High Altitude Retinopathy

Key Points at a Glance

Essentials of this disease

• High altitude retinopathy (HAR) is a general term for retinal changes that occur in the hypobaric hypoxic environment at high altitudes.
• It usually occurs above 12,000 feet (approximately 3,650 m) and is a clinical entity of altitude sickness.
• Most cases are asymptomatic and resolve spontaneously upon descent.
• Typical findings include dilation and tortuosity of retinal vessels, retinal hemorrhage, and papilledema; severity is assessed using the Wiedman-Tabin classification (grades I–IV).
• No specific treatment has been established; if visual impairment occurs, descend to a lower altitude promptly and administer supplemental oxygen.
• NSAIDs, steroids, and acetazolamide are ineffective for retinal hemorrhage.

1. What is High Altitude Retinopathy?

High Altitude Retinopathy (HAR) is a general term for retinal changes occurring in unacclimatized individuals exposed to hypobaric hypoxia at high altitudes. It was first systematically described by Singh in 1969.

HAR is considered one of the four clinical entities of altitude sickness¹⁾.

Acute Mountain Sickness (AMS)

Main symptoms: Headache, nausea, vomiting, fatigue

Features: Most common form of altitude sickness. Usually develops within 6 hours to 3 days after arrival at high altitude.

High Altitude Cerebral Edema (HACE)

Main symptoms: Ataxia, altered consciousness

Features: Main pathology is cerebral edema. Considered a severe form of AMS.

High Altitude Pulmonary Edema (HAPE)

Main symptoms: Dyspnea, cyanosis

Features: Main pathology is pulmonary edema. Leading cause of altitude sickness-related death.

High Altitude Retinopathy (HAR)

Main symptoms: Retinal hemorrhage, papilledema

Features: Most cases are asymptomatic. Spontaneous resolution occurs upon descent.

It usually occurs at altitudes above 12,000 feet (approximately 3,650 m). It can occur at lower altitudes in the presence of dehydration or pre-existing conditions. At the summit of Mount Fuji (3,776 m), the atmospheric pressure drops to about 0.6 atm, and at the summit of Mount Everest (8,842 m), it drops to about 0.3 atm.

Affected individuals are usually asymptomatic, and the typical course is spontaneous resolution of findings upon descent.

Q At what altitude can high-altitude retinopathy develop?

A

The risk typically arises at altitudes above 12,000 feet (approximately 3,650 m). However, it can occur at lower altitudes in the presence of dehydration or pre-existing conditions. Cases have been reported in patients with cystic fibrosis at altitudes of 4,900–9,800 feet, as well as cases associated with commercial airline flights.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Most cases remain asymptomatic. When symptoms occur, they are as follows.

• Painless floaters: May appear with vitreous hemorrhage.
• Blurred vision / decreased visual acuity: Caused by macular hemorrhage, vitreous hemorrhage, or macular edema. Bilateral visual acuity loss at high altitude is multifactorial¹⁾.

Causes of decreased visual acuity include macular hemorrhage, vitreous hemorrhage, nerve fiber layer infarction, macular edema, macular ischemia, and optic atrophy.

Clinical Findings

Since the first description by Singh in 1969, the following typical fundus findings have been established.

• Dilation and tortuosity of retinal vessels: The most frequent finding.
• Retinal hemorrhage: Takes both preretinal and intraretinal forms. Soft exudates and Roth spots are also observed.
• Vitreous hemorrhage: Occurs in severe cases.
• Papilledema, peripapillary congestion, optic disc edema: Reflects increased intracranial pressure. HAR presents with papilledema, vitreous hemorrhage, soft exudates, and rarely retinal vein occlusion (RVO)¹⁾.
• Others: Retinal vein occlusion, CRAO (central retinal artery occlusion), NAION (non-arteritic anterior ischemic optic neuropathy).

The Wiedman-Tabin classification (1999) is used to assess severity.

Grade	Venous dilation (V:A ratio)	Extent of retinal hemorrhage
I	Mild (3:2)	Within 1 DD
II	Moderate (3.5:2)	Within 2 DD
III	Severe (4:2)	3 DD, near macula, mild vitreous hemorrhage
IV	Engorgement (4.5:2)	3DD ultrasound, macular hemorrhage, severe vitreous hemorrhage, papilledema

Q Is retinal hemorrhage in high-altitude retinopathy more often found during ascent or after descent?

A

In a series of 28 cases by Barthelmes et al., hemorrhage was almost absent during ascent, and 79% were detected on fundus examination after descent. The appearance of retinal hemorrhage is unlikely to be a warning sign of impending altitude sickness.

3. Causes and Risk Factors

Main Causes

• Hypobaric hypoxia: The main environmental factor at high altitude. It is exacerbated by physical exertion and the Valsalva maneuver (straining or intense exercise).

Risk Factors

The table below shows common risk factors for altitude sickness and HAR-specific risk factors.

Category	Risk Factors
Common to altitude sickness	Altitude reached, rate of ascent, individual susceptibility
HAR-specific	Prolonged stay, low SpO2, high hematocrit, high intraocular pressure

It occurs more frequently in young, physically fit individuals who engage in strenuous activities at high altitudes.

The following associations with existing diseases have been reported.

• Cystic fibrosis: Cases of retinal hemorrhage have been reported at relatively low altitudes of 4,900 to 9,800 feet.
• Commercial aircraft: Two cases of onset related to cabin pressurization have been reported.
• Age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy: Adaptation is more easily impaired, and special caution is needed for prolonged high-altitude exposure.
• Sickle cell trait: It has been suggested that there may be increased susceptibility to proliferative diabetic retinopathy-like changes.

For those planning high-altitude climbing or travel

• Ascend slowly and avoid rapid altitude gain.
• If you have eye diseases such as age-related macular degeneration, diabetic retinopathy, or retinitis pigmentosa, consult an ophthalmologist before departure.
• If you experience decreased vision or floaters while at high altitude, consider descending promptly.
• Ensure adequate hydration.

Q Do people with existing eye diseases need to be especially careful at high altitudes?

A

For those with age-related macular degeneration, retinitis pigmentosa, or diabetic retinopathy, adaptation to hypoxia is more easily impaired, so prolonged high-altitude exposure should be avoided. People with sickle cell trait may also have increased susceptibility to proliferative changes and should be cautious.

4. Diagnosis and Examination Methods

Basics of Diagnosis

The diagnosis is based on a history of ascent to high altitude and confirmation of typical retinal changes.

Main Examination Methods

• Dilated fundus examination: Assesses retinal vascular dilation, tortuosity, hemorrhages, and optic disc findings. Severity is graded according to the Wiedman-Tabin classification (see Severity Classification).
• Fluorescein angiography (FA): Evaluates increased vascular permeability, ischemic areas, and capillary non-perfusion zones.
• Optical coherence tomography (OCT): Quantitatively assesses the presence of macular edema and subretinal fluid. Enhanced depth imaging (EDI-SDOCT) is used to evaluate choroidal thickness.
• Visual field testing: Used to evaluate optic nerve damage.

Differential Diagnosis

The differential diagnosis of bilateral visual loss at high altitude includes cerebral edema with optic disc edema, cerebrovascular disorders, and occipital lobe stroke ¹⁾.

Differential Diagnosis	Key Differentiating Features
Diabetic retinopathy	History of diabetes, microaneurysms
Hypertensive retinopathy	History of hypertension, arteriolar narrowing
Valsalva retinopathy	History of increased intrathoracic pressure
Leukemic retinopathy	Abnormal blood tests, splenomegaly

When Roth spots are present, differentiation from subacute bacterial endocarditis, sepsis, leukemia, diabetes, hypertension, etc. is also important¹⁾.

5. Standard Treatment

Basic Policy

For HAR with visual impairment, immediate descent to lower altitude and supplemental oxygen administration should be performed. This is the most effective intervention, and spontaneous improvement is achieved in most cases.

• Mild: Oxygen inhalation, acetazolamide administration, aspirin administration with observation.
• Moderate or severe: Prompt descent is the principle.

Limitations of Specific Treatment

There is no specific or proven treatment for HAR.

• NSAIDs: Efficacy for retinal hemorrhage has not been demonstrated.
• Steroids: Efficacy for retinal hemorrhage has not been demonstrated.
• Acetazolamide: Efficacy for retinal hemorrhage has not been demonstrated.
• Furosemide: Conclusion on efficacy is pending.

If complications such as retinal vein occlusion occur, manage individually according to the standard treatment protocol for each disease.

Precautions in treatment

• NSAIDs, steroids, and acetazolamide are known to be ineffective for retinal hemorrhage.
• If visual impairment occurs, it is important to descend promptly and consult an ophthalmologist without self-monitoring.
• Concurrent optic disc edema, cerebral edema, and pulmonary edema are life-threatening, so simultaneous assessment of systemic condition is essential.

Q Is there a specific drug for high-altitude retinopathy?

A

No specific proven treatment has been established. NSAIDs, steroids, and acetazolamide have not shown efficacy for retinal hemorrhage. Descent to lower altitude and supplemental oxygen are the most effective measures, and most cases resolve spontaneously.

6. Pathophysiology and detailed mechanisms

When the body is exposed to a hypobaric hypoxic environment, multiple compensatory mechanisms are activated.

Systemic compensatory mechanisms

• Increased cardiac output and ventilation
• Rightward shift of the oxygen dissociation curve
• Secondary polycythemia (increased hematocrit and hemoglobin)

Retinal and choroidal changes

Hypoxia directly affects the retina and choroid.

• Increased retinal blood flow and vasodilation: shortened circulation time and increased blood volume occur.
• Increased choroidal thickness: Studies using EDI-SDOCT have confirmed that acute high-altitude exposure increases choroidal thickness, which recovers after returning to low altitude.

Increased vascular permeability

Mechanism: Hypoxia increases the expression of NO (nitric oxide) and VEGF, leading to disruption of the inner blood-retinal barrier.

Result: Vasodilation, increased permeability, and capillary proliferation occur, leading to retinal hemorrhage and macular edema.

Increased blood viscosity

Mechanism: Secondary polycythemia increases Ht and Hb, raising blood viscosity.

Result: Shear stress on the vascular endothelium increases, causing microcirculatory disturbances and capillary rupture.

Increased intracranial pressure

Mechanism: Hypoxia-induced cerebral edema increases intracranial pressure (ICP).

Result: Edema of the optic disc (papilledema) occurs. Valsalva-like maneuvers further increase intravascular pressure.

Molecular mechanisms

The following hypoxia-induced molecular changes have been identified.

• Stabilization of HIF-1α (hypoxia-inducible factor-1α) leading to increased production of VEGF and EPO
• Increased NO production causing vascular smooth muscle relaxation and increased permeability
• Enhanced platelet aggregation and activation of the coagulation system leading to microthrombus formation

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7. Latest Research and Future Prospects (Research Stage Reports)

For Patients: Please Read Carefully

The following content is currently in the research stage or under clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Biomarker Discovery Using Bioinformatics

Su et al. (2021) identified potential biomarker genes and miRNAs involved in HAR through bioinformatics analysis. miRNAs such as miR-3177-3p were found to be elevated, while the expression of FOS, IL10, and IL7R was suppressed. These molecular targets may be promising candidates for future diagnostic and therapeutic development.

Protective Effects of Resveratrol

Xin et al. (2017) reported that the antioxidant resveratrol suppresses Trx1/Trx2 (thioredoxin) and reduces the expression of caspase-3, HSP90, and HIF-1 mRNA. Resveratrol may alleviate hypoxia-induced cell damage, and its application for the prevention and treatment of HAR is being investigated.

Long-Term High-Altitude Residence and Retinal Structural Changes

Research is ongoing on changes in foveal thickness and retinal nerve fiber layer thickness in long-term high-altitude residents. By clarifying the effects of long-term adaptation to hypoxia on retinal structure, it is expected that the association with chronic mountain sickness will also be elucidated.

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8. References

1. Gupta R, Shukla A, Mathew B. Bilateral vision loss at high altitude: A diagnostic dilemma. Med J Armed Forces India. 2024;80:224-226.
2. Lang GE, Kuba GB. High-altitude retinopathy. Am J Ophthalmol. 1997;123(3):418-20. PMID: 9063263.
3. Han C, Zheng XX, Zhang WF. High altitude retinopathy: An overview and new insights. Travel Med Infect Dis. 2024;58:102689. PMID: 38295966.