Ophthalmic, clinical and visual electrophysiological findings in children born to mothers prescribed substitute methadone in pregnancy.

BACKGROUND AND AIMS: There are growing concerns regarding visual outcome of infants exposed to opiates (including substitute methadone) and/or benzodiazepines in utero. We describe the combined ophthalmology and visual electrophysiology findings in 20 infants and children who had been exposed to substitute methadone and other drugs of misuse in utero. METHODS: This was a descriptive case series of 20 patients, all of whom had been referred to a paediatric visual electrophysiology service because of concerns regarding visual function, and all of whom had been exposed to methadone in utero. All children underwent a full ophthalmic and orthoptic examination as well as visual electrophysiology testing deemed appropriate on an individual basis. A review was undertaken of paediatric case notes and of maternal antenatal urine toxicology. RESULTS: Ophthalmic abnormalities included reduced acuity (95%), nystagmus (70%), delayed visual maturation (50%), strabismus (30%), refractive errors (30%), and cerebral visual impairment (25%). Visual electrophysiology was abnormal in 60%. A quarter of the children had associated neurodevelopmental abnormalities. The majority of children with nystagmus (79%) had been treated for neonatal abstinence syndrome (NAS). CONCLUSION: Infants born to drug-misusing mothers prescribed methadone in pregnancy are at risk of a range of visual problems, the underlying causes of which are not clear. Those infants with NAS severe enough to receive pharmaceutical treatment may be at particular risk of developing nystagmus. The inclusion of visual electrophysiology in comprehensive visual assessment of children exposed to substance misuse in utero may help clarify the underlying causes by differentiating abnormalities of retinal and cortical origin.

Visual evoked potentials in infants exposed to methadone in utero.

We investigated the effects of maternal drug misuse on neonatal visual evoked potentials (VEPs). Flash VEPs were recorded within 4 days of birth from 21 term infants of mothers misusing drugs and prescribed substitute methadone and 20 controls. Waveforms were classified as typical, atypical, immature or non-detectable, and amplitude and latencies were measured. VEPs from drug-exposed infants were less likely to be of typical waveform and more likely to be immature or non-detectable (p<0.01) than those of control infants. They were also smaller in amplitude (median 10.8 vs 24.4 microV, p<0.001). VEPs of drug-exposed infants had matured after 1 week but remained of lower amplitude than VEPs of newborn controls (p<0.01) and were non-detectable in 15%. Flash VEPs differ between maternal drug-exposed and non-drug-exposed newborns. Future research should address the specific effects of maternal methadone and/or other illicit drug misuse on infant VEPs, and associations between neonatal VEPs and subsequent visual development.

A visual skills inventory for children with neurological impairments.

Children with neurological impairments often have visual deficits that are difficult to quantify. We have compared visual skills evaluated by carers with results of a comprehensive visual assessment. Participants were 76 children with mild to profound intellectual and/or motor impairment (33 males, 43 females; age range 7mo-16y; mean age 5y 1mo [SD 4y 2mo]) who completed a visual skills inventory before attending a special vision clinic. The inventory included 16 questions about visual skills and responses to familiar situations. Responses were augmented by taking a structured clinical history, compared with visual evoked potential (VEP) and/or acuity card measures of visual acuity, and examined using exploratory factor analysis. Acuity ranged from normal to no light perception, and was positively associated with responses to individual questions. After excluding four uninformative questions, an association between the remaining questions and two significant independent factors was found. Factor 1 was associated with questions about visual recognition (e.g. 'Does your child see a small silent toy?') and these items were correlated with both the VEP and acuity card thresholds. Factor 2 was associated primarily with questions about visually mediated social interactions (e.g. 'Does he/she return your silent smile?'). Evaluation of visual skills in children with neurological impairment can provide valid information about the quality of children's vision. Questions with the highest validity for predicting vision are identified.

Contact lens electroretinography in preterm infants from 32 weeks after conception: a development in current methodology.

AIM: To assess the feasibility of using a contact lens electrode to record the electroretinogram (ERG) in preterm infants less than 35 weeks after conception. METHODS: The ERG was recorded from seven very low birthweight preterm infants on a total of 14 occasions using an infant monkey contact lens electrode. Age at recording the first ERG ranged from 23 to 51 days (gestational age 32-34 weeks), and weight ranged upwards from 1100 g. RESULTS: No complications were observed. With advancing age and maturity the dark adapted rod threshold decreased, indicating increased retinal sensitivity. CONCLUSIONS: Contact lens recording of the ERG from extremely small immature preterm infants is a practicable and well tolerated procedure. This method of recording the ERG will enable further evaluation of retinal development in this vulnerable population.

Transorbital optic nerve sheath ultrasonography in normal children.

AIM: Early diagnosis of acute intracranial hypertension is essential to enable prompt, optimal treatment. The optic nerve sheath diameter (ONSD) is increased in raised ICP and there has been recent interest in the use of ultrasound to diagnose and indirectly monitor raised ICP by ONSD measurement. The advantages of the technique include its non-invasiveness, wide availability, portability, low cost and the absence of ionizing radiation. This prospective study was designed to establish the range of normal values for ONSD in infants and children up to 15 years of age. PATIENTS AND METHODS: One hundred and two children attending the hospital for other reasons were recruited to the study. Three measurements of the ONSD were taken for each eye, 3 mm behind the optic nerve head using a 7 MHz sector probe. RESULTS: The range for ONSD was 2.1-4.3 mm, mean 3.08 (SD 0.36). There were no significant differences on ONSD measurement between boys and girls (P = 0.59) or between right and left eyes (P=0.66). When the data were grouped and analysed, a correlation between increasing age and increasing ONSD was seen (r2=0.48), with the greatest increase occurring in the first 2 months of life. CONCLUSION: Using the technique described here, our results suggest that an ONSD of greater than 4 mm in infants less than 1 year, and 45 mm or greater in older children, should be regarded as abnormal.

Habituation-like effects cause a significant decrease in response in MRI neuroactivation during visual stimulation.

A wide range of rest/stimulus cycle durations (40-360 sec) is reported to have been used by various groups for MRI neuroactivation studies of the visual cortex. In this paper we demonstrate a clear habituation-like response for longer cycle durations which results in a halving of apparent activation between cycle durations of 138 and 276 sec. This has important implications, not only in terms of optimizing the technique, but also in providing an insight into the underlying physiological mechanisms.

Objective detection of hemifield and quadrantic field defects by visual evoked cortical potentials.

AIMS/BACKGROUND: An objective method for detecting hemifield and quadrantic visual field defects has been developed using steady state visual evoked cortical potentials (VECPs), an adaptive noise canceller (ANC), and Hotelling's t2 statistic. The purpose of this study was to determine the sensitivity and specificity of the technique. METHODS: Nine subjects (mean age 44 years) were investigated with field loss due to a variety of causes including both anterior and posterior visual pathway lesions. Dynamic perimetry was performed by means of a Goldmann or Tübingen perimeter. VECP recordings were made from each visual field quadrant (23 degrees X 23 degrees) by means of a steady state reversing checkerboard (7.7 rev/s). The central 5 degrees of the visual field and the vertical and horizontal meridians were masked during these measurements. Recordings were made from three electrode sites, positioned over the visual cortex, relative to a mid frontal electrode. Each recording lasted 2 minutes, during which time fixation was monitored. The data from each recording were divided into 4 second segments, and the amplitude and phase of the VECP signal measured using the ANC. Hotelling's t2 statistic was applied to determine the probability of signal detection. Receiver operating characteristic curves were used to find the optimum signal detection threshold for identification of the visual field defects. RESULTS: The results of the study confirmed patterns of subjective visual field loss. The technique had a sensitivity and a specificity of 81% and 85%, respectively, for detecting 'non-seeing' areas in the inferior visual field, and 82% and 89%, respectively, for detecting 'non-seeing' areas in the superior visual field. CONCLUSION: These results demonstrate that the technique is of potential clinical value to ophthalmologists and neurologists when subjective perimetry is not possible.

Quantitative assessment of the blue-light hazard during indirect ophthalmoscopy and the increase in the "safe" operating period achieved using a yellow lens.

PURPOSE: The indirect ophthalmoscope presents a blue-light hazard with the potential for causing photochemical injury to the retina. In this study, this hazard was assessed with respect to the threshold limit values (TLVs) recently adopted by the American Conference of Governmental Industrial Hygienists. METHOD: Spectral radiometric measurements were made from a standard indirect ophthalmoscope headset used in conjunction with either a clear or a yellow lens. The results were weighted spectrally with the published blue-light hazard function. RESULTS: When the clear lens was used, the TLV was exceeded after approximately 2.5 minutes. The yellow lens filtered out the more hazardous blue wavelengths of light and this increased the "safe" operating period by a factor of approximately 20. CONCLUSION: In clinical practice, with a clear lens, the TLV could be exceeded easily if the patient is subjected to prolonged or repeated examination because the blue-light hazard is additive in a linear manner for periods as long as 3 hours with a potential for a cumulative effect over longer periods. Furthermore, some ophthalmic patients, such as those with aphakia, are less tolerant of blue-light than healthy subjects. In the interests of patient safety, it is recommended that yellow lenses are considered for use for routine indirect ophthalmoscopy.

Comparison of visual assessment tests in multiply handicapped children.

The aims of this study were to compare acuity estimates achieved with visual evoked potential (VEP) and acuity card techniques and to examine the success rates of each test in a group of multiply handicapped children. Subjects were 52 children (3-183 months) with multiple handicaps associated with prematurity (n = 17), congenital anomalies (n = 16), hypoxic insult (n = 10) and other disorders (n = 9). Success rates for completing the tests were: VEP 88% and acuity cards 85% (Keeler or Cardiff). The acuity card tests were less likely to be successfully completed in the severely disabled (p < 0.05) and in those children with nystagmus (p < 0.05). When both acuity cards were successful, results agreed to within +/- 1.75 octaves. Acuity card thresholds were significantly correlated with VEP thresholds (p < 0.02), but thresholds achieved with VEPs were better in children with poor vision.

The effect of motion on pattern-onset visual evoked potentials in adults and children.

Visual evoked potentials can be elicited by a variety of visual stimuli, including pattern-onset and motion-onset. It may be desirable to combine pattern-onset with motion-onset stimuli, for example, to make a direct comparison between optokinetic nystagmus and visual evoked potential acuity thresholds. Both procedures employ grating stimuli; however, the gratings must be moving to produce optokinetic nystagmus. We compared pattern-onset visual evoked potentials with both a static and a moving pattern to investigate the effect of motion on the pattern-onset visual evoked potential waveform. Visual evoked potential recordings were made from 10 adults (aged 20-37 years) and 10 children (aged 5-7 years) with the active electrode at Oz. Stimuli consisted of onset of high-contrast vertical bars of three sizes (12', 30' and 60') both with and without motion (3 cycles/s). In a subgroup of subjects, visual evoked potentials were recorded to motion onset of constantly present gratings. Motion of the pattern had no significant effect on any of the latency components of the visual evoked potential waveform in adults or children. The amplitude of the C2-C3 component was significantly increased (p < 0.001) in adults. The motion appears to add a late negative component to the visual evoked potential similar to that produced by the motion-only stimulus. The latency of the early components of the pattern-onset visual evoked potential was unaffected by the presence of motion. Therefore, pattern-onset visual evoked potentials with moving gratings could be used to estimate visual acuity, and direct comparisons could be made between visual evoked potential and optokinetic nystagmus acuity thresholds with the use of the same stimulus parameters.

The measurement of steady-state visual evoked cortical potentials using an adaptive noise canceller.

A new software method for measuring steady-state visual evoked cortical potentials (VECPs) has been developed using the principle of adaptive noise cancelling. The steady-state VECP is composed of narrow-band frequency components at harmonics of the stimulus frequency. In clinical recordings, these signal components are masked by wide-band noise, predominantly electroencephalographic activity and muscle noise. The stimulus frequency is exactly known and by using a reference sinusoid at the stimulus frequency (or its harmonics) the adaptive noise canceller (ANC) is able to cancel uncorrelated noise components from the recording. In effect, the ANC functions as an adaptive narrow-band-pass filter at the reference frequency. The performance of the ANC has been evaluated using both simulated and physiological signals. The output of the ANC provides temporal information on the signal amplitude and phase, and can be used to calculate the reliability of signal detection. For this application, the ANC has a number of advantages over the fast Fourier transform: it is a more sensitive detector, it requires fewer calculations, it is less computationally intensive, it requires less memory and it can be implemented in real time.

A personal computer-based visual evoked potential stimulus and recording system.

A system for recording electroretinograms and visual evoked cortical potentials has been constructed with the use of a personal computer and a digital signal processing card. The system is based on widely available commercial hardware. It has been designed to be capable of performing routine visual electrophysiology as well as allowing the development of novel visual stimuli and signal detection techniques. The system enables both transient and steady-state stimulation rates. Pattern stimuli can be presented in pattern-reversal, pattern-onset, pattern-offset or motion-onset modes. In addition to conventional signal averaging, the digital signal processing card can also provide on-line Fourier analysis and is facilitating the development of adaptive filtering techniques for the detection of steady-state visual evoked cortical potentials. This versatile system is in regular clinical use for the measurement of electroretinograms and visual evoked cortical potentials.

Effects of daily high-intensity exercise on myocardial perfusion in angina pectoris.

Forty male patients with chronic stable angina pectoris and no prior myocardial infarction were studied by planar thallium scintigraphy with use of circumferential profile analysis. Ischemic defects were assessed by measuring degrees of circumference involved and area of defect. Data were collected for 3 vascular regions in each of 3 views (anterior, 45 degrees and 65 degrees left anterior oblique projection). Patients were then randomized to exercise and control groups, the former training for a period of 1 year using the Canadian Airforce plan for physical fitness. After 1 year, both groups were restudied. Exercise training produced a 34% reduction in degrees of ischemia overall (p less than 0.02), the most significant change being seen on the anterior view (72 degrees +/- 59 degrees before vs 30 degrees +/- 35 degrees after training). Regional analysis showed markedly improved perfusion anterolaterally and apically on the anterior view and anteroseptally on the 65 degrees left anterior oblique view. These improvements support the hypothesis that exercise training improves myocardial perfusion by enhanced collateral function.

Angiotensin II as a potential method of targeting cytotoxic-loaded microspheres in patients with colorectal liver metastases.

Regional chemotherapy is commonly used to treat patients with colorectal liver metastases. However, improvement in survival has still not been demonstrated. Cytotoxic loaded albumin microspheres for arterial administration have been described as a means of improving the the therapeutic index, but their distribution depends upon the prevailing pattern of arterial blood-flow at the time of injection. In this study, the ability of the vasoactive drug angiotensin II to target arterially injected microspheres to colorectal liver metastases is assessed in nine patients using scintigraphic planar and tomographic imaging. The median tumour: normal ratio in nine patients with colorectal liver metastases was 3.4:1 before the administration of angiotensin II. The corresponding ratio after administration of angiotensin II was 7.3:1. The median improvement factor was 1.8 (P less than 0.05). The data suggest that worthwhile tumour targeting can be achieved with angiotensin II in patients with colorectal liver metastases.

A system for the quality audit of treatment dose delivery in radiotherapy.

Treatment planning is a process requiring the cooperation of a number of different staff groups. The possibility for error is well recognised and quality control procedures are necessary to ensure that the chances of errors in planning leading to incorrect treatments are as low as possible. An audit system is described which is based on the calculation of the dose delivered to the patient using the parameters set for treatment as input data. The calculated dose is compared with the prescribed dose and errors greater than a defined limit are flagged. During a period of 19 months during which this audit procedure has been operating a total of 14 errors in excess of 5% were discovered and corrected, this is approximately 0.5% of the total number of plans checked.

Clinical evaluation of angiotensin II enhanced perfusion scintigraphy in metastatic liver disease.

The hepatic perfusion index (HPI) may be of value in the diagnosis of liver micro-metastases. However, raised values of HPI also occur in some benign liver conditions (e.g. cirrhosis), thereby weakening the diagnostic power of this test. It has been suggested that infusion of the vaso-active agent angiotensin II might improve the predictive value of dynamic scintigraphy because it has been shown to alter liver perfusion in patients with metastatic liver disease. Basal HPI values were not significantly different in a group of patients with metastases (n = 10) and a group with cirrhosis (n = 9). A significant rise in HPI occurred in the metastatic group using angiotensin II enhancement (p less than 0.01, Wilcoxon test). In the cirrhotic group there was no significant increase in the HPI with angiotensin II enhancement. Within the groups, there was considerable variation in response, with eight of ten metastatic and five of nine cirrhotic patients showing a rise in HPI during an angiotensin II infusion. As a result, there was complete overlap in the angiotensin II enhanced HPI for the two groups. Angiotensin II enhancement of HPI is therefore unlikely to improve the diagnostic power of dynamic scintigraphy in individual patients with established hepatic disease.

Single photon emission computed tomographic studies (SPECT) of hepatic arterial perfusion scintigraphy (HAPS) in patients with colorectal liver metastases: improved tumour targetting by microspheres with angiotensin II.

As intra-arterial chemotherapy for liver metastases of colorectal origin becomes accepted, methods of further improving drug delivery to the tumour have been devised. Degradable microspheres have been shown to reduce regional blood flow by transient arteriolar capillary block, thereby improving uptake of a co-administered drug, when injected into the hepatic artery. In our study of five patients, we combined hepatic arterial perfusion scintigraphy (HAPS) and SPECT to assess the localization of approximately 1 X 10(5) labelled microspheres of human serum albumin (99Tcm MSA) in tumour. In addition, in three patients, we assessed the effect of an intra-arterial infusion of the vasoactive agent angiotension II during HAPS. Results were interpreted by comparing transaxial slices with corresponding slices of a tin colloid liver-spleen scan. Two of five patients showed good localization of 99Tcm MSA in tumour without an angiotensin II infusion. Of the three patients receiving angiotensin II, all showed good tumour targetting with the vasoconstrictor compared with only one of these three before its use. Thus, hepatic arterial infusion of angiotensin II greatly improves microsphere localization in tumour in some patients with colorectal liver metastases. This technique may be useful in the assessment of tumour targetting before and during locoregional therapy.

Arteriovenous shunting of microspheres in patients with colorectal liver metastases: errors in assessment due to free pertechnetate, and the effect of angiotensin II.

In patients receiving locoregional therapy for liver metastases degradable microspheres are being increasingly used in an attempt to improve cytotoxic delivery to the tumour. However, counterproductive arteriovenous shunting through the liver following intrahepatic arterial injection can occur, leading to deposition in the lung. Measurement of the degree of shunting is important in the monitoring of this kind of therapy. In this study we describe the use of technetium-labelled microspheres of serum albumin (99Tcm MSA) to measure baseline shunting during hepatic arterial perfusion scintigraphy in five patients with liver metastases of colorectal origin, and assess the significance of the values obtained for relative lung uptake (RLU) which we define as: RLU = Activity in lung field/Activity in liver + lung fields X 100%. We found that shunting was less than 5% in all cases, zero shunting occurring in 14 of the 16 patients studied. The sources of error in this technique have been assessed, the most important being the presence of free pertechnetate in the injectate. The use of Boots 10 ml vials and glass syringes respectively to dispense and administer this radiopharmaceutical reduces this error to a small predictable level. In our small group of patients, we found no evidence to suggest that use of the vasoactive agent angiotensin II significantly increases baseline shunting in patients with colorectal liver tumour.