What's Your Diagnosis?

Young, pregnant woman complains of ‘smudge’ in vision

A 33-year-old Native American female presented with a chief complaint of a “smudge” in the vision of her right eye, which began 2 days earlier. She had looked at the sun that day and thought that had caused it. She said when she squints, the smudge disappears. The patient denied any pain or the onset of new flashes or floaters.

Her significant medical history included diabetes mellitus 2 without ocular complications. She was 22 weeks pregnant on the day of her exam, and she had a history of a miscarriage and preeclampsia during a previous pregnancy. Her medications included prenatal vitamins. She denied a history of smoking. The patient’s ocular history was unremarkable. Her last comprehensive diabetic eye examination was performed 9 months prior to this visit and revealed no signs of retinopathy.

Images taken at the initial visit.
Images: Johns P

Best corrected visual acuity tested by Snellen with spectacles was 20/20- OU. Pupils were equal, round and reactive to light. Extraocular muscles had full range of motion with orthophoria on cover test at distance. Confrontation fields were full to finger count in both eyes. Anterior segment examination on slit lamp was unremarkable. Intraocular pressure measured by applanation tonometry was 18 mm Hg OD and 18 mm Hg OS at 10:30 a.m. The patient was then dilated with one drop of 1% tropicamide and one drop of 2.5% phenylephrine in each eye, with punctal occlusion.

Posterior segment examination revealed a cup-to-disc ratio of 0.35 in both eyes, with round, perfused and healthy nerves without notching. The macula was anatomically uniform and flat and had a foveal light reflex in both eyes. The vessels in both eyes had no crossing changes, tortuosity or other abnormalities. The right eye had a focal, whitened area of the retina located superiorly between the macula and optic nerve head. No embolus was seen on ophthalmoscopy. The peripheral retina revealed no holes, tears or detachments in either eye.

What’s your diagnosis?
See answer on the next page.

The clinical picture is consistent with a territorial branch retinal arteriole obstruction/occlusion. Other than a cotton-wool spot, the differential diagnoses are limited. Clinical observation of an excavation rather than swelling of the site makes the distinction.

Branch retinal artery occlusions (BRAOs) result in a limited area of retinal ischemia. Patients typically complain of a spot of missing vision or blur in one eye. If blood flow is restricted for more than 240 minutes, the patient will likely have permanent vision loss; however, most patients have a good visual outcome with a best corrected visual acuity of 20/40 or better.

Although retinal arteriole occlusions typically affect older adults with chronic, systemic diseases such as hyperlipidemia, young people may also suffer from this ocular event. In this younger population, underlying, procoagulant conditions as well as medications such as oral contraceptives may increase the risk of thromboembolism and subsequent retinal artery occlusion. Pregnancy also has the potential to cause thrombotic events throughout the body with an increased risk for a vascular occlusive event if the patient has a procoagulant condition such as a thrombophilia. A diagnosis of thrombophilia requires referral to an internist for prophylactic treatment. This is especially crucial during a pregnancy to decrease the risk of obstetric complications.

Ashely Luke

Differential diagnoses for the underlying cause of the BRAO included the following:

Pregnancy changes affect coagulation throughout the body, increasing the patient’s risk for a thrombotic event. The expression of coagulation factors is adjusted throughout the duration of the pregnancy, resulting in an overall procoagulant state. The risk of a vascular occlusion increases, but is still relatively low.

Paula Johns

Diabetes is a systemic disease resulting in damaged blood vessels. Blood flow becomes irregular due to the increased viscosity of glycosylated red blood cells. Diabetic retinopathy consists of hemorrhages, cotton-wool spots, exudates, edema, neovascularization and tractional retinal detachments. Pregnancy has been shown to worsen the severity of pregestational diabetic retinopathy, especially for those with more advanced retinopathy.

Hypertension is a systemic disease in which chronically elevated levels of blood pressure damage blood vessels. To lessen the increased blood flow, the vessels narrow, often resulting in occlusions.

Atherosclerotic disease, including hyperlipidemia and carotid artery disease, is a common cause for retinal artery occlusions. An embolus is often visualized at the site of the occlusion. This type of disease most often affects older patients. These patients have a high risk of suffering a stroke and must be referred for prophylactic treatment.

Autoimmune disorders such as systemic lupus erythematosus and antiphospholipid antibody syndrome disproportionately affect women. Although these conditions can affect any part of the eye, most often, the retinal vasculature is involved. The severity varies in lupus, ranging from hemorrhages to vascular occlusions. With antiphospholipid antibody syndrome, the patient is at a high risk of suffering a severe thrombotic event.

Thrombophilias are blood dyscrasias that cause both artery and vein occlusions. This is a significant cause of venous thromboembolism in young people. The risk of experiencing a thrombotic event is higher in patients who have an underlying thrombophilia.

The following tests should be ordered to rule out systemic, procoagulant conditions:

  • Complete blood count (CBC)
  • Prothrombin time and international normalized ratio (PT & INR)
  • Partial thromboplastin time (PTT)
  • Factor V Leiden mutation
  • Prothrombin G20210A mutation
  • Protein S antigen
  • Protein C activity
  • Antithrombin III activity
  • Antiphospholipid antibodies twice, 3 months apart (lupus anticoagulant antibody, anticardiolipin antibody and anti-beta-2-glycoprotein-1 antibody)
  • Homocysteine level/MTHFR

This patient’s diagnosis

The BRAO warranted thrombophilia screening due to the patient’s age and lack of significant risk factors. The optometrist spoke with the patient’s primary care provider and recommended testing for thrombophilia markers.

The patient was scheduled for a follow-up exam at the eye clinic to ensure resolution of the retinal findings and to monitor for neovascularization.

The results of the laboratory studies, measured at 24 weeks gestation, are listed in the accompanying table.

At a follow-up appointment, the patient reported delivering her baby earlier than anticipated due to a diagnosis of severe preeclampsia. No additional pathology was diagnosed at any subsequent follow-up examination.

Follow-up

The right eye at a follow-up visit.

Based on the results of the blood testing, the patient was assumed to have suffered this artery occlusion due to normal changes in the blood components during pregnancy.

Although the patient was diagnosed with pregestational diabetes, she had a history of well-controlled glucose levels. She also had four dilated eye examinations with no history of diabetic retinopathy dating back to 2011. Per her last primary care provider’s exam note, the patient was taken off diabetic medications due to three consecutive and normal HbA1c level measurements in spite of poor medication compliance.

The patient’s INR was flagged as low, indicating an increased likelihood of coagulation; however, the PT and PTT values were within the normal range. All three of these values should remain unchanged during pregnancy. Considering that her INR was just shy of being within the normal reference range, repeating these laboratory tests would be recommended, especially if the patient were to experience another thrombotic event.

Her protein S levels were also flagged as low, but the reference value applies to non-pregnant patients. The levels measured were deemed normal for her gestational age and were not diagnostic for a protein S deficiency.

Prior to the third trimester of her pregnancy and excluding her past diagnosis of preeclampsia, the patient’s blood pressure was controlled and within the normal reference range. Finally, with regular laboratory work-ups, the patient was never diagnosed with hyperlipidemia.

Although the laboratory testing did not lead to a diagnosis of thrombophilia, the patient is still considered a suspect for a blood coagulation disorder. It is important to note that the patient was not referred for homocysteine level or antinuclear antibody testing. If future thrombotic complications arise, she should be referred for both of these omitted tests to rule out hyperhomocysteinemia and systemic lupus erythematosus. The patient’s BRAO, history of a miscarriage and diagnosis of recurrent preeclampsia all point toward an underlying procoagulant, systemic condition.

No treatment

Because there was no macular involvement, only a relatively small area of the retina was affected, and no embolus was visible in the retinal vessels, treatment was not initiated or indicated. However, pregnant women diagnosed with a retinal vascular occlusion should be referred for additional testing due to the higher incidence rates of a concurrent thrombophilia in this demographic.

Discussion

Kurtz and colleagues found that many patients with a history of thrombophilia have suffered from retinal artery occlusions, among other ocular issues. In a study conducted by Chapin and colleagues, 58.8% of those diagnosed with a retinal artery occlusion tested positive for a thrombophilia.

Specifically, hyperhomocysteinemia and antiphosopholipid antibody syndrome have been linked to an increased risk of artery occlusions. Furthermore, Dixon and colleagues found that among patients referred solely for ocular vascular occlusions, pregnancy loss was much higher than in the general population.

Becoming pregnant affects a woman’s body down to the vascular level, presumably to protect the mother and her unborn child from complications during the pregnancy and birthing process. Coagulation is promoted, which unfortunately results in an increased incidence of thrombotic events. Pregnancy is considered an acquired thrombophilia, raising the possibility of blood clotting by four- to five-fold (Hollenhorst et al., and Galambosi et al.), and maternal thrombophilias put the fetus at risk.

Numerous studies have shown that women with an inherited thrombophilia are much more likely to experience adverse thrombotic events during their pregnancies than those without that diagnosis. An estimated 15% of people are affected by a thrombophilia, with Factor V Leiden and prothrombin abnormalities being most prevalent (Ormesher et al., and Davenport et al.). Protein S, protein C and antithrombin deficiencies are rare, with an estimated prevalence of 0.16% to 0.21%, 0.14% to 0.50% and 0.02% to 0.17%, respectively, yet, these thrombophilias cause a notable increase in the risk of a venous thromboembolism (Hollenhorst et al.).

Researchers agree that the next step in managing healthy patients suffering from an ocular vascular occlusion is to rule out a thrombophilia. As thrombotic events are more common during pregnancy, lab testing provides significant data that may result in a change in patient management. Proper treatment will improve the maternal and fetal outcomes of both the current and any future pregnancies. Karada and colleagues found that treating thrombophilic pregnant patients with low molecular weight heparin and aspirin resulted in more successful pregnancies and births than in the control group.

Many studies have found a link between thrombophilia and preeclampsia (Dixon et al. and Saghafi et al.). Errera and colleagues define preeclampsia as “elevated blood pressure with elevated protein loss [that] occurs toward the end of pregnancy.”

An estimated 3% to 5% of pregnant women are affected by this condition (Ataullakhanov et al. and Roberge et al.). Preeclampsia affects the eye in many ways, with the most common finding being arteriolar spasm. In severe cases, cortical blindness and serous retinal detachment may occur. Auger and colleagues recently published their finding that women diagnosed with preeclampsia are more likely to suffer retinal complications later in life.

According to McLaughlin and colleagues, preeclampsia risk can be reliably predicted by the second trimester. Significant medical history, such as a diagnosis of preeclampsia in the past, and systemic conditions, such as hypertension and obesity, increase a patient’s risk. Davenport and colleagues found preeclampsia recurrence to be double the rate in patients with thrombophilia than those without that diagnosis. Specifically, four thrombophilias have been linked to preeclampsia: Factor V Leiden, prothrombin, protein C deficiency and hyperhomocysteinemia.

It has been generally accepted to start treatment for high-risk preeclampsia patients before gestational week 16. Anticoagulant treatment has resulted in more successful pregnancies and births for women diagnosed with a thrombophilia, and studies have shown that anticoagulant treatment in pregnancy has no detrimental effect on the mother or fetus (Davenport et al. and Aracic et al.). This highlights the importance of early referral to the patient’s primary care provider.

Diagnosing a young, healthy, pregnant woman with a BRAO warrants further testing to determine the cause of the vascular issue. Although it is possible to suffer from a BRAO because of normal changes in coagulation that occur with pregnancy, diagnosing a patient with a thrombophilia will have many long-term benefits. The potential to lessen the risk of pregnancy complications for both the mother and fetus warrants further investigation into the explanation for a thrombotic event in a young, healthy, pregnant woman.

Disclosures: Johns and Luke report no relevant financial disclosures. Semes is an advisor or on the speakers bureau for Alcon, Allergan, Bausch + Lomb, Genentech, Maculogix, OptoVue, Shire and ZeaVision. He is a stockholder with HPO.

A 33-year-old Native American female presented with a chief complaint of a “smudge” in the vision of her right eye, which began 2 days earlier. She had looked at the sun that day and thought that had caused it. She said when she squints, the smudge disappears. The patient denied any pain or the onset of new flashes or floaters.

Her significant medical history included diabetes mellitus 2 without ocular complications. She was 22 weeks pregnant on the day of her exam, and she had a history of a miscarriage and preeclampsia during a previous pregnancy. Her medications included prenatal vitamins. She denied a history of smoking. The patient’s ocular history was unremarkable. Her last comprehensive diabetic eye examination was performed 9 months prior to this visit and revealed no signs of retinopathy.

Images taken at the initial visit.
Images: Johns P

Best corrected visual acuity tested by Snellen with spectacles was 20/20- OU. Pupils were equal, round and reactive to light. Extraocular muscles had full range of motion with orthophoria on cover test at distance. Confrontation fields were full to finger count in both eyes. Anterior segment examination on slit lamp was unremarkable. Intraocular pressure measured by applanation tonometry was 18 mm Hg OD and 18 mm Hg OS at 10:30 a.m. The patient was then dilated with one drop of 1% tropicamide and one drop of 2.5% phenylephrine in each eye, with punctal occlusion.

Posterior segment examination revealed a cup-to-disc ratio of 0.35 in both eyes, with round, perfused and healthy nerves without notching. The macula was anatomically uniform and flat and had a foveal light reflex in both eyes. The vessels in both eyes had no crossing changes, tortuosity or other abnormalities. The right eye had a focal, whitened area of the retina located superiorly between the macula and optic nerve head. No embolus was seen on ophthalmoscopy. The peripheral retina revealed no holes, tears or detachments in either eye.

What’s your diagnosis?
See answer on the next page.

PAGE BREAK

The clinical picture is consistent with a territorial branch retinal arteriole obstruction/occlusion. Other than a cotton-wool spot, the differential diagnoses are limited. Clinical observation of an excavation rather than swelling of the site makes the distinction.

Branch retinal artery occlusions (BRAOs) result in a limited area of retinal ischemia. Patients typically complain of a spot of missing vision or blur in one eye. If blood flow is restricted for more than 240 minutes, the patient will likely have permanent vision loss; however, most patients have a good visual outcome with a best corrected visual acuity of 20/40 or better.

Although retinal arteriole occlusions typically affect older adults with chronic, systemic diseases such as hyperlipidemia, young people may also suffer from this ocular event. In this younger population, underlying, procoagulant conditions as well as medications such as oral contraceptives may increase the risk of thromboembolism and subsequent retinal artery occlusion. Pregnancy also has the potential to cause thrombotic events throughout the body with an increased risk for a vascular occlusive event if the patient has a procoagulant condition such as a thrombophilia. A diagnosis of thrombophilia requires referral to an internist for prophylactic treatment. This is especially crucial during a pregnancy to decrease the risk of obstetric complications.

Ashely Luke

Differential diagnoses for the underlying cause of the BRAO included the following:

Pregnancy changes affect coagulation throughout the body, increasing the patient’s risk for a thrombotic event. The expression of coagulation factors is adjusted throughout the duration of the pregnancy, resulting in an overall procoagulant state. The risk of a vascular occlusion increases, but is still relatively low.

Paula Johns

Diabetes is a systemic disease resulting in damaged blood vessels. Blood flow becomes irregular due to the increased viscosity of glycosylated red blood cells. Diabetic retinopathy consists of hemorrhages, cotton-wool spots, exudates, edema, neovascularization and tractional retinal detachments. Pregnancy has been shown to worsen the severity of pregestational diabetic retinopathy, especially for those with more advanced retinopathy.

Hypertension is a systemic disease in which chronically elevated levels of blood pressure damage blood vessels. To lessen the increased blood flow, the vessels narrow, often resulting in occlusions.

Atherosclerotic disease, including hyperlipidemia and carotid artery disease, is a common cause for retinal artery occlusions. An embolus is often visualized at the site of the occlusion. This type of disease most often affects older patients. These patients have a high risk of suffering a stroke and must be referred for prophylactic treatment.

PAGE BREAK

Autoimmune disorders such as systemic lupus erythematosus and antiphospholipid antibody syndrome disproportionately affect women. Although these conditions can affect any part of the eye, most often, the retinal vasculature is involved. The severity varies in lupus, ranging from hemorrhages to vascular occlusions. With antiphospholipid antibody syndrome, the patient is at a high risk of suffering a severe thrombotic event.

Thrombophilias are blood dyscrasias that cause both artery and vein occlusions. This is a significant cause of venous thromboembolism in young people. The risk of experiencing a thrombotic event is higher in patients who have an underlying thrombophilia.

The following tests should be ordered to rule out systemic, procoagulant conditions:

  • Complete blood count (CBC)
  • Prothrombin time and international normalized ratio (PT & INR)
  • Partial thromboplastin time (PTT)
  • Factor V Leiden mutation
  • Prothrombin G20210A mutation
  • Protein S antigen
  • Protein C activity
  • Antithrombin III activity
  • Antiphospholipid antibodies twice, 3 months apart (lupus anticoagulant antibody, anticardiolipin antibody and anti-beta-2-glycoprotein-1 antibody)
  • Homocysteine level/MTHFR

This patient’s diagnosis

The BRAO warranted thrombophilia screening due to the patient’s age and lack of significant risk factors. The optometrist spoke with the patient’s primary care provider and recommended testing for thrombophilia markers.

The patient was scheduled for a follow-up exam at the eye clinic to ensure resolution of the retinal findings and to monitor for neovascularization.

The results of the laboratory studies, measured at 24 weeks gestation, are listed in the accompanying table.

At a follow-up appointment, the patient reported delivering her baby earlier than anticipated due to a diagnosis of severe preeclampsia. No additional pathology was diagnosed at any subsequent follow-up examination.

Follow-up

The right eye at a follow-up visit.

Based on the results of the blood testing, the patient was assumed to have suffered this artery occlusion due to normal changes in the blood components during pregnancy.

Although the patient was diagnosed with pregestational diabetes, she had a history of well-controlled glucose levels. She also had four dilated eye examinations with no history of diabetic retinopathy dating back to 2011. Per her last primary care provider’s exam note, the patient was taken off diabetic medications due to three consecutive and normal HbA1c level measurements in spite of poor medication compliance.

PAGE BREAK

The patient’s INR was flagged as low, indicating an increased likelihood of coagulation; however, the PT and PTT values were within the normal range. All three of these values should remain unchanged during pregnancy. Considering that her INR was just shy of being within the normal reference range, repeating these laboratory tests would be recommended, especially if the patient were to experience another thrombotic event.

Her protein S levels were also flagged as low, but the reference value applies to non-pregnant patients. The levels measured were deemed normal for her gestational age and were not diagnostic for a protein S deficiency.

Prior to the third trimester of her pregnancy and excluding her past diagnosis of preeclampsia, the patient’s blood pressure was controlled and within the normal reference range. Finally, with regular laboratory work-ups, the patient was never diagnosed with hyperlipidemia.

Although the laboratory testing did not lead to a diagnosis of thrombophilia, the patient is still considered a suspect for a blood coagulation disorder. It is important to note that the patient was not referred for homocysteine level or antinuclear antibody testing. If future thrombotic complications arise, she should be referred for both of these omitted tests to rule out hyperhomocysteinemia and systemic lupus erythematosus. The patient’s BRAO, history of a miscarriage and diagnosis of recurrent preeclampsia all point toward an underlying procoagulant, systemic condition.

No treatment

Because there was no macular involvement, only a relatively small area of the retina was affected, and no embolus was visible in the retinal vessels, treatment was not initiated or indicated. However, pregnant women diagnosed with a retinal vascular occlusion should be referred for additional testing due to the higher incidence rates of a concurrent thrombophilia in this demographic.

Discussion

Kurtz and colleagues found that many patients with a history of thrombophilia have suffered from retinal artery occlusions, among other ocular issues. In a study conducted by Chapin and colleagues, 58.8% of those diagnosed with a retinal artery occlusion tested positive for a thrombophilia.

Specifically, hyperhomocysteinemia and antiphosopholipid antibody syndrome have been linked to an increased risk of artery occlusions. Furthermore, Dixon and colleagues found that among patients referred solely for ocular vascular occlusions, pregnancy loss was much higher than in the general population.

PAGE BREAK

Becoming pregnant affects a woman’s body down to the vascular level, presumably to protect the mother and her unborn child from complications during the pregnancy and birthing process. Coagulation is promoted, which unfortunately results in an increased incidence of thrombotic events. Pregnancy is considered an acquired thrombophilia, raising the possibility of blood clotting by four- to five-fold (Hollenhorst et al., and Galambosi et al.), and maternal thrombophilias put the fetus at risk.

Numerous studies have shown that women with an inherited thrombophilia are much more likely to experience adverse thrombotic events during their pregnancies than those without that diagnosis. An estimated 15% of people are affected by a thrombophilia, with Factor V Leiden and prothrombin abnormalities being most prevalent (Ormesher et al., and Davenport et al.). Protein S, protein C and antithrombin deficiencies are rare, with an estimated prevalence of 0.16% to 0.21%, 0.14% to 0.50% and 0.02% to 0.17%, respectively, yet, these thrombophilias cause a notable increase in the risk of a venous thromboembolism (Hollenhorst et al.).

Researchers agree that the next step in managing healthy patients suffering from an ocular vascular occlusion is to rule out a thrombophilia. As thrombotic events are more common during pregnancy, lab testing provides significant data that may result in a change in patient management. Proper treatment will improve the maternal and fetal outcomes of both the current and any future pregnancies. Karada and colleagues found that treating thrombophilic pregnant patients with low molecular weight heparin and aspirin resulted in more successful pregnancies and births than in the control group.

Many studies have found a link between thrombophilia and preeclampsia (Dixon et al. and Saghafi et al.). Errera and colleagues define preeclampsia as “elevated blood pressure with elevated protein loss [that] occurs toward the end of pregnancy.”

An estimated 3% to 5% of pregnant women are affected by this condition (Ataullakhanov et al. and Roberge et al.). Preeclampsia affects the eye in many ways, with the most common finding being arteriolar spasm. In severe cases, cortical blindness and serous retinal detachment may occur. Auger and colleagues recently published their finding that women diagnosed with preeclampsia are more likely to suffer retinal complications later in life.

According to McLaughlin and colleagues, preeclampsia risk can be reliably predicted by the second trimester. Significant medical history, such as a diagnosis of preeclampsia in the past, and systemic conditions, such as hypertension and obesity, increase a patient’s risk. Davenport and colleagues found preeclampsia recurrence to be double the rate in patients with thrombophilia than those without that diagnosis. Specifically, four thrombophilias have been linked to preeclampsia: Factor V Leiden, prothrombin, protein C deficiency and hyperhomocysteinemia.

It has been generally accepted to start treatment for high-risk preeclampsia patients before gestational week 16. Anticoagulant treatment has resulted in more successful pregnancies and births for women diagnosed with a thrombophilia, and studies have shown that anticoagulant treatment in pregnancy has no detrimental effect on the mother or fetus (Davenport et al. and Aracic et al.). This highlights the importance of early referral to the patient’s primary care provider.

Diagnosing a young, healthy, pregnant woman with a BRAO warrants further testing to determine the cause of the vascular issue. Although it is possible to suffer from a BRAO because of normal changes in coagulation that occur with pregnancy, diagnosing a patient with a thrombophilia will have many long-term benefits. The potential to lessen the risk of pregnancy complications for both the mother and fetus warrants further investigation into the explanation for a thrombotic event in a young, healthy, pregnant woman.

Disclosures: Johns and Luke report no relevant financial disclosures. Semes is an advisor or on the speakers bureau for Alcon, Allergan, Bausch + Lomb, Genentech, Maculogix, OptoVue, Shire and ZeaVision. He is a stockholder with HPO.