Central Retinal Artery Occlusion in Young Adults at High Altitude: Thin Air,High Stakes

Abstract

Rana, Vipin, Pradeep Kumar, Sandeepan Bandopadhyay, Vijay K. Sharma, Meenu Dangi, Dattakiran Joshi, Sanjay Kumar Mishra, Satyabrat Srikumar, and V.A. Arun. Central retinal artery occlusion in young adults at high altitude: thin air, high stakes. High Alt Med Biol. 00:000–000, 2024.—We present five cases of young security personnel who were posted at high altitude (HA) for a duration of at least 6 months and presented with a sudden decrease of vision in one eye. The diagnosis of central retinal artery occlusion (CRAO) was made in all patients. Fundus fluorescein angiography and optical coherence tomography of the macula supported the diagnosis. None of these cases had any preexisting comorbidities. Erythrocytosis was noticed in all patients, and two of them had hyperhomocysteinemia. Four out of five patients showed either middle cerebral artery or internal carotid artery (ICA) thrombosis on computed tomography angiography. The patients were managed by a team of ophthalmologist, hematologist, vascular surgeon, and neurologist. In cases of incomplete ICA occlusion, patients were managed surgically. However, in the case of complete ICA occlusion, management was conservative with antiplatelet drugs. This case series highlights HA-associated erythrocytosis and hyperhomocysteinemia as important risk factors for CRAO in young individuals stationed at HA.

Introduction

Central retinal artery occlusion (CRAO) is a rare ophthalmic emergency characterized by acute, painless, and often irreversible vision loss due to occlusion of the central retinal artery or its branches (Hayreh, 2009). While CRAO is more commonly seen in elderly individuals with underlying cardiovascular risk factors such as hypertension, hyperlipidemia, and diabetes, it can rarely be seen in young individuals, particularly those posted at high altitude (HA) (Rudkin et al., 2009).

We report five cases of CRAO in young security personnel who were lowlanders and were posted in HA, having no comorbidities. Our study will provide further insight into the relationship between HA, increased hematocrit levels, and the risk of thrombosis of the common carotid artery (CCA) or internal carotid artery (ICA) leading to CRAO in young individuals.

Case Report

Case 1

A 37-year-old male stationed at 14,000 feet for a year presented with sudden loss of vision in right eye. The best-corrected visual acuity (BCVA) in the right eye was perception of light positive and the left eye had a BCVA of 20/20. Anterior segment of the right eye revealed a relative afferent pupillary defect, and the posterior segment showed a cherry red spot at the fovea along with sclerosed arteries. Fundus fluorescein angiography was consistent with CRAO in the right eye. Computed tomography angiography showed complete occlusion of the distal one-third of the right CCA and the entire right ICA. Cardiology and hematological workup were normal except for increased hematocrit and hemoglobin (Hb) (Table 1).

Table 1.

Demographic and Clinical Characteristics of Patients

Case	Age (years)	Altitude (feet)	Reported to ophthalmologist (days)	Duration of stay in HA (months)	Smoking	Hb ^a (g/dL)	Hematocrit normal (41%–50%)	Hematological work up ^b	CT Angio graphy ^c
1	37	14,200	2	12	No	19.0	60	Normal	Complete occlusion of the distal one-third of the right CCA and the entire right ICA
2	39	15,500	4	6	Yes	18.6	58	Normal	Complete occlusion of the left ICA
3	34	15,000	1	12	No	19.2	62	34 μmol/l	Complete occlusion of the distal 1/3rd of the right ICA
4	33	18,200	2	11	No	18.6	58	36 μmol/l	80% blockage of the right ICA
5	32	16,000	2	20	No	18.4	56	Normal	Normal

Hemoglobin.

Hematological work up showed increased serum homocysteine in cases 3 and 4. (Normal range of serum homocysteine: 5–15 μmol/l).

Contrast-enhanced computed tomography angiography of brain, neck, and orbit.

CCA, common carotid artery; HA, high altitude; ICA, internal carotid artery.

Case 2

A 39-year-old male stationed at 15,500 feet for 6 months developed an ischemic stroke in left middle cerebral artery territory and a sudden loss of vision in the left eye. BCVA was 20/20 in the right eye, and left eye had a vision of hand movement close to the face. Ocular examination in the right eye revealed superior quadrantopia on the confrontation test, which was confirmed on the visual field. The left eye revealed a relative afferent pupillary defect and a cherry red spot at the fovea. Computed tomography angiography showed complete occlusion of the left ICA. A 2D echo and hematological workup were normal except for increased hematocrit and Hb (Table 1).

Case 3

A 34-year-old male stationed at 15,000 feet for a year presented with sudden loss of vision in the right eye. BCVA of the right eye was perception of light positive, and the left eye was 20/20. The patient had a history of amaurosis fugax a day prior. The right eye revealed relative afferent pupillary defect, and a cherry red spot at the fovea. Fundus fluorescein angiography and optical coherence tomography of the right macula confirmed CRAO in the right eye. Computed tomography angiography showed complete occlusion of the distal one-third of the right ICA. Cardiology and hematological workup were normal except for increased hematocrit, Hb, and serum homocysteine (Table 1).

Case 4

A 33-year-old male stationed at 18,200 feet for 11 months presented with sudden loss of vision in the right eye. BCVA of the right eye was perception of light positive, and the left eye was 20/20. The right eye revealed relative afferent pupillary defect and cherry red spot at the fovea (Fig. 1A). Computed tomography angiography showed ∼80% blockage of the right ICA due to calcified plaque (Fig. 1B). Cardiology and hematological workup were normal except for increased hematocrit, Hb, and serum homocysteine (Table 1).

FIG. 1.

(A) Fundus photograph of the left eye showing cherry red spot at the macula (white arrowhead) surrounded by whitish retina in the posterior pole. (B) Computed tomography angiography of the carotid vessels shows approximately 80% blockage of the left internal carotid artery. (C) Optical coherence tomography of the macula shows hyper-reflectivity of the retinal layers suggestive of central retinal artery occlusion and inset on the right side shows the location of passing of slice navigator.

Case 5

A 32-year-old male stationed at 16,000 feet for 20 months, presented with sudden loss of vision in the right eye. BCVA in the right eye was perception of light positive, and the left eye was 20/20. The right eye revealed relative afferent pupillary defect and a cherry red spot at the fovea. Fundus fluorescein angiography was consistent with CRAO. Computed tomography angiography showed bilateral normal ICA, CCA, and orbital arteries. Cardiology and hematological workup were normal except for increased hematocrit and Hb (Table 1).

All patients underwent complete hematological work up viz hemogram, serum erythropoietin level, anticardiolipin and antiβ2GPI antibodies, paroxysmal nocturnal hemoglobinuria assay by flow cytometry, serum homocysteine levels, JAK2 V617 F and JAK exon 12 mutation, lipid profile, 2D echocardiography and carotid Doppler. Patients with positive carotid Doppler studies were further evaluated by computed tomography angiography. The ophthalmologist treated all five cases with ocular massage and paracentesis. Cases 1, 2, and 3 had complete ICA occlusion and were therefore started on dual antiplatelet agents (oral aspirin 75 mg + oral clopidogrel 75 mg). Case 4 underwent endarterectomy as the right ICA showed 80% occlusion. Case 5 was managed with oral aspirin. Presently, all patients are under follow-up and having BCVA of hand movement close to face or less and are on antiplatelet drugs.

Discussion

Our study highlights five cases of young security personnel who developed CRAO while stationed in HA. Four of the five cases had associated CCA/ICA obstruction. Persistent erythrocytosis was noted in all patients and hyperhomocysteinemia was noticed in two of these patients (Table 1). In contrast to our case series, where acquired hypercoagulable state was seen in all patients, a study done among 53 Indian Army soldiers having pulmonary embolism revealed a hereditary thrombophilic condition in 9 out of 53 patients, and 44 cases were idiopathic (Dutta et al., 2018). A prospective longitudinal study of thrombotic events at HA in 960 healthy lowland sojourners noted a prothrombotic state with suppressed naturally occurring anticoagulants, dampened fibrinolysis, endothelial activation, platelet activation, and raised proinflammatory markers in index cases (Nair et al., 2022).

We speculate that artery-to-artery embolism must have obstructed the central retinal artery in our first four cases and led to CRAO. The exact mechanism by which CCA/ICA thrombosis occur in young people stationed at HA is unknown. However, hypoxia-induced erythropoietic drive results in erythrocytosis and an increase in Hb and hematocrit at HA (Azad and Haddad, 2018). Thus, increased hematocrit levels along with chronic hypoxia are thought to cause changes in blood flow dynamics, which could lead to endothelial damage and platelet activation leading to CCA/ICA thrombosis (Bärtsch and Gibbs, 2007).

Other factors, such as dehydration, cold exposure, and physical exertion may also contribute to thrombosis development in this population. There is no evidence to support an association between inherited thrombophilia and arterial thrombosis in adults. Hence, testing for heritable thrombophilia is not recommended in patients with arterial thrombosis. However, testing for antiphospholipid antibodies, myeloproliferative neoplasm, and paroxysmal nocturnal hemoglobinuria should be considered in patients with arterial thrombosis in the absence of other vascular risk factors or significant atherosclerosis, especially in younger patients as this may have a significant impact on management (Arachchillage et al., 2022).

While CRAO can occur at any altitude, it is more common in elderly people with underlying comorbidities such as hyperlipidemia, hypertension, and diabetes. In contrast, the cases highlighted in our study are young lowlanders who were posted in HA. They didn't have any prior comorbidities and four out of five were nonsmokers. Acquired HA-associated erythrocytosis, and hyperhomocysteinemia were identified as important risk factors which led to acquired hypercoagulable state which probably led to CCA/ICA occlusion. In the elderly, atherosclerotic plaque commonly causes obstruction at the level of the carotid bulb; however, in young people, this obstruction can occur anywhere involving a segment of the ICA or CCA. Also, an interesting study by Sukun et al. (2022) showed that people who reside at HA (>5 years) have a significantly lower rate of carotid stenosis, and lower atherogenic lipid profile values, which indicate a protective effect of HA on atherosclerosis. However, there is scarcity of literature on HA effects on carotid stenosis among young individuals who are lowlanders.

When lowlanders acclimatize to HA, their cerebral vessels, particularly the Middle Cerebral Artery, undergo significant dilation, which may return to sea-level diameter within 1 to 3 weeks. A study found substantial expansion at peak altitudes, promptly countered by oxygen introduction (Wilson et al., 2011). In light of Poiseuille's Law, accurate blood flow measurements necessitate accounting for arterial diameter variations. Concurrently, retinal arterioles and venules adapt, with the latter showing more pronounced dilation due to reduced oxygen (Willmann et al., 2014). However, this response, though initially beneficial, becomes fraught with risks as HA-induced polycythemia increases blood viscosity. Combined with potential vasoconstriction or endothelial dysfunction, the risk of CRAO, characterized by sudden vision loss, intensifies, illustrate the intricate vascular adaptations and their repercussions in lowlanders at HAs.

There is a scarcity of literature on CRAO in HA and on literature search only three cases have been reported. The first case involved CRAO caused by intraocular gas expansion at HA (Fang and Huang, 2002). The second case involved bilateral optic nerve head drusens that manifested as CRAO in HA (Newsom et al., 1995). The third and most recent case revealed ICA thrombosis and increased hematocrit as cause of CRAO in young security personnel stationed at HA (Nadda et al., 2022). Given the limited available literature, further research is needed to better understand the mechanisms and risk factors associated with CRAO in HA.

Conclusion

In conclusion, this study provides further insight into the pathophysiology of CRAO in young individuals stationed at HA. Specifically, the study highlights, HA-associated erythrocytosis and hyperhomocysteinemia as probable risk factors for thrombosis of CCA/ICA which led to CRAO in HA. Role of HA, polycythemia, hypoxia, and various procoagulant factors needs evaluation in well planned randomized controlled trials. The findings may aid health care professionals in better understanding the underlying mechanisms of CRAO in these individuals, allowing them to make more informed decisions regarding timely screening so as prevent this devastating complication.

Footnotes

Acknowledgments

We would like to acknowledge and thank our patients for help with this article.

Authors' Contributions

Article draft and background research by V.R., revision of the article by P.K., article design and concept by S.B., expert guidance regarding high altitude by D.J. and S.K.M., expert guidance regarding radiological findings by SB, expert guidance regarding medical and surgical intervention by V.K.S. and V.A.A.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

References

Arachchillage

, Mackillop

, Chandratheva

, et al. Thrombophilia testing: A British Society for Haematology guideline. Br J Haematol, 2022; 198:443–458; doi: 10.1111/bjh.18239

Azad

, Haddad

. Molecular basis of hypoxia-induced excessive erythrocytosis of high altitude. FASEB J, 2018; 32:lb405.

Bärtsch

, Gibbs

. Effect of altitude on the heart and the lungs. Circulation, 2007; 116(19):2191–2202; doi: 10.1161/circulationaha.106.650796

Dutta

, Singh

, Kumar

, et al. Profile of pulmonary embolism in service personnel posted at high altitude area. Indian Heart J, 2018; 70(3):427–429; doi: 10.1016/j.ihj.2017.08.002

Fang

, Huang

. Central retinal artery occlusion caused by expansion of intraocular gas at high altitude. Am J Ophthalmol, 2002; 134(4):603–605; doi: 10.1016/s0002-9394(02)01631-8

Hayreh

. Ischemic optic neuropathy. Prog Retin Eye Res, 2009; 28(6):34–62; doi: 10.1016/j.preteyeres.2009.07.001

Nadda

, Sheoran

, Sachar

, et al. Central retinal artery occlusion secondary to high altitude exposure. DJO, 2022; 32(4):61–65.

Nair

, Singh

, Ashraf

, et al. Epidemiology and pathophysiology of vascular thrombosis in acclimatized lowlanders at high altitude: A prospective longitudinal study. Lancet Reg Health Southeast Asia, 2022; 3:100016.

Newsom

, Trew

, Leonard

. Bilateral buried optic nerve drusen presenting with central retinal artery occlusion at high altitude. Eye (Lond), 1995; 9(Pt 6):806–808; doi: 10.1038/eye.1995.202

10.

Rudkin

, Lee

, Chen

. Vascular risk factors for central retinal artery occlusion. Eye, 2010; 24:678–681; doi: 10.1038/eye.2009.142

11.

Sukun

, Onal

, Tufanoğlu

. The effect of living at high altitude on carotid intima-media thickness in the elderly: A comparative study. Acta Radiol, 2022; 63(7):986–992; doi: 10.1177/02841851211022503

12.

Willmann

, Fischer

, Schommer

, et al. Missing correlation of retinal vessel diameter with high-altitude headache. Ann Clin Transl Neurol, 2014; 1(1):59–63; doi: 10.1002/acn3.18

13.

Wilson

, Edsell

, Davagnanam

, et al. Cerebral artery dilatation maintains cerebral oxygenation at extreme altitude and in acute hypoxia—An ultrasound and MRI study. J Cereb Blood Flow Metab, 2011; 31:2019–2029.