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Research Letters |

Retinal Vessel Leakage at High Altitude FREE

Gabriel Willmann, MD; M. Dominik Fischer, MD; Andreas Schatz, MD; Kai Schommer, MD; Florian Gekeler, MD
[+] Author Affiliations

Author Affiliations: Centre for Ophthalmology, University of Tübingen, Tübingen, Germany (Drs Willmann, Fischer, Schatz, and Gekeler) (gekeler@uni-tuebingen.de); and Department of Sports Medicine, Medical Clinic, University of Heidelberg, Heidelberg, Germany (Dr Schommer).


Letters Section Editor: Jody W. Zylke, MD, Senior Editor.

More Author Information
JAMA. 2013;309(21):2210-2212. doi:10.1001/jama.2013.5550.
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Published online

To the Editor: Exposure to high altitude can cause acute mountain sickness (AMS) and, in severe cases, cerebral or pulmonary edema. Capillary leakage has been hypothesized to play a role in the pathogenesis of AMS, although the mechanism of altitude-related illnesses remains largely unknown. As a directly observable part of the brain, the retina offers a window to study altitude-related vascular changes of the central nervous system.

High-altitude retinopathy is characterized by optic disc edema, retinal hemorrhages, cotton wool spots, and increased tortuosity and dilation of retinal vessels.1,2 Vessel leakage in the retinal periphery has not been investigated. Our objective was to assess retinal vessel integrity at high altitude using fluorescein angiography.

Fourteen healthy, unacclimatized volunteers (7 male and 7 female white participants aged 25-54 years; mean [SD] age, 35 [4] years) were recruited from the University of Tübingen by mass e-mail and studied at baseline (341 m), after ascent to 4559 m within 24 hours, and more than 14 days after return by fluorescein angiography with a confocal scanning laser ophthalmoscope (Spectralis, Heidelberg Engineering). Photographs were independently graded in random order by 4 masked ophthalmologists for presence and location of leakage.

To quantify the severity of AMS, the Lake Louise (LL) and AMS cerebral (AMS-C) scores3 containing self-reported and objective clinical evaluation were acquired. The cutoff criterion for AMS was LL score (range, 0-15) of 5 or greater and AMS-C score (range, 0-4.99) of 0.7 or greater. Peripheral oxygen saturation (SpO2) was measured by pulse oximeter.

Correlations were tested using the Fisher exact test and differences between SpO2 levels were analyzed using an independent, 2-sided t test at a significance level of P < .05; JMP version 8.0.2 statistical software was used (SAS Institute Inc). The study was approved by the ethics committee of the University of Tübingen; all participants gave written informed consent.

Retinal abnormalities were not noted at baseline in any of the participants. At high altitude, marked bilateral leakage of peripheral retinal vessels was observed in 7 of 14 participants (50%; Figure 1). Leakage uniformly occurred in the following distinct pattern: always present in the temporal-inferior and absent in the nasal-superior periphery (Figure 2), favoring venules more than arterioles. Staining of the optic disc was detected in 57% (8/14); no leakage was found in the central retina (Figure 2).

Place holder to copy figure label and caption
Figure 1. Fluorescein Angiography Showing Leakage of Peripheral Retinal Vessels in 1 Participant at High Altitude
Graphic Jump Location

At baseline altitude (left) peripheral retinal vasculature shows no fluorescein leakage while at high altitude (center) marked leakage is visible in the wide temporal periphery. Findings completely reversed after return to baseline altitude (right). This participant had no symptoms of acute mountain sickness (Lake Louise score: 0; acute mountain sickness cerebral score: 0.18).

Place holder to copy figure label and caption
Figure 2. Distribution of Leakage of Retinal Vessels in 7 Participants and Composite Fundus Image Showing Leakage in 1 Participant
Graphic Jump Location

Although none of the participants showed leakage in the nasal-superior periphery, all showed leakages in the temporal periphery.

All findings completely reversed after descent (Figure 1). Incidence of AMS at high altitude was 50% (7/14). Leakage was not correlated with AMS (LL, P = .90; AMS-C, P = .86) as 4 of 7 participants without AMS (57%) and 3 of 7 with AMS (43%) showed leakage in an undistinguishable pattern. Leakage did not correlate with levels of SpO2 (with leakage, 70.1% [95% CI, 64.8%-75.5%]; without leakage, 74.1% [95% CI, 68.9%-79.4%]; P = .21). No significant difference in SpO2 was noted in participants with (71.1% [95% CI, 64.4%-77.9%]) or without AMS (73.1% [95% CI, 69.2%-77.1%]) (P = .54). Only 1 participant showed a retinal hemorrhage; there was no leakage detectable in the area of hemorrhage.

We found bilateral leakage of retinal vessels during altitude exposure with a uniform presentation in the temporal peripheral crescent. To our knowledge, this finding in the most distal vascular bed of the retina (where tissue hypoxia is most severe) has not been detected in previous studies.4,5 Retinal capillary leakage should be considered a part of the spectrum of high-altitude retinopathy.

A comparable hemispherical presentation occurs in zone III of retinopathy of prematurity.6 Leakage of retinal vessels with vasogenic edema of surrounding tissue suggests impairment in the tight junctions of the retinal capillary endothelial cells, the blood-retinal barrier. Whether similar disruptions in the blood-brain barrier cause AMS is unknown, but (taking into account the moderate sample size of this study) the lack of correlation between the retinal findings and AMS does not support this hypothesis.

Author Contributions: Dr Gekeler had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Willmann, Gekeler.

Acquisition of data: Willmann, Fischer, Schatz, Schommer, Gekeler.

Analysis and interpretation of data: Willmann, Fischer, Schatz, Schommer, Gekeler.

Drafting of the manuscript: Willmann, Schatz, Gekeler.

Critical revision of the manuscript for important intellectual content: Willmann, Fischer, Schatz, Schommer, Gekeler.

Statistical analysis: Schatz.

Obtained funding: Willmann, Fischer, Gekeler.

Administrative, technical, or material support: Willmann, Fischer, Gekeler.

Study supervision: Willmann, Schatz, Schommer, Gekeler.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Gekeler reported serving as a consultant to Retina Implant AG. No other author reported disclosures.

Funding/Support: The study was supported by the Charles S. Houston Award from the Wilderness Medical Society. Heidelberg Engineering (Heidelberg, Germany) provided the confocal scanning laser ophthalmoscope.

Role of the Sponsor: The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Peter Bärtsch, MD (Department of Sports Medicine, Medical Clinic, University of Heidelberg, Heidelberg, Germany), for invaluable intellectual support during conception of our study, evaluation of data, and drafting of the manuscript. We also thank Faik Gelisken, MD (Centre for Ophthalmology, University of Tübingen, Tübingen, Germany), for critical review of our findings and grading of angiographies. Neither Dr Bärtsch nor Dr Gelisken received compensation for his contribution.

Singh I, Khanna PK, Srivastava MC, Lal M, Roy SB, Subramanyam CS. Acute mountain sickness.  N Engl J Med. 1969;280(4):175-184
PubMed   |  Link to Article
McFadden DM, Houston CS, Sutton JR, Powles AC, Gray GW, Roberts RS. High-altitude retinopathy.  JAMA. 1981;245(6):581-586
PubMed   |  Link to Article
Roach RC, Bartsch P, Oelz O,  et al; Lake Louise Consensus Committee.  The Lake Louise acute mountain sickness scoring system. In: Hypoxia and Molecular Medicine. Burlington, VT: Charles S. Houston; 1993:272-274
Frayser R, Houston CS, Bryan AC, Rennie ID, Gray G. Retinal hemorrhage at high altitude.  N Engl J Med. 1970;282(21):1183-1184
PubMed   |  Link to Article
Frayser R, Houston CS, Gray GW, Bryan AC, Rennie ID. The response of the retinal circulation to altitude.  Arch Intern Med. 1971;127(4):708-711
PubMed   |  Link to Article
Albert DM, Miller JW, Azar DT, Blodi BA. Albert & Jakobiec's Principles and Practice of Ophthalmology. 3rd ed. Philadelphia, PA: Saunders/Elsevier; 2008

Figures

Place holder to copy figure label and caption
Figure 1. Fluorescein Angiography Showing Leakage of Peripheral Retinal Vessels in 1 Participant at High Altitude
Graphic Jump Location

At baseline altitude (left) peripheral retinal vasculature shows no fluorescein leakage while at high altitude (center) marked leakage is visible in the wide temporal periphery. Findings completely reversed after return to baseline altitude (right). This participant had no symptoms of acute mountain sickness (Lake Louise score: 0; acute mountain sickness cerebral score: 0.18).

Place holder to copy figure label and caption
Figure 2. Distribution of Leakage of Retinal Vessels in 7 Participants and Composite Fundus Image Showing Leakage in 1 Participant
Graphic Jump Location

Although none of the participants showed leakage in the nasal-superior periphery, all showed leakages in the temporal periphery.

Tables

References

Singh I, Khanna PK, Srivastava MC, Lal M, Roy SB, Subramanyam CS. Acute mountain sickness.  N Engl J Med. 1969;280(4):175-184
PubMed   |  Link to Article
McFadden DM, Houston CS, Sutton JR, Powles AC, Gray GW, Roberts RS. High-altitude retinopathy.  JAMA. 1981;245(6):581-586
PubMed   |  Link to Article
Roach RC, Bartsch P, Oelz O,  et al; Lake Louise Consensus Committee.  The Lake Louise acute mountain sickness scoring system. In: Hypoxia and Molecular Medicine. Burlington, VT: Charles S. Houston; 1993:272-274
Frayser R, Houston CS, Bryan AC, Rennie ID, Gray G. Retinal hemorrhage at high altitude.  N Engl J Med. 1970;282(21):1183-1184
PubMed   |  Link to Article
Frayser R, Houston CS, Gray GW, Bryan AC, Rennie ID. The response of the retinal circulation to altitude.  Arch Intern Med. 1971;127(4):708-711
PubMed   |  Link to Article
Albert DM, Miller JW, Azar DT, Blodi BA. Albert & Jakobiec's Principles and Practice of Ophthalmology. 3rd ed. Philadelphia, PA: Saunders/Elsevier; 2008

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