The TUDID Study - Background and Design of a Prospective Cohort.

Prevalence of both type 1 and type 2 diabetes mellitus is growing worldwide and one major cause for morbidity and mortality. However, not every patient develops diabetes-related complications, but causes for the individual susceptibility are still not fully understood. As a platform to address this, we initiated the TUDID (TUebingen DIabetes Database) study, a prospective, monocentric, observational study that includes adults with diabetes mellitus who are treated in the inpatient clinic of a University Hospital in southern Germany. Besides a thorough clinical examination and extensive laboratory tests (with integrated biobanking), major study focuses are the kidneys, the eyes, the vasculature as well as cognition and mood where standardized investigations for early stages for diabetes complications are performed. Analyses of the data generated by this precise characterization of diabetes-related complications will contribute to our understanding of the development and course of such complications, and thus facilitate the implementation of tailored treatment options that can reduce the risk and severity of diabetes-related complications.

Disinhibition of intrinsic photosensitive retinal ganglion cells in patients with X-linked congenital stationary night blindness.

PURPOSE: To assess the pupil light response (PLR) to chromatic stimulation in patients with different types of X-linked congenital stationary night blindness (CSNB). METHODS: Eight patients with CSNB due to CACNA1F and NYX mutations were exposed to blue and red light stimuli, and PLR was evaluated using infrared video pupillography. Pupil responses were compared between CSNB patients and healthy subjects (n = 34) at baseline, at maximum of constriction, for post-illumination pupil responses (PIPR) and the slope of redilation using Cohen's d. A subgroup comparison was performed descriptively between CACNA1F and NYX associated CSNB patients using the same parameters. RESULTS: In CSNB, smaller baseline pupil diameters compared to healthy subjects were measured both before blue and red light stimulation (d = 1.44-1.625). The maximum constriction to blue light stimuli was smaller for the CSNB group compared to healthy subjects (d = 1.251) but not for red light stimuli (d = 0.449). Pupil response latencies were prolonged in CSNB for both light stimuli (d = -1.53 for blue and d = -1.011 for red stimulation). No relevant differences were found between the CSNB group and healthy subjects for PIPR (d = 0.01), but the slope of redilation was smaller for CSNB patients (d = 2.12). Paradoxical pupil constriction at light offset was not seen in our patients. CONCLUSION: A reduced redilation and smaller baseline pupil diameters for patients with CSNB indicate a disinhibition of intrinsically photosensitive retinal ganglion cells due to affected post-photoreceptor transduction via bipolar cells and can explain the pupillary behavior in our patient group.

Decreased contrast sensitivity at high altitude.

BACKGROUND/AIMS: The aim of this study was to investigate a change in visual acuity and contrast sensitivity (CS) during high altitude exposure in healthy subjects due to the effects of hypobaric hypoxia. This study is related to the Tübingen High Altitude Ophthalmology study. METHODS: Visual acuity and Weber CS were tested monocularly using the Freiburger Visual Acuity and Contrast Test under standardised conditions in 14 healthy subjects at high altitude at the Capanna Margherita (4559 m, Italy) and compared with baseline measurements in Tübingen (341 m, Germany). Intraindividual differences between baseline and follow-up examinations were calculated by multivariate analysis of variance for repeated measures. Clinical parameters of peripheral oxygen saturation (SpO2) and heart rate (HR) as well as scores for acute mountain sickness (AMS) were correlated to psychophysical tests by Pearson's correlation coefficient. RESULTS: A significant decrease in CS with a mean effect size of -0.13 logCS was found for Weber CS (day 1=-0.16±0.22, p=0.01; day 2=-0.10±0.2, p=0.049; day 3=-0.12±0.19, p=0.03) at high altitude compared with baseline. Visual acuity remained unchanged. Decreased CS correlated with SpO2 (r=0.53, p=0.046) but not with HR (r=- 0.16, p=0.59) and occurred irrespective of AMS at high altitude. CONCLUSION: High altitude exposure leads to decreased CS. Changes occur independent of AMS. This finding is of clinical importance to trekkers and mountaineers exposed to high altitude as visual processing in particular under mesopic conditions at dusk and dawn is altered. Furthermore, it provides novel insight into hypoxia related changes in CS function.

Macular sensitivity in patients with congenital stationary night-blindness.

AIM: To evaluate and correlate mean light sensitivity thresholds (MLST) in patients with congenital stationary night-blindness (CSNB) in comparison with healthy subjects using microperimetry (MP1). METHODS: Eleven patients with CSNB and 13 healthy subjects were compared. In all subjects, static threshold perimetry was performed using MP1 evaluating the central 6 mm of the retina. This central retinal area was divided into three rings through using the ETDRS grid algorithm with an innermost (1 mm), inner (3 mm) and outer ring (6 mm). The MLSTs were acquired in nine sectors of the ETDRS grid. A comparison of MLST was performed between both groups using a t-test (significance level p<0.005). RESULTS: A significant reduction of MLST in the fovea (innermost ring, 1 mm) was observed for patients with CSNB (7.2±3.90 dB) in comparison to healthy subjects (19.7±0.75; p<0.0001). Similarly, comparison of MLST in all other sectors (superior/inferior/temporal and nasal) within the inner and outer ring revealed a statistically significant reduction in patients with CSNB compared with healthy subjects (p<0.001). CONCLUSIONS: Examination of macular retinal sensitivity intensity using MP1 revealed for the first time a significant reduction of MLST within the central 6 mm of the retina in patients with CSNB compared with healthy subjects. This finding supports MP1 as an additional diagnostic tool when examining patients with retinal dysfunctions such as CSNB.

Optic nerve oedema at high altitude occurs independent of acute mountain sickness.

BACKGROUND/AIMS: The study aims to investigate changes in the optic nerve sheath diameter (ONSD) at high altitude and to assess correlation to optic disc oedema (ODE) and acute mountain sickness (AMS). This investigation is part of the Tübingen High Altitude Ophthalmology study. METHODS: Fourteen volunteers ascended to 4559 m for 4 days before returning to low altitude. Ultrasonography of ONSD, quantification of optic disc parameters using a scanning laser ophthalmoscope and fluorescein angiography were performed at 341 m and at high altitude. Pearson's coefficient was used to correlate changes in ONSD with the optic disc and AMS. Assessment of AMS was performed using the Lake Louise (LL) and AMS-cerebral (AMS-C) scores of the Environmental Symptom Questionnaire-III. All volunteers were clinically monitored for heart rate (HR) and oxygen saturation (SpO2). RESULTS: The mean ONSD at high altitude (4.6±0.3 mm, p<0.05) was significantly increased compared with baseline (3.8±0.4 mm) and remained enlarged throughout high-altitude exposure. This change in ONSD did not correlate with AMS (AMS-C, r=0.26, p=0.37; LL, r=0.21, p=0.48) and high-altitude headache (r=0.54, p=0.046), or clinical parameters of SpO2 (r=0.11, p=0.72) and HR (r=0.22, p=0.44). Increased ONSD did not correlate with altered key stereometric parameters of the optic disc describing ODE at high altitude (r<0.1, p>0.5). CONCLUSION: High-altitude exposure leads to marked oedema formation of the optic nerve independent of AMS. Increased ONSD and ODE reflect hypoxia-driven oedema formation of the optic nerve at high altitude, providing important pathophysiological insight into high-altitude illness development and for future research.

Foveal thickness reduction after anti-vascular endothelial growth factor treatment in chronic diabetic macular edema.

AIM: To report foveal thickness reduction in eyes with resolution of macular edema and recovery of a foveal depression after one-year of anti-vascular endothelial growth factor (anti-VEGF) therapy for center-involving diabetic macular edema (DME). METHODS: Foveal thickness was assessed with optical coherence tomography to determine the central subfield foveal thickness (CSFT) and macular volume in 42 eyes with DME (CSFT>275 µm). Evaluations also included measurement of best-corrected visual acuity (BCVA), and were performed at baseline, and upon foveal depression recovery achieved after 12 monthly intravitreal injections of either 1.5 mg/0.06 mL bevacizumab (n=21) or 0.5 mg/0.05 mL ranibizumab (n=21). Data was compared to 42 eyes of normally sighted, non-diabetic, healthy individuals with similar age, gender and race distributions. RESULTS: Mean baseline BCVA was 0.59±0.04 and 0.32± 0.03 logMAR (P<0.001) after treatment and resolution of DME, with all, but 3 eyes, showing BCVA improvement. Mean CSFT before treatment was 422.0±20.0 µm, and after treatment, decreased to 241.6±4.6 µm (P<0.001), which is significantly thinner than CSFT found in control subjects (272.0±3.4 µm; P<0.001). Moreover, in 33/42 DM eyes (79%), CSTF was thinner than the matched control eye. Macular volume showed comparable results, but with lower differences between groups (control: 8.5±0.4 mm3; DME: 8.2±1.0 mm3; P=0.0267). CONCLUSION: DME eyes show significantly lower foveal thickness than matched controls after DME resolution achieved with one-year anti-VEGF therapy. Further investigation into the reasonsfor this presumable retinal atrophy using fluorescein angiography and functional parameters as well as establishing possible predictors is warranted. This finding should be considered during the treatment of DME.

Effect of High Altitude Exposure on Intraocular Pressure Using Goldmann Applanation Tonometry.

Willmann, Gabriel, Kai Schommer, Maximilian Schultheiss, M. Dominik Fischer, Karl-Ulrich Bartz-Schmidt, Florian Gekeler, and Andreas Schatz. Effect of high altitude exposure on intraocular pressure using Goldmann applanation tonometry. High Alt Med Biol. 18:114-120, 2017. AIMS: The aim of the study was to quantify changes of intraocular pressure (IOP) during exposure to 4559 m using the state-of-the-art method of Goldmann applanation tonometry for IOP measurement and to detect correlations between IOP and acute mountain sickness (AMS) in a prospective manner. METHODS: IOP was measured using a Goldmann applanation tonometer AT 900® (Haag-Streit, Switzerland) and central corneal thickness (CCT) with the anterior segment module of a Spectralis™ HRA+OCT® device (Heidelberg Engineering, Germany) at baseline and high altitude. Assessment of AMS was performed using the Lake Louise and AMS-C questionnaires, and Pearson's correlation coefficient was calculated for association between IOP and AMS. RESULTS: Raw IOP values at high altitude were not significantly changed compared to baseline. IOP adjusted to the increase in CCT at high altitude, which is known to alter IOP levels, showed a significant reduction for corrected IOP values on day 3 of exposure (morning -2.1 ± 1.2 mmHg; evening -2.3 ± 1.1 mmHg; p < 0.05). No correlation of IOP with AMS or clinical parameters (heart rate and SpO2) at high altitude was noted. CONCLUSIONS: IOP showed a significant reduction of IOP levels when corrected for increased CCT values at high altitude. Furthermore, the prospective measurement of IOP is not useful in diagnosing AMS or for the prediction of more severe high altitude related illnesses as the decrease in IOP and symptoms of AMS do not correlate during altitude exposure.

Transcorneal Electrical Stimulation for Patients With Retinitis Pigmentosa: A Prospective, Randomized, Sham-Controlled Follow-up Study Over 1 Year.

Purpose: After promising results of an exploratory study, this study was designed to assess the safety and efficacy of transcorneal electrical stimulation (TES) over 1 year in patients with retinitis pigmentosa (RP). Methods: We included 52 RP patients in this prospective, randomized, partially-masked study which was done in accordance with rules of good clinical practice. Transcorneal electrical stimulation by Okustim was applied monocularly for 30 minutes per week for 52 consecutive weeks. Patients were assigned randomly to the groups: sham, 150%, or 200% of individual electrical phosphene threshold (EPT). Visual acuity (retroilluminated Snellen charts), visual field (VF; Octopus 900), electroretinography (ERG), rod and cone full-field stimulus threshold, EPTs and IOP were assessed. Primary outcome measures were VF area; secondary outcome measures were development of ERG parameters. Results: The application of TES was tolerated well. Dry eye symptoms (31 of 52 patients) were registered as the main adverse event. Throughout the study period, the VF area showed only a trend for prevention of VF loss in the 200% group (P = 0.24). A significant improvement of light-adapted single flash b-wave was noted for the 200% (P < 0.0001) and 150% (P = 0.006) groups compared to the sham group. Tendencies of improved function were observed for scotopic b-wave amplitude for the 200% group (P = 0.097). Other examination methods did not reach statistical significance. Conclusions: The safety and acceptable tolerability of weekly TES self-administered by patients at home was confirmed over the course of 1 year. Objectively measured improvements in retinal function with ERG provide support for the potential benefits of TES for RP patients.

Ultraviolet Keratitis: From the Pathophysiological Basis to Prevention and Clinical Management.

Ultraviolet keratitis is caused by the toxic effects of acute high-dose ultraviolet radiation (UVR) reflecting the sensitivity of the ocular surface to photochemical injury. The clinical syndrome presents with ocular pain, tearing, conjunctival chemosis, blepharospasm, and deterioration of vision typically several hours after exposure, lasting up to 3 days. Mountaineers, skiers, and beach recreationalists are particularly at risk to suffer from ultraviolet (UV) keratitis as the reflectivity of UVR in these environments is extremely high. The aim of this review is to raise awareness about the potential of UV damage on the eye with an emphasis on UV keratitis, to highlight the pathophysiological basis of corneal phototoxicity, and to provide practical guidance for the prevention and clinical management of UV keratitis commonly known as snow blindness.

Reversible Increase of Central Choroidal Thickness During High-Altitude Exposure.

PURPOSE: This study aimed to quantify the impact of high altitude on choroidal thickness and relate changes of altered choroidal blood flow to clinical parameters and acute mountain sickness (AMS). This work is related to the Tübingen High Altitude Ophthalmology (THAO) study. METHODS: Enhanced depth imaging spectral-domain optical coherence tomography was used to quantify macular choroidal layer thickness. Peripheral oxygen saturation, heart rate, and AMS scores were assessed in eight healthy subjects at baseline (altitude, 341 m) and at altitude (4559 m) for respective correlations. RESULTS: Longitudinal analysis revealed a significant (P = 0.011, ANOVA) increase in central choroidal thickness (CCT) during altitude exposure (CCT baseline = 271 ± 9 µm; CCT altitude = 288 ± 9 µm) due to an increased choroidal blood flow. Incidence of AMS at altitude was 50%, peripheral oxygen saturation decreased by 25%, and heart rate increased by 39%. All changes were completely reversible after descent to low altitudes. CONCLUSIONS: A small but significant increase in choroidal thickness was observed upon acute altitude exposure to 4559 m. This increase in choroidal blood flow was not related to AMS and was fully reversible after return to low altitude.

Missing correlation of retinal vessel diameter with high-altitude headache.

The most common altitude-related symptom, high-altitude headache (HAH), has recently been suggested to originate from restricted cerebral venous drainage in the presence of increased inflow caused by hypoxia. In support of this novel hypothesis, retinal venous distension was shown to correlate with the degree of HAH. We quantified for the first time retinal vessel diameter changes at 4559 m using infrared fundus images obtained from a state of the art Spectralis™ HRA+OCT with a semiautomatic VesselMap 1® software. High-altitude exposure resulted in altered arterial and venous diameter changes at high altitude, however, independent of headache burden.

Update on high altitude cerebral edema including recent work on the eye.

This review summarizes recent research on high altitude cerebral edema (HACE) and on the eye with focus on the retina and optic nerve as visible brain tissue at high altitude. Hemosiderin deposits in the corpus callosum have been characterized as rather specific long-lasting footprints of HACE, indicating a leak of the blood-brain barrier (BBB) and resulting in microhemorrhages. These are compatible with the concept of increased capillary pressure due to venous outflow limitation as suggested by Wilson et al. There are no human data on the role of vascular permeability in HACE, while animal models of uncertain relevance for human HACE suggest that an impaired integrity of the BBB through VEGF and ROS is more important than hemodynamic changes. Examinations by ultrasound show an inconsistent increase of the optic nerve sheath diameter, whereas unequivocal optic disc swelling (ODS), increased retinal vessel diameter, as well as retinal vessel leakage occur at high altitude. However, whether these morphological changes correlate with symptoms of AMS as a possible precursor of HACE or high altitude headache supporting the concept of venous outflow limitation remains questionable and is discussed in detail in this article.

Exposure to high altitude alters tear film osmolarity and breakup time.

AIMS: High altitude provides environmental conditions with dry air and cold temperatures that may facilitate the development of dry eye symptoms. This study investigated, for the first time, the quality of the tear film during high altitude exposure in healthy subjects. This study is related to the Tübingen High Altitude Ophthalmology (THAO) study. METHODS: Tear film osmolarity (TFO), tear film breakup time (TBUT), and Schirmer I and II were used to assess tear film properties under standardized conditions in 14 healthy subjects on day 1, 2, and 4 during exposure to high altitude at the Capanna Margherita (CM; 4559 m, Italy) compared to baseline measurements in Tübingen (341 m, Germany) before (BL1) and after (BL2) exposure. RESULTS: Upon arrival at CM, a significant increase in intra-individual TFO (309.1 ± 19.3, 332.2 ± 24.1, 335.5 ± 28.7, 329.7 ± 19.0, and 308.5 ± 15.3 mOsms/L at BL1, day 1, 2, 4, and BL2, respectively) and a significant decrease of TBUT (11.2 ± 5.2, 7.3 ± 5.2, 7.2 ± 11.6, 4.5 ± 2.3, and 8.7 ± 4.6 seconds at BL1, day 1, 2, 4, and BL2, respectively) were found. Schirmer test changes at high altitude remained statistically nonsignificant compared to baseline. Comparisons of parameters between BL1 and BL2 showed no statistically significant differences and recordings of right and left eyes for TBUT and Schirmer did not differ significantly on any day measured. CONCLUSION: High altitude exposure leads to an altered tear film resulting in an increased TFO and a reduced TBUT. These changes were fully reversible after descent. This is of clinical importance to populations living in high altitude areas and to trekkers and mountaineers exposed to high altitude due to their ever-increasing number.

Attenuation of S-cone function at high altitude assessed by electroretinography.

As impaired S-cone function has been reported psychophysically this study assessed S-cone function during high altitude exposure using electroretinography (ERG) and investigated a possible association with severity of acute mountain sickness (AMS). This work is related to the Tübingen High Altitude Ophthalmology (THAO) study. Standard ERG equipment was used (Diagnosys LLC, Cambridge, UK) with special protocol settings to extract S-cone function. Twelve subjects were analyzed in the current study and examinations were performed in Tübingen, Germany (341m) as baseline and thereafter at the Capanna Margherita, Italy (4559m) at high altitude. Results were compared using a paired t-test. Correlations between ERG measurements and oxygen saturation (SpO2), heart rate (HR) and scores of acute mountain sickness (AMS-C and LL) were calculated using Pearson's correlation coefficients. Amplitudes of S-cone b-waves decreased significantly at high altitude (p=0.02). No significant changes were observed for implicit times of b-waves (p=0.63), a-waves (p=0.75) or for a-wave amplitudes (p=0.78). The incidence of AMS was 50% at high altitude according to AMS-C and LL scores (AMS-C⩾0.7 and LL⩾5). Heart rate increased to 84±10min(-1) and SpO2 decreased to 71.9±5.7% at high altitude. No significant correlation was found between S-cone ERG parameters and SpO2, HR, AMS-C and LL. For the first time our study defines a significant impairment of S-cone function at high altitude time using objective state of the art examination methods. No correlation between the functional impairment of S-cones and levels of AMS was detected.

Pupillary light reaction during high altitude exposure.

PURPOSE: This study aimed to quantify the pupillary light reaction during high altitude exposure using the state of the art Compact Integrated Pupillograph (CIP) and to investigate a potential correlation of altered pupil reaction with severity of acute mountain sickness (AMS). This work is related to the Tübingen High Altitude Ophthalmology (THAO) study. METHODS: Parameters of pupil dynamics (initial diameter, amplitude, relative amplitude, latency, constriction velocity) were quantified in 14 healthy volunteers at baseline (341 m) and high altitude (4559 m) over several days using the CIP. Scores of AMS, peripheral oxygen saturation and heart rate were assessed for respective correlations with pupil dynamics. For statistical analysis JMP was used and data are shown in terms of intra-individual normalized values (value during exposure/value at baseline) and the 95% confidence interval for each time point. RESULTS: During high altitude exposure the initial diameter size was significantly reduced (p<0.05). In contrast, the amplitude, the relative amplitude and the contraction velocity of the light reaction were significantly increased (p<0.05) on all days measured at high altitude. The latency did not show any significant differences at high altitude compared to baseline recordings. Changes in pupil parameters did not correlate with scores of AMS. CONCLUSIONS: Key parameters of the pupillary light reaction are significantly altered at high altitude. We hypothesize that high altitude hypoxia itself as well as known side effects of high altitude exposure such as fatigue or exhaustion after ascent may account for an altered pupillogram. Interestingly, none of these changes are related to AMS.

Electroretinographic assessment of retinal function during acute exposure to normobaric hypoxia.

BACKGROUND: The current study aimed to investigate retinal function during exposure to normobaric hypoxia. METHODS: Standard Ganzfeld ERG equipment (Diagnosys LLC, Cambridge, UK) using an extended ISCEV protocol was applied to explore intensity-response relationship in dark- and light- adapted conditions in 13 healthy volunteers (mean age 25 ± 3 years). Baseline examinations were performed under atmospheric air conditions at 341 meters above sea level (FIO2 of 21 %), and were compared to hypoxia (FIO2 of 13.2 %) by breathing a nitrogen-enriched gas mixture for 45 min. All subjects were monitored using infrared oximetry and blood gas analysis. RESULTS: The levels of PaCO2 changed from 38.4 ± 2.7 mmHg to 36.4 ± 3.0 mmHg, PaO2 from 95.5 ± 1.9 mmHg to 83.7 ± 4.6 mmHg, and SpO2 from 100 ± 0 % to 87 ± 4 %, from baseline to hypoxia respectively. A significant decrease (p < 0.05) was found for saturation amplitude of the dark-adapted b-wave intensity-response function (Vmax), dark-adapted a- and b-wave amplitudes of combined rod and cone responses (3 and 10 cd.s/m(2)), light-adapted b-wave amplitudes of single flash (3 and 10 cd.s/m(2)), and flicker responses (5-45 Hz) during hypoxia compared to baseline, without changes in implicit times. The a-wave slope of combined rod and cone responses (3 and 10 cd.s/m(2)) and the oscillatory potentials were significantly lower during hypoxia (p < 0.05). A isolated light-adapted ON response (250 ms flash) showed a reduction of amplitudes at hypoxia (p < 0.05), but no changes were observed for the OFF response. CONCLUSIONS: The results show significant impairment of retinal function during simulated normobaric short-term hypoxia affecting specific retinal cells of rod and cone pathways.

Electroretinographic assessment of retinal function at high altitude.

Although hypoxia plays a key role in the pathophysiology of many common and well studied retinal diseases, little is known about the effects of high-altitude hypoxia on retinal function. The aim of the present study was to assess retinal function during exposure to high-altitude hypoxia using electroretinography (ERG). This work is related to the Tübingen High Altitude Ophthalmology (THAO) study. Electroretinography was performed in 14 subjects in Tübingen, Germany (341 m) and at high altitude at La Capanna Regina Margherita, Italy (4,559 m) using an extended protocol to assess functional integrity of various retinal layers. To place findings in the context of acute mountain sickness, correlations between ERG measurements and oxygen saturation, heart rate, and scores of acute mountain sickness (AMS) were calculated. At high altitude, the maximum response of the scotopic sensitivity function, the implicit times of the a- and b-wave of the combined rod-cone responses, and the implicit times of the photopic negative responses (PhNR) were significantly altered. A-wave slopes and i-waves were significantly decreased at high altitude. The strongest correlation was found for PhNR and O2 saturation (r = 0.68; P < 0.05). Of all tested correlations, only the photopic b-wave implicit time (10 cd·s/m(2)) was significantly correlated with severity of AMS (r = 0.57; P < 0.05). ERG data show that retinal function of inner, outer, and ganglion cell layer is altered at high-altitude hypoxia. Interestingly, the most affected ERG parameters are related to combined rod-cone responses, which indicate that phototransduction and visual processing, especially under conditions of rod-cone interaction, are primarily affected at high altitude.