Retinal Vein Occlusion in High Altitude

Abstract

Gupta, Atul, Surinderpal Singh, Tejinder Singh Ahluwalia, and Anurag Khanna. Retinal vein occlusion in high altitude. High Alt. Med. Biol. 12:393–397.—Staying at high altitude has been reported to be associated with thrombosis in lowlanders. We report 3 cases of retinal vein occlusion in high altitude. Two were males 31 and 37 years of age, who developed nonischemic central retinal vein occlusion while staying at high altitude. The former developed central retinal vein occlusion after 90 days at 6309 m, while the latter was affected at an altitude of 3353 m where he had been for the past 1 year and had recurrence of central retinal vein occlusion in the other eye on re-entry to the same altitude. The third case is that of a 40-year-old female who developed inferotemporal branch retinal vein occlusion on the second day after entry into high altitude (3353 m) by air, while ascending further in a vehicle at an altitude of approximately 4572 m. All three did not have any systemic disease and showed complete recovery on descent to a lower altitude.

Introduction

Ascent to high altitude (HA), defined typically as elevations above 9000 ft (2700 m), exposes individuals to hypobaric hypoxia, cold, and low ambient humidity. Acclimatization to hypobaric hypoxia begins immediately on exposure and continues over days, weeks, and indeed months of stay at HA, thereby reducing the risk of high altitude illness, and also allowing improved performance at HA. However, some changes that occur in the process of acclimatization itself are implicated in the pathophysiology of HA ailments (e.g., increased hematocrit may lead to chronic mountain sickness). The development of a prothrombotic milieu at HA is debatable but well-known effects of HA such as increased hematocrit (Douglas et al, 1913), enforced inactivity, dehydration, and tight clothing may all predispose individuals to thrombosis. An increased risk of spontaneous vascular thrombosis has been reported with prolonged stay at high altitude (Anand et al, 2001). Case reports of thrombosis in people predisposed due to thrombophilias, but asymptomatic at near sea level suggest that hypoxia may potentiate the effects of such a predisposition. Here, we report three cases of retinal vein occlusion in healthy young individuals with no known predisposing conditions. All three cases were initially managed at a hospital at an altitude of 3353 m.

Case Histories

Case 1

A 31-year-old man, who had been at 6309 m (approx 20,700 ft) for 90 days, developed complaint of sudden onset, painless, and diminution of vision in his right eye accompanied with floaters. He descended over 14 days to a hospital at 3353 m, experiencing some improvement in his vision. Descent had caused his vision to improve from perception of hand movement close to the face to counting fingers at 3 m distance. There was no improvement of vision with pinhole in the right eye. Distance visual acuity in the left eye was 6/6.

Case 2

A 37-year-old male sojourner, who had been at an altitude of 11,000 feet (3353 m) for 1 year, developed sudden onset, painless, diminution of vision in the right eye. Visual acuity was reduced to 6/60 in the affected eye, while the left eye had normal vision.

Case 3

A 40-year-old female presented with complaint of sudden onset sectorial loss of vision in her right eye involving the superior half of the field of vision. She had arrived a day before at 3353 m on a 70-min flight from near sea level. On the second day at HA, she was ascending further in a vehicle when symptoms of visual disturbance occurred at an altitude of about 15,000 ft (4572 m). Immediate descent was associated with partial resolution of symptoms in the 2 hours it took to reach 3353 m. On examination, visual acuity in the right eye was 6/12 and 6/6 in the left eye.

Diminution in vision was not accompanied by symptoms of redness of the eye, colored halos, headache, metamorphopsia, flashes, photophobia, or altered sensorium in any patient. They did not smoke, had not exerted unusually, nor suffered any illness that could lead to dehydration before the onset of symptoms. On the contrary, they had been consuming large amounts of fluids as advised by their physicians on ascent to high altitude. The patients did not suffer from hypertension, diabetes mellitus, or chronic obstructive pulmonary disease (COPD), and did not have features suggestive of hyperthyroidism. The third patient was not on oral contraceptives. All patients were found to be healthy on general and systemic examination.

The eyes were examined by direct as well indirect ophthalmoscopy, and findings in all patients are summarized in Table 1. The unaffected eye was normal on examination in all cases. Blood hematocrit, coagulation profile, qualitative D-dimer assay (Tulip Diagnostics, India), and routine biochemical profile was investigated in all patients and found to be within normal limits.

Table 1.

Summary of Ocular Findings

	RAPD	Media	Optic disc	Retinal artery	Retinal vein	Hemorrhage	Cotton wool spots	Macula	IOT (mmhg)
CASE 1	No	Clear	Edematous, hyperemic, cup filled	Normal	Dilated, tortuous in all quadrants	Superficial and deep all quadrants	Few all quadrants	Edema, hemorrhage, dull foveal reflex	14
CASE 2	No	Clear	Edematous, hyperemic, cup filled	Normal	Dilated, tortuous in all quadrants	Superficial and deep all quadrants	Few all quadrants	Edema, hemorrhage, dull foveal reflex	13
CASE 3	No	Clear	Normal	Normal	Dilated, tortuous inferotemporal quadrant	Superficial and deep inferotemporal quadrant	Few inferotemporal quadrant	Edema, hemorrhage in inferior part, dull foveal reflex	10

IOT, intraocular tension; RAPD, relative afferent papillary defect.

Carotid Doppler was performed to rule out atheroma and ECG recorded to investigate cardiac pathology. Investigation findings are presented in Table 2.

Table 2.

Summary of Investigations

	Hb	PCV	Blood sugar (mg/dl)	Serum lipid profile (mg/dl)	PT (sec)	PTTK (sec)	INR	D-Dimer	VDRL	ECG	Carotid Doppler
CASE 1	14 gm/dl	42%	F-70	TC-187	C-14	C-32	1.2	Negative	Nonreactor	NAD	Normal
			PP-110	TG-162	P-16	P-34
				HDL-40
				LDL-115
				VLDL-32
CASE 2	16 gm/dl	45%	F-80	TC-190	C-14	C-30	1.2	Negative	Nonreactor	NAD	Normal
			PP- 120	TG-160	P-16	P-32
				HDL-42
				LDL-113
				VLDL-35
CASE 3	11 gm/dl	40%	F-90	TC-192	C-12	C-30	1.2	Negative	Nonreactor	NAD	Normal
			PP-130	TG-162	P-14	P-32
				HDL-42
				LDL-110
				VLDL-40

C, control; F, fasting; P, patient; PP, postprandial; TC, total cholesterol; TG, triglyceride.

Case 1 was diagnosed to have central retinal vein occlusion (CRVO) of the right eye, was hospitalized, and observed for about 1 week, with no specific treatment. On subsequent transfer to a hospital near sea level, he was observed for neovascularization of the retina and iris. However, all signs and symptoms resolved spontaneously within 6 weeks. The second case also recovered completely over 8 weeks of stay at near sea level. On recovery, he returned to high altitude (3353 m). Six months later, he again developed features suggestive of CRVO; this time in the left eye. The clinical and ocular examination picture resembled that seen earlier in the other eye. Hematological, coagulation, biochemical, and carotid Doppler findings were all within normal limits. He was then sent to a hospital near sea level with advice not to visit high altitude areas again. He recovered completely over the next 6 weeks.

The third case was diagnosed to have inferotemporal branch retinal vein occlusion of the right eye. She descended to sea level by air after 48 h. All signs resolved over 4 weeks and she regained full visual acuity of 6/6 in her right eye.

Discussion

Central retinal vein occlusion (CRVO) occurs as a result of thrombosis at or just behind the lamina cribrosa. At this place, the central retinal vein is bound in a tight adventitial sheath with the central retinal artery. Also, since the retinal venous circulation is a relatively high resistance, low flow system, it is sensitive to hematological factors. (Morley and Heier, 2004) The mechanisms by which the clinical picture of CRVO occurs may be divided into conditions that produce a physical block at the lamina cribrosa, and those in which hemodynamic factors result in obstructed blood flow. These mechanisms probably coexist in many patients with CRVO. The flow of blood through the central retinal vein becomes increasingly turbulent as the vein progressively narrows at the lamina cribrosa, where it may be further impinged upon by arteriosclerosis of the adjacent central retinal artery. The turbulence damages the endothelium in the retrolaminar vein, which exposes collagen and initiates platelet aggregation and thrombosis. Thus, as flow velocities increase, the chances of thrombosis also increase.

The known risk factors for CRVO are systemic hypertension, diabetes mellitus, increased erythrocyte sedimentation rate (ESR), and glaucoma (The Eye Disease Case-Control Study Group, 1996). The risk factors for developing branch retinal vein occlusion (BRVO) are similar. In case of BRVO, the block occurs at arteriovenous crossings where the vessels are bound in a tight adventitial sheath. CRVO and BRVO commonly affect individuals between 50 and 70 years of age (Hayreh et al, 1994). When these occur below the age of 50 years, thrombophilic screening is suggested to exclude activated protein C resistance, lupus anticoagulant, anticardiolipin antibodies, elevated factor V Leiden, deficiency of protein C or protein S, and antithrombin III levels. (Morley and Heier, 2004).

Thrombophilias such as deficient APC (Kappert et al, 2008), Protein S (Nair et al, 2008) and Factor V Leiden mutation have also been implicated in venous thrombosis, stroke, and myocardial infarction at high altitude in otherwise healthy individuals. However, factors other than thrombophilia may contribute to a greater risk of thrombosis at high altitude. These include hemoconcentration, raised hematocrit, forced inactivity, constrictive clothing, and extreme cold. The sum of these physical and patho-physiological factors appears to manifest as a greater propensity to thrombosis in acclimatized lowlanders at HA. Based on the Indian army experience, Anand et al. reported a thirty times greater risk of spontaneous vascular thrombosis at HA (Anand AC et al, 2001). An increased risk of venous thrombosis after long haul flights is also known and has been suggested to be due to factors other than prolonged immobilization (Schreijer et al, 2006). Altered rheology of blood has been reported at HA (Palareti et al, 1984) and platelet numbers, activation, and aggregation have been variably reported to be increased, decreased, and unaltered at high altitude (Chatterji et al, 1982; Hudson et al, 1999; Lehmann et al, 2006; Sharma, 1980). The coagulation cascade and fibrinolysis have also been studied with inconclusive evidence for a role in thrombosis at HA. (Bartsch et al, 1989a; 1982b; 1989c; Grover and Bartsch, 2001). Increased homocysteine levels at HA have been suggested to predispose to thrombosis at HA (Kotwal et al, 2007) and patients with high altitude pulmonary edema were shown to have systemic endothelial dysfunction that may activate coagulation (Berger et al, 2005). It is, therefore, likely that high altitude exposure may contribute to venous thrombo-embolism, especially in people predisposed by thrombophilias. However, an increased predisposition has been difficult to prove because of the multifactorial nature of the disease and in the absence of well controlled epidemiological studies (Van Veen and Makris, 2008).

As regards hemodynamic factors, retinal circulatory flow and flow velocity have been shown to increase with altitudes up to 5500 m and with duration of stay (Bosch et al, 2009; Frayser et al, 1971; 1974). Accelerated blood flow velocity may activate platelets by shear stress or by exposure to the capillary basement membrane due to damage caused by high transmural pressures (Lehmann et al, 2006). The increased velocities of flow, as suggested earlier, may lead to increased turbulence, especially at points of venous narrowing such as the A-V crossings and behind the lamina cribrosa. This may cause endothelial damage and accentuate platelet activation and aggregation induced by hypobaric hypoxia, thereby precipitating thrombosis of the retinal vein. This phenomenon might be accentuated in those predisposed by thrombophilias or oral contraceptive intake.

The cases reported here did not have any of the known risk factors. Neither was evidence of increased fibrin formation present as seen by the negative D-dimer test. The first two cases did not have history suggesting dehydration, cold exposure, use of tight constrictive clothing, or enforced inactivity. The third, who had entered HA a day before developing complaints, had been traveling for 2 h in a vehicle when she suffered partial loss of vision. Inactivity could possibly have contributed in this case. Hemoglobin values were well within normal limits in all three patients.

This is somewhat surprising in the patient who had spent 90 days at extreme high altitude. This however may be a manifestation of nutritional deficiencies reported in up to 24.3% of adult Indian men aged 15–49 years (Nair and Iyengar, 2009). Bosch et al. have reported stable retinal oxygen delivery throughout a 20-day high altitude expedition consequent to increased retinal vessel diameter and greater blood flow velocity with increasing altitude to 5500 m. Subsequent decrease in blood flow velocity with altitude has been attributed to increase in hematocrit with time spent at altitude (Bosch et al, 2009). Our patient from an extreme altitude location did not show a commensurate increase in hematocrit. Retinal blood flow velocities are likely to have been high in this individual leading to venous endothelial damage. The second patient who developed CRVO twice probably suffered from a thrombophilia resulting in a predisposition to venous thrombosis, although this could not be confirmed. The third case might have developed BRVO mainly as a result of increased retinal blood flow combined with endothelial dysfunction and platelet activation as a result of exposure to acute hypoxia. An element of hemoconcentration known to occur due to fluid loss early in the process of acclimatization as well as inactivity (she was traveling in the vehicle for almost 2 h before the onset of the symptoms) may also have contributed.

All the possible etiologies are postulations. Thrombophilic screening in these cases could have helped in further understanding the mechanism of venous occlusion in high altitude. However, thrombophilias could not be ruled out, owing to laboratory investigations for these being not available in the hospitals where they were admitted either on presentation at high altitude or for convalescence near sea level.

We are aware of one earlier report of CRVO and one reported case of retinal arterial thrombosis at HA (Butler et al, 1992; Anand et al, 2001a). Here we have presented three cases of retinal vein occlusion, all occurring at HA but at different durations of stay and at different altitudes. All three occurred in individuals who had no known predisposing conditions and were in a younger age group than is typical of retinal vein occlusion. One suffered from CRVO twice at a moderate high altitude. While likely etiologies may differ in all three it is very tempting to see hypobaric hypoxia at HA as the unifying factor in causation of retinal vein occlusion in these cases. In the face of such likelihood, the role of adequate hydration, regular activity, well fitting and adequate clothing is especially important for prevention of venous thrombosis during sojourns at HA. This advice may also be relevant for patients suffering chronic hypoxia at near sea level due to disease such as COPD; especially if they concomitantly have a thrombophilia. It may also be relevant to screen patients of COPD for thrombophilias, since chronic hypoxia might be the factor responsible for the higher risk of retinal vein occlusion in patients suffering from COPD. The role of hyper-homocysteinemia in venous thrombosis at HA deserves further study, especially since the reduced availability of fresh vegetables in HA areas might cause elevation of homocysteine that may be rather easily avoided by supplementation with folate and vitamins B6 and B12. Dietary supplementation with folate has been shown to reduce the risk of primary stroke by 18% (Wang et. al, 2007).

Whether patients with thrombophilias should be advised against sojourns at HA may be established only with longitudinal cohort studies of such populations ascending to HA. The role of anti-thrombotic prophylaxis in these individuals, allowing successful sojourns at high altitude also needs to be explored.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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