Assessment of Retinal Structural and Functional Characteristics in Eyes with Autoimmune Retinopathy.

PURPOSE: To evaluate the thicknesses of individual retinal layers, and the correlation between structural changes and functional loss using spectral domain optical coherence tomography (SD-OCT) scans and electroretinograms (ERG), in eyes with autoimmune retinopathy (AIR). METHODS: SD-OCT raster scans of 12 eyes from 6 patients serologically diagnosed with AIR were evaluated. Retinal layers were segmented along a 5 mm horizontal scan passing through the fovea. Retinal layers analyzed include full retinal thickness (FRT), retinal pigment epithelium and Bruch's membrane complex (RPE+BM complex), photoreceptor layer (PRL), inner nuclear layer (INL), combined ganglion cell and inner plexiform layers (GCL+), nerve fiber layer (NFL), and combined GCL+ and NFL layers (GCL+/NFL). Changes in the thicknesses of the layers were assessed in 0.5 mm increments along the B-scan in the central, nasal, and temporal regions. These recorded values were compared to corresponding values of 51 eyes from 51 subjects with no known ocular pathology. Full-field ERGs were obtained at corresponding visits and were interpreted by a grader masked to the diagnoses and OCT findings. RESULTS: The mean age of the patients was 59.5 years (range, 33-83), with 4 males (66.6%). Within the control population of 51 subjects, mean age was 51.5 years (range, 40-75), with 25 males (49%). Eyes with AIR showed a loss of retinal tissue compared to eyes with no known ocular pathology at the fovea. Specifically, the FRT, RPE+BM complex, and PRL exhibited thinning of statistically significance. ERG findings demonstrated a functional deficit which showed a good correlation with structural loss. Fifty (50) percent of eyes experienced central photoreceptor (rod and cone) dysfunction and 75% of eyes displayed peripheral photoreceptor (rod and cone) dysfunction. CONCLUSIONS: Eyes with AIR show a loss of retinal tissue compared to eyes with no known ocular pathology. The greatest loss appears to occur in the RPE and PRL. ERG findings correlate strongly with the loss of tissue seen in these layers. Thus, therapeutic options may be targeted to preserve these regions of the retina.

XIAP-mediated neuroprotection in retinal ischemia.

Retinal ischemia results in the loss of vision in a number of ocular diseases including acute glaucoma, diabetic retinopathy, hypertensive retinopathy and retinal vascular occlusion. Recent studies have shown that most of the neuronal death that leads to loss of vision results from apoptosis. XIAP-mediated gene therapy has been shown to protect a number of neuronal types from apoptosis but has never been assessed in retinal neurons following ischemic-induced cell death. We injected an adeno-associated viral vector expressing XIAP or GFP into rat eyes and 6 weeks later, rendered them ischemic by raising intraocular pressure. Functional analysis revealed that XIAP-treated eyes retained larger b-wave amplitudes than GFP-treated eyes up to 4 weeks post-ischemia. The number of cells in the inner nuclear layer (INL) and the thickness of the inner retina were significantly preserved in XIAP-treated eyes compared to GFP-treated eyes. Similarly, there was no significant reduction in optic nerve axon numbers in XIAP-treated eyes. There were also significantly fewer TUNEL (TdT-dUTP terminal nick end labeling) positive cells in the INL of XIAP-treated retinas at 24 h post-ischemia. Thus, XIAP-mediated gene therapy imparts both functional and structural protection to the retina after a transient ischemic episode.

Vigabatrin effect on inner retinal function.

OBJECTIVE: To determine the degree of electroretinal dysfunction in a group of patients taking Vigabatrin (VGB). Additionally, to investigate the role of cumulative dosage, the role of VGB alone or in combination with other anticonvulsants, and whether recent discontinuance of VGB affects electroretinal function as measured by the electroretinogram (ERG). DESIGN: Retrospective, comparative case series. PARTICIPANTS: Forty patients (18 male, 22 female) with a mean age of 35 years were studied as three groups: the VGB multitherapy group (n = 24) included those taking VGB with other anticonvulsants, the VGB monotherapy group (n = 9) included those taking VGB alone, and the off-VGB group (n = 7) included those who had discontinued VGB in the last 6 months. METHODS: Scotopic flash, photopic flash, and 30-Hz flicker ERG results were recorded according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standard. The clinical electro-oculogram (EOG) results were recorded according to the ISCEV standard. MAIN OUTCOME MEASURES: Implicit time and amplitudes of the A- and B-waves of the flash and 30-Hz flicker ERGs were recorded. Summed amplitude of the first three oscillatory potential wavelets were recorded. The light-peak to-dark-trough Arden ratio of the EOG was evaluated. RESULTS: Although photopic ERG B-wave reduction was most frequent in patients in the VGB multitherapy group (48% of eyes), a significant number of eyes in all three groups had scotopic ERG B-wave reduction. The 30-Hz flicker ERG result was abnormally reduced in all three groups. There was no significant difference in the frequency of occurrence in ERG result abnormalities between the VGB monotherapy and VGB multitherapy groups. The EOG results revealed reduced Arden ratios in all three groups; however, there was a significantly lower frequency of EOG abnormalities noted in the off-VGB group (P = 0. 0373). There was no statistically significant relationship between the frequency of electrodiagnostic abnormalities and the duration of use or the total cumulative dosage of Vigabatrin in any of the three groups. CONCLUSIONS: These findings of scotopic ERG result abnormalities suggest that VGB alone has an effect on inner electroretinal function at the level of the Müller cell. Concomitant EOG abnormalities suggest a substantial effect of VGB on outer retinal function that may be reversible after cessation of VGB treatment.

Impairment of ocular blood flow during regional orbital anesthesia.

BACKGROUND: Regional anesthesia for ophthalmic surgery has been associated with ischemic complications, such as central retinal vascular occlusion, optic atrophy and ischemic optic neuropathy. Impairment of pulsatile ocular blood flow (POBF) may occur with regional orbital anesthesia. In this study we quantified POBF in patients undergoing regional orbital anesthesia. METHODS: Eleven patients (12 eyes) with a mean age of 76.5 years having regional orbital anesthesia for cataract or retinal surgery at a private refractive surgical centre in Calgary had POBF monitoring before, during and 15 minutes after induction of anesthesia. RESULTS: There were no significant changes in intraocular pressure or heart rate during the induction phase or 15 minutes after induction of regional orbital anesthesia. However, ocular blood flow indices, including pulse amplitude, pulse volume and POBF, were significantly reduced following attainment of regional orbital blockade (p < 0.05). With time there was recovery in these variables, but they all remained significantly reduced from baseline 15 minutes later. INTERPRETATION: Ocular blood flow appears to be significantly impaired during regional orbital anesthesia, induced as described. There could be benefit in monitoring POBF to reveal otherwise undetectable deleterious effects on retinal circulation in patients having retrobulbar injections, orbital compression or digital manipulation of the globe.

Symptomatic and asymptomatic visual loss in patients taking vigabatrin.

PURPOSE: To investigate the clinical, perimetric, and electrophysiologic findings in patients with visual field loss on long-term treatment with the antiepileptic medication vigabatrin. DESIGN: Consecutive observational case series. PARTICIPANTS: Forty-one consecutive subjects taking vigabatrin referred for screening ophthalmologic assessment were studied. Twelve subjects with evidence of peripheral visual field constriction are presented. METHODS: Twelve subjects with evidence of peripheral visual field constriction on 60-4 perimetry underwent central 30-2 and blue-on-yellow (B/Y) perimetry, as well as electroretinography (ERG), electro-oculography (EOG), and visual-evoked potential (VEP) testing. MAIN OUTCOME MEASURES: Visual acuity; fundus abnormalities; visual field loss; and ERG, EOG, or VEP abnormalities were the main outcome measures. RESULTS: Eight of the 12 subjects with constricted visual fields were asymptomatic. The central 30-2 perimetry demonstrated bilateral visual field constriction in 9 of 12 patients and the B/Y perimetry in 8 of 9 patients tested. Of the ten patients tested electrophysiologically, four had abnormal ERGs, five had abnormal EOGs, and three had delayed VEPs. CONCLUSIONS: The incidence of visual field constriction in patients taking vigabatrin may be higher, and asymptomatic visual field loss more common, than reported previously. The authors postulate a possible Muller cell dysfunction in the peripheral retina. Patients taking vigabatrin should have regular peripheral visual field examinations.

Somatosensory evoked potential monitoring during cardiac surgery: an examination of brachial plexus dysfunction.

OBJECTIVE: To observe the effects of the Favoloro and sternal retractors on the ulnar and median nerve somatosensory evoked potentials (SSEPs) and to identify any relationship with postoperative brachial plexus injury. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Twenty cardiac patients. INTERVENTIONS: SSEPs were studied in patients undergoing cardiac surgery using normothermic cardiopulmonary bypass. Evoked potentials were obtained from bilateral median and ulnar nerves. MEASUREMENTS: The incidence of nerve-specific SSEP changes and their temporal relationship to retractor usage were determined. The overall incidence of SSEP changes was 75%. There were no differences (p > 0.05) between the group showing changes (n = 15) and the group with no changes (n = 5) with respect to age, body surface area, weight, cross-clamp or cardiopulmonary bypass times. There also were no differences (p > 0.05) between the frequencies of left- and right-sided changes, or in nerve-specific SSEP changes. Seventy-four percent of SSEP changes correlated with retractor usage. No SSEP changes were associated with the Favoloro retractor. Significant SSEP depression, assessed by either percentage reduction in amplitude or persistent amplitude reduction, occurred in the absence of postoperative neurological deficits. There were no detected postoperative brachial plexus injuries. CONCLUSIONS: SSEP changes correlate with the use of the sternal retractor but not the Favoloro retractor. It was not possible to replicate the results of previous investigators in predicting postoperative neurological deficits based on the SSEP changes, and therefore the routine application of SSEP as a monitor cannot be recommended on the basis on these data.

Early macular dysfunction detected by focal electroretinographic recording in non-insulin-dependent diabetics without retinopathy.

The focal electroretinogram, which measures the functional integrity of the distal retina of the macula, was recorded with a hand-held stimulator-ophthalmoscope in 26 eyes from patients with non-insulin-dependent diabetes mellitus with normal fundus photography, and in 52 control eyes of similar age range. Implicit time and amplitude of the responses were studied as a function of the age, glycemic control through glycosylated hemoglobin measurement and duration of diabetes. Implicit time and amplitude were significantly delayed (F=5.05, p=0.028) and reduced (F=11.26, p=0.013) in diabetic patients without diabetic retinopathy compared to control subjects. Moreover, there was a significant relationship between the implicit time (r=0.57, p=0.002) and amplitude (r=-0.65, p=0.0004) with the duration of diabetes but not with hemoglobin Alc. These results strongly suggest an early macular dysfunction in non-insulin-dependent diabetes mellitus before the appearance of diabetic retinopathy.

Postischemic therapy with MK-801 (dizocilpine) in a primate model of transient focal brain ischemia.

The purpose of this study was to develop a primate model for assessing EEG, behavior and histology, and to test the effect of NMDA receptor blockade in transient focal ischemia. Squirrel monkeys (Saimiri sciureus) under halothane anesthesia were subjected to 110 min of transient focal ischemia (n = 15) by temporary clip occlusion of the MCA. An eight-lead EEG was recorded. Neurobehavioral testing was done in a subgroup of animals (n = 6). Brain temperature (37.5 degrees C) was monitored and controlled to avoid hypothermia or intergroup temperature differences, and blood pressure was regulated to 60 mmHg. The entire brain was subserially sectioned, and 52 standardized coronal sections encompassing the infarct were examined histologically 2 wk after the ischemia. Animals were randomized to receive either (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) 1 mg/kg of maleate salt or carrier solution, 20 min and again at 12 h after the onset of ischemia. Cingulate and retrosplenial cortex were examined for NMDA-antagonist-induced neuronal necrosis. No reduction, or trend toward reduction of neurobehavioral deficit was seen with MK-801. MCA occulsion reduced EEG power over the ischemic hemisphere. MK-801 appeared to cause brain activation, and globally increased power at several frequencies. MK-801 did not reduce infarction in either neocortex (p > 0.05) or striatum (p > 0.05). No selective neuronal necrosis was seen in the cingulate or retrosplenial cortex. We conclude that MK-801 given 20 min after the onset of transient ischemia offers no significant neuroprotective effect against either neurobehavioral deficit or ischemic infarction in this model of transient focal ischemia. Further experiments in unanesthetized animals are necessary to determine if MK-801-induced necrosis exists in the gyrencephalic brain, but the enhancement of primate brain electrical activity by MK-801 suggests that brain activation occurs in primates as it does in rodents.

The electroretinogram during orbital compression following intraorbital regional block for cataract surgery.

The electroretinogram (ERG) is a transient biopotential that reflects the electrical response of the distal retina to photostimulation. Disturbances in retinal circulation produce characteristic abnormalities in the ERG wave form. The objective of this study was to investigate the changes in the ERG produced by combined retrobulbar and peribulbar injections of a large volume (8 ml) of local anaesthetic, followed by ocular compression. Electroretinogram recordings were obtained from skin electrodes placed on the infero orbital ridge in response to stroboscopic flash stimulation in 34 adult patients undergoing cataract surgery: (a) prior to regional anaesthesia (baseline condition); (b) within one minute after regional anaesthesia of the orbit (block condition); (c) after ten minutes of orbital compression with a Honan's device at 30 mmHg. (compression condition); (d) and five minutes after removal of orbital compression (recovery condition). The ERG implicit times of both a- and b-wave increased (P < 0.001) after anaesthetic block. The amplitude of the a- and b-waves also decreased (P < 0.001) immediately following anaesthetic block and continued to decrease following application of the compression device (P < 0.01). Following removal of ocular compression the amplitude of the b-wave increased (P < 0.01). Only the a-wave implicit time (P < 0.005) decreased with release of ocular compression. These findings are compatible with the ERG changes of transient retinal ischaemia produced by ocular compression.

The relation between head size and auditory brain-stem response interpeak latency maturation.

In developmental populations, duration of auditory brain-stem response (ABR) I-III, III-V, and I-V vary substantially across individuals, particularly among preterm infants. Adult ABR interpeak latency has a strong correlation with brain-stem size and weaker correlation with head size. To determine if head size might contribute to this increased interpeak latency variability among infants, ABR data were normalized based on head circumference. Normalization by head circumference did not reduce interpeak variability. Further analyses revealed a negative correlation between interpeak latency and head circumference that varied as a function of age. Before 42 weeks conceptional age (CA), a significant relation exists between increased head circumference and decreased duration of the III-V and I-V intervals, but not the I-III interval. For infants older than 42 weeks CA, there was a significant relation between increased head circumference and decreased duration for the I-III intervals but not the III-V and I-V intervals. An age-dependent correlation between decreasing interpeak latency and increasing head circumference suggests that improved neural transmission through the auditory nerve and brain-stem pathway offset or even overcompensate for developmental lengthening of the sensory pathway. Also, developmental time constants obtained from nonlinear curve fit analyses were shorter for normalized than non-normalized data, particularly for the I-V interval. Therefore, correction of ABR data for the length of the sensory pathway may be important to estimate accurately maturation rate for developmental populations.

Asymmetry quantification utilizing hand radiographs.

Asymmetry can be either directional or fluctuating. Detection of abnormal amounts of asymmetry has important implications for clinical diagnosis, but measurement of subtle levels is very difficult. We describe a method and normative values for asymmetry quantification using hand radiographs.

Frequency-specific maturation of the eighth nerve and brain-stem auditory pathway: evidence from derived auditory brain-stem responses (ABRs).

Previous studies of human auditory development using frequency-specific auditory brain-stem responses (ABRs) have reported that maturation for both peak and interpeak latencies occurs earlier for responses generated by low-frequency stimuli. In two of these studies, low-frequency ABRs presumed to originate from apical locations in the cochlea were likely dominated by activity from higher frequency regions closer to the base. In the present study, the high-pass noise-masking technique was used to generate derived ABRs that represent activity from isolated place specific regions along the basilar membrane. Analysis of auditory brain-stem maturation based on I-V interpeak latency differences with adult means revealed a frequency-specific pattern of development. Developmental changes occurred faster and mature function was attained earlier for ABRs from the mid-center-frequency (CF) derived conditions than from either the highest or lowest CF derived conditions. The differential maturation of mid-CF derived ABRs may reflect the delayed effects of the pattern of development that occurs in the cochlea.

Assessment of cisplatin-induced ototoxicity using derived-band ABRs.

Ototoxicity is an adverse side effect of numerous therapeutic agents (amino-glycoside antibiotics, blood chelating agents, diuretics and oncologic drugs) used in treatment of both adult and pediatric patients. Recently, there has been increasing interest in using the auditory brainstem response (ABR) to detect both short-term effects of ototoxicity in adults and long-term effects of drug administration on neonates and children. Since click ABRs have relatively poor frequency selectivity they best approximate the pure-tone hearing threshold in the 2000-4000 Hz frequency range. Hearing loss above or below that frequency range can be present without producing significant abnormalities in the ABR waveform parameters. Frequency-specific ABRs can be obtained using the derived response technique. The purpose of this study was to investigate early cisplatin ototoxicity using both the broadband click and derived ABR and to monitor progressive hearing loss with repeated drug trials in 18 patients studied over a 2-year period. ABRs were obtained serially prior to and following intravenous administration of cisplatin. Derived ABRs were found to be more sensitive than broadband click ABR in detecting early high-frequency hearing loss. For click ABRs, the cumulative dosage of cisplatin at age of ABR examination was correlated with hearing loss in only those patients under 3 years of age. No significant correlation was found between cumulative cisplatin dosage when tested and degree of hearing loss in those patients over 3 years of age.

Maturation of the traveling-wave delay in the human cochlea.

The maturation of the traveling-wave delay in the human cochlea was investigated in 227 subjects ranging in age from 29 weeks conceptional age to 49 years by using frequency specific auditory brain-stem responses (ABRs). The derived response technique was applied to ABRs obtained with click stimuli (presented at a fixed level equal to 60-dB sensation level in normal hearing adults) in the presence of high-pass noise masking (slope 96 dB/oct) to obtain frequency specific responses from octave-wide bands. The estimate of traveling-wave delay was obtained by taking the difference between wave I latencies from adjacent derived bands. It was found that the traveling-wave delay between the octave band with center frequency (CF) of 11.3 kHz and that with CF of 5.7 kHz decreased (about 0.4 ms on average) in exponential fashion with age to reach adult values at 3-6 months of age. This decrease was in agreement with reported data in kitten auditory-nerve fibers. The traveling-wave delays between adjacent octave bands with successive lower CF did not change with age.

Frequency dependent maturation of the cochlea and brainstem evoked potentials.

The anatomical development of the human cochlea starts in the middle basal turn and progresses both toward the base and the apex. Behavioral responses, in contrast, appear to emerge for lower frequencies first. Cochlear tuning may continue to change during early development and so effect electrophysiological and behavioral measures of maturation. The maturation of the cochlear traveling wave delay as well as the ABR I-V interval was investigated using the derived response technique which permits a frequency dependent analysis of this maturation. It was found that the traveling wave delay decreased significantly with age for the most basal part of the cochlea; however, it was not affected by age for more apical locations. The I-V delay difference with the adult values was found significantly shorter in the derived octave band with CF = 2.8 kHz than in all other bands for the preterm, term and infant groups. This suggests that the frequency dependent electrophysiological maturation of the brainstem parallels the anatomical development of the cochlea.

Variable expressivity in X-linked congenital stationary night blindness.

X-linked congenital stationary night blindness (CSNB) is a well-documented disorder in which the most striking clinical features are impaired night vision, nystagmus and myopia. Recent reports have highlighted differing features between families, and it has been suggested that these discrepancies may be the result of two loci on the X chromosome or of two mutant alleles. We outline the clinical and visual function findings in 42 affected members from 10 families and 1 adopted person. There was a relative unawareness of the disorder in clinical practice. At least one of the main features of CSNB was absent in 75% of the patients. The visual function values varied widely, both between and within families (visual acuity 20/30 to 20/400, refractive error +1.50 to -22.50 and rod segment elevation 1.5 to 3.0 log units). The findings are consistent with a single allele exhibiting a wide variation in clinical expression.

Visual and auditory evoked potential correlates of cerebral malformations.

To date there are no systematic studies of the evoked potential correlates of cerebral malformations. A total of 109 sensory evoked potential studies (20 ERGs, 61 VEPs and 28 ABRs) were performed in 27 children with defined cerebral malformations. Diagnoses were confirmed by CT scan, supplemented by MRI, cranial ultrasound, or neuropathological examination. Sensory evoked potential studies were abnormal in over half of patients studied, but the VEP was unable to identify or distinguish specific supratentorial cerebral malformations. ABR abnormalities were documented in cases of holoprosencephaly, lissencephaly, pachygyria and generalized megalencephaly. ABR abnormalities were not observed in septo-optic dysplasia or focal dysplasia of the cerebral cortex. We conclude that evoked potentials are not a diagnostic criterion of severe dysplasias, but rather serve as a supplementary tool for detecting the variable associated abnormalities of brain development that may affect visual and central auditory pathways or their cerebral cortical or brainstem targets.

Variability in clinically measured photopic oscillatory potentials.

Oscillatory potentials found on the ascending phase of the electroretinogram b-wave probably originate in some element(s) of the inner plexiform layer. As oscillatory potentials are particularly sensitive to changes in retinal, and possibly choroidal, blood flow, they have been used extensively to provide clinical measures of the degree of retinal ischemia during the progression of diabetic retinopathy. Recent studies in our laboratories have disclosed previously unreported significant variability in the photopic oscillatory potentials on repeated measures even in tightly controlled conditions. The amplitude of five recordable light-adapted wavelets exhibited considerable intra- and inter-subject variability. Until further investigation can determine factors affecting standardization of testing, it appears that changes in oscillatory potential implicit times rather than in amplitudes are a better measurement in clinical neurophysiology.

ERG electrode in pediatric patients: comparison of DTL fiber, PVA-gel, and non-corneal skin electrodes.

Hard contact lens electrodes have been the type most frequently used in pediatric electroretinography but they are not well-tolerated by patients. The Dawson Trick Litzkow fiber electrode is better tolerated but it is fragile and difficult to sterilize. A new electrode made from anomalous polyvinyl alcohol gel is inexpensive, has stable electrical recording properties, and can be discarded after use. Dermal electrodes have been used for electroretinogram recording for some time; however, there are few reports that directly compare their performance against standard contact lens assemblies. We compared the DTL and the polyvinyl gel electrodes in the same group of subjects and investigated their recording characteristics along with non corneal skin electrodes placed on the infraorbital ridge. Signal-averaged electroretinogram were obtained under both scotopic and photopic stimulation conditions and the implicit time and amplitudes of the a- and b-waves were determined. Overall, dermal recordings generally had shorter implicit times and lower amplitudes than with the fiber or gel electrodes. The dermal electrodes were best tolerated and outlasted the corneal in repeated use. Since amplitude characteristics of the dermal electrodes were generally about 50% of that obtained with corneal electrodes, we feel that under standardized conditions they are acceptable for most clinical recording situations in infants and young children.