High altitude retinopathy

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High altitude retinopathy encompasses a spectrum of pathological retinal changes occurring in unacclimatized individuals exposed to hypobaric hypoxia encountered at high altitudes. Affected individuals are usually asymptomatic and typical features, including retinal hemorrhages and papilledema, generally resolve spontaneously without adverse visual outcomes on descent to lower altitudes.

Climbers on Mount Everest. (© 2016, Mário Simoes. Used under a Creative Commons Attribution License.)

Disease Entity

ICD-10:

  • H35.09 - other intra-retinal microvascular abnormalities
  • T70.29 - other effects of high altitude

Disease

High altitude retinopathy (HAR) is one of four clinical entities comprising the altitude illness syndrome; the others being acute mountain sickness (AMS), high altitude cerebral edema (HACE) and high altitude pulmonary edema (HAPE). High altitude retinopathy encompasses a spectrum of pathological retinal changes occurring in unacclimatized individuals exposed to hypobaric hypoxia encountered at high altitudes and may reflect individual susceptibility to pathology.

Etiology

Various vascular compensatory mechanisms and pathological responses induced by hypobaric hypoxia, and potentially exacerbated by physical exertion and Valsalva effects, are thought to cause the physiological and pathological retinal changes observed in individuals ascending to high altitudes.[1][2]

Risk Factors

Sequential color fundus photographs in a case of high altitude retinopathy, demonstrating the development of retinal hemorrhages over the course of high altitude ascent and descent. (© 2011, Daniel Barthelmes et al.[6] Used under a Creative Commons Attribution License.)

Altitude illness

Independent risk factors for the development of altitude illness include:[3][4]

  • altitude reached;
  • individual susceptibility;
  • rate of ascent.

High altitude retinopathy

Specific risk factors for HAR include:[5][6][7]

HAR has also been noted to occur more frequently in young and physically well-trained individuals, especially those undergoing strenuous activity at high altitudes.[8][9]

Use of non-steroidal anti-inflammatory drugs (NSAIDs) has been implicated as a possible risk factor for HAR, but study findings are contradictory.[6][7]

Physiology

Systemic

Hypobaric hypoxia experienced at high altitudes induces a number of compensatory physiologic mechanisms to counteract the resultant hypoxemia. Such homeostatic mechanisms include an increase in cardiac output and ventilation; modification of blood flow by local and systemic auto-regulatory adjustments in regional vascular systems; a right shift of the oxygen-hemoglobin dissociation curve; and a later secondary polycythemia resulting in an increased hemoglobin concentration and hematocrit.[9]

Regional

Increased retinal blood flow, decreased retinal circulation time, retinal vasodilation and an absolute increase in retinal vascular blood volume are important auto-regulatory responses aimed at maintaining tissue oxygenation in eyes exposed to chronic hypoxia.[10] These regional compensatory responses typically cause a clinically observable increase in the diameter and tortuosity of retinal vessels and disc hyperemia, which are considered normal responses and are seen in almost all individuals at high altitude.[1][5] Choroidal vessels can also auto-regulate but early studies suggest that choroidal vessels do not operate normally at full-flow capacity.[11] Studies are providing more information as available tools to study the choroid are reported.

Pathophysiology

The development of HAR is hypothesized to involve systemic hypoxic effects on the eye despite regulatory attempts by the retinal circulation to achieve homeostasis.[6] In addition to the physiological changes mentioned above, various superimposed pathological factors are thought to contribute to the development of HAR.[12] However, due to difficulties with experimentation at high altitude, the following may be based on retinal pathophysiology at normal oxygen concentrations and should be carefully reviewed to assess various questions vision scientists may have:
Proposed pathophysiological mechanism for the development of typical features of high altitude retinopathy (adapted from Shults et al., 1975[2]).
  • Increased expression of nitric oxide (NO) and vascular endothelial growth factor (VEGF) cause a breakdown of the inner blood-retinal barrier, leading to vasodilation, increased vascular permeability and capillary proliferation.[13][14]
  • Increased hematocrit and hemoglobin concentration leads to increased blood viscosity, increased coagulability and decreased oxygen transport capacity.[8]
  • Elevated blood viscosity may increase shear stress to the pre-damaged vascular endothelial cells.[15]
  • Hypoxia-induced increase in cerebral blood flow and decreased blood-brain barrier integrity result in cerebral edema, leading to an increase in brain volume and optic disc swelling (papilledema).[16][12]
  • Cerebral edema, pulmonary edema and local factors may all lead to an increase in retinal venous pressures.[1][2][10]
  • Coughing, vomiting, straining, strenuous exercise and other Valsalva-like maneuvers further increase intra-vascular pressures.[1][2][10]
  • Local stasis caused by impaired micro-circulation and local high vascular pressure peaks may lead to capillary bursts.[1][2]
  • Pre-existing medical conditions may exacerbate retinal vessel fragility (e.g. retinal microvascular diseases, such as diabetic or hypertensive retinopathy), coagulability (e.g. anti-phospholipid syndrome) or systemic hypoxia (e.g. chronic obstructive pulmonary disease or cystic fibrosis).[5][15][17][18][19][20]
  • Genetic susceptibility to the effects of high altitude, or protection against high altitude, may also play a role in the pathophysiology of HAR.[21]

General pathology

Retinal hemorrhages from capillary bursts or leakage from the arterial side of the retinal vascular bed are a predominant pathological finding in HAR.[5][22] These hemorrhages may be punctate or diffuse, intra-retinal or pre-retinal, and peripheral or central. The cause of the bleeding is not clear but one consideration is that low oxygen stimulates expression of factors that increase vascular permeability, such as VEGF.

Small hemorrhages are initially punctate and intra-retinal with a flame-shaped or feathery appearance, following the anatomy of the nerve fiber layer.[15] More extensive vessel damage may result in larger or diffuse hemorrhages, which tend to be more prominent and well-defined and are often situated pre-retinally.[15] In cases where the posterior vitreous is not adherent to retina, these bleeds may be dispersed into the vitreous cavity.[15] Retinal hemorrhages tend to occur peripherally but occasionally may involve the macula.[10] Differences in regional retinal blood flow and arteriovenous transit time are hypothesised to be the reason for this clinical finding.[10]

Hemorrhage, hypoxia, hypoperfusion, fluctuations in vascular pressures and vascular dysfunction may all contribute to retinal nerve fiber layer infarcts, disruption of axoplasmic flow (resulting in cotton wool spots), micro-embolisation of platelet aggregates (resulting in Roth spots) and retinal vein occlusions.[5][6][7][23]

Increased intra-cranial pressure (ICP) as a result of hypoxia-induced changes in cerebral blood flow and blood-brain barrier function lead to papilledema.[15][16]

Visual morbidity in HAR may be the consequence of:

Prevention

Primary

Avoidance of ascent to high altitude.

Secondary

The severity of HAR may be mitigated by acclimatization, slower ascent, maintenance of higher SpO2 (e.g. supplemental oxygen) and avoidance of strenuous activities, Valsalva maneuvers and NSAIDs while at high altitude.[5][6][7][8][9] If symptoms of high altitude (which may include visual disturbances, nausea and headaches) arise, descent to lower altitudes may be considered and is recommended.

Diagnosis

History

Current or recent ascent to high altitude, with or without associated visual complaints.

Physical examination

Clinical features of HAR are apparent on dilated fundus examination.

Color fundus photographs in a case of high altitude retinopathy, demonstrating optic disc swelling in both eyes and retinal hemorrhages in the right eye. (© 2019, Manju Benjankar.[24] Used under a Creative Commons Attribution License.)

Signs

Description

First described by Singh in 1969, typical features include:[25]

  • increasingly dilated retinal vessels (veins and arteries);
  • pre- and intra-retinal hemorrhages (punctate or diffuse, peripheral or central);
  • papillary hemorrhage;
  • peri-papillary hyperemia;
  • papilledema.

Cotton wool spots, Roth spots and retinal vein occlusions (both branch and central) have also been described in association with HAR.[4][6][7][8]

Classification

Wiedman and Tabin established a classification system for HAR in 1999, based on progressive severity of clinical signs:[26]

  • Grade I
    • A: Mildly dilated retinal veins (venule:arteriole ratio 3:2)
    • B: Retinal hemorrhages up to one disc area
  • Grade II
    • A: Moderately dilated retinal veins (venule:arteriole ratio 3.5:2)
    • B: Retinal hemorrhages up to two disc areas
  • Grade III
    1. A: Greatly dilated retinal veins (venule:arteriole ratio 4:2)
    2. B: 1) Retinal hemorrhages up to three disc areas; 2) para-macular retinal hemorrhages; 3) vitreous hemorrhage (minor, <3 disc areas)
  • Grade IV
    • A: Engorged retinal veins (venule:arteriole ratio 4.5:2)
    • B: 1) Retinal hemorrhages more than three disc areas; 2) macular retinal hemorrhages; 3) vitreous hemorrhage (major, >3 disc areas); 4) papilledema

Symptoms

Affected individuals are usually asymptomatic. Infrequent symptoms may include: sudden painless onset of floaters, blurring and/or loss of vision.

Clinical diagnosis

Based on the identification of typical retinal changes in an individual with current or recent ascent to high altitude. May be an incidental finding or be prompted by the onset of new visual complaints.

Diagnostic procedures

Fundus fluorescein angiography in a case of high altitude retinopathy (same case as above), demonstrating active disc hyperfluorescence in both eyes and areas of hypofluorescence corresponding to retinal hemorrhages in the right eye. (© 2019, Manju Benjankar.[24] Used under a Creative Commons Attribution License.)
HAR is predominately a clinical diagnosis but a number of special investigations have been utilized to better define the extent, severity and complications of the condition, as well as for monitoring and follow up purposes. These include:

Laboratory tests

Generally not indicated for diagnostic purposes but may reveal elevated hemoglobin concentration and hematocrit.

Differential diagnosis

Automated visual field analysis in a case of high altitude retinopathy (same case as above), demonstrating a central scotoma in the left eye and a normal field in the right eye. (© 2019, Manju Benjankar.[24] Used under a Creative Commons Attribution License.)

Management

General treatment

HAR is usually asymptomatic and typical retinal changes are often only detected incidentally after descent to lower altitudes or not detected at all. If vision-involving HAR develops at high altitude, general treatment measures include immediate descent to lower altitudes and administration of supplemental oxygen.[10]

Medical therapy

The majority of cases of HAR resolve spontaneously with no long-term adverse visual outcomes.[5][6] Besides the general measures mentioned above, no specific therapies for HAR have been proven, although it may be necessary to treat the acute manifestations of altitude illness or the chronic ocular complications of the condition (e.g. retinal vein occlusion). Medications such as NSAIDs, corticosteroids and acetazolamide have been shown to have no impact on retinal hemorrhages.[6] The use of furosemide is inconclusive.[23]

Medical follow up

Follow up is generally not necessary but may be required in certain cases to monitor and/or treat complications.

Surgery

Surgical management of HAR has not been described.

Complications

Ocular

Documented complications of HAR include:[2][5][6][8][10]

  • residual scotomata;
  • visual field shrinkage;
  • vision loss from a variety of causes (see General pathology above).

Systemic

Although HAR itself has no systemic complications, the severity of retinopathy has been shown to correlate with the development of HACE and HAPE, and these life-threatening conditions should always be considered in individuals at high altitudes.[8][26] Despite these observations, the usefulness of HAR as a predictive tool for the more severe manifestations of altitude illness remains uncertain.[15]

Prognosis

Figures for both the incidence and visual prognosis of HAR vary widely. HAR has been documented to occur in anywhere between 0-79% of individuals ascending to high altitudes.[6][10] Various individual- and ascent-related factors are likely responsible for these disparate findings. Visual prognosis is therefore likely dependent on similar factors. In a single study, 75% of individuals with HAR had full visual recovery at 12 weeks; 19% had only partial visual recovery even at 24 weeks; and 6% showed no visual recovery at 24 weeks.[8] Numerous other studies have reported lower rates of adverse visual outcomes.[1][5][6][7]

Additional Resources

References

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  2. 2.0 2.1 2.2 2.3 2.4 Shults WT, Swan KC. High Altitude Retinopathy in Mountain Climbers. Arch Ophthalmol. 1975;93:404-408. doi:10.1001/archopht.1975.010100204180
  3. Schneider M, Bernasch D, Weymann J, Holle R, Bartsch P. Acute mountain sickness: influence of susceptibility, preexposure, and ascent rate. Med Sci Sports Exerc. 2002;34(12):1886–1891. doi:10.1097/00005768-200212000-00005
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  24. Benjankar M, Ranjitkar EP. Retinal Changes in a Case of High Altitude Retinopathy (HAR). J Clin Ophthalmol Eye Disord. 2019;3(1):1029.
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