Anne Kurtenbach

Visual field constriction and electrophysiological changes associated with vigabatrin

Purpose: We investigated functional, morphological and electrophysiological changes in patients under anti-epileptic therapy with vigabatrin (VGB), a GABA aminotransferase inhibitor. Methods: 20 epileptic patients treated with vigabatrin (age range 25–66 years) were enrolled in this study. The referrals were made by the treating neurologist, based on suspected or known visual field changes in these patients. Two patients had vigabatrin monotherapy, 18 patients were treated with vigabatrin in combination with other antiepileptic drugs. None of the patients reported visual complaints. Patients were examined with psychophysical tests including colour vision (Farnsworth D15), dark adaptation threshold, Goldmann visual fields and Tuebingen Automated Perimetry (90°). A Ganzfeld ERG and an EOG following the ISCEV standard protocol were also obtained. Additionally, all patients were examined with the VERIS multifocal ERG including recordings of multifocal oscillatory potentials. Results: Visual acuity, anterior and posterior segments, colour vision and dark adaptation thresholds were normal in all patients. Of 20 patients, 18 presented visual field constriction. All patients with visual field defects revealed altered oscillatory potentials waveforms in the ERG, especially in those patients with marked visual field defects. Multifocal oscillatory potentials were also delayed in those patients. In some patients a delayed cone single flash response (6/20), a reduced mERG amplitude (12/20) and a reduced Arden ratio (9/20) were found. Conclusions: The present data indicate an effect of vigabatrin on the inner retinal layers. Since abnormalities of the oscillatory potentials were seen in all patients with visual field defects a dysfunction of GABA-ergic retinal cell transmission might be assumed.

Brightness matching and colour discrimination in young diabetics without retinopathy

This study used the methods of the Farnsworth-Munsell 100-hue test (FM-100), heterochromatic brightness matching (HBM) and wavelength discrimination to test the sensitivity and colour vision of 20 juvenile diabetics with no (16) or very mild (4) retinopathy. Their results were compared to an age-matched control group. The FM-100 results showed a significant increase in error scores throughout the spectrum in comparison to the controls. This deterioration in colour vision was confirmed in the results for the wavelength discrimination task, tested between 440 and 640 nm, where the just noticeable difference in colour was, in general, larger for the diabetic group than the control group. Only at 460 nm were the results of the diabetics similar to those of the controls. The diabetic group were also less sensitive than the control group in the HBM task between 480 and 600 nm. The results show that a deficit in sensitivity and colour vision occurs in diabetics before the onset of a clinically visible retinopathy.

Preretinopic changes in the colour vision of juvenile diabetics

AIMS To examine the colour vision of juvenile patients suffering from diabetes mellitus without retinopathy in relation to metabolic and ophthalmic state. METHODS Metameric matches, both Rayleigh (red/green) and Moreland (blue/green) were used to test the colour vision yearly of 10 juvenile patients. The patients were monitored over 4 years, and during the final year, their blood glucose level was determined directly after testing colour vision. An ophthalmic examination was performed on the day of colour vision testing and blood and urine were analysed regularly throughout the 4 years. Their results are compared with an aged matched control group of 20 subjects, seven of whom were retested after 9–16 months. RESULTS After 4 years, the colour vision results show an enlarged matching range for the Moreland match, as well as a smaller increase in the matching range for the Rayleigh match. No significant correlation was found between blood glucose at the time of testing and any of the variables measured. CONCLUSION The pattern of colour vision deficits in metameric matching shown by juvenile diabetics is consistent with post-receptoral alterations of the inner retina, at this preretinopic stage of disease. Duration of diabetes is correlated with both colour vision changes and morphological alteration of the retina.

Anomaloscope matches in patients with diabetes mellitus

Abstract.Background: Functional visual deficits can occur in patients with diabetes mellitus who show no visible morphological alterations in the retina. In this study we examined the colour vision of diabetic patients using metameric matches. Patients with and without retinopathy, as well as those who had been treated with laser photocoagulation, were examined to ascertain how the functional alterations in the diabetic eye alter with disease status. Methods: Rayleigh (red–green) and Moreland (blue–green) metameric matches were determined in a total of 51 diabetic patients (24 patients with no retinopathy, 12 patients with background retinopathy and 15 patients who had undergone laser therapy). Their results are compared to those of a control group of 25 subjects with normal colour vision. Results: A deficit in blue–green colour discrimination found in patients without retinopathy becomes worse with the appearance of vascular alterations in the retina. There is also a significant shift towards green in the Rayleigh match midpoint and towards blue in the Moreland match midpoint, which is at least in part explicable by alterations in lens opacity. Patients who have undergone laser therapy show, on average, better colour discrimination than those with retinopathy, but there is a large variation in their results. Conclusion: The alterations in the colour vision of diabetics indicate that at least the early functional changes are occurring at an inner retinal location. Lens opacity changes also play a large role as the age of the patients increases.

Hyperoxia, hyperglycemia, and photoreceptor sensitivity in normal and diabetic subjects

The aim of this study was to investigate the effects of an increase in the saturation of blood oxygen (SaO2) and/or serum glucose on photoreceptor sensitivity in normal subjects and in patients with diabetes mellitus. We monitored cone and rod sensitivity by recording dark-adaptation curves to both green and red test stimuli while inhaling either air (20% O2 + 80% N2) or 100% oxygen in 12 normal subjects and 12 diabetic patients with no (10) or mild (2) retinopathy. We also repeated the experiment in 10 of the normal subjects under hyperglycemia (mean serum glucose: 161 mg/dl). Results show that in normal subjects the dark-adapted cone sensitivity is improved by an increase in SaO2 or by hyperglycemia. Final rod sensitivity is unchanged during hyperoxia and during hyperglycemia when measured with a green test spot. However the kinetics of dark adaptation are altered during hyperglycemia, and an increase in final sensitivity is observed when measured with the red test spot. Inhalation of oxygen during hyperglycemia in normal subjects reduces cone sensitivity compared to that found during hyperglycemia alone (Pasteur effect). In diabetic subjects the dark-adapted cone threshold is comparable to that found in normal subjects, and sensitivity also increases with an increase in SaO2. The final rod threshold, however, is impaired compared to that of the control group, and rod sensitivity is improved by increasing the SaO2. The results suggest that the metabolism of rods and cones may differ in normal subjects: in cones, the rate of metabolism can be augmented by increasing the available oxygen or glucose, whereas rods appear more insensitive to increased blood oxygen saturation and hyperglycemia. In diabetic subjects, both cone and rod metabolism can be increased by supplemental oxygen, indicative of an early rod deficit. The study lends weight to the hypothesis that dark-adapted rods in diabetics are hypoxic before the onset of retinopathy.

Quantification of stato-kinetic dissociation by semi-automated perimetry.

The difference in threshold sensitivities that are found when examining the visual field (VF) with static versus kinetic perimetric methods is called stato-kinetic dissociation (SKD). In this pilot study, we describe a semi-automated procedure for quantifying SKD. Fifteen patients with VF defects were examined with kinetic and static perimetry. SKD values were defined as positive when the static scotoma was larger than the kinetic one. We found significant local variations of SKD along scotoma borders with the individual reaction time as an important criterion when determining kinetic thresholds. There was a verifiable SKD in all patients with locally negative values in eight subjects.

An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients

Usher syndrome (USH), the most prevalent cause of hereditary deafness–blindness, is an autosomal recessive and genetically heterogeneous disorder. Three clinical subtypes (USH1–3) are distinguishable based on the severity of the sensorineural hearing impairment, the presence or absence of vestibular dysfunction, and the age of onset of the retinitis pigmentosa. A total of 10 causal genes, 6 for USH1, 3 for USH2, and 1 for USH3, and an USH2 modifier gene, have been identified. A robust molecular diagnosis is required not only to improve genetic counseling, but also to advance gene therapy in USH patients. Here, we present an improved diagnostic strategy that is both cost- and time-effective. It relies on the sequential use of three different techniques to analyze selected genomic regions: targeted exome sequencing, comparative genome hybridization, and quantitative exon amplification. We screened a large cohort of 427 patients (139 USH1, 282 USH2, and six of undefined clinical subtype) from various European medical centers for mutations in all USH genes and the modifier gene. We identified a total of 421 different sequence variants predicted to be pathogenic, about half of which had not been previously reported. Remarkably, we detected large genomic rearrangements, most of which were novel and unique, in 9% of the patients. Thus, our strategy led to the identification of biallelic and monoallelic mutations in 92.7% and 5.8% of the USH patients, respectively. With an overall 98.5% mutation characterization rate, the diagnosis efficiency was substantially improved compared with previously reported methods.

Age-related changes in retinal functional topography.

PURPOSE To perform a detailed topographical analysis of functional age-related changes over the retina. METHODS Fifty-nine normal phakic subjects aged 10 to 69 years were divided into six groups, according to decade of age. mfERG traces were recorded from the central 60 degrees of the retina, with a resolution of 61 and 103 scaled hexagons. Group medians of peak amplitude and latency of the first- and second-order (first slice) responses were used to generate 3-D topographical maps. RESULTS With age, there was a continuous loss of amplitude and delay of implicit time of the first- and the second-order response components, but the topography of the loss was not uniform across the retina. Trend analyses on ring group data showed a significant decrease in amplitude of first- and second-order responses although the age relationship of second-order responses was more complex. The loss of first-order kernel amplitude was generally accompanied by a rise in implicit time. Second-order kernel latencies showed no uniform alteration with age. CONCLUSIONS Consistent with previous work, a steady loss of amplitude and increase of implicit time was observed with age. The topographical 3-D data, however, reveal age-related functional alterations in the retina beyond those found in ring averages, suggesting that these are masked by the standard analysis. Thus, the choice of physiologically coherent regions of interest may increase the sensitivity of detecting age-related change in multifocal analysis of retinal function.

Development of brightness matching and colour vision deficits in juvenile diabetics

We studied hue discrimination and brightness matching throughout the spectrum in ten juvenile patients suffering from diabetes mellitus (Type I) with no (eight patients) or mild (two patients) retinopathy. In addition, the FM 100-Hue test was performed. The data were collected once every year over 5 years. Over the 5 years, the diabetics show a continual change in the shape of their brightness matching function. Wavelength discrimination ability remains quite stable with time at the long end of the spectrum but is variable at short wavelengths. FM-100 error scores remain similar over the period tested, at a level slightly higher than that of a control group. Additional experiments show that the sensitivity of the S-cone in the diabetic group is similar to that of controls. The results can be explained by an early relative reduction in the sensitivity of post-receptoral processes in juvenile diabetics.

The multifocal pattern electroretinogram (mfPERG) and cone-isolating stimuli

The number of L cones in the retina normally exceeds that of the M cones. Because normal color vision does not depend on the ratio of L- and M-photoreceptors, their signals must undergo an alteration in gain before being analyzed in the cortex. Previous studies have shown that this gain must take place before the cortex, but after the bipolar/amacrine cell layer of the retina. The aim of this study was to obtain topographical information about L- and M-cone activity at the ganglion cell layer using multifocal pattern electroretinography (mfPERG). A standard (black and white) stimulus was used, as well as stimuli modulating only the long wavelength-sensitive (L) or only the middle wavelength-sensitive (M) cones. The L:M ratio was calculated from the amplitude of the L-cone isolating mfPERG to that of the M-cone isolating mfPERG of 10 trichromats. Both the positive and negative components of the waveform were analyzed. Additional recordings of single cone modulated mfERGs were obtained from nine of the 10 subjects. We also recorded from one protanope and one deuteranope. The L:M cone amplitude ratios for both deflections of the mfPERG in the trichromats were around unity (medians 1.18 and 1.16, respectively) for the central 8 degrees of retina. In the peripheral retina between 12.8 degrees and 26 degrees , this ratio increased to 1.42 for the positive component, and 1.37 for the negative component. The median L:M cone amplitude ratios for the mfPERG were higher and ranged between 1.00-2.78 in the central 8 degrees and 1.29-2.78 in the periphery. The results indicate that a major gain adjustment of the retinal signals takes place at the ganglion cell level, and that the ratio is higher at eccentric locations than in the central retinal area.