Rushad Patell, MD

An 83-year-old man presented to the emergency department with acute, painless loss of vision in his left eye. His vision in that eye had been normal in the middle of the night when he woke to use the restroom, but on awakening 6 hours later he could perceive only light or darkness.

He denied headache, scalp tenderness, jaw claudication, fever, weight loss, myalgia, or other neurologic symptoms. He had not experienced any recent change in his vision before this presentation, including halos around lights, floaters, eye pain, or redness. However, 6 months ago he had undergone left cataract surgery (left phacoemulsification with intraocular implant) without complications. And he said that when he was 3 years old, he had sustained a serious injury to his right eye.

His medical history included ischemic heart disease and hypertension. His medications included losartan, furosemide, amlodi­pine, atorvastatin, and aspirin.

CAUSES OF ACUTE MONOCULAR VISION LOSS

1. Which of the following is the least likely cause of this patient’s acute monocular vision loss?

• Optic neuritis
• Retinal vein occlusion
• Retinal artery occlusion
• Pituitary apoplexy
• Retinal detachment

Acute vision loss is often so distressing to the patient that the emergency department may be the first step in evaluation. While its diagnosis and management often require an interdisciplinary effort, early evaluation and triage of this potential medical emergency is often done by clinicians without specialized training in ophthalmology.

The physiology of vision is complex and the list of possible causes of vision loss is long, but the differential diagnosis can be narrowed quickly by considering the time course of vision loss and the anatomic localization.¹

The time course (including onset and tempo) of vision loss can classified as:

• Transient (ie, vision returned to normal by the time seen by clinician)
• Acute (instantaneous onset, ie, within seconds to minutes)
• Subacute (progression over days to weeks)
• Chronic (insidious progression over months to years).

Although acute vision loss is usually dramatic, insidious vision loss may occasionally be unnoticed for a surprisingly long time until the normal eye is inadvertently shielded.

Anatomic localization. Lesions anterior to the optic chiasm cause monocular vision loss, whereas lesions at or posterior to the chiasm lead to bilateral visual field defects. Problems leading to monocular blindness can be broadly divided into 3 anatomic categories (Figure 1):

• Ocular medial (including the cornea, anterior chamber, and lens)
• Retinal
• Neurologic (including the optic nerve and chiasm).

Clues from the history

A careful ophthalmic history is an essential initial step in the evaluation (Table 1). In addition, nonvisual symptoms can help narrow the differential diagnosis.

Nausea and vomiting often accompany acute elevation of intraocular pressure.

Focal neurologic deficits or other neurologic symptoms can point to a demyelinating disease such as multiple sclerosis.

Risk factors for vascular atherosclerotic disease such as diabetes, hypertension, and coronary artery disease raise concern for retinal, optic nerve, or cerebral ischemia.

Medications with anticholinergic and adrenergic properties can also precipitate monocular vision loss with acute angle-closure glaucoma.

Can we rule out anything yet?

Our patient presented with painless monocular vision loss. As discussed, causes of monocular vision loss can be localized to ocular abnormalities and prechiasmatic neurologic ones. Retinal detachment, occlusion of a retinal artery or vein, and optic neuritis are all important potential causes of acute monocular vision loss.

Pituitary apoplexy, on the other hand, is characterized by an acute increase in pituitary volume, often leading to compression of the optic chiasm resulting in a visual-field defect. It is most often characterized by binocular deficits (eg, bitemporal hemianopia) but is less likely to cause monocular vision loss.¹

CASE CONTINUED: EXAMINATION

On examination, the patient appeared comfortable. His temperature was 97.6°F (36.4°C), pulse 59 beats per minute, respiratory rate 18 per minute, and blood pressure 153/56 mm Hg.

Heart and lung examinations were notable for a grade 3 of 6 midsystolic, low-pitched murmur in the aortic area radiating to the neck, bilateral carotid bruits, and clear lungs. The cardiac impulse was normal in location and character. There was no evidence of aortic insufficiency (including auscultation during exhalation phase while sitting upright).

Eye examination. Visual acuity in the right eye was 20/200 with correction (owing to his eye injury at age 3). With the left eye, he could see only light or darkness. The conjunctiva and sclera were normal.

The right pupil was irregular and measured 3 mm (baseline from his previous eye injury). The left pupil was 3.5 mm. The direct pupillary response was preserved, but a relative afferent pupillary defect was present: on the swinging flashlight test, the left pupil dilated when the flashlight was passed from the right to the left pupil. Extraocular movements were full and intact bilaterally. The rest of the neurologic examination was normal.

An ophthalmologist was urgently consulted. A dilated funduscopic examination of the left eye revealed peripapillary atrophy, tortuous vessels, a cherry red macular spot, and flame hemorrhages, but no disc edema or pallor (Figure 2).

FURTHER WORKUP

2. Which of the following investigations would be least useful and not indicated at this point for this patient?

• Carotid ultrasonography
• Electrocardiography and echocardiography
• Magnetic resonance angiography of the brain
• Computed tomographic (CT) angiography of the head and neck
• Testing for the factor V Leiden and prothrombin gene mutations

A systematic ocular physical examination can offer important diagnostic information (Table 2). Ophthalmoscopy directly examines the optic disc, macula, and retinal vasculature. To interpret the funduscopic examination, we need a basic understanding of the vascular supply to the eye (Figure 3).

Information from references 4 and 5.

For example, the cherry red spot within the macula in our patient is characteristic of central retinal artery occlusion and highlights the relationship between anatomy and pathophysiology. The retina’s blood supply is compromised, leading to an ischemic, white background (secondary to edema of the inner third of the retina), but the macula continues to be nourished by the posterior ciliary arteries. This contrast in color is accentuated by the underlying structures composing the fovea, which lacks the nerve fiber layer and ganglion cell layer, making the vascular bed more visible.^2,3

Also in our patient, the marked reduction in visual acuity and relative afferent pupillary defect in the left eye point to unilateral optic nerve (or retinal ganglion cell) dysfunction. The findings on direct funduscopy were consistent with acute central retinal artery ischemia or occlusion. Central retinal artery occlusion can be either arteritic (due to inflammation, most often giant cell arteritis) or nonarteritic (due to atherosclerotic vascular disease).

Thus, carotid ultrasonography, electrocardiography, and transthoracic and transesophageal echocardiography are important components of the further workup. In addition, urgent brain imaging including either CT angiography or magnetic resonance angiography of the head and neck is indicated in all patients with central retinal artery occlusion.

Thrombophilia testing, including tests for the factor V Leiden and prothrombin gene mutations, is indicated in specific cases when a hypercoagulable state is suggested by components of the history, physical examination, and laboratory and radiologic testing. Thrombophilia testing would be low-yield and should not be part of the first-line testing in elderly patients with several atherosclerotic risk factors, such as our patient.

CASE CONTINUED: LABORATORY AND IMAGING EVIDENCE

Initial laboratory work showed:

• Mild microcytic anemia
• Erythrocyte sedimentation rate 77 mm/hour (reference range 1–10)
• C-reactive protein 4.0 mg/dL (reference range < 0.9).

The rest of the complete blood cell count and metabolic profile were unremarkable. His hemoglobin A_1c value was 5.3% (reference range 4.8%–6.2%).

A neurologist was urgently consulted.

Magnetic resonance imaging of the brain without contrast revealed nonspecific white-matter disease with no evidence of ischemic stroke.

Magnetic resonance angiography of the head and neck with contrast demonstrated 20% to 40% stenosis in both carotid arteries with otherwise patent anterior and posterior circulation.

Continuous monitoring of the left carotid artery with transcranial Doppler ultrasonography was also ordered, and the study concluded there were no undetected microembolic events.

Transthoracic echocardiography showed aortic sclerosis with no other abnormalities.

Ophthalmic fluorescein angiography was performed and showed patchy choroidal hypoperfusion, severe delayed filling, and extensive pruning of the arterial circulation with no  involvement of the posterior ciliary arteries.

Given the elevated inflammatory markers, pulse-dose intravenous methylprednisolone was started, and a temporal artery biopsy was planned.

CENTRAL RETINAL ARTERY OCCLUSION: NONARTERITIC VS ARTERITIC CAUSES

3. Which of the following is least useful to differentiate arteritic from nonarteritic causes of central retinal artery occlusion?

• Finding emboli in the retinal vasculature on funduscopy
• Temporal artery biopsy
• Measuring the C-reactive protein level and the erythrocyte sedimentation rate
• Echocardiography
• Positron-emission tomography (PET)
• Retinal fluorescein angiography

In patients diagnosed with central retinal artery occlusion, the next step is to differentiate between nonarteritic and arteritic causes, since separating them has therapeutic relevance.

The carotid artery is the main culprit for embolic disease affecting the central retinal artery, leading to the nonarteritic subtype. Thus, evaluation of acute retinal ischemia secondary to nonarteritic central retinal artery occlusion is similar to the evaluation of patients with an acute cerebral stroke.⁴ Studies have shown that 25% of patients diagnosed with central retinal artery occlusion have an additional ischemic insult in the cerebrovascular system, and these patients are at high risk of recurrent ocular or cerebral infarction. Workup includes diffusion-weighted MRI, angiography, echocardiography, and telemetry.⁵

Arteritic central retinal artery occlusion is most often caused by giant cell arteritis. The American College of Rheumatology classification criteria for giant cell arteritis include 3 of the following 5:

• Age 50 or older
• New onset of localized headache
• Temporal artery tenderness or decreased temporal artery pulse
• Erythrocyte sedimentation rate 50 mm/hour or greater
• Positive biopsy findings.⁶  

Temporal artery biopsy is the gold standard for the diagnosis of giant cell arteritis and should be done whenever the disease is suspected.^7,8 However, the test is invasive and imperfect, as a negative result does not completely rule out giant cell arteritis.⁹

Although a unilateral temporal artery biopsy can be falsely negative, several studies evaluating the efficacy of bilateral biopsies did not show significant improvement in the diagnostic yield.^10,11

Ophthalmic fluorescein angiography is another helpful test for distinguishing nonarteritic from arteritic central retinal artery occlusion.¹² Involvement of the posterior ciliary arteries usually occurs in giant cell arteritis, and this leads to choroidal malperfusion with or without retinal involvement. The optic nerve may also be infarcted by closure of the paraoptic vessels fed by the posterior ciliary vessels.^12,13 Such involvement of multiple vessels would not be typical with nonarteritic central retinal artery occlusion. Thus, this finding is helpful in making the final diagnosis along with supplying possible prognostic information.¹³

PET-CT is emerging as a test for early inflammation in extracranial disease, but its utility for diagnosing intracranial disease is limited by high uptake of the tracer fluoro­deoxyglucose by the brain and low resolution.¹⁴ Currently, it has no established role in the evaluation of patients with central retinal artery occlusion and would have no utility in differentiating arteritic vs nonarteritic causes of central retinal artery occlusion.

If giant cell arteritis is suspected, it is essential to start intravenous pulse-dose methyl­prednisolone early to prevent further vision loss in the contralateral eye. Treatment should not be delayed for invasive testing or temporal artery biopsy. Improvement in headache, jaw claudication, or scalp tenderness once steroids are initiated also helps support the diagnosis of giant cell arteritis.⁷

Unfortunately, visual symptoms may be irreversible despite treatment.

Our patient’s central retinal artery occlusion

This case highlights how difficult it is in practice to distinguish nonarteritic from arteritic central retinal artery occlusion.

Our patient had numerous cardiovascular risk factors, including known carotid and coronary artery disease, favoring a nonarteritic diagnosis.

On the other hand, his elevated inflammatory markers suggested an underlying inflammatory response. He lacked the characteristic headache and other systemic signs of giant cell arteritis, but this has been described in about 25% of patients.¹⁵ If emboli are seen on funduscopy, further workup for arteritic central retinal artery occlusion is not warranted, but emboli are not always present. Then again, absence of posterior ciliary artery involvement on fluorescein angiography pointed away from giant cell arteritis.

CASE CONTINUED: FINAL DIAGNOSIS

Biopsy of the left temporal artery showed intimal thickening with focal destruction of the internal elastic lamina by dystrophic calcification with no evidence of inflammatory infiltrates, giant cells, or granulomata in the adventitia, media, or intima. Based on the results of biopsy study and fluorescein angiography, we concluded that this was nonarteritic central retinal artery occlusion related to atherosclerotic disease.

Methylprednisolone was discontinued. The patient was discharged on aspirin, losartan, furosemide, amlodipine, and high-dose atorvastatin for standard stroke prevention. He was followed by the medical team and the ophthalmology department. At 6 weeks, there was only marginal improvement in the visual acuity of the left eye.

4. Management of nonarteritic central retinal artery occlusion could include all of the following except which one?

• Ocular massage
• Intravenous thrombolysis
• Intra-arterial thrombolysis
• Risk-factor modification
• Intraocular steroid injection

In patients with acute vision loss from nonarteritic central retinal artery occlusion, acute strategies to restore retinal perfusion include noninvasive “standard” therapies and thrombolysis (intravenous or intra-arterial). Unfortunately, consensus and guidelines are lacking.

Traditional therapies include sublingual isosorbide dinitrate, systemic pentoxifylline, inhalation of a carbogen, hyperbaric oxygen, ocular massage, intravenous acetazolamide and mannitol, anterior chamber paracentesis, and systemic steroids. However, none of these have been shown to be more effective than placebo.¹⁶

Thrombolytic therapy, analogous to the treatment of patients with ischemic stroke or myocardial infarction, is more controversial in acute central retinal artery occlusion.¹³ Data from small case-series suggested that intra-arterial or intravenous thrombolysis might improve visual acuity with reasonable safety.¹⁷ On the other hand, a randomized study from the United Kingdom that compared intra-arterial thrombolysis within a 24-hour window and conservative measures concluded that thrombolysis should not be used.¹⁸

Thrombolysis is thus used only in selected patients on a case-specific basis with involvement of a multispecialty team including stroke neurologists, especially if patients present within hours of onset and have concomitant neurologic symptoms.

Treatment beyond the acute phase focuses on preventing complications of the eye ischemia and aggressively managing systemic atherosclerotic risk factors to decrease the incidence of further ischemic events. Other interventions  include endarterectomy for significant carotid stenosis and anticoagulation to prevent cardioembolic embolization (such as atrial fibrillation). Most experts agree on the addition of an antiplatelet agent.^13,19

Intraocular steroid injection can be used in the management of some retinal disorders but has no value in nonarteritic central retinal artery occlusion.

Vision recovery in nonarteritic central retinal artery occlusion is variable, but the prognosis is generally poor. The visual acuity on presentation, the onset of the symptoms, and collateral vessels are major factors influencing long-term recovery. Most of the recovery occurs within 7 days and involves peripheral vision rather than central vision. Several studies report some recovery in peripheral vision in approximately 30% to 35% of affected eyes.^20–22

PROMPT ACTION MAY SAVE SIGHT

Vision loss is a common presenting symptom in the emergency setting. A meticulous history and systematic physical examination can narrow the differential diagnosis of this neuro-ophthalmologic emergency. Acute retinal ischemia from central retinal artery occlusion is the ocular equivalent of an ischemic stroke, and they share risk factors, diagnostic workup, and management approaches.

Both etiologic subtypes (ie, arteritic and nonarteritic) require prompt intervention by front-line physicians. If giant cell arteritis is suspected, corticosteroid therapy must be initiated to save the contralateral retina from ischemia. Suspicion of central retinal artery occlusion warrants immediate evaluation by a neurologist to consider thrombolysis. Prompt action and interdisciplinary care involving an ophthalmologist, neurologist, and emergency or internal medicine physician may save a patient from permanent visual disability.

KEY POINTS

• Monocular vision loss requires urgent evaluation with a multidisciplinary management approach.
• There are no consensus treatment guidelines for nonarteritic central retinal artery occlusion, but the workup includes a comprehensive stroke evaluation.
• Arteritic central retinal artery occlusion is most often due to giant cell arteritis, and when it is suspected, the patient should be empirically treated with steroids.

An 83-year-old man presented to the emergency department with acute, painless loss of vision in his left eye. His vision in that eye had been normal in the middle of the night when he woke to use the restroom, but on awakening 6 hours later he could perceive only light or darkness.

He denied headache, scalp tenderness, jaw claudication, fever, weight loss, myalgia, or other neurologic symptoms. He had not experienced any recent change in his vision before this presentation, including halos around lights, floaters, eye pain, or redness. However, 6 months ago he had undergone left cataract surgery (left phacoemulsification with intraocular implant) without complications. And he said that when he was 3 years old, he had sustained a serious injury to his right eye.

His medical history included ischemic heart disease and hypertension. His medications included losartan, furosemide, amlodi­pine, atorvastatin, and aspirin.

CAUSES OF ACUTE MONOCULAR VISION LOSS

1. Which of the following is the least likely cause of this patient’s acute monocular vision loss?

• Optic neuritis
• Retinal vein occlusion
• Retinal artery occlusion
• Pituitary apoplexy
• Retinal detachment

Acute vision loss is often so distressing to the patient that the emergency department may be the first step in evaluation. While its diagnosis and management often require an interdisciplinary effort, early evaluation and triage of this potential medical emergency is often done by clinicians without specialized training in ophthalmology.

The physiology of vision is complex and the list of possible causes of vision loss is long, but the differential diagnosis can be narrowed quickly by considering the time course of vision loss and the anatomic localization.¹

The time course (including onset and tempo) of vision loss can classified as:

• Transient (ie, vision returned to normal by the time seen by clinician)
• Acute (instantaneous onset, ie, within seconds to minutes)
• Subacute (progression over days to weeks)
• Chronic (insidious progression over months to years).

Although acute vision loss is usually dramatic, insidious vision loss may occasionally be unnoticed for a surprisingly long time until the normal eye is inadvertently shielded.

Anatomic localization. Lesions anterior to the optic chiasm cause monocular vision loss, whereas lesions at or posterior to the chiasm lead to bilateral visual field defects. Problems leading to monocular blindness can be broadly divided into 3 anatomic categories (Figure 1):

• Ocular medial (including the cornea, anterior chamber, and lens)
• Retinal
• Neurologic (including the optic nerve and chiasm).

Clues from the history

A careful ophthalmic history is an essential initial step in the evaluation (Table 1). In addition, nonvisual symptoms can help narrow the differential diagnosis.

Nausea and vomiting often accompany acute elevation of intraocular pressure.

Focal neurologic deficits or other neurologic symptoms can point to a demyelinating disease such as multiple sclerosis.

Risk factors for vascular atherosclerotic disease such as diabetes, hypertension, and coronary artery disease raise concern for retinal, optic nerve, or cerebral ischemia.

Medications with anticholinergic and adrenergic properties can also precipitate monocular vision loss with acute angle-closure glaucoma.

Can we rule out anything yet?

Our patient presented with painless monocular vision loss. As discussed, causes of monocular vision loss can be localized to ocular abnormalities and prechiasmatic neurologic ones. Retinal detachment, occlusion of a retinal artery or vein, and optic neuritis are all important potential causes of acute monocular vision loss.

Pituitary apoplexy, on the other hand, is characterized by an acute increase in pituitary volume, often leading to compression of the optic chiasm resulting in a visual-field defect. It is most often characterized by binocular deficits (eg, bitemporal hemianopia) but is less likely to cause monocular vision loss.¹

CASE CONTINUED: EXAMINATION

On examination, the patient appeared comfortable. His temperature was 97.6°F (36.4°C), pulse 59 beats per minute, respiratory rate 18 per minute, and blood pressure 153/56 mm Hg.

Heart and lung examinations were notable for a grade 3 of 6 midsystolic, low-pitched murmur in the aortic area radiating to the neck, bilateral carotid bruits, and clear lungs. The cardiac impulse was normal in location and character. There was no evidence of aortic insufficiency (including auscultation during exhalation phase while sitting upright).

Eye examination. Visual acuity in the right eye was 20/200 with correction (owing to his eye injury at age 3). With the left eye, he could see only light or darkness. The conjunctiva and sclera were normal.

The right pupil was irregular and measured 3 mm (baseline from his previous eye injury). The left pupil was 3.5 mm. The direct pupillary response was preserved, but a relative afferent pupillary defect was present: on the swinging flashlight test, the left pupil dilated when the flashlight was passed from the right to the left pupil. Extraocular movements were full and intact bilaterally. The rest of the neurologic examination was normal.

An ophthalmologist was urgently consulted. A dilated funduscopic examination of the left eye revealed peripapillary atrophy, tortuous vessels, a cherry red macular spot, and flame hemorrhages, but no disc edema or pallor (Figure 2).

FURTHER WORKUP

2. Which of the following investigations would be least useful and not indicated at this point for this patient?

• Carotid ultrasonography
• Electrocardiography and echocardiography
• Magnetic resonance angiography of the brain
• Computed tomographic (CT) angiography of the head and neck
• Testing for the factor V Leiden and prothrombin gene mutations

A systematic ocular physical examination can offer important diagnostic information (Table 2). Ophthalmoscopy directly examines the optic disc, macula, and retinal vasculature. To interpret the funduscopic examination, we need a basic understanding of the vascular supply to the eye (Figure 3).

Information from references 4 and 5.

For example, the cherry red spot within the macula in our patient is characteristic of central retinal artery occlusion and highlights the relationship between anatomy and pathophysiology. The retina’s blood supply is compromised, leading to an ischemic, white background (secondary to edema of the inner third of the retina), but the macula continues to be nourished by the posterior ciliary arteries. This contrast in color is accentuated by the underlying structures composing the fovea, which lacks the nerve fiber layer and ganglion cell layer, making the vascular bed more visible.^2,3

Also in our patient, the marked reduction in visual acuity and relative afferent pupillary defect in the left eye point to unilateral optic nerve (or retinal ganglion cell) dysfunction. The findings on direct funduscopy were consistent with acute central retinal artery ischemia or occlusion. Central retinal artery occlusion can be either arteritic (due to inflammation, most often giant cell arteritis) or nonarteritic (due to atherosclerotic vascular disease).

Thus, carotid ultrasonography, electrocardiography, and transthoracic and transesophageal echocardiography are important components of the further workup. In addition, urgent brain imaging including either CT angiography or magnetic resonance angiography of the head and neck is indicated in all patients with central retinal artery occlusion.

Thrombophilia testing, including tests for the factor V Leiden and prothrombin gene mutations, is indicated in specific cases when a hypercoagulable state is suggested by components of the history, physical examination, and laboratory and radiologic testing. Thrombophilia testing would be low-yield and should not be part of the first-line testing in elderly patients with several atherosclerotic risk factors, such as our patient.

CASE CONTINUED: LABORATORY AND IMAGING EVIDENCE

Initial laboratory work showed:

• Mild microcytic anemia
• Erythrocyte sedimentation rate 77 mm/hour (reference range 1–10)
• C-reactive protein 4.0 mg/dL (reference range < 0.9).

The rest of the complete blood cell count and metabolic profile were unremarkable. His hemoglobin A_1c value was 5.3% (reference range 4.8%–6.2%).

A neurologist was urgently consulted.

Magnetic resonance imaging of the brain without contrast revealed nonspecific white-matter disease with no evidence of ischemic stroke.

Magnetic resonance angiography of the head and neck with contrast demonstrated 20% to 40% stenosis in both carotid arteries with otherwise patent anterior and posterior circulation.

Continuous monitoring of the left carotid artery with transcranial Doppler ultrasonography was also ordered, and the study concluded there were no undetected microembolic events.

Transthoracic echocardiography showed aortic sclerosis with no other abnormalities.

Ophthalmic fluorescein angiography was performed and showed patchy choroidal hypoperfusion, severe delayed filling, and extensive pruning of the arterial circulation with no  involvement of the posterior ciliary arteries.

Given the elevated inflammatory markers, pulse-dose intravenous methylprednisolone was started, and a temporal artery biopsy was planned.

CENTRAL RETINAL ARTERY OCCLUSION: NONARTERITIC VS ARTERITIC CAUSES

3. Which of the following is least useful to differentiate arteritic from nonarteritic causes of central retinal artery occlusion?

• Finding emboli in the retinal vasculature on funduscopy
• Temporal artery biopsy
• Measuring the C-reactive protein level and the erythrocyte sedimentation rate
• Echocardiography
• Positron-emission tomography (PET)
• Retinal fluorescein angiography

In patients diagnosed with central retinal artery occlusion, the next step is to differentiate between nonarteritic and arteritic causes, since separating them has therapeutic relevance.

The carotid artery is the main culprit for embolic disease affecting the central retinal artery, leading to the nonarteritic subtype. Thus, evaluation of acute retinal ischemia secondary to nonarteritic central retinal artery occlusion is similar to the evaluation of patients with an acute cerebral stroke.⁴ Studies have shown that 25% of patients diagnosed with central retinal artery occlusion have an additional ischemic insult in the cerebrovascular system, and these patients are at high risk of recurrent ocular or cerebral infarction. Workup includes diffusion-weighted MRI, angiography, echocardiography, and telemetry.⁵

Arteritic central retinal artery occlusion is most often caused by giant cell arteritis. The American College of Rheumatology classification criteria for giant cell arteritis include 3 of the following 5:

• Age 50 or older
• New onset of localized headache
• Temporal artery tenderness or decreased temporal artery pulse
• Erythrocyte sedimentation rate 50 mm/hour or greater
• Positive biopsy findings.⁶  

Temporal artery biopsy is the gold standard for the diagnosis of giant cell arteritis and should be done whenever the disease is suspected.^7,8 However, the test is invasive and imperfect, as a negative result does not completely rule out giant cell arteritis.⁹

Although a unilateral temporal artery biopsy can be falsely negative, several studies evaluating the efficacy of bilateral biopsies did not show significant improvement in the diagnostic yield.^10,11

Ophthalmic fluorescein angiography is another helpful test for distinguishing nonarteritic from arteritic central retinal artery occlusion.¹² Involvement of the posterior ciliary arteries usually occurs in giant cell arteritis, and this leads to choroidal malperfusion with or without retinal involvement. The optic nerve may also be infarcted by closure of the paraoptic vessels fed by the posterior ciliary vessels.^12,13 Such involvement of multiple vessels would not be typical with nonarteritic central retinal artery occlusion. Thus, this finding is helpful in making the final diagnosis along with supplying possible prognostic information.¹³

PET-CT is emerging as a test for early inflammation in extracranial disease, but its utility for diagnosing intracranial disease is limited by high uptake of the tracer fluoro­deoxyglucose by the brain and low resolution.¹⁴ Currently, it has no established role in the evaluation of patients with central retinal artery occlusion and would have no utility in differentiating arteritic vs nonarteritic causes of central retinal artery occlusion.

If giant cell arteritis is suspected, it is essential to start intravenous pulse-dose methyl­prednisolone early to prevent further vision loss in the contralateral eye. Treatment should not be delayed for invasive testing or temporal artery biopsy. Improvement in headache, jaw claudication, or scalp tenderness once steroids are initiated also helps support the diagnosis of giant cell arteritis.⁷

Unfortunately, visual symptoms may be irreversible despite treatment.

Our patient’s central retinal artery occlusion

This case highlights how difficult it is in practice to distinguish nonarteritic from arteritic central retinal artery occlusion.

Our patient had numerous cardiovascular risk factors, including known carotid and coronary artery disease, favoring a nonarteritic diagnosis.

On the other hand, his elevated inflammatory markers suggested an underlying inflammatory response. He lacked the characteristic headache and other systemic signs of giant cell arteritis, but this has been described in about 25% of patients.¹⁵ If emboli are seen on funduscopy, further workup for arteritic central retinal artery occlusion is not warranted, but emboli are not always present. Then again, absence of posterior ciliary artery involvement on fluorescein angiography pointed away from giant cell arteritis.

CASE CONTINUED: FINAL DIAGNOSIS

Biopsy of the left temporal artery showed intimal thickening with focal destruction of the internal elastic lamina by dystrophic calcification with no evidence of inflammatory infiltrates, giant cells, or granulomata in the adventitia, media, or intima. Based on the results of biopsy study and fluorescein angiography, we concluded that this was nonarteritic central retinal artery occlusion related to atherosclerotic disease.

Methylprednisolone was discontinued. The patient was discharged on aspirin, losartan, furosemide, amlodipine, and high-dose atorvastatin for standard stroke prevention. He was followed by the medical team and the ophthalmology department. At 6 weeks, there was only marginal improvement in the visual acuity of the left eye.

4. Management of nonarteritic central retinal artery occlusion could include all of the following except which one?

• Ocular massage
• Intravenous thrombolysis
• Intra-arterial thrombolysis
• Risk-factor modification
• Intraocular steroid injection

In patients with acute vision loss from nonarteritic central retinal artery occlusion, acute strategies to restore retinal perfusion include noninvasive “standard” therapies and thrombolysis (intravenous or intra-arterial). Unfortunately, consensus and guidelines are lacking.

Traditional therapies include sublingual isosorbide dinitrate, systemic pentoxifylline, inhalation of a carbogen, hyperbaric oxygen, ocular massage, intravenous acetazolamide and mannitol, anterior chamber paracentesis, and systemic steroids. However, none of these have been shown to be more effective than placebo.¹⁶

Thrombolytic therapy, analogous to the treatment of patients with ischemic stroke or myocardial infarction, is more controversial in acute central retinal artery occlusion.¹³ Data from small case-series suggested that intra-arterial or intravenous thrombolysis might improve visual acuity with reasonable safety.¹⁷ On the other hand, a randomized study from the United Kingdom that compared intra-arterial thrombolysis within a 24-hour window and conservative measures concluded that thrombolysis should not be used.¹⁸

Thrombolysis is thus used only in selected patients on a case-specific basis with involvement of a multispecialty team including stroke neurologists, especially if patients present within hours of onset and have concomitant neurologic symptoms.

Treatment beyond the acute phase focuses on preventing complications of the eye ischemia and aggressively managing systemic atherosclerotic risk factors to decrease the incidence of further ischemic events. Other interventions  include endarterectomy for significant carotid stenosis and anticoagulation to prevent cardioembolic embolization (such as atrial fibrillation). Most experts agree on the addition of an antiplatelet agent.^13,19

Intraocular steroid injection can be used in the management of some retinal disorders but has no value in nonarteritic central retinal artery occlusion.

Vision recovery in nonarteritic central retinal artery occlusion is variable, but the prognosis is generally poor. The visual acuity on presentation, the onset of the symptoms, and collateral vessels are major factors influencing long-term recovery. Most of the recovery occurs within 7 days and involves peripheral vision rather than central vision. Several studies report some recovery in peripheral vision in approximately 30% to 35% of affected eyes.^20–22

PROMPT ACTION MAY SAVE SIGHT

Vision loss is a common presenting symptom in the emergency setting. A meticulous history and systematic physical examination can narrow the differential diagnosis of this neuro-ophthalmologic emergency. Acute retinal ischemia from central retinal artery occlusion is the ocular equivalent of an ischemic stroke, and they share risk factors, diagnostic workup, and management approaches.

Both etiologic subtypes (ie, arteritic and nonarteritic) require prompt intervention by front-line physicians. If giant cell arteritis is suspected, corticosteroid therapy must be initiated to save the contralateral retina from ischemia. Suspicion of central retinal artery occlusion warrants immediate evaluation by a neurologist to consider thrombolysis. Prompt action and interdisciplinary care involving an ophthalmologist, neurologist, and emergency or internal medicine physician may save a patient from permanent visual disability.

KEY POINTS

• Monocular vision loss requires urgent evaluation with a multidisciplinary management approach.
• There are no consensus treatment guidelines for nonarteritic central retinal artery occlusion, but the workup includes a comprehensive stroke evaluation.
• Arteritic central retinal artery occlusion is most often due to giant cell arteritis, and when it is suspected, the patient should be empirically treated with steroids.

An 83-year-old man presented to the emergency department with acute, painless loss of vision in his left eye. His vision in that eye had been normal in the middle of the night when he woke to use the restroom, but on awakening 6 hours later he could perceive only light or darkness.

He denied headache, scalp tenderness, jaw claudication, fever, weight loss, myalgia, or other neurologic symptoms. He had not experienced any recent change in his vision before this presentation, including halos around lights, floaters, eye pain, or redness. However, 6 months ago he had undergone left cataract surgery (left phacoemulsification with intraocular implant) without complications. And he said that when he was 3 years old, he had sustained a serious injury to his right eye.

His medical history included ischemic heart disease and hypertension. His medications included losartan, furosemide, amlodi­pine, atorvastatin, and aspirin.

CAUSES OF ACUTE MONOCULAR VISION LOSS

1. Which of the following is the least likely cause of this patient’s acute monocular vision loss?

• Optic neuritis
• Retinal vein occlusion
• Retinal artery occlusion
• Pituitary apoplexy
• Retinal detachment

Acute vision loss is often so distressing to the patient that the emergency department may be the first step in evaluation. While its diagnosis and management often require an interdisciplinary effort, early evaluation and triage of this potential medical emergency is often done by clinicians without specialized training in ophthalmology.

The physiology of vision is complex and the list of possible causes of vision loss is long, but the differential diagnosis can be narrowed quickly by considering the time course of vision loss and the anatomic localization.¹

The time course (including onset and tempo) of vision loss can classified as:

• Transient (ie, vision returned to normal by the time seen by clinician)
• Acute (instantaneous onset, ie, within seconds to minutes)
• Subacute (progression over days to weeks)
• Chronic (insidious progression over months to years).

Although acute vision loss is usually dramatic, insidious vision loss may occasionally be unnoticed for a surprisingly long time until the normal eye is inadvertently shielded.

Anatomic localization. Lesions anterior to the optic chiasm cause monocular vision loss, whereas lesions at or posterior to the chiasm lead to bilateral visual field defects. Problems leading to monocular blindness can be broadly divided into 3 anatomic categories (Figure 1):

• Ocular medial (including the cornea, anterior chamber, and lens)
• Retinal
• Neurologic (including the optic nerve and chiasm).

Clues from the history

A careful ophthalmic history is an essential initial step in the evaluation (Table 1). In addition, nonvisual symptoms can help narrow the differential diagnosis.

Nausea and vomiting often accompany acute elevation of intraocular pressure.

Focal neurologic deficits or other neurologic symptoms can point to a demyelinating disease such as multiple sclerosis.

Risk factors for vascular atherosclerotic disease such as diabetes, hypertension, and coronary artery disease raise concern for retinal, optic nerve, or cerebral ischemia.

Medications with anticholinergic and adrenergic properties can also precipitate monocular vision loss with acute angle-closure glaucoma.

Can we rule out anything yet?

Our patient presented with painless monocular vision loss. As discussed, causes of monocular vision loss can be localized to ocular abnormalities and prechiasmatic neurologic ones. Retinal detachment, occlusion of a retinal artery or vein, and optic neuritis are all important potential causes of acute monocular vision loss.

Pituitary apoplexy, on the other hand, is characterized by an acute increase in pituitary volume, often leading to compression of the optic chiasm resulting in a visual-field defect. It is most often characterized by binocular deficits (eg, bitemporal hemianopia) but is less likely to cause monocular vision loss.¹

CASE CONTINUED: EXAMINATION

On examination, the patient appeared comfortable. His temperature was 97.6°F (36.4°C), pulse 59 beats per minute, respiratory rate 18 per minute, and blood pressure 153/56 mm Hg.

Heart and lung examinations were notable for a grade 3 of 6 midsystolic, low-pitched murmur in the aortic area radiating to the neck, bilateral carotid bruits, and clear lungs. The cardiac impulse was normal in location and character. There was no evidence of aortic insufficiency (including auscultation during exhalation phase while sitting upright).

Eye examination. Visual acuity in the right eye was 20/200 with correction (owing to his eye injury at age 3). With the left eye, he could see only light or darkness. The conjunctiva and sclera were normal.

The right pupil was irregular and measured 3 mm (baseline from his previous eye injury). The left pupil was 3.5 mm. The direct pupillary response was preserved, but a relative afferent pupillary defect was present: on the swinging flashlight test, the left pupil dilated when the flashlight was passed from the right to the left pupil. Extraocular movements were full and intact bilaterally. The rest of the neurologic examination was normal.

An ophthalmologist was urgently consulted. A dilated funduscopic examination of the left eye revealed peripapillary atrophy, tortuous vessels, a cherry red macular spot, and flame hemorrhages, but no disc edema or pallor (Figure 2).

FURTHER WORKUP

2. Which of the following investigations would be least useful and not indicated at this point for this patient?

• Carotid ultrasonography
• Electrocardiography and echocardiography
• Magnetic resonance angiography of the brain
• Computed tomographic (CT) angiography of the head and neck
• Testing for the factor V Leiden and prothrombin gene mutations

A systematic ocular physical examination can offer important diagnostic information (Table 2). Ophthalmoscopy directly examines the optic disc, macula, and retinal vasculature. To interpret the funduscopic examination, we need a basic understanding of the vascular supply to the eye (Figure 3).

Information from references 4 and 5.

For example, the cherry red spot within the macula in our patient is characteristic of central retinal artery occlusion and highlights the relationship between anatomy and pathophysiology. The retina’s blood supply is compromised, leading to an ischemic, white background (secondary to edema of the inner third of the retina), but the macula continues to be nourished by the posterior ciliary arteries. This contrast in color is accentuated by the underlying structures composing the fovea, which lacks the nerve fiber layer and ganglion cell layer, making the vascular bed more visible.^2,3

Also in our patient, the marked reduction in visual acuity and relative afferent pupillary defect in the left eye point to unilateral optic nerve (or retinal ganglion cell) dysfunction. The findings on direct funduscopy were consistent with acute central retinal artery ischemia or occlusion. Central retinal artery occlusion can be either arteritic (due to inflammation, most often giant cell arteritis) or nonarteritic (due to atherosclerotic vascular disease).

Thus, carotid ultrasonography, electrocardiography, and transthoracic and transesophageal echocardiography are important components of the further workup. In addition, urgent brain imaging including either CT angiography or magnetic resonance angiography of the head and neck is indicated in all patients with central retinal artery occlusion.

Thrombophilia testing, including tests for the factor V Leiden and prothrombin gene mutations, is indicated in specific cases when a hypercoagulable state is suggested by components of the history, physical examination, and laboratory and radiologic testing. Thrombophilia testing would be low-yield and should not be part of the first-line testing in elderly patients with several atherosclerotic risk factors, such as our patient.

CASE CONTINUED: LABORATORY AND IMAGING EVIDENCE

Initial laboratory work showed:

• Mild microcytic anemia
• Erythrocyte sedimentation rate 77 mm/hour (reference range 1–10)
• C-reactive protein 4.0 mg/dL (reference range < 0.9).

The rest of the complete blood cell count and metabolic profile were unremarkable. His hemoglobin A_1c value was 5.3% (reference range 4.8%–6.2%).

A neurologist was urgently consulted.

Magnetic resonance imaging of the brain without contrast revealed nonspecific white-matter disease with no evidence of ischemic stroke.

Magnetic resonance angiography of the head and neck with contrast demonstrated 20% to 40% stenosis in both carotid arteries with otherwise patent anterior and posterior circulation.

Continuous monitoring of the left carotid artery with transcranial Doppler ultrasonography was also ordered, and the study concluded there were no undetected microembolic events.

Transthoracic echocardiography showed aortic sclerosis with no other abnormalities.

Ophthalmic fluorescein angiography was performed and showed patchy choroidal hypoperfusion, severe delayed filling, and extensive pruning of the arterial circulation with no  involvement of the posterior ciliary arteries.

Given the elevated inflammatory markers, pulse-dose intravenous methylprednisolone was started, and a temporal artery biopsy was planned.

CENTRAL RETINAL ARTERY OCCLUSION: NONARTERITIC VS ARTERITIC CAUSES

3. Which of the following is least useful to differentiate arteritic from nonarteritic causes of central retinal artery occlusion?

• Finding emboli in the retinal vasculature on funduscopy
• Temporal artery biopsy
• Measuring the C-reactive protein level and the erythrocyte sedimentation rate
• Echocardiography
• Positron-emission tomography (PET)
• Retinal fluorescein angiography

In patients diagnosed with central retinal artery occlusion, the next step is to differentiate between nonarteritic and arteritic causes, since separating them has therapeutic relevance.

The carotid artery is the main culprit for embolic disease affecting the central retinal artery, leading to the nonarteritic subtype. Thus, evaluation of acute retinal ischemia secondary to nonarteritic central retinal artery occlusion is similar to the evaluation of patients with an acute cerebral stroke.⁴ Studies have shown that 25% of patients diagnosed with central retinal artery occlusion have an additional ischemic insult in the cerebrovascular system, and these patients are at high risk of recurrent ocular or cerebral infarction. Workup includes diffusion-weighted MRI, angiography, echocardiography, and telemetry.⁵

Arteritic central retinal artery occlusion is most often caused by giant cell arteritis. The American College of Rheumatology classification criteria for giant cell arteritis include 3 of the following 5:

• Age 50 or older
• New onset of localized headache
• Temporal artery tenderness or decreased temporal artery pulse
• Erythrocyte sedimentation rate 50 mm/hour or greater
• Positive biopsy findings.⁶  

Temporal artery biopsy is the gold standard for the diagnosis of giant cell arteritis and should be done whenever the disease is suspected.^7,8 However, the test is invasive and imperfect, as a negative result does not completely rule out giant cell arteritis.⁹

Although a unilateral temporal artery biopsy can be falsely negative, several studies evaluating the efficacy of bilateral biopsies did not show significant improvement in the diagnostic yield.^10,11

Ophthalmic fluorescein angiography is another helpful test for distinguishing nonarteritic from arteritic central retinal artery occlusion.¹² Involvement of the posterior ciliary arteries usually occurs in giant cell arteritis, and this leads to choroidal malperfusion with or without retinal involvement. The optic nerve may also be infarcted by closure of the paraoptic vessels fed by the posterior ciliary vessels.^12,13 Such involvement of multiple vessels would not be typical with nonarteritic central retinal artery occlusion. Thus, this finding is helpful in making the final diagnosis along with supplying possible prognostic information.¹³

PET-CT is emerging as a test for early inflammation in extracranial disease, but its utility for diagnosing intracranial disease is limited by high uptake of the tracer fluoro­deoxyglucose by the brain and low resolution.¹⁴ Currently, it has no established role in the evaluation of patients with central retinal artery occlusion and would have no utility in differentiating arteritic vs nonarteritic causes of central retinal artery occlusion.

If giant cell arteritis is suspected, it is essential to start intravenous pulse-dose methyl­prednisolone early to prevent further vision loss in the contralateral eye. Treatment should not be delayed for invasive testing or temporal artery biopsy. Improvement in headache, jaw claudication, or scalp tenderness once steroids are initiated also helps support the diagnosis of giant cell arteritis.⁷

Unfortunately, visual symptoms may be irreversible despite treatment.

Our patient’s central retinal artery occlusion

This case highlights how difficult it is in practice to distinguish nonarteritic from arteritic central retinal artery occlusion.

Our patient had numerous cardiovascular risk factors, including known carotid and coronary artery disease, favoring a nonarteritic diagnosis.

On the other hand, his elevated inflammatory markers suggested an underlying inflammatory response. He lacked the characteristic headache and other systemic signs of giant cell arteritis, but this has been described in about 25% of patients.¹⁵ If emboli are seen on funduscopy, further workup for arteritic central retinal artery occlusion is not warranted, but emboli are not always present. Then again, absence of posterior ciliary artery involvement on fluorescein angiography pointed away from giant cell arteritis.

CASE CONTINUED: FINAL DIAGNOSIS

Biopsy of the left temporal artery showed intimal thickening with focal destruction of the internal elastic lamina by dystrophic calcification with no evidence of inflammatory infiltrates, giant cells, or granulomata in the adventitia, media, or intima. Based on the results of biopsy study and fluorescein angiography, we concluded that this was nonarteritic central retinal artery occlusion related to atherosclerotic disease.

Methylprednisolone was discontinued. The patient was discharged on aspirin, losartan, furosemide, amlodipine, and high-dose atorvastatin for standard stroke prevention. He was followed by the medical team and the ophthalmology department. At 6 weeks, there was only marginal improvement in the visual acuity of the left eye.

4. Management of nonarteritic central retinal artery occlusion could include all of the following except which one?

• Ocular massage
• Intravenous thrombolysis
• Intra-arterial thrombolysis
• Risk-factor modification
• Intraocular steroid injection

In patients with acute vision loss from nonarteritic central retinal artery occlusion, acute strategies to restore retinal perfusion include noninvasive “standard” therapies and thrombolysis (intravenous or intra-arterial). Unfortunately, consensus and guidelines are lacking.

Traditional therapies include sublingual isosorbide dinitrate, systemic pentoxifylline, inhalation of a carbogen, hyperbaric oxygen, ocular massage, intravenous acetazolamide and mannitol, anterior chamber paracentesis, and systemic steroids. However, none of these have been shown to be more effective than placebo.¹⁶

Thrombolytic therapy, analogous to the treatment of patients with ischemic stroke or myocardial infarction, is more controversial in acute central retinal artery occlusion.¹³ Data from small case-series suggested that intra-arterial or intravenous thrombolysis might improve visual acuity with reasonable safety.¹⁷ On the other hand, a randomized study from the United Kingdom that compared intra-arterial thrombolysis within a 24-hour window and conservative measures concluded that thrombolysis should not be used.¹⁸

Thrombolysis is thus used only in selected patients on a case-specific basis with involvement of a multispecialty team including stroke neurologists, especially if patients present within hours of onset and have concomitant neurologic symptoms.

Treatment beyond the acute phase focuses on preventing complications of the eye ischemia and aggressively managing systemic atherosclerotic risk factors to decrease the incidence of further ischemic events. Other interventions  include endarterectomy for significant carotid stenosis and anticoagulation to prevent cardioembolic embolization (such as atrial fibrillation). Most experts agree on the addition of an antiplatelet agent.^13,19

Intraocular steroid injection can be used in the management of some retinal disorders but has no value in nonarteritic central retinal artery occlusion.

Vision recovery in nonarteritic central retinal artery occlusion is variable, but the prognosis is generally poor. The visual acuity on presentation, the onset of the symptoms, and collateral vessels are major factors influencing long-term recovery. Most of the recovery occurs within 7 days and involves peripheral vision rather than central vision. Several studies report some recovery in peripheral vision in approximately 30% to 35% of affected eyes.^20–22

PROMPT ACTION MAY SAVE SIGHT

Vision loss is a common presenting symptom in the emergency setting. A meticulous history and systematic physical examination can narrow the differential diagnosis of this neuro-ophthalmologic emergency. Acute retinal ischemia from central retinal artery occlusion is the ocular equivalent of an ischemic stroke, and they share risk factors, diagnostic workup, and management approaches.

Both etiologic subtypes (ie, arteritic and nonarteritic) require prompt intervention by front-line physicians. If giant cell arteritis is suspected, corticosteroid therapy must be initiated to save the contralateral retina from ischemia. Suspicion of central retinal artery occlusion warrants immediate evaluation by a neurologist to consider thrombolysis. Prompt action and interdisciplinary care involving an ophthalmologist, neurologist, and emergency or internal medicine physician may save a patient from permanent visual disability.

KEY POINTS

• Monocular vision loss requires urgent evaluation with a multidisciplinary management approach.
• There are no consensus treatment guidelines for nonarteritic central retinal artery occlusion, but the workup includes a comprehensive stroke evaluation.
• Arteritic central retinal artery occlusion is most often due to giant cell arteritis, and when it is suspected, the patient should be empirically treated with steroids.

A 40-year-old woman with hypertrophic   obstructive cardiomyopathy presents to the hematology clinic for a second opinion regarding a history of headaches and fatigue for the past 10 years. She has been diagnosed with idiopathic erythrocytosis, presumed to be due to polycythemia vera. She periodically undergoes phlebotomy to keep her hematocrit below 41%, and this markedly improves her headaches. She denies shortness of breath, cough, fever, weight loss, joint pain, and visual or other neurologic symptoms. She has never reported pruritus related to bathing or exposure to water.

She does not smoke, drink alcohol, or use illicit drugs. She works as a pharmacy technician. She says her father died of cancer (no further details available) and describes a family history of gastrointestinal malignancy in her grandfather and paternal aunt. She takes aspirin, metoprolol, and spironolactone for her cardiomyopathy.

Physical examination reveals generalized plethora, more marked on her cheeks and face, and mild bilateral pitting pedal edema. No lymphadenopathy or hepatosplenomegaly can be palpated. Other systems, including the cardiac, respiratory, and nervous systems, are normal.

ERYTHROCYTOSIS AND POLYCYTHEMIA VERA

1. In patients with erythrocytosis, which of the following is not characteristic of polycythemia vera?

• Erythromelalgia and postbathing pruritus
• Splenomegaly
• History of thrombosis
• Gout
• Hematuria

Erythrocytosis—an abnormally high concentration of red blood cells in the peripheral blood—is a laboratory finding. It often reflects an increase in the total quantity or mass of red blood cells in the body (polycythemia) but can sometimes be due to decreased plasma volume (spurious polycythemia).¹ Erythrocytosis can be caused by a number of diseases, hereditary and acquired, and can be classified as primary or secondary (Table 1).

Symptoms arise from an increase in the total blood volume and red blood cell mass, often leading to dilated capillaries and other blood vessels. Symptoms can occur regardless of the cause and classically include headache (often described as diffuse heaviness), dizziness, and a tendency for bleeding or thrombosis.² Symptoms are relieved when the hematocrit is lowered.

Several features in the history and physical examination of a patient being evaluated for erythrocytosis can suggest an underlying cause. Smoking, chronic respiratory insufficiency, and congenital cyanotic heart disease point to secondary erythrocytosis and can usually be identified at the outset. A history of occupational exposure to carbon monoxide (such as engine exhaust) should be elicited carefully. A family history of erythrocytosis should raise suspicion of a heritable condition such as a hemoglobinopathy associated with increased oxygen affinity or rare forms of primary erythrocytosis associated with endogenous overproduction of erythropoietin or activating mutations of the erythropoietin receptor.³ Iatrogenic causes such as androgen supplementation, erythropoietin abuse, and postrenal-transplant erythrocytosis should also be considered.

Secretion of erythropoietin or erythropoietinlike proteins by a malignant neoplasm is a rare but important cause of erythrocytosis. For example, renal cell carcinoma may present with erythrocytosis secondary to excessive erythropoietin production, and hematuria can be an early symptom.

Polycythemia vera

Polycythemia vera, a myeloproliferative neoplasm, is characterized by increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis. The bone marrow shows a panmyelosis that is often accompanied by leukocytosis or thrombocytosis, or both, in the peripheral blood.

Symptoms such as severe itching after exposure to hot water (aquagenic pruritus) and periodic attacks of redness, swelling, and pain in the hands or feet, or both (erythromelalgia), have been described in patients with polycythemia vera. Splenomegaly is relatively common, seen in approximately two-thirds of patients.⁴ Hyperuricemia (from increased cell turnover) and gout are also associated with polycythemia vera, as is a history of arterial and venous thrombosis.⁵

Hematuria is not commonly seen in polycythemia vera, although bleeding from the bladder, vagina, or uterus has been described.

CASE RESUMED: INITIAL LABORATORY TESTS

Results of our patient’s initial laboratory tests are:

• Hemoglobin 16.9 g/dL (reference range 11.5–15.5)
• Hematocrit 48.8% (36.0–46.0)
• Mean corpuscular volume 85.2 fL (80–100)
• Platelet count 328 × 10⁹/L (150–400)
• White blood cell count 9.14 × 10⁹/L (3.7–11.0)
• Absolute neutrophil count 5.95 × 10⁹/L (1.45–7.5)
• Blood urea nitrogen 12 mg/dL (8–25)
• Creatinine 0.5 mg/dL (0.7–1.4)
• Lactate dehydrogenase 180 U/L (100–220)
• Uric acid 3.0 mg/dL (2.0–7.0)
• Thyroid-stimulating hormone 2.2 µU/mL (0.4–5.5).

The patient undergoes additional tests, including a serum erythropoietin level and hemoglobinopathy screen. Bone marrow aspiration and biopsy are performed, with cytogenetic analysis, chromosomal microarray analysis, and molecular testing for mutation of the Janus kinase 2 (JAK2) gene.

CONFIRMING SUSPECTED POLYCYTHEMIA VERA

2. In patients with suspected polycythemia vera, which of the following laboratory tests is most useful in making the diagnosis?

• Hemoglobin, hematocrit, and red blood cell mass
• Serum erythropoietin level
• Arterial blood gases with co-oximetry
• Testing for the JAK2 mutation
• Bone marrow aspiration and biopsy

The aim of the initial workup of erythrocytosis is to differentiate polycythemia vera from secondary causes of erythrocytosis.

Hemoglobin, hematocrit, red cell mass

Erythrocytosis is defined by an abnormal elevation in the hematocrit (> 48% in women or > 49% in men), hemoglobin concentration (> 16.0 g/dL in women or > 16.5 g/dL in men), or red blood cell mass. The red blood cell count should not be used as a surrogate for red blood cell mass, since some anemias (especially thalassemia minor) can be associated with an increase in the number of red blood cells but a low hemoglobin concentration.

Isotope dilution techniques to determine the red cell mass and plasma volume can differentiate true erythrocytosis from a spurious elevation due to a decrease in plasma volume.^6,7 However, this is an expensive, time-consuming test that is not widely available and so is rarely performed.⁸

JAK2 mutation testing

The initial evaluation of a patient with erythrocytosis has changed significantly in the past 10 years with the discovery of the JAK2 gene and its role in the pathogenesis of polycythemia vera and other myeloproliferative neoplasms.

JAK2, located at 9p24, codes for a tyrosine kinase important for signal transduction in hematopoietic cells. Mutations in this gene have been shown to promote hypersensitivity to cytokines, including erythropoietin.⁹ The most common somatic mutation occurs within exon 14 at base pair 1849 and results in a phenylalanine-for-valine amino acid substitution in the JAK2 protein, designated V617F. Less commonly, mutations occur elsewhere in exons 12 to 15, with more than 50 different mutations described; nonpolymorphic mutations are assumed to have biologic effects similar to those of V617F.

Taken together, the JAK2 V617F and non-V617F mutations have a diagnostic sensitivity of 98% to 100% for polycythemia vera. For practical purposes, this means that the presence of a JAK2 mutation can be used as a clonal marker to distinguish polycythemia vera from reactive secondary causes of erythrocytosis. A JAK2 mutation is one of three major diagnostic criteria for polycythemia vera in the 2016 revision to the 2008 World Health Organization criteria (Table 2).¹⁰ Of note, this mutation is not specific for polycythemia vera and can also be found in other myeloproliferative neoplasms, including primary myelofibrosis and essential thrombocythemia.

Absence of a JAK2 mutation makes polycythemia vera unlikely, so this test is most useful in making the diagnosis.

Serum erythropoietin

Serum erythropoietin testing can be very useful to distinguish polycythemia vera from secondary erythrocytosis. Low levels suggest polycythemia vera, while high levels are seen in secondary processes.¹¹

This test is best used along with JAK2 V617F mutation analysis as an initial step in evaluating patients with erythrocytosis. When JAK2 V617F mutation analysis is negative, a low serum erythropoietin level should prompt further testing for non-V617F JAK2 mutations, whereas a normal or elevated erythropoietin level should be evaluated further with tests to distinguish hereditary from acquired secondary causes of erythrocytosis.

Arterial blood gas analysis and co-oximetry

Arterial blood gas analysis can reveal hypoxemia, pointing to a cardiorespiratory process driving the erythrocytosis, whereas co-oximetry can be used to identify the presence and amount of carboxyhemoglobin in the blood.

Bone marrow biopsy

An increase in pleomorphic megakaryocytes in the bone marrow without stainable iron is often described as characteristic in polycythemia vera patients, but it is not diagnostic. Panmyelosis with increased cellularity is the norm but can be seen in other myeloproliferative neoplasms. The morphologic features of bone marrow are now included as one of the major diagnostic criteria for polycythemia vera (Table 2).

OUR PATIENT’S FURTHER WORKUP

Our patient’s erythropoietin level is 34.2 mIU/mL (reference range 4.7–28.6). Her oxygen saturation is 96%, and her carboxyhemoglobin level is 1.1% (0–5).

She undergoes bone marrow biopsy. Analysis finds that the marrow is normocellular (60%) with trilineage hematopoiesis and decreased stainable iron.

Cytogenetic analysis shows a 46,XX[20] karyotype. Chromosomal microarray analysis shows no pathogenic copy-number changes. There is no detectable JAK2 V617F or exon 12-to-15 mutation.

The patient’s erythrocytosis and abnormal hemoglobin electrophoresis study raise suspicion for a variant type of hemoglobin that has a higher affinity for oxygen than normal.

3. What is the next best step to evaluate this patient?

• Red-cell oxygen equilibrium curve to calculate the P50 (the partial pressure of oxygen that is required to saturate 50% of the hemoglobin.)
• High-performance liquid chromatography
• Globin gene DNA sequencing
• Testing 2,3-bisphosphoglycerate mutase (BPGM) activity

Nearly 200 mutational variants in alpha and beta globin chains that lead to an increased affinity of hemoglobin for oxygen have been reported.¹² While not all mutations are clinically significant, increased oxygen affinity variants can lead to impaired oxygen delivery to tissues, especially the kidneys, resulting in a physiologic increase in erythropoietin and erythrocytosis.

In patients being evaluated for a high-oxygen-affinity hemoglobinopathy, a two-step approach has been outlined.¹³ The first involves measuring the oxygen-binding properties of a freshly collected sample of blood by directly measuring the oxygen saturation of the hemoglobin and pO₂ using a co-oximeter. This information is used to create a red cell oxygen equilibrium curve and to calculate the P50. A low P50 correlates with an abnormally high affinity of hemoglobin for oxygen.

The second step is to identify the abnormal hemoglobin. High-performance liquid chromatography is now widely available as a screening test but does not detect all variants. For many years, sequencing of globin chain DNA has been a gold standard for identifying specific mutations. Subsequent to analyzing a catalog of known hemoglobin variants, mass spectrometry can serve as a screening and identification technique. Mass spectroscopy can also detect known rare variants with posttranslational modifications¹⁴ that are not recognized by DNA analysis. Mass spectroscopy and DNA sequencing are complementary techniques available only in specialized reference laboratories.

Erythrocytosis due to BPGM deficiency is very rare. Clinical and laboratory features mimic those of high-oxygen-affinity hemoglobin, but patients do not have a demonstrable mutation in alpha or beta globin genes. The level of BPGM is low, and the diagnosis is established by measuring BPGM levels and sequencing the BPGM gene.¹⁵

RESULTS OF THE ADDITIONAL WORKUP

In our patient, hemoglobin electrophoresis reveals an abnormal hemoglobin variant. High-performance liquid chromatography reveals an abnormal peak that comprises approximately 23.7% of the total hemoglobin, consistent with an alpha globin variant. Further characterization (using a sample of venous blood) shows an oxygen dissociation P50 of 22 mm Hg (normal 24–30 mm Hg) (Figure 1).

Mass spectrometry identifies the variant as hemoglobin Tarrant. This variant is characterized by a substitution of asparagine for aspartic acid at position 126 of the alpha globin chain, a known site of contact between the alpha 1 and beta 1 chains.¹⁶ It has been seen in patients of Hispanic heritage and clinically correlates with mild erythrocytosis. Indeed, this woman’s mother was from Mexico.

EDUCATING PATIENTS

4. What should patients know about their high-oxygen-affinity hemoglobinopathy?

• High altitudes and air travel can be risky
• Pregnancy may have adverse outcomes
• Systemic anticoagulation may lower the risk of venous thromboembolism
• Periodic phlebotomy may help control symptoms

Most patients with high-oxygen-affinity hemoglobin do not require specific clinical management but only counseling and education about their condition. Establishing an accurate diagnosis is important in order to avoid further inappropriate, invasive, and expensive testing.

Although exposure to high altitudes may be associated with decreased ambient oxygen levels, hypoxia is usually not a problem because of hemoglobin’s high affinity for oxygen.

Impaired delivery of oxygen across the placenta may be anticipated in a mother with high-oxygen-affinity hemoglobin, but this has not been observed clinically.¹⁷

Compared with patients with polycythemia vera, patients with high-oxygen-affinity hemoglobin have fewer complications from hyperviscosity and thrombosis, even with comparable degrees of erythrocytosis.

Although patients usually do not require treatment, phlebotomy may be helpful for symptoms that can be attributed to the higher hemoglobin concentration.

Our patient continues to be seen in clinic for periodic blood counts and phlebotomy for her headaches, as required.

HEMOGLOBIN: RELAXED OR TENSE

Normal adult hemoglobin is a tetramer composed of two pairs of globin polypeptide chains: alpha and beta (Figure 2). The intrinsic properties of the constituent globin chains and their allosteric conformation—as well as extrinsic factors including temperature, pH, and the binding of hydrogen ion and 2,3-BPG—play important roles in modifying the affinity of hemoglobin for oxygen. The major modulator of hemoglobin-oxygen affinity in human erythrocytes is 2,3-BPG.

The hemoglobin tetramer, consisting of two identical halves, alpha 1-beta 1 and alpha 2-beta 2, oscillates between two quaternary conformations, “relaxed” (fully oxygenated) and “tense” (fully deoxygenated).¹⁸ High-oxygen-affinity hemoglobins can result from factors that enhance the relaxed state, either by stabilizing the relaxed state or by destabilizing the tense state. Structural modifications in hemoglobin typically affect the main contacts involved in the transition from the deoxygenated to the oxygenated state, the 2,3-BPG binding sites, the heme pocket, or elongation of globin chains by various mutations. In hemoglobin Tarrant, the mutation prevents formation of noncovalent salt bridges in the alpha 1-beta 1 contact that normally stabilize the deoxygenated conformation of hemoglobin. As a result, the deoxygenated (tense) state is destabilized, shifting the allosteric equilibrium in favor of the oxygenated (relaxed) state with consequent high oxygen affinity.¹⁶

MORE ABOUT HIGH-OXYGEN-AFFINITY HEMOGLOBINS

The first case of erythrocytosis due to an abnormal hemoglobin was identified in 1966. This was an alpha chain variant with an arginine-to-leucine substitution at position 92, named hemoglobin Chesapeake.¹⁹

High-oxygen-affinity hemoglobin variants are usually transmitted as autosomal dominant traits. Patients are most often identified because of unexplained erythrocytosis detected on a routine blood cell count, as in our patient.

Not all high-oxygen-affinity hemoglobinopathies are associated with erythrocytosis. The degree of increased oxygen affinity may only be mild or the abnormal hemoglobin may be slightly unstable, thereby masking the usual clinical signs and symptoms.

Therapeutic phlebotomy should be used cautiously since it can decrease delivery of oxygen to tissues. A subset of patients whose symptoms are related to an elevated red cell mass may experience some relief, as did our patient.

A 40-year-old woman with hypertrophic   obstructive cardiomyopathy presents to the hematology clinic for a second opinion regarding a history of headaches and fatigue for the past 10 years. She has been diagnosed with idiopathic erythrocytosis, presumed to be due to polycythemia vera. She periodically undergoes phlebotomy to keep her hematocrit below 41%, and this markedly improves her headaches. She denies shortness of breath, cough, fever, weight loss, joint pain, and visual or other neurologic symptoms. She has never reported pruritus related to bathing or exposure to water.

She does not smoke, drink alcohol, or use illicit drugs. She works as a pharmacy technician. She says her father died of cancer (no further details available) and describes a family history of gastrointestinal malignancy in her grandfather and paternal aunt. She takes aspirin, metoprolol, and spironolactone for her cardiomyopathy.

Physical examination reveals generalized plethora, more marked on her cheeks and face, and mild bilateral pitting pedal edema. No lymphadenopathy or hepatosplenomegaly can be palpated. Other systems, including the cardiac, respiratory, and nervous systems, are normal.

ERYTHROCYTOSIS AND POLYCYTHEMIA VERA

1. In patients with erythrocytosis, which of the following is not characteristic of polycythemia vera?

• Erythromelalgia and postbathing pruritus
• Splenomegaly
• History of thrombosis
• Gout
• Hematuria

Erythrocytosis—an abnormally high concentration of red blood cells in the peripheral blood—is a laboratory finding. It often reflects an increase in the total quantity or mass of red blood cells in the body (polycythemia) but can sometimes be due to decreased plasma volume (spurious polycythemia).¹ Erythrocytosis can be caused by a number of diseases, hereditary and acquired, and can be classified as primary or secondary (Table 1).

Symptoms arise from an increase in the total blood volume and red blood cell mass, often leading to dilated capillaries and other blood vessels. Symptoms can occur regardless of the cause and classically include headache (often described as diffuse heaviness), dizziness, and a tendency for bleeding or thrombosis.² Symptoms are relieved when the hematocrit is lowered.

Several features in the history and physical examination of a patient being evaluated for erythrocytosis can suggest an underlying cause. Smoking, chronic respiratory insufficiency, and congenital cyanotic heart disease point to secondary erythrocytosis and can usually be identified at the outset. A history of occupational exposure to carbon monoxide (such as engine exhaust) should be elicited carefully. A family history of erythrocytosis should raise suspicion of a heritable condition such as a hemoglobinopathy associated with increased oxygen affinity or rare forms of primary erythrocytosis associated with endogenous overproduction of erythropoietin or activating mutations of the erythropoietin receptor.³ Iatrogenic causes such as androgen supplementation, erythropoietin abuse, and postrenal-transplant erythrocytosis should also be considered.

Secretion of erythropoietin or erythropoietinlike proteins by a malignant neoplasm is a rare but important cause of erythrocytosis. For example, renal cell carcinoma may present with erythrocytosis secondary to excessive erythropoietin production, and hematuria can be an early symptom.

Polycythemia vera

Polycythemia vera, a myeloproliferative neoplasm, is characterized by increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis. The bone marrow shows a panmyelosis that is often accompanied by leukocytosis or thrombocytosis, or both, in the peripheral blood.

Symptoms such as severe itching after exposure to hot water (aquagenic pruritus) and periodic attacks of redness, swelling, and pain in the hands or feet, or both (erythromelalgia), have been described in patients with polycythemia vera. Splenomegaly is relatively common, seen in approximately two-thirds of patients.⁴ Hyperuricemia (from increased cell turnover) and gout are also associated with polycythemia vera, as is a history of arterial and venous thrombosis.⁵

Hematuria is not commonly seen in polycythemia vera, although bleeding from the bladder, vagina, or uterus has been described.

CASE RESUMED: INITIAL LABORATORY TESTS

Results of our patient’s initial laboratory tests are:

• Hemoglobin 16.9 g/dL (reference range 11.5–15.5)
• Hematocrit 48.8% (36.0–46.0)
• Mean corpuscular volume 85.2 fL (80–100)
• Platelet count 328 × 10⁹/L (150–400)
• White blood cell count 9.14 × 10⁹/L (3.7–11.0)
• Absolute neutrophil count 5.95 × 10⁹/L (1.45–7.5)
• Blood urea nitrogen 12 mg/dL (8–25)
• Creatinine 0.5 mg/dL (0.7–1.4)
• Lactate dehydrogenase 180 U/L (100–220)
• Uric acid 3.0 mg/dL (2.0–7.0)
• Thyroid-stimulating hormone 2.2 µU/mL (0.4–5.5).

The patient undergoes additional tests, including a serum erythropoietin level and hemoglobinopathy screen. Bone marrow aspiration and biopsy are performed, with cytogenetic analysis, chromosomal microarray analysis, and molecular testing for mutation of the Janus kinase 2 (JAK2) gene.

CONFIRMING SUSPECTED POLYCYTHEMIA VERA

2. In patients with suspected polycythemia vera, which of the following laboratory tests is most useful in making the diagnosis?

• Hemoglobin, hematocrit, and red blood cell mass
• Serum erythropoietin level
• Arterial blood gases with co-oximetry
• Testing for the JAK2 mutation
• Bone marrow aspiration and biopsy

The aim of the initial workup of erythrocytosis is to differentiate polycythemia vera from secondary causes of erythrocytosis.

Hemoglobin, hematocrit, red cell mass

Erythrocytosis is defined by an abnormal elevation in the hematocrit (> 48% in women or > 49% in men), hemoglobin concentration (> 16.0 g/dL in women or > 16.5 g/dL in men), or red blood cell mass. The red blood cell count should not be used as a surrogate for red blood cell mass, since some anemias (especially thalassemia minor) can be associated with an increase in the number of red blood cells but a low hemoglobin concentration.

Isotope dilution techniques to determine the red cell mass and plasma volume can differentiate true erythrocytosis from a spurious elevation due to a decrease in plasma volume.^6,7 However, this is an expensive, time-consuming test that is not widely available and so is rarely performed.⁸

JAK2 mutation testing

The initial evaluation of a patient with erythrocytosis has changed significantly in the past 10 years with the discovery of the JAK2 gene and its role in the pathogenesis of polycythemia vera and other myeloproliferative neoplasms.

JAK2, located at 9p24, codes for a tyrosine kinase important for signal transduction in hematopoietic cells. Mutations in this gene have been shown to promote hypersensitivity to cytokines, including erythropoietin.⁹ The most common somatic mutation occurs within exon 14 at base pair 1849 and results in a phenylalanine-for-valine amino acid substitution in the JAK2 protein, designated V617F. Less commonly, mutations occur elsewhere in exons 12 to 15, with more than 50 different mutations described; nonpolymorphic mutations are assumed to have biologic effects similar to those of V617F.

Taken together, the JAK2 V617F and non-V617F mutations have a diagnostic sensitivity of 98% to 100% for polycythemia vera. For practical purposes, this means that the presence of a JAK2 mutation can be used as a clonal marker to distinguish polycythemia vera from reactive secondary causes of erythrocytosis. A JAK2 mutation is one of three major diagnostic criteria for polycythemia vera in the 2016 revision to the 2008 World Health Organization criteria (Table 2).¹⁰ Of note, this mutation is not specific for polycythemia vera and can also be found in other myeloproliferative neoplasms, including primary myelofibrosis and essential thrombocythemia.

Absence of a JAK2 mutation makes polycythemia vera unlikely, so this test is most useful in making the diagnosis.

Serum erythropoietin

Serum erythropoietin testing can be very useful to distinguish polycythemia vera from secondary erythrocytosis. Low levels suggest polycythemia vera, while high levels are seen in secondary processes.¹¹

This test is best used along with JAK2 V617F mutation analysis as an initial step in evaluating patients with erythrocytosis. When JAK2 V617F mutation analysis is negative, a low serum erythropoietin level should prompt further testing for non-V617F JAK2 mutations, whereas a normal or elevated erythropoietin level should be evaluated further with tests to distinguish hereditary from acquired secondary causes of erythrocytosis.

Arterial blood gas analysis and co-oximetry

Arterial blood gas analysis can reveal hypoxemia, pointing to a cardiorespiratory process driving the erythrocytosis, whereas co-oximetry can be used to identify the presence and amount of carboxyhemoglobin in the blood.

Bone marrow biopsy

An increase in pleomorphic megakaryocytes in the bone marrow without stainable iron is often described as characteristic in polycythemia vera patients, but it is not diagnostic. Panmyelosis with increased cellularity is the norm but can be seen in other myeloproliferative neoplasms. The morphologic features of bone marrow are now included as one of the major diagnostic criteria for polycythemia vera (Table 2).

OUR PATIENT’S FURTHER WORKUP

Our patient’s erythropoietin level is 34.2 mIU/mL (reference range 4.7–28.6). Her oxygen saturation is 96%, and her carboxyhemoglobin level is 1.1% (0–5).

She undergoes bone marrow biopsy. Analysis finds that the marrow is normocellular (60%) with trilineage hematopoiesis and decreased stainable iron.

Cytogenetic analysis shows a 46,XX[20] karyotype. Chromosomal microarray analysis shows no pathogenic copy-number changes. There is no detectable JAK2 V617F or exon 12-to-15 mutation.

The patient’s erythrocytosis and abnormal hemoglobin electrophoresis study raise suspicion for a variant type of hemoglobin that has a higher affinity for oxygen than normal.

3. What is the next best step to evaluate this patient?

• Red-cell oxygen equilibrium curve to calculate the P50 (the partial pressure of oxygen that is required to saturate 50% of the hemoglobin.)
• High-performance liquid chromatography
• Globin gene DNA sequencing
• Testing 2,3-bisphosphoglycerate mutase (BPGM) activity

Nearly 200 mutational variants in alpha and beta globin chains that lead to an increased affinity of hemoglobin for oxygen have been reported.¹² While not all mutations are clinically significant, increased oxygen affinity variants can lead to impaired oxygen delivery to tissues, especially the kidneys, resulting in a physiologic increase in erythropoietin and erythrocytosis.

In patients being evaluated for a high-oxygen-affinity hemoglobinopathy, a two-step approach has been outlined.¹³ The first involves measuring the oxygen-binding properties of a freshly collected sample of blood by directly measuring the oxygen saturation of the hemoglobin and pO₂ using a co-oximeter. This information is used to create a red cell oxygen equilibrium curve and to calculate the P50. A low P50 correlates with an abnormally high affinity of hemoglobin for oxygen.

The second step is to identify the abnormal hemoglobin. High-performance liquid chromatography is now widely available as a screening test but does not detect all variants. For many years, sequencing of globin chain DNA has been a gold standard for identifying specific mutations. Subsequent to analyzing a catalog of known hemoglobin variants, mass spectrometry can serve as a screening and identification technique. Mass spectroscopy can also detect known rare variants with posttranslational modifications¹⁴ that are not recognized by DNA analysis. Mass spectroscopy and DNA sequencing are complementary techniques available only in specialized reference laboratories.

Erythrocytosis due to BPGM deficiency is very rare. Clinical and laboratory features mimic those of high-oxygen-affinity hemoglobin, but patients do not have a demonstrable mutation in alpha or beta globin genes. The level of BPGM is low, and the diagnosis is established by measuring BPGM levels and sequencing the BPGM gene.¹⁵

RESULTS OF THE ADDITIONAL WORKUP

In our patient, hemoglobin electrophoresis reveals an abnormal hemoglobin variant. High-performance liquid chromatography reveals an abnormal peak that comprises approximately 23.7% of the total hemoglobin, consistent with an alpha globin variant. Further characterization (using a sample of venous blood) shows an oxygen dissociation P50 of 22 mm Hg (normal 24–30 mm Hg) (Figure 1).

Mass spectrometry identifies the variant as hemoglobin Tarrant. This variant is characterized by a substitution of asparagine for aspartic acid at position 126 of the alpha globin chain, a known site of contact between the alpha 1 and beta 1 chains.¹⁶ It has been seen in patients of Hispanic heritage and clinically correlates with mild erythrocytosis. Indeed, this woman’s mother was from Mexico.

EDUCATING PATIENTS

4. What should patients know about their high-oxygen-affinity hemoglobinopathy?

• High altitudes and air travel can be risky
• Pregnancy may have adverse outcomes
• Systemic anticoagulation may lower the risk of venous thromboembolism
• Periodic phlebotomy may help control symptoms

Most patients with high-oxygen-affinity hemoglobin do not require specific clinical management but only counseling and education about their condition. Establishing an accurate diagnosis is important in order to avoid further inappropriate, invasive, and expensive testing.

Although exposure to high altitudes may be associated with decreased ambient oxygen levels, hypoxia is usually not a problem because of hemoglobin’s high affinity for oxygen.

Impaired delivery of oxygen across the placenta may be anticipated in a mother with high-oxygen-affinity hemoglobin, but this has not been observed clinically.¹⁷

Compared with patients with polycythemia vera, patients with high-oxygen-affinity hemoglobin have fewer complications from hyperviscosity and thrombosis, even with comparable degrees of erythrocytosis.

Although patients usually do not require treatment, phlebotomy may be helpful for symptoms that can be attributed to the higher hemoglobin concentration.

Our patient continues to be seen in clinic for periodic blood counts and phlebotomy for her headaches, as required.

HEMOGLOBIN: RELAXED OR TENSE

Normal adult hemoglobin is a tetramer composed of two pairs of globin polypeptide chains: alpha and beta (Figure 2). The intrinsic properties of the constituent globin chains and their allosteric conformation—as well as extrinsic factors including temperature, pH, and the binding of hydrogen ion and 2,3-BPG—play important roles in modifying the affinity of hemoglobin for oxygen. The major modulator of hemoglobin-oxygen affinity in human erythrocytes is 2,3-BPG.

The hemoglobin tetramer, consisting of two identical halves, alpha 1-beta 1 and alpha 2-beta 2, oscillates between two quaternary conformations, “relaxed” (fully oxygenated) and “tense” (fully deoxygenated).¹⁸ High-oxygen-affinity hemoglobins can result from factors that enhance the relaxed state, either by stabilizing the relaxed state or by destabilizing the tense state. Structural modifications in hemoglobin typically affect the main contacts involved in the transition from the deoxygenated to the oxygenated state, the 2,3-BPG binding sites, the heme pocket, or elongation of globin chains by various mutations. In hemoglobin Tarrant, the mutation prevents formation of noncovalent salt bridges in the alpha 1-beta 1 contact that normally stabilize the deoxygenated conformation of hemoglobin. As a result, the deoxygenated (tense) state is destabilized, shifting the allosteric equilibrium in favor of the oxygenated (relaxed) state with consequent high oxygen affinity.¹⁶

MORE ABOUT HIGH-OXYGEN-AFFINITY HEMOGLOBINS

The first case of erythrocytosis due to an abnormal hemoglobin was identified in 1966. This was an alpha chain variant with an arginine-to-leucine substitution at position 92, named hemoglobin Chesapeake.¹⁹

High-oxygen-affinity hemoglobin variants are usually transmitted as autosomal dominant traits. Patients are most often identified because of unexplained erythrocytosis detected on a routine blood cell count, as in our patient.

Not all high-oxygen-affinity hemoglobinopathies are associated with erythrocytosis. The degree of increased oxygen affinity may only be mild or the abnormal hemoglobin may be slightly unstable, thereby masking the usual clinical signs and symptoms.

Therapeutic phlebotomy should be used cautiously since it can decrease delivery of oxygen to tissues. A subset of patients whose symptoms are related to an elevated red cell mass may experience some relief, as did our patient.

A 40-year-old woman with hypertrophic   obstructive cardiomyopathy presents to the hematology clinic for a second opinion regarding a history of headaches and fatigue for the past 10 years. She has been diagnosed with idiopathic erythrocytosis, presumed to be due to polycythemia vera. She periodically undergoes phlebotomy to keep her hematocrit below 41%, and this markedly improves her headaches. She denies shortness of breath, cough, fever, weight loss, joint pain, and visual or other neurologic symptoms. She has never reported pruritus related to bathing or exposure to water.

She does not smoke, drink alcohol, or use illicit drugs. She works as a pharmacy technician. She says her father died of cancer (no further details available) and describes a family history of gastrointestinal malignancy in her grandfather and paternal aunt. She takes aspirin, metoprolol, and spironolactone for her cardiomyopathy.

Physical examination reveals generalized plethora, more marked on her cheeks and face, and mild bilateral pitting pedal edema. No lymphadenopathy or hepatosplenomegaly can be palpated. Other systems, including the cardiac, respiratory, and nervous systems, are normal.

ERYTHROCYTOSIS AND POLYCYTHEMIA VERA

1. In patients with erythrocytosis, which of the following is not characteristic of polycythemia vera?

• Erythromelalgia and postbathing pruritus
• Splenomegaly
• History of thrombosis
• Gout
• Hematuria

Erythrocytosis—an abnormally high concentration of red blood cells in the peripheral blood—is a laboratory finding. It often reflects an increase in the total quantity or mass of red blood cells in the body (polycythemia) but can sometimes be due to decreased plasma volume (spurious polycythemia).¹ Erythrocytosis can be caused by a number of diseases, hereditary and acquired, and can be classified as primary or secondary (Table 1).

Symptoms arise from an increase in the total blood volume and red blood cell mass, often leading to dilated capillaries and other blood vessels. Symptoms can occur regardless of the cause and classically include headache (often described as diffuse heaviness), dizziness, and a tendency for bleeding or thrombosis.² Symptoms are relieved when the hematocrit is lowered.

Several features in the history and physical examination of a patient being evaluated for erythrocytosis can suggest an underlying cause. Smoking, chronic respiratory insufficiency, and congenital cyanotic heart disease point to secondary erythrocytosis and can usually be identified at the outset. A history of occupational exposure to carbon monoxide (such as engine exhaust) should be elicited carefully. A family history of erythrocytosis should raise suspicion of a heritable condition such as a hemoglobinopathy associated with increased oxygen affinity or rare forms of primary erythrocytosis associated with endogenous overproduction of erythropoietin or activating mutations of the erythropoietin receptor.³ Iatrogenic causes such as androgen supplementation, erythropoietin abuse, and postrenal-transplant erythrocytosis should also be considered.

Secretion of erythropoietin or erythropoietinlike proteins by a malignant neoplasm is a rare but important cause of erythrocytosis. For example, renal cell carcinoma may present with erythrocytosis secondary to excessive erythropoietin production, and hematuria can be an early symptom.

Polycythemia vera

Polycythemia vera, a myeloproliferative neoplasm, is characterized by increased red blood cell production independent of the mechanisms that normally regulate erythropoiesis. The bone marrow shows a panmyelosis that is often accompanied by leukocytosis or thrombocytosis, or both, in the peripheral blood.

Symptoms such as severe itching after exposure to hot water (aquagenic pruritus) and periodic attacks of redness, swelling, and pain in the hands or feet, or both (erythromelalgia), have been described in patients with polycythemia vera. Splenomegaly is relatively common, seen in approximately two-thirds of patients.⁴ Hyperuricemia (from increased cell turnover) and gout are also associated with polycythemia vera, as is a history of arterial and venous thrombosis.⁵

Hematuria is not commonly seen in polycythemia vera, although bleeding from the bladder, vagina, or uterus has been described.

CASE RESUMED: INITIAL LABORATORY TESTS

Results of our patient’s initial laboratory tests are:

• Hemoglobin 16.9 g/dL (reference range 11.5–15.5)
• Hematocrit 48.8% (36.0–46.0)
• Mean corpuscular volume 85.2 fL (80–100)
• Platelet count 328 × 10⁹/L (150–400)
• White blood cell count 9.14 × 10⁹/L (3.7–11.0)
• Absolute neutrophil count 5.95 × 10⁹/L (1.45–7.5)
• Blood urea nitrogen 12 mg/dL (8–25)
• Creatinine 0.5 mg/dL (0.7–1.4)
• Lactate dehydrogenase 180 U/L (100–220)
• Uric acid 3.0 mg/dL (2.0–7.0)
• Thyroid-stimulating hormone 2.2 µU/mL (0.4–5.5).

The patient undergoes additional tests, including a serum erythropoietin level and hemoglobinopathy screen. Bone marrow aspiration and biopsy are performed, with cytogenetic analysis, chromosomal microarray analysis, and molecular testing for mutation of the Janus kinase 2 (JAK2) gene.

CONFIRMING SUSPECTED POLYCYTHEMIA VERA

2. In patients with suspected polycythemia vera, which of the following laboratory tests is most useful in making the diagnosis?

• Hemoglobin, hematocrit, and red blood cell mass
• Serum erythropoietin level
• Arterial blood gases with co-oximetry
• Testing for the JAK2 mutation
• Bone marrow aspiration and biopsy

The aim of the initial workup of erythrocytosis is to differentiate polycythemia vera from secondary causes of erythrocytosis.

Hemoglobin, hematocrit, red cell mass

Erythrocytosis is defined by an abnormal elevation in the hematocrit (> 48% in women or > 49% in men), hemoglobin concentration (> 16.0 g/dL in women or > 16.5 g/dL in men), or red blood cell mass. The red blood cell count should not be used as a surrogate for red blood cell mass, since some anemias (especially thalassemia minor) can be associated with an increase in the number of red blood cells but a low hemoglobin concentration.

Isotope dilution techniques to determine the red cell mass and plasma volume can differentiate true erythrocytosis from a spurious elevation due to a decrease in plasma volume.^6,7 However, this is an expensive, time-consuming test that is not widely available and so is rarely performed.⁸

JAK2 mutation testing

The initial evaluation of a patient with erythrocytosis has changed significantly in the past 10 years with the discovery of the JAK2 gene and its role in the pathogenesis of polycythemia vera and other myeloproliferative neoplasms.

JAK2, located at 9p24, codes for a tyrosine kinase important for signal transduction in hematopoietic cells. Mutations in this gene have been shown to promote hypersensitivity to cytokines, including erythropoietin.⁹ The most common somatic mutation occurs within exon 14 at base pair 1849 and results in a phenylalanine-for-valine amino acid substitution in the JAK2 protein, designated V617F. Less commonly, mutations occur elsewhere in exons 12 to 15, with more than 50 different mutations described; nonpolymorphic mutations are assumed to have biologic effects similar to those of V617F.

Taken together, the JAK2 V617F and non-V617F mutations have a diagnostic sensitivity of 98% to 100% for polycythemia vera. For practical purposes, this means that the presence of a JAK2 mutation can be used as a clonal marker to distinguish polycythemia vera from reactive secondary causes of erythrocytosis. A JAK2 mutation is one of three major diagnostic criteria for polycythemia vera in the 2016 revision to the 2008 World Health Organization criteria (Table 2).¹⁰ Of note, this mutation is not specific for polycythemia vera and can also be found in other myeloproliferative neoplasms, including primary myelofibrosis and essential thrombocythemia.

Absence of a JAK2 mutation makes polycythemia vera unlikely, so this test is most useful in making the diagnosis.

Serum erythropoietin

Serum erythropoietin testing can be very useful to distinguish polycythemia vera from secondary erythrocytosis. Low levels suggest polycythemia vera, while high levels are seen in secondary processes.¹¹

This test is best used along with JAK2 V617F mutation analysis as an initial step in evaluating patients with erythrocytosis. When JAK2 V617F mutation analysis is negative, a low serum erythropoietin level should prompt further testing for non-V617F JAK2 mutations, whereas a normal or elevated erythropoietin level should be evaluated further with tests to distinguish hereditary from acquired secondary causes of erythrocytosis.

Arterial blood gas analysis and co-oximetry

Arterial blood gas analysis can reveal hypoxemia, pointing to a cardiorespiratory process driving the erythrocytosis, whereas co-oximetry can be used to identify the presence and amount of carboxyhemoglobin in the blood.

Bone marrow biopsy

An increase in pleomorphic megakaryocytes in the bone marrow without stainable iron is often described as characteristic in polycythemia vera patients, but it is not diagnostic. Panmyelosis with increased cellularity is the norm but can be seen in other myeloproliferative neoplasms. The morphologic features of bone marrow are now included as one of the major diagnostic criteria for polycythemia vera (Table 2).

OUR PATIENT’S FURTHER WORKUP

Our patient’s erythropoietin level is 34.2 mIU/mL (reference range 4.7–28.6). Her oxygen saturation is 96%, and her carboxyhemoglobin level is 1.1% (0–5).

She undergoes bone marrow biopsy. Analysis finds that the marrow is normocellular (60%) with trilineage hematopoiesis and decreased stainable iron.

Cytogenetic analysis shows a 46,XX[20] karyotype. Chromosomal microarray analysis shows no pathogenic copy-number changes. There is no detectable JAK2 V617F or exon 12-to-15 mutation.

The patient’s erythrocytosis and abnormal hemoglobin electrophoresis study raise suspicion for a variant type of hemoglobin that has a higher affinity for oxygen than normal.

3. What is the next best step to evaluate this patient?

• Red-cell oxygen equilibrium curve to calculate the P50 (the partial pressure of oxygen that is required to saturate 50% of the hemoglobin.)
• High-performance liquid chromatography
• Globin gene DNA sequencing
• Testing 2,3-bisphosphoglycerate mutase (BPGM) activity

Nearly 200 mutational variants in alpha and beta globin chains that lead to an increased affinity of hemoglobin for oxygen have been reported.¹² While not all mutations are clinically significant, increased oxygen affinity variants can lead to impaired oxygen delivery to tissues, especially the kidneys, resulting in a physiologic increase in erythropoietin and erythrocytosis.

In patients being evaluated for a high-oxygen-affinity hemoglobinopathy, a two-step approach has been outlined.¹³ The first involves measuring the oxygen-binding properties of a freshly collected sample of blood by directly measuring the oxygen saturation of the hemoglobin and pO₂ using a co-oximeter. This information is used to create a red cell oxygen equilibrium curve and to calculate the P50. A low P50 correlates with an abnormally high affinity of hemoglobin for oxygen.

The second step is to identify the abnormal hemoglobin. High-performance liquid chromatography is now widely available as a screening test but does not detect all variants. For many years, sequencing of globin chain DNA has been a gold standard for identifying specific mutations. Subsequent to analyzing a catalog of known hemoglobin variants, mass spectrometry can serve as a screening and identification technique. Mass spectroscopy can also detect known rare variants with posttranslational modifications¹⁴ that are not recognized by DNA analysis. Mass spectroscopy and DNA sequencing are complementary techniques available only in specialized reference laboratories.

Erythrocytosis due to BPGM deficiency is very rare. Clinical and laboratory features mimic those of high-oxygen-affinity hemoglobin, but patients do not have a demonstrable mutation in alpha or beta globin genes. The level of BPGM is low, and the diagnosis is established by measuring BPGM levels and sequencing the BPGM gene.¹⁵

RESULTS OF THE ADDITIONAL WORKUP

In our patient, hemoglobin electrophoresis reveals an abnormal hemoglobin variant. High-performance liquid chromatography reveals an abnormal peak that comprises approximately 23.7% of the total hemoglobin, consistent with an alpha globin variant. Further characterization (using a sample of venous blood) shows an oxygen dissociation P50 of 22 mm Hg (normal 24–30 mm Hg) (Figure 1).

Mass spectrometry identifies the variant as hemoglobin Tarrant. This variant is characterized by a substitution of asparagine for aspartic acid at position 126 of the alpha globin chain, a known site of contact between the alpha 1 and beta 1 chains.¹⁶ It has been seen in patients of Hispanic heritage and clinically correlates with mild erythrocytosis. Indeed, this woman’s mother was from Mexico.

EDUCATING PATIENTS

4. What should patients know about their high-oxygen-affinity hemoglobinopathy?

• High altitudes and air travel can be risky
• Pregnancy may have adverse outcomes
• Systemic anticoagulation may lower the risk of venous thromboembolism
• Periodic phlebotomy may help control symptoms

Most patients with high-oxygen-affinity hemoglobin do not require specific clinical management but only counseling and education about their condition. Establishing an accurate diagnosis is important in order to avoid further inappropriate, invasive, and expensive testing.

Although exposure to high altitudes may be associated with decreased ambient oxygen levels, hypoxia is usually not a problem because of hemoglobin’s high affinity for oxygen.

Impaired delivery of oxygen across the placenta may be anticipated in a mother with high-oxygen-affinity hemoglobin, but this has not been observed clinically.¹⁷

Compared with patients with polycythemia vera, patients with high-oxygen-affinity hemoglobin have fewer complications from hyperviscosity and thrombosis, even with comparable degrees of erythrocytosis.

Although patients usually do not require treatment, phlebotomy may be helpful for symptoms that can be attributed to the higher hemoglobin concentration.

Our patient continues to be seen in clinic for periodic blood counts and phlebotomy for her headaches, as required.

HEMOGLOBIN: RELAXED OR TENSE

Normal adult hemoglobin is a tetramer composed of two pairs of globin polypeptide chains: alpha and beta (Figure 2). The intrinsic properties of the constituent globin chains and their allosteric conformation—as well as extrinsic factors including temperature, pH, and the binding of hydrogen ion and 2,3-BPG—play important roles in modifying the affinity of hemoglobin for oxygen. The major modulator of hemoglobin-oxygen affinity in human erythrocytes is 2,3-BPG.

The hemoglobin tetramer, consisting of two identical halves, alpha 1-beta 1 and alpha 2-beta 2, oscillates between two quaternary conformations, “relaxed” (fully oxygenated) and “tense” (fully deoxygenated).¹⁸ High-oxygen-affinity hemoglobins can result from factors that enhance the relaxed state, either by stabilizing the relaxed state or by destabilizing the tense state. Structural modifications in hemoglobin typically affect the main contacts involved in the transition from the deoxygenated to the oxygenated state, the 2,3-BPG binding sites, the heme pocket, or elongation of globin chains by various mutations. In hemoglobin Tarrant, the mutation prevents formation of noncovalent salt bridges in the alpha 1-beta 1 contact that normally stabilize the deoxygenated conformation of hemoglobin. As a result, the deoxygenated (tense) state is destabilized, shifting the allosteric equilibrium in favor of the oxygenated (relaxed) state with consequent high oxygen affinity.¹⁶

MORE ABOUT HIGH-OXYGEN-AFFINITY HEMOGLOBINS

The first case of erythrocytosis due to an abnormal hemoglobin was identified in 1966. This was an alpha chain variant with an arginine-to-leucine substitution at position 92, named hemoglobin Chesapeake.¹⁹

High-oxygen-affinity hemoglobin variants are usually transmitted as autosomal dominant traits. Patients are most often identified because of unexplained erythrocytosis detected on a routine blood cell count, as in our patient.

Not all high-oxygen-affinity hemoglobinopathies are associated with erythrocytosis. The degree of increased oxygen affinity may only be mild or the abnormal hemoglobin may be slightly unstable, thereby masking the usual clinical signs and symptoms.

Therapeutic phlebotomy should be used cautiously since it can decrease delivery of oxygen to tissues. A subset of patients whose symptoms are related to an elevated red cell mass may experience some relief, as did our patient.