Rod and Cone Function Measured Objectively by Chromatic Pupil Campimetry Show a Different Preservation Between Distinct Genotypes in Retinitis Pigmentosa.

Purpose: Verifying whether specific genotypes causing retinitis pigmentosa (RP) show differences in the preservation of rod and cone function measured by chromatic pupil campimetry (CPC). Methods: Sixty-three RP eyes (37 male, 14-58 years) were measured using CPC with specific photopic and scotopic protocols, and the relative maximal constriction amplitudes and latencies to constriction onset were analyzed per genotype (RP due to variants in EYS, n = 14; PDE6A, n = 10; RPE65, n = 15; USH2A, n = 10; and RPGR, n = 14). Correlation analyses between the pupillary responses were performed with age, full-field stimulus threshold (FST), and optical coherence tomography (OCT) for cones and rods, respectively, to the genotype. Results: Pupillary responses were most severely reduced in RPE65-RP. Patients with disease-associated variants in EYS and USH2A were accompanied with better-preserved rod function compared with the other subgroups, reaching statistical significance between EYS and RPE65. Cone function was statistically significantly correlated with age in USH2A-RP with an annual decline of 2.4%. Correlations of pupillary responses were found with FST but barely with the ellipsoid zone area in OCT. Latency was significantly more prolonged in RPE65-RP compared with the other genotypes for cones. Conclusions: Rod and cone function measured objectively by CPC showed a different preservation between genotypes in RP. However, heterogeneity inside the same genotype was present. CPC data correlated with FST, but structural OCT parameters seem to be limited indicators for photoreceptor function in RP. Prolonged time dynamics for cones in RPE65 mutations suggest an impact on cone processing and might provide additional information in the evaluation of therapy effects.

Influence of Patient Age and Presence of Optic Disc Drusen on Fluctuations in Retinal Nerve Fiber Layer Thickness.

BACKGROUND: It is generally believed that optic disc drusen (ODD) change only over long periods of time. Because, in our experience, this does not apply to younger patients, we investigated the natural course of changes of the peripapillary retinal nerve fiber layer (RNFL) in patients with ODD. METHODS: In this retrospective study, 40 eyes with and 40 eyes without ODD were examined, both cohorts were equally subdivided into younger subjects (20 years or younger) and older subjects (21 years or older). Three optical coherence tomography (OCT) scans of the peripapillary RNFL that had an interval of at least 1 month were required for each patient to be included in this study. The largest difference in total RNFL thickness (delta RNFL-t) and in RNFL thickness of the most differing sector (delta RNFL max) measured by OCT was compared. RESULTS: The differences in total RNFL thickness and in the most differing RNFL sector in the group of patients with ODD younger than 21 years were significantly larger than in each of the other 3 groups ( P = 0.0001). The other 3 groups did not differ significantly. CONCLUSIONS: Patients with ODD younger than 21 years have distinct variations in peripapillary RNFL thickness without evidence of increased intracranial pressure. In the absence of further pathological findings or neurological symptoms, an observational approach seems adequate in these patients.

Central retina plays a decisive role in the suppression of pupillary escape.

PURPOSE: To explore the pupil redilation during persistent light exposure (pupillary escape phenomenon) at the macula and periphery with monochromatic light stimuli. METHODS: Forty healthy subjects aged 18-64 years (24 females) were examined by chromatic pupil campimetry (CPC) using red and blue 4-s stimuli of 10° radius at the center and 20°-peripheral locations one per quadrant. One glaucoma patient and one achromatopsia patient served as disease models. For statistical analyses, linear mixed-effects models were performed followed by post hoc t-tests. RESULTS: A distinct pupillary escape could be demonstrated peripherally (blue 0.099%*s, red 0.153%*s); at the central healthy retina, there was no relevant escape, neither for blue nor red stimulation. Comparing central versus peripheral stimulation revealed highly significant differences in the escape (difference blue 0.100 ± 0.013, red 0.144 ± 0.013, < 0.0001, respectively). In the periphery, the escape was significantly more pronounced for red compared with blue stimulation (difference 0.054 ± 0.013; p = 0.0001). Enhanced pupillary escape outside of the 95% confidence interval of the linear mixed-effects model of the healthy population could be exemplarily shown in a patient with glaucomatous ganglion cell damage. In the achromatopsia example, no relevant escape was found for blue stimulation, but for red stimulation in the periphery in a comparable range to healthy controls. CONCLUSION: The results emphasize that an intact inner retinal network of nerve fibers arising from the central macular region is necessary for maintaining pupillary constriction during a bright 4-s light stimulus and preventing increase of pupillary escape. Increasing receptive field sizes towards the periphery on the level of retinal ganglion cells and less input from central 1:1 connections could be one of the driving mechanisms for pupillary escape.

Frequency-dependent retinal responsiveness to sinusoidal electrical stimulation in achromatopsia.

Recently, we proposed a method to assess cell-specific retinal functions based on the frequency-dependent responses to sinusoidal transcorneal electrostimulation. In this study, we evaluated the alterations in responsiveness in achromatopsia patients to explore the frequency-selectivity of photoreceptors. The electrical stimulation was applied to one eye of genetically confirmed achromatopsia patients via corneal electrodes. The stimulus was composed of amplitude-modulated sine waves with variable carrier frequencies (4-30 Hz) and a steady low-frequency envelope. The retinal responsiveness across the spectrum was calculated based on the velocity and the synchronicity of the electrically evoked pupillary oscillations. Achromats displayed a characteristic peak in responsiveness in the 6-10 Hz range. In contrast, stimulus frequencies above 16 Hz elicited only weak pupil responses and weak phosphenes. Compared to the tuning curve of the healthy retina, responses to low-frequency stimulation appear to reflect mainly rod activation while higher frequencies seem to activate cones. The possibility to examine cell-specific retinal functions independently from their responses to light may improve our understanding of the structural changes in the retina induced by gene therapy.

[Optical coherence tomography in the differential diagnostics of important neuro-ophthalmological disease patterns]. / Die optische Kohärenztomographie in der Differenzialdiagnostik wichtiger neuroophthalmologischer Krankheitsbilder.

There are many disease patterns that are treated jointly by neurologists and ophthalmologists, for which optical coherence tomography (OCT) is of important differential diagnostic significance. In this context neurologists are mainly confronted by two patient collectives: patients with an acute ischemic event, who present with an acute but painless monocular visual deterioration (for central retinal artery occlusion) or with a monocular visual field defect (for arterial branch occlusion or anterior ischemic optic neuropathy). The second collective is patients without ophthalmological symptoms but with conspicuous optic nerve findings (papilledema or optic disc drusen). In this overview article both patient collectives are considered separately. In addition, the most important OCT findings for optic neuritis are presented. Before the disease patterns are described in detail, the normal OCT findings and the diagnostic possibilities of OCT are explained.

Cell-specific electrical stimulation of human retinal neurons assessed by pupillary response dynamics in vivo.

Studies on the electrical excitability of retinal neurons show that photoreceptors and other cell types can be selectively activated by distinct stimulation frequencies in vitro. Yet, this principle still needs to be validated in humans in vivo. As a first step, this study explored the frequency preferences of human rods by means of transcorneal electrostimulation (TES), using the electrically-elicited pupillary responses (EEPRs) as an objective readout. The stimulation paradigm contained a 1.2 Hz sinusoidal envelope, which was superimposed on variable carrier frequencies (4-30 Hz). These currents were delivered to one of the participant's eyes via a corneal electrode and consensual pupillary reactions were recorded from the contralateral eye. The responsiveness of the retina at each frequency was assessed based on the EEPR dynamics. Differences between healthy participants and patients with retinitis pigmentosa were evaluated to identify the preferred frequency range of rods. The responsiveness of healthy individuals revealed a clear peak around 6-8 Hz. In contrast, the pupillary responses of patients were significantly reduced in the lower frequency range. These findings suggest that the responses in this frequency bin were selectively mediated by rods. This work provides evidence that different retinal cell types can be selectively activated via TES in vivo, and that this effect can be captured noninvasively using EEPRs. This knowledge may be exploited for the diagnostics and therapy of retinal diseases, e.g., to design cell-specific functional tests for the degenerating retina, or to optimize stimulation paradigms which are currently used by retinal prostheses.

[Optical coherence tomography in the differential diagnostics of important neuro-ophthalmological disease patterns]. / Die optische Kohärenztomographie in der Differenzialdiagnostik wichtiger neuroophthalmologischer Krankheitsbilder.

There are many disease patterns that are treated jointly by neurologists and ophthalmologists, for which optical coherence tomography (OCT) is of important differential diagnostic significance. In this context neurologists are mainly confronted by two patient collectives: patients with an acute ischemic event, who present with an acute but painless monocular visual deterioration (for central retinal artery occlusion) or with a monocular visual field defect (for arterial branch occlusion or anterior ischemic optic neuropathy). The second collective is patients without ophthalmological symptoms but with conspicuous optic nerve findings (papilledema or optic disc drusen). In this overview article both patient collectives are considered separately. In addition, the most important OCT findings for optic neuritis are presented. Before the disease patterns are described in detail, the normal OCT findings and the diagnostic possibilities of OCT are explained.

Characteristics of peripapillary retinal nerve fiber layer atrophy in glaucoma, optic nerve sheath meningioma, and sphenoid wing meningioma.

BACKGROUND/OBJECTIVES: The correct classification of a slowly progressing optic atrophy can be challenging. The aim of this work was to find out if the characteristics of peripapillary retinal nerve fiber layer (RNFL) thickness loss differ between open angle glaucoma (POAG), optic nerve sheath meningioma (ONSM), and sphenoid wing meningioma (SWM). METHODS: A total of 45 patients with POAG, ONSM, and SWM were included in the retrospective study. The peripapillary RNFL thickness measured by spectral-domain optical coherence tomography was analyzed using the Heidelberg Engineering glaucoma module©. RESULTS: Each group consisted of 15 patients. The temporal sector of the RNFL thickness showed a median decrease of - 17 µm in glaucoma patients (range + 6/-34 µm), - 43 µm in ONSM (range - 19/ - 52 µm), and - 44 µm in SWM patients (range - 25/ - 52 µm). The RNFL thickness of the temporal sector of glaucoma patients differed significantly from the other groups (p < 0.001). All other sectors showed no significant difference between the 3 groups. CONCLUSION: The peripapillary RNFL thickness of the temporal sector of patients with beginning to moderate POAG is usually inside normal limits or borderline. In contrast, patients with ONSM and SWM are much more likely to show a considerable reduction in RNFL thickness of the temporal sector. RNFL thickness of the temporal sector marked outside normal limits occurred exclusively in meningioma patients. Considering the presence of this condition as a predictor for meningioma, sensitivity and specificity were 0.8 and 1.0, respectively. In patients with significant reduction in RNFL thickness of the temporal sector, magnetic resonance imaging of the head should be considered to rule out compression of the optic nerves.

How lesions at different locations along the visual pathway influence pupillary reactions to chromatic stimuli.

PURPOSE: To examine systematically how prechiasmal, chiasmal, and postchiasmal lesions along the visual pathway affect the respective pupillary responses to specific local monochromatic stimuli. METHODS: Chromatic pupil campimetry (CPC) was performed in three patient groups (10 subjects with status after anterior ischemic optic neuropathy, 6 with chiasmal lesions, and 12 with optic tract or occipital lobe lesions (tumor, ischemia)) using red, low-intensity red, and blue local stimuli within the central 30° visual field. Affected areas - as determined by visual field defects revealed using conventional static perimetry - were compared with non-affected areas. Outcome parameters were the relative maximal constriction amplitude (relMCA) and the latency to constriction onset of the pupillary responses. RESULTS: A statistically significant relMCA reduction was observed in the affected areas of postchiasmal lesions with red (p = 0.004) and low-intensity red stimulation (p = 0.001). RelMCA reduction in the affected areas seemed more pronounced for low-intensity red stimulation (46.5% mean reduction compared to non-affected areas; 36% for red stimulation), however statistically not significant. In prechiasmal lesions, a statistically significant latency prolongation could be demonstrated in the affected areas with low-intensity red stimulation (p = 0.015). CONCLUSION: Our results indicate that the choice of stimulus characteristics is relevant in detecting defects in the pupillary pathway of impairment along the visual pathway, favoring red stimuli of low intensity over blue stimuli. Such knowledge opens the door for further fundamental research in pupillary pathways and is important for future clinical application of pupillography in neuro-ophthalmologic patients.

Effect of central and peripheral cone- and rod-specific stimulation on the pupillary light reflex.

PURPOSE: To assess the effect of central and peripheral stimulation on the pupillary light reflex. The aim was to detect possible differences between cone- and rod-driven reactions. METHODS: Relative maximal pupil constriction amplitude (relMCA) and latency to constriction onset (latency) to cone- and rod-specific stimuli of 30 healthy participants (24 ± 5 years (standard deviation)) were measured using chromatic pupil campimetry. Cone- and rod-specific stimuli had different intensities and wavelengths according to the Standards in Pupillography. Five filled circles with radii of 3°, 5°, 10°, 20° and 40° and four rings with a constant outer radius of 40° and inner radii of 3°, 5°, 10° and 20° were used as stimuli. RESULTS: For cone-and rod-specific stimuli, relMCA increased with the stimulus area for both, circles and rings. However, increasing the area of a cone-specific ring by minimizing its inner radius with constant outer radius increased relMCA significantly stronger than the same did for a rod-specific ring. For cones and rods, a circle stimulus with a radius of 40° created a lower relMCA than the summation of the relMCAs to the corresponding ring and circle stimuli which combined create a 40° circle-stimulus. Latency was longer for rods than for cones. It decreased with increasing stimulus area for circle stimuli while it stayed nearly constant with increasing ring stimulus area for cone- and rod-specific stimuli. CONCLUSION: The effect of central stimulation on relMCA is more dominant for cone-specific stimuli than for rod-specific stimuli while latency dynamics are similar for both conditions.

Dissociation between red and white stimulus perception: A perimetric quantification of protanopic color vision deficiencies.

SIGNIFICANCE: Horizontal visual field extension was assessed for red and white stimuli in subjects with protanopia using semi-automated kinetic perimetry. In contrast to a conventional anomaloscope, the "red/white dissociation ratio" (RWR) allows to describe protanopia numerically. For the majority of subjects with protanopia a restriction for faint red stimuli was found. PURPOSE: Comparing the horizontal visual field extensions for red and white stimuli in subjects with protanopia and those with normal trichromacy and assessing the related intra-subject intra-session repeatability. METHODS: The subjects were divided into groups with protanopia and with normal trichromacy, based on color vision testing (HMC anomaloscope, Oculus, Wetzlar/FRG). Two stimulus characteristics, III4e and III1e, according to the Goldmann-classification, were presented with semi-automated kinetic perimetry (Octopus 900 perimeter, Haag-Streit, Köniz/CH). They moved along the horizontal meridian, with an angular velocity of 3°/s towards the visual field center, starting from either the temporal or nasal periphery. If necessary, a 20° nasal fixation point offset was chosen to capture the temporal periphery of the visual field. For each condition the red/white dissociation ratio (RWR); Pat Appl. DPMA DRN 43200082D) between the extent of the isopter for red (RG610, Schott, Mainz/ FRG) and white stimuli along the horizontal meridian was determined. RESULTS: All data are listed as median/interquartile range: Five males with protanopia (age 22.1/4.5 years) and six males with normal trichromacy (control group, age 30.5/15.2 years) were enrolled. The RWR is listed for the right eye, as no clinically relevant difference between right and left eye occurred. Protanopes' RWR for mark III4e (in brackets: control group) was 0.941/0.013 (0.977/0.019) and for mark III1e 0.496/0.062 (0.805/0.051), respectively. CONCLUSIONS: In this exploratory "proof-of-concept study" red/white dissociation ratio perimetry is introduced as a novel technique aiming at assessing and quantifying the severity of protanopia. Further effort is needed to understand the magnitude of the observed red-/white dissociation and to extend this methodology to a wider age range of the sample and to anomalous trichromacies (protanomalia) with varying magnitude.

Visual Phenomena Associated With Migraine and Their Differential Diagnosis.

BACKGROUND: Visual phenomena are of many different kinds; their differential diagnosis is usually possible with directed history-taking. In this review, we describe common visual phenomena that must be distinguished from a migraine aura. METHODS: This review is based on publications retrieved by a selective search in PubMed and the Web of Knowledge/Science, with special attention to the current classification of the International Headache Society and the recommendations of the German Migraine and Headache Society. The following search terms were used: "visual phenomena/phenomenon," "migraine aura," and "persistent/complication/ long-lasting/ongoing." RESULTS: The most helpful questions for differential diagnosis are whether the symptoms are present in one eye only or in both, whether their onset was sudden or over minutes or days, and whether the phenomenon has occurred only once or repeatedly, or is persistently present. A visual aura associated with migraine must be distinguished, in rare cases, from an isolated epileptic aura, from cerebral/retinal ischemia, or from visual snow. Further differential diagnoses include a persisting perceptual disturbance after hallucinogen use (HPPD, "hallucinogen persisting perception disorder") and the Charles Bonnet syndrome (CBS); the latter arises as a consequence of severely impaired vision. Posterior reversible encephalopathy syndrome (PRES) is rare and generally reveals itself over its further course through the appearance of additional clinical manifestations. Primary ophthalmological causes can usually be readily identified and classified by ophthalmological examination. CONCLUSION: Patients with visual phenomena typically consult physicians from various medical specialties. A correct differential diagnosis can be made based on the history if the physician views the symptoms in their overall context to determine the particular disease entity that is responsible.

Mutation spectrum of the OPA1 gene in a large cohort of patients with suspected dominant optic atrophy: Identification and classification of 48 novel variants.

Autosomal dominant optic atrophy is one of the most common inherited optic neuropathies. This disease is genetically heterogeneous, but most cases are due to pathogenic variants in the OPA1 gene: depending on the population studied, 32-90% of cases harbor pathogenic variants in this gene. The aim of this study was to provide a comprehensive overview of the entire spectrum of likely pathogenic variants in the OPA1 gene in a large cohort of patients. Over a period of 20 years, 755 unrelated probands with a diagnosis of bilateral optic atrophy were referred to our laboratory for molecular genetic investigation. Genetic testing of the OPA1 gene was initially performed by a combined analysis using either single-strand conformation polymorphism or denaturing high performance liquid chromatography followed by Sanger sequencing to validate aberrant bands or melting profiles. The presence of copy number variations was assessed using multiplex ligation-dependent probe amplification. Since 2012, genetic testing was based on next-generation sequencing platforms. Genetic screening of the OPA1 gene revealed putatively pathogenic variants in 278 unrelated probands which represent 36.8% of the entire cohort. A total of 156 unique variants were identified, 78% of which can be considered null alleles. Variant c.2708_2711del/p.(V903Gfs*3) was found to constitute 14% of all disease-causing alleles. Special emphasis was placed on the validation of splice variants either by analyzing cDNA derived from patients´ blood samples or by heterologous splice assays using minigenes. Splicing analysis revealed different aberrant splicing events, including exon skipping, activation of exonic or intronic cryptic splice sites, and the inclusion of pseudoexons. Forty-eight variants that we identified were novel. Nine of them were classified as pathogenic, 34 as likely pathogenic and five as variant of uncertain significance. Our study adds a significant number of novel variants to the mutation spectrum of the OPA1 gene and will thereby facilitate genetic diagnostics of patients with suspected dominant optic atrophy.

First German Guideline on Diagnostics and Therapy of Clinically Non-Functioning Pituitary Tumors.

Although non-functioning pituitary tumors are frequent, diagnostic and therapeutic concepts are not well standardized. We here present the first German multidisciplinary guideline on this topic. The single most important message is to manage the patients by a multidisciplinary team (consisting at least of an endocrinologist, a neurosurgeon, and a (neuro-) radiologist). The initial diagnostic work-up comprises a detailed characterization of both biochemical (focusing on hormonal excess or deficiency states) and morphological aspects (with magnetic resonance imaging of the sellar region). An ophthalmological examination is only needed in presence of symptoms or large tumors affecting the visual system. Asymptomatic, hormonally inactive tumors allow for a 'wait and scan' strategy. In contrast, surgical treatment by an experienced pituitary surgeon is standard of care in case of (impending) visual impairment. Therapeutic options for incompletely resected or recurrent tumors include re-operation, radiotherapy, and observation; the individual treatment plan should be developed multidisciplinary. Irrespective of the therapeutic approach applied, patients require long-term follow-up. Patient with larger pituitary tumors or former surgery/radiotherapy should be regularly counseled regarding potential symptoms of hormonal deficiency states.

Leber's hereditary optic neuropathy: course of disease in consideration of idebenone treatment and type of mutation.

PURPOSE: In September 2015, the first and so far only medication for treatment of Leber's hereditary optic neuropathy (LHON) was approved in the EU. The drug in question is idebenone (©Raxone) and has been given to all newly diagnosed patients of the University Eye Hospital Tuebingen since the approval of the drug. The aim of the study was to find out whether regular administration of the drug led to an improvement in vision. We retrospectively examined 2 cohorts of consecutive patients with newly occurred visual impairment and LHON diagnosis: One with the initial diagnosis made from January 2010 until April 2014 and a second from October 2015 until January 2020. METHODS: Retrospective, observational cohort study. All electronic medical files of newly diagnosed and genetically confirmed LHON patients of the University Eye Hospital Tuebingen from January 2010 until April 2014 (cohort 1) and October 2015 until January 2020 (cohort 2) with at least 12 months of follow-up examinations have been analyzed. RESULTS: Five patients were included in the first and 7 patients in the second cohort. Patients of cohort 1 received no medication; patients of cohort 2, a daily dose of 900 mg idebenone. The primary visual acuity (VA) ranged between 0.03 and 0.5 in cohort 1 and did not improve during the observation period (median 60 months, range 23-87 months). The patients of cohort 2 have been observed for a median of 23 months (range 12-35 m). The primary VA ranged from 0.01 to 0.16. A recovery in one or both eyes with a final VA from 0.8 to 1.0 was experienced in 3 out of 7 patients. All patients showing a recovery of VA carried the m.11778G>A mutation. CONCLUSION: The observed improvement in the treated cohort may be considered as a hint on the efficacy of idebenone in LHON. The time course of improvement suggests that idebenone should be given 1.5 years in newly diagnosed LHON cases.

The Swinging Flashlight Test - Flawed Execution and Interpretation in Ophthalmological Routine. / Der Swinging-Flashlight-Test ­ mangelhafte Durchführung und Interpretation in der augenärztlichen Routine.

BACKGROUND: The swinging flashlight test is a standard diagnostic procedure to detect relative afferent pupillary defects. The advantages of the test lie within its objectivity and minimal effort. However, its value depends on its correct execution and interpretation. This questionnaire-based survey investigates whether this is given among German speaking ophthalmologists. METHODS: A multiple-choice questionnaire with 14 questions on the use of the swinging flashlight test was designed. It was presented to German speaking ophthalmology specialists (primary data) and orthoptists (secondary data) on specialist conferences or by telephone interviews. RESULTS: 249 ophthalmologists and 76 orthoptists participated in the survey. Only 2% of ophthalmologists answered all 14 questions correctly. On average 66% (range 29 - 100%) of the questions were answered correctly by the ophthalmologists. The question with the lowest result had a rate of 19%, the question with the highest result was correctly answered by 95%. The orthoptists achieved similar results. CONCLUSION: The rate of correct answers appears disturbingly low. The swinging flashlight test being a basic tool and an obligatory test in a number of guidelines should rather be performed nearly error-free. In light of the high error rates, misdiagnoses and treatment errors must be feared. Better training seems necessary.

Correction to: Retrospective analysis of fractionated intensity-modulated radiotherapy (IMRT) in the interdisciplinary management of primary optic nerve sheath meningiomas.

An amendment to this paper has been published and can be accessed via the original article.