IOP measurement in normal, healthy subjects using the iCare rebound tonometer appears insensitive to misalignments. An IOP underestimation of <1 mmHg with the probe deviated 10 degrees nasally reached statistical but not clinical significance levels. © 2013 Ian G. Beasley et al.