A 43-year-old woman presents to the emergency department with substernal chest pressure of moderate intensity that started approximately 6 hours ago. The pressure radiates to both arms and is accompanied by nausea. She says she has had no emesis, diaphoresis, fevers, chills, shortness of breath, abdominal pain, melena, dysuria, weight loss, headaches, change in vision, seizures, joint pain, or skin rashes. She also says she has had no prior similar episodes and has no history of myocardial infarction (MI) or stroke.

The patient has a history of gastroesophageal reflux disease and uterine fibroids. She has had three pregnancies, one ending in spontaneous abortion at 12 weeks and two ending with healthy children delivered by cesarean section. She does not take any daily medications. She has smoked one pack per day over the last 25 years. She denies using alcohol or illicit drugs.

The patient’s mother had idiopathic deep vein thrombosis (DVT) at age 46, her father had an MI at age 65, and her sister had an MI at age 43.

On examination, she is in mild distress but is alert and oriented. Her temperature is 99.0°F (37.2°C), blood pressure 98/66 mm Hg, heart rate 65 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on room air. Her body mass index is 19.5 (normal range 18.5–24.9). Her skin appears normal. Her head and neck show no obvious abnormalities, lymphadenopathy, thyromegaly, or bruits. Her heart, lungs, and abdomen are normal, as are her strength, sensation, reflexes, and gait.

Laboratory values at the time of admission:

• White blood cell count 12.58 × 10⁹/L (reference range 4.0–11.0)
• Hemoglobin 15.4 g/dL (12.0–16.0)
• Platelet count 122 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.1 (0.9–1.1)
• Activated partial thromboplastin time 29.1 seconds (24.6–34).

A heart attack, and then a stroke

An initial electrocardiogram shows normal sinus rhythm, left anterior hemiblock, and nonspecific T-wave abnormalities. Cardiac enzymes are measured at intervals: her troponin T level is less than 0.01 ng/mL at the time of admission but rises to 0.75 ng/mL 3 hours later (normal range 0.0–0.1 ng/mL). Similarly, her creatine kinase-MB level is 3.3 ng/mL at admission but rises to 71.9 ng/mL 3 hours later (normal range 0.0–8.0 ng/mL).

The patient is diagnosed with non-ST-elevation MI. An intravenous heparin drip is started, and she is sent for urgent cardiac catheterization, which shows a total occlusion in a lateral obtuse marginal branch of the left circumflex artery due to a thrombus in the vessel. Otherwise, her coronary arteries are angiographically free of disease. The heparin drip is continued, and treatment is started with abciximab (ReoPro) and tissue plasminogen activator (Alteplase). She is sent to the cardiac intensive care unit for recovery, where she is placed on continuous cardiac monitoring, with no evidence of arrhythmia.

One day later, the left side of her face is drooping, her left arm is weak, and her speech is slurred. Magnetic resonance imaging of the brain shows an acute ischemic infarct in the right temporoparietal area and multiple areas of subacute to chronic ischemia. Magnetic resonance angiography of the brain indicates patent vessels. Both transthoracic and transesophageal echocardiography are performed and indicate normal left ventricular size, ejection fraction of 55%, valves without thrombus or vegetations, aorta with mild atheroma, and no patent foramen ovale by Doppler flow or agitated saline contrast study. Carotid artery Doppler ultrasonography shows 40% to 59% stenosis bilaterally.

ARTERIAL THROMBOSIS

1. Which of the following is a risk factor for arterial thrombosis?

• Atherosclerosis
• Protein C deficiency
• Use of oral contraceptive pills
• The factor V Leiden mutation

Protein C deficiency, the use of oral contraceptives, and the factor V Leiden mutation are typically associated with venous thrombosis¹; they have been documented as a cause of arterial thrombosis only in some case reports. In contrast, atherosclerosis is a well-established risk factor for arterial thrombosis.

Arterial occlusion can be due to thrombosis, embolism, or trauma

The causes of arterial occlusion can be categorized as thrombotic, embolic, or traumatic (Table 1).

Atherosclerosis is a risk factor for thrombosis and can be a source of emboli. Atherosclerotic plaque rupture may release inflammatory mediators, which also predispose to thrombosis.² This patient’s coronary arteries are essentially free of atherosclerotic disease per angiography. However, studies of intravascular ultrasonography have shown that coronary angiography may not detect all atherosclerotic plaques, as angiography can show only the lumen of the artery and not the plaque itself.³ For that reason, atherosclerosis has not been ruled out completely, and further workup is needed to evaluate other possible causes of her thrombotic events.

Embolism is the most likely cause of her stroke, however. Cases of arterial embolism can be classified on the basis of the origin of the thrombus, ie, the heart, an artery, or the venous system via a patent foramen ovale (paradoxical embolism). This patient’s echocardiogram reveals mild aortic atheroma, which can be a source of emboli, especially soon after intervention.

Case continues: Acute and recurrent DVT

While recovering from her MI and stroke, the patient develops edema and pain in both legs. Doppler ultrasonography is performed, which reveals acute DVT in the right gastrocnemius and posterior tibial veins and left soleal vein, despite her continued heparin therapy.

Her platelet count is 189 × 10⁹/L, so heparin-induced thrombocytopenia is not suspected; the new DVT is thought to be due to her hospitalization. Several days later, oral warfarin (Coumadin) is started and titrated to an INR of 2.0 to 3.0, the heparin is phased out, and the patient is sent home.

In the first few months after discharge, the patient presents to the emergency department three times with severe leg pain, and each time she is found to have extensive DVT in various leg veins even though she is complying with her warfarin therapy. At each visit, her INR is in the range of 2.5 to 3.1.

Comment. Her recurrent DVT warrants further evaluation for risk factors for venous thrombosis, which can be divided into hereditary and acquired factors.

Hereditary risk factors include the factor V Leiden mutation, the prothrombin gene mutation, hyperhomocysteinemia, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

Acquired risk factors include the antiphospholipid antibody syndrome, cancer, immobilization, surgery, congestive heart failure, pregnancy, use of hormonal contraceptives, hormone replacement therapy, nephrotic syndrome, trauma, and infection.^1,4

TESTING FOR HYPERCOAGULABLE STATES

2. In view of our patient’s recurrent thrombotic episodes, should she be tested for hypercoagulable states?

• Yes
• No

Testing for hypercoagulable conditions is warranted if it will affect the patient’s management or outcome. Some authorities recommend testing patients who are clinically characterized as “strongly” thrombophilic,⁵ ie, those who present with DVT and are younger than age 50, have recurrent thrombotic episodes, have a first-degree relative with documented thromboembolism before age 50, or have thrombotic episodes despite warfarin therapy.

This patient should be tested for hypercoagulable conditions because her initial DVT occurred before age 50 (at age 43), she has had recurrent, apparently idiopathic thrombotic episodes, she has a family history of thromboembolism, and she had clots while on therapeutic warfarin therapy, all of which suggest a hypercoagulable state. Furthermore, the confirmation of her diagnosis may affect her medical management, as it may determine if further testing and therapies are needed.

Case continues: Tests are negative

Laboratory tests for hypercoagulable conditions are performed and are negative for the factor V Leiden mutation, the prothrombin gene mutation, antithrombin deficiency, and protein C and S deficiencies. A screen for antiphospholipid antibodies is indeterminate.

TREATMENT AFFECTS TEST RESULTS

3. If a patient is on warfarin therapy, which test results may be affected?

• Antithrombin levels
• Protein C and S levels
• Factor V Leiden mutation

Warfarin decreases the levels of proteins C and S; therefore, the levels of these substances cannot be accurately interpreted in a patient taking warfarin.

All anticoagulants prolong the clotting time and may affect the results of assays based on the clotting time, such as the prothrombin time, the partial thromboplastin time, the dilute Russell’s viper venom time (DRVVT), the hexagonal phase phospholipid neutralization assay, the thrombin time, and clottable protein C and protein S. Heparin reduces the level of antithrombin; however, laboratories now have heparin-binding agents that reduce the effect of heparin in clotting studies.

Acute thrombotic states lower the levels of antithrombin and proteins C and S.

Assays not based on the clotting time (immunogenic or genetic tests such as those for anticardiolipin antibodies and the factor V Leiden and prothrombin gene mutations) are not affected by anticoagulant use.⁵

However, the presence or absence of a hypercoagulable state should not affect the treatment of acute DVT, and a full 6- to 12-month course of anticoagulation should be completed.^6,7 If possible, lupus anticoagulant testing should be repeated 2 weeks after anticoagulation is stopped.⁸

This patient needs lifelong anticoagulation because of her repeated thrombotic episodes. Stopping the medication for 2 weeks for testing would increase the risk of rethrombosis in this patient, and most experts would not advise it.

In summary, testing for hypercoagulable conditions is not recommended during an acute thrombotic episode and is preferably performed while the patient is not on anticoagulation therapy. If the patient is already on anticoagulation, the results of tests for hypercoagulable conditions should be interpreted with caution.

Case continues: Another stroke

During the subsequent year, the patient’s primary care physician monitors her warfarin use and sends her for age-appropriate cancer screening, including a breast examination, Papanicolaou smear, and mammography. Also, given her history of smoking, a chest radiograph is ordered. All of these studies are normal. In addition, evaluations for hematologic disorders such as myelodysplastic syndrome, polycythemia vera, and Waldenström macroglobulinema reveal normal complete blood counts and normal results on serum and urine protein electrophoresis.

Later that year, she returns to the emergency department with complete aphasia and total right-sided paralysis. Magnetic resonance imaging shows an acute infarct in the left frontal operculum, a subacute infarct in the right cerebellum, and multiple chronic cortical and subcortical infarcts throughout the brain. Ultrasonography shows an extensive new DVT in her right leg. Her INR at this time is 3.1.

WHAT CONDITIONS CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

4. Given that the patient has evidence of both recurrent arterial and venous thromboses, which of the following conditions is likely?

• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia
• Malignancy
• All of the above

Conditions associated with both arterial and venous thrombosis include antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, malignancy, paradoxical embolism, hyperhomocysteinemia, myeloproliferative disorders, myelodysplastic disorder, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.^1,4

At present, the exact mechanism that causes Trousseau syndrome is unknown. Some hypotheses implicate mucin (produced by the cancer),¹⁰ tissue factor,¹¹ tumor-associated cysteine proteinase,¹² tumor hypoxia,¹³ and oncogene activation as plausible triggers for this syndrome.

DOES SHE HAVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME?

5. The patient is positive for lupus anticoagulant. Does she have antiphospholipid antibody syndrome?

• Yes
• No
• Repeat testing is needed to meet the diagnostic criteria

The Sapporo criteria¹⁵ indicate that antiphospholipid antibody syndrome is present if at least one clinical criterion and one laboratory criterion are met. The clinical criteria are one or more episodes of arterial or venous thrombosis or pregnancy-related morbidity, ie:

• Unexplained intrauterine fetal death at 10 weeks gestation or later with no apparent fetal abnormality
• Premature births of a morphologically normal fetus at less than 34 weeks of gestation due to preeclampsia, eclampsia, or placental insufficiency
• Three or more spontaneous abortions at 10 weeks of gestation or earlier, with no known paternal chromosomal abnormalities or maternal hormonal abnormalities and normal maternal anatomy.

The laboratory criteria are:

• Lupus anticoagulant present
• Anticardiolipin antibody (IgG or IgM) titer greater than 40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or higher than the 99th percentile of the testing laboratory normal reference range
• Anti-beta-2 glycoprotein-I antibody (IgG or IgM) titer greater than 20 GPL or MPL or higher than the 99th percentile of the testing laboratory normal reference range.

The patient likely has antiphospholipid antibody syndrome because her lupus anticoagulant screen is positive and she meets the clinical criteria of thrombosis, and she should continue to be treated accordingly. However, to officially meet the revised Sapporo criteria, she would need to have laboratory tests that are positive on two or more occasions at least 12 weeks apart.

Case continues: Lung cancer is found

The patient reports that she has lost 10 pounds in 4 months. Since age-appropriate cancer testing was previously performed, a more extensive evaluation for weight loss is undertaken, with computed tomography of the chest, abdomen, and pelvis. These tests reveal a nodule in the right upper lobe of the lung, scarring in the right middle and left lower lung lobes, and hilar lymphadenopathy. Bronchoscopy with transbronchial biopsy confirms that she has adenocarcinoma of the lung.

6. What is suggested as a sufficient workup for malignancy in patients with idiopathic venous thromboembolism?

• Computed tomography of the chest, abdomen, and pelvis for every patient with idiopathic venous thromboembolism
• Positron emission tomography and tumor marker levels
• A comprehensive history and physical examination, routine laboratory tests, chest radiography, age- and sex-specific cancer screening, and patient-specific testing as indicated clinically

To date, there is no evidence to support a cancer evaluation beyond a comprehensive medical history and physical examination, routine laboratory testing, chest radiography, and age- and sex-specific cancer screening unless it is dictated by the patient’s clinical presentation. A study by Cornuz et al¹⁶ suggested that this approach is appropriate for detecting cancer in patients with idiopathic venous thromboembolism.

A 2004 study¹⁷ attempted to answer the question of what to do about patients who have idiopathic venous thromboembolism but no other signs or symptoms that raise any clinical suspicion of cancer. This study randomized patients with idiopathic venous thromboembolism to undergo either routine medical management or an extensive malignancy evaluation. The evaluation included ultrasonography of the abdomen and pelvis, computed tomography of the abdomen and pelvis, gastroscopy or a double-contrast barium swallow study, colonoscopy or sigmoidoscopy followed by a barium enema, stool occult blood testing, and sputum cytology. Women were also tested for the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and CA-125, and they underwent mammography and Papanicolaou testing; men were tested for prostate-specific antigen and underwent ultrasonography of the prostate. The results of the study did not reveal a statistically significant survival benefit in the group that underwent extensive cancer evaluation.

These studies indicate that the decision to test for cancer should be guided by clinical suspicion. Our patient lost 10 pounds in 4 months, smokes, and has had recurrent venous thromboembolism, so testing was appropriate.

After her diagnosis with adenocarcinoma of the lung, the patient has yet another DVT despite an INR of 3.1 and treatment with warfarin and aspirin.

LOW-MOLECULAR-WEIGHT HEPARIN FOR PATIENTS WITH CANCER?

7. True or false? Low-molecular-weight heparin is more effective than warfarin in preventing DVT in cancer patients without increasing the bleeding risk.

• True
• False

This statement is true. The American College of Chest Physicians (ACCP) recommends immediate treatment of DVT with low-molecular-weight heparin for 6 to 12 months after a thrombotic event in a patient with malignancy.^6,18

Two major studies provide evidence for these recommendations: the Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT)¹⁹ and the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE)²⁰ studies.

The CLOT¹⁹ study showed that dalteparin (Fragmin) 200 IU/kg subcutaneously once daily for l month and then 150 IU/kg once daily was more effective than oral warfarin titrated to an INR of 2.5 and did not increase the risk of bleeding.

The LITE trial²⁰ showed the efficacy of tinzaparin (Innohep) 175 IU/kg subcutaneously daily, which can be used as an alternative.

Enoxaparin sodium (Lovenox) 1.5 mg/kg once daily has also been used. However, if low-molecular-weight heparin is not available, warfarin titrated to an INR of 2 to 3 is also acceptable.¹⁸

The ACCP consensus panel recommends giving anticoagulation for an initial 6 to 12 months and continuing it as long as there is evidence of active malignancy.⁶ The American Society for Clinical Oncology also recommends placement of an inferior vena cava filter for patients who have contraindications to anticoagulation or for whom low-molecular-weight heparin fails.¹⁸

Case continues: Summing up

In conclusion, our patient had an underlying malignancy, causing Trousseau syndrome. Before her cancer was diagnosed, she also had test results that suggested antiphospholipid antibody syndrome. Both of these conditions likely contributed to her hypercoagulable state, increasing her propensity for clotting and causing her recurrent thrombosis. The patient is currently on low-molecular-weight heparin and is undergoing palliative chemotherapy for metastatic adenocarcinoma of the lung. To this date, she has not had any new thrombotic events.

TAKE-HOME POINTS

• Risk factors for arterial occlusion can be divided into thrombotic, embolic, and traumatic categories.
• Risk factors for venous thrombosis can be divided into hereditary and acquired categories.
• Evaluation for hypercoagulable conditions is recommended if it will affect patient management or outcome. Patients to be considered for testing include those with idiopathic DVT and who are under age 50, those with a history of recurrent thrombosis, and those with a first-degree relative with documented venous thromboembolism before age 50.
• Evaluation for hypercoagulable conditions should ideally be performed either before starting anticoagulation therapy or 2 weeks after completing it.
• Potential causes of both arterial and venous thrombosis include antiphospholipid antibody syndrome, cancer, hyperhomocysteinemia, heparin-induced thrombocytopenia, paradoxical emboli, myeloproliferative disorders, myelodysplastic syndrome, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.
• Current evidence does not support an extensive cancer evaluation in patients with idiopathic venous thromboembolism, unless dictated by the patient’s clinical condition.
• In patients with venous thromboembolism and active malignancy, anticoagulation is recommended for at least 6 to 12 months and as long as there is evidence of active malignancy.

A 43-year-old woman presents to the emergency department with substernal chest pressure of moderate intensity that started approximately 6 hours ago. The pressure radiates to both arms and is accompanied by nausea. She says she has had no emesis, diaphoresis, fevers, chills, shortness of breath, abdominal pain, melena, dysuria, weight loss, headaches, change in vision, seizures, joint pain, or skin rashes. She also says she has had no prior similar episodes and has no history of myocardial infarction (MI) or stroke.

The patient has a history of gastroesophageal reflux disease and uterine fibroids. She has had three pregnancies, one ending in spontaneous abortion at 12 weeks and two ending with healthy children delivered by cesarean section. She does not take any daily medications. She has smoked one pack per day over the last 25 years. She denies using alcohol or illicit drugs.

The patient’s mother had idiopathic deep vein thrombosis (DVT) at age 46, her father had an MI at age 65, and her sister had an MI at age 43.

On examination, she is in mild distress but is alert and oriented. Her temperature is 99.0°F (37.2°C), blood pressure 98/66 mm Hg, heart rate 65 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on room air. Her body mass index is 19.5 (normal range 18.5–24.9). Her skin appears normal. Her head and neck show no obvious abnormalities, lymphadenopathy, thyromegaly, or bruits. Her heart, lungs, and abdomen are normal, as are her strength, sensation, reflexes, and gait.

Laboratory values at the time of admission:

• White blood cell count 12.58 × 10⁹/L (reference range 4.0–11.0)
• Hemoglobin 15.4 g/dL (12.0–16.0)
• Platelet count 122 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.1 (0.9–1.1)
• Activated partial thromboplastin time 29.1 seconds (24.6–34).

A heart attack, and then a stroke

An initial electrocardiogram shows normal sinus rhythm, left anterior hemiblock, and nonspecific T-wave abnormalities. Cardiac enzymes are measured at intervals: her troponin T level is less than 0.01 ng/mL at the time of admission but rises to 0.75 ng/mL 3 hours later (normal range 0.0–0.1 ng/mL). Similarly, her creatine kinase-MB level is 3.3 ng/mL at admission but rises to 71.9 ng/mL 3 hours later (normal range 0.0–8.0 ng/mL).

The patient is diagnosed with non-ST-elevation MI. An intravenous heparin drip is started, and she is sent for urgent cardiac catheterization, which shows a total occlusion in a lateral obtuse marginal branch of the left circumflex artery due to a thrombus in the vessel. Otherwise, her coronary arteries are angiographically free of disease. The heparin drip is continued, and treatment is started with abciximab (ReoPro) and tissue plasminogen activator (Alteplase). She is sent to the cardiac intensive care unit for recovery, where she is placed on continuous cardiac monitoring, with no evidence of arrhythmia.

One day later, the left side of her face is drooping, her left arm is weak, and her speech is slurred. Magnetic resonance imaging of the brain shows an acute ischemic infarct in the right temporoparietal area and multiple areas of subacute to chronic ischemia. Magnetic resonance angiography of the brain indicates patent vessels. Both transthoracic and transesophageal echocardiography are performed and indicate normal left ventricular size, ejection fraction of 55%, valves without thrombus or vegetations, aorta with mild atheroma, and no patent foramen ovale by Doppler flow or agitated saline contrast study. Carotid artery Doppler ultrasonography shows 40% to 59% stenosis bilaterally.

ARTERIAL THROMBOSIS

1. Which of the following is a risk factor for arterial thrombosis?

• Atherosclerosis
• Protein C deficiency
• Use of oral contraceptive pills
• The factor V Leiden mutation

Protein C deficiency, the use of oral contraceptives, and the factor V Leiden mutation are typically associated with venous thrombosis¹; they have been documented as a cause of arterial thrombosis only in some case reports. In contrast, atherosclerosis is a well-established risk factor for arterial thrombosis.

Arterial occlusion can be due to thrombosis, embolism, or trauma

The causes of arterial occlusion can be categorized as thrombotic, embolic, or traumatic (Table 1).

Atherosclerosis is a risk factor for thrombosis and can be a source of emboli. Atherosclerotic plaque rupture may release inflammatory mediators, which also predispose to thrombosis.² This patient’s coronary arteries are essentially free of atherosclerotic disease per angiography. However, studies of intravascular ultrasonography have shown that coronary angiography may not detect all atherosclerotic plaques, as angiography can show only the lumen of the artery and not the plaque itself.³ For that reason, atherosclerosis has not been ruled out completely, and further workup is needed to evaluate other possible causes of her thrombotic events.

Embolism is the most likely cause of her stroke, however. Cases of arterial embolism can be classified on the basis of the origin of the thrombus, ie, the heart, an artery, or the venous system via a patent foramen ovale (paradoxical embolism). This patient’s echocardiogram reveals mild aortic atheroma, which can be a source of emboli, especially soon after intervention.

Case continues: Acute and recurrent DVT

While recovering from her MI and stroke, the patient develops edema and pain in both legs. Doppler ultrasonography is performed, which reveals acute DVT in the right gastrocnemius and posterior tibial veins and left soleal vein, despite her continued heparin therapy.

Her platelet count is 189 × 10⁹/L, so heparin-induced thrombocytopenia is not suspected; the new DVT is thought to be due to her hospitalization. Several days later, oral warfarin (Coumadin) is started and titrated to an INR of 2.0 to 3.0, the heparin is phased out, and the patient is sent home.

In the first few months after discharge, the patient presents to the emergency department three times with severe leg pain, and each time she is found to have extensive DVT in various leg veins even though she is complying with her warfarin therapy. At each visit, her INR is in the range of 2.5 to 3.1.

Comment. Her recurrent DVT warrants further evaluation for risk factors for venous thrombosis, which can be divided into hereditary and acquired factors.

Hereditary risk factors include the factor V Leiden mutation, the prothrombin gene mutation, hyperhomocysteinemia, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

Acquired risk factors include the antiphospholipid antibody syndrome, cancer, immobilization, surgery, congestive heart failure, pregnancy, use of hormonal contraceptives, hormone replacement therapy, nephrotic syndrome, trauma, and infection.^1,4

TESTING FOR HYPERCOAGULABLE STATES

2. In view of our patient’s recurrent thrombotic episodes, should she be tested for hypercoagulable states?

• Yes
• No

Testing for hypercoagulable conditions is warranted if it will affect the patient’s management or outcome. Some authorities recommend testing patients who are clinically characterized as “strongly” thrombophilic,⁵ ie, those who present with DVT and are younger than age 50, have recurrent thrombotic episodes, have a first-degree relative with documented thromboembolism before age 50, or have thrombotic episodes despite warfarin therapy.

This patient should be tested for hypercoagulable conditions because her initial DVT occurred before age 50 (at age 43), she has had recurrent, apparently idiopathic thrombotic episodes, she has a family history of thromboembolism, and she had clots while on therapeutic warfarin therapy, all of which suggest a hypercoagulable state. Furthermore, the confirmation of her diagnosis may affect her medical management, as it may determine if further testing and therapies are needed.

Case continues: Tests are negative

Laboratory tests for hypercoagulable conditions are performed and are negative for the factor V Leiden mutation, the prothrombin gene mutation, antithrombin deficiency, and protein C and S deficiencies. A screen for antiphospholipid antibodies is indeterminate.

TREATMENT AFFECTS TEST RESULTS

3. If a patient is on warfarin therapy, which test results may be affected?

• Antithrombin levels
• Protein C and S levels
• Factor V Leiden mutation

Warfarin decreases the levels of proteins C and S; therefore, the levels of these substances cannot be accurately interpreted in a patient taking warfarin.

All anticoagulants prolong the clotting time and may affect the results of assays based on the clotting time, such as the prothrombin time, the partial thromboplastin time, the dilute Russell’s viper venom time (DRVVT), the hexagonal phase phospholipid neutralization assay, the thrombin time, and clottable protein C and protein S. Heparin reduces the level of antithrombin; however, laboratories now have heparin-binding agents that reduce the effect of heparin in clotting studies.

Acute thrombotic states lower the levels of antithrombin and proteins C and S.

Assays not based on the clotting time (immunogenic or genetic tests such as those for anticardiolipin antibodies and the factor V Leiden and prothrombin gene mutations) are not affected by anticoagulant use.⁵

However, the presence or absence of a hypercoagulable state should not affect the treatment of acute DVT, and a full 6- to 12-month course of anticoagulation should be completed.^6,7 If possible, lupus anticoagulant testing should be repeated 2 weeks after anticoagulation is stopped.⁸

This patient needs lifelong anticoagulation because of her repeated thrombotic episodes. Stopping the medication for 2 weeks for testing would increase the risk of rethrombosis in this patient, and most experts would not advise it.

In summary, testing for hypercoagulable conditions is not recommended during an acute thrombotic episode and is preferably performed while the patient is not on anticoagulation therapy. If the patient is already on anticoagulation, the results of tests for hypercoagulable conditions should be interpreted with caution.

Case continues: Another stroke

During the subsequent year, the patient’s primary care physician monitors her warfarin use and sends her for age-appropriate cancer screening, including a breast examination, Papanicolaou smear, and mammography. Also, given her history of smoking, a chest radiograph is ordered. All of these studies are normal. In addition, evaluations for hematologic disorders such as myelodysplastic syndrome, polycythemia vera, and Waldenström macroglobulinema reveal normal complete blood counts and normal results on serum and urine protein electrophoresis.

Later that year, she returns to the emergency department with complete aphasia and total right-sided paralysis. Magnetic resonance imaging shows an acute infarct in the left frontal operculum, a subacute infarct in the right cerebellum, and multiple chronic cortical and subcortical infarcts throughout the brain. Ultrasonography shows an extensive new DVT in her right leg. Her INR at this time is 3.1.

WHAT CONDITIONS CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

4. Given that the patient has evidence of both recurrent arterial and venous thromboses, which of the following conditions is likely?

• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia
• Malignancy
• All of the above

Conditions associated with both arterial and venous thrombosis include antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, malignancy, paradoxical embolism, hyperhomocysteinemia, myeloproliferative disorders, myelodysplastic disorder, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.^1,4

At present, the exact mechanism that causes Trousseau syndrome is unknown. Some hypotheses implicate mucin (produced by the cancer),¹⁰ tissue factor,¹¹ tumor-associated cysteine proteinase,¹² tumor hypoxia,¹³ and oncogene activation as plausible triggers for this syndrome.

DOES SHE HAVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME?

5. The patient is positive for lupus anticoagulant. Does she have antiphospholipid antibody syndrome?

• Yes
• No
• Repeat testing is needed to meet the diagnostic criteria

The Sapporo criteria¹⁵ indicate that antiphospholipid antibody syndrome is present if at least one clinical criterion and one laboratory criterion are met. The clinical criteria are one or more episodes of arterial or venous thrombosis or pregnancy-related morbidity, ie:

• Unexplained intrauterine fetal death at 10 weeks gestation or later with no apparent fetal abnormality
• Premature births of a morphologically normal fetus at less than 34 weeks of gestation due to preeclampsia, eclampsia, or placental insufficiency
• Three or more spontaneous abortions at 10 weeks of gestation or earlier, with no known paternal chromosomal abnormalities or maternal hormonal abnormalities and normal maternal anatomy.

The laboratory criteria are:

• Lupus anticoagulant present
• Anticardiolipin antibody (IgG or IgM) titer greater than 40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or higher than the 99th percentile of the testing laboratory normal reference range
• Anti-beta-2 glycoprotein-I antibody (IgG or IgM) titer greater than 20 GPL or MPL or higher than the 99th percentile of the testing laboratory normal reference range.

The patient likely has antiphospholipid antibody syndrome because her lupus anticoagulant screen is positive and she meets the clinical criteria of thrombosis, and she should continue to be treated accordingly. However, to officially meet the revised Sapporo criteria, she would need to have laboratory tests that are positive on two or more occasions at least 12 weeks apart.

Case continues: Lung cancer is found

The patient reports that she has lost 10 pounds in 4 months. Since age-appropriate cancer testing was previously performed, a more extensive evaluation for weight loss is undertaken, with computed tomography of the chest, abdomen, and pelvis. These tests reveal a nodule in the right upper lobe of the lung, scarring in the right middle and left lower lung lobes, and hilar lymphadenopathy. Bronchoscopy with transbronchial biopsy confirms that she has adenocarcinoma of the lung.

6. What is suggested as a sufficient workup for malignancy in patients with idiopathic venous thromboembolism?

• Computed tomography of the chest, abdomen, and pelvis for every patient with idiopathic venous thromboembolism
• Positron emission tomography and tumor marker levels
• A comprehensive history and physical examination, routine laboratory tests, chest radiography, age- and sex-specific cancer screening, and patient-specific testing as indicated clinically

To date, there is no evidence to support a cancer evaluation beyond a comprehensive medical history and physical examination, routine laboratory testing, chest radiography, and age- and sex-specific cancer screening unless it is dictated by the patient’s clinical presentation. A study by Cornuz et al¹⁶ suggested that this approach is appropriate for detecting cancer in patients with idiopathic venous thromboembolism.

A 2004 study¹⁷ attempted to answer the question of what to do about patients who have idiopathic venous thromboembolism but no other signs or symptoms that raise any clinical suspicion of cancer. This study randomized patients with idiopathic venous thromboembolism to undergo either routine medical management or an extensive malignancy evaluation. The evaluation included ultrasonography of the abdomen and pelvis, computed tomography of the abdomen and pelvis, gastroscopy or a double-contrast barium swallow study, colonoscopy or sigmoidoscopy followed by a barium enema, stool occult blood testing, and sputum cytology. Women were also tested for the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and CA-125, and they underwent mammography and Papanicolaou testing; men were tested for prostate-specific antigen and underwent ultrasonography of the prostate. The results of the study did not reveal a statistically significant survival benefit in the group that underwent extensive cancer evaluation.

These studies indicate that the decision to test for cancer should be guided by clinical suspicion. Our patient lost 10 pounds in 4 months, smokes, and has had recurrent venous thromboembolism, so testing was appropriate.

After her diagnosis with adenocarcinoma of the lung, the patient has yet another DVT despite an INR of 3.1 and treatment with warfarin and aspirin.

LOW-MOLECULAR-WEIGHT HEPARIN FOR PATIENTS WITH CANCER?

7. True or false? Low-molecular-weight heparin is more effective than warfarin in preventing DVT in cancer patients without increasing the bleeding risk.

• True
• False

This statement is true. The American College of Chest Physicians (ACCP) recommends immediate treatment of DVT with low-molecular-weight heparin for 6 to 12 months after a thrombotic event in a patient with malignancy.^6,18

Two major studies provide evidence for these recommendations: the Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT)¹⁹ and the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE)²⁰ studies.

The CLOT¹⁹ study showed that dalteparin (Fragmin) 200 IU/kg subcutaneously once daily for l month and then 150 IU/kg once daily was more effective than oral warfarin titrated to an INR of 2.5 and did not increase the risk of bleeding.

The LITE trial²⁰ showed the efficacy of tinzaparin (Innohep) 175 IU/kg subcutaneously daily, which can be used as an alternative.

Enoxaparin sodium (Lovenox) 1.5 mg/kg once daily has also been used. However, if low-molecular-weight heparin is not available, warfarin titrated to an INR of 2 to 3 is also acceptable.¹⁸

The ACCP consensus panel recommends giving anticoagulation for an initial 6 to 12 months and continuing it as long as there is evidence of active malignancy.⁶ The American Society for Clinical Oncology also recommends placement of an inferior vena cava filter for patients who have contraindications to anticoagulation or for whom low-molecular-weight heparin fails.¹⁸

Case continues: Summing up

In conclusion, our patient had an underlying malignancy, causing Trousseau syndrome. Before her cancer was diagnosed, she also had test results that suggested antiphospholipid antibody syndrome. Both of these conditions likely contributed to her hypercoagulable state, increasing her propensity for clotting and causing her recurrent thrombosis. The patient is currently on low-molecular-weight heparin and is undergoing palliative chemotherapy for metastatic adenocarcinoma of the lung. To this date, she has not had any new thrombotic events.

TAKE-HOME POINTS

• Risk factors for arterial occlusion can be divided into thrombotic, embolic, and traumatic categories.
• Risk factors for venous thrombosis can be divided into hereditary and acquired categories.
• Evaluation for hypercoagulable conditions is recommended if it will affect patient management or outcome. Patients to be considered for testing include those with idiopathic DVT and who are under age 50, those with a history of recurrent thrombosis, and those with a first-degree relative with documented venous thromboembolism before age 50.
• Evaluation for hypercoagulable conditions should ideally be performed either before starting anticoagulation therapy or 2 weeks after completing it.
• Potential causes of both arterial and venous thrombosis include antiphospholipid antibody syndrome, cancer, hyperhomocysteinemia, heparin-induced thrombocytopenia, paradoxical emboli, myeloproliferative disorders, myelodysplastic syndrome, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.
• Current evidence does not support an extensive cancer evaluation in patients with idiopathic venous thromboembolism, unless dictated by the patient’s clinical condition.
• In patients with venous thromboembolism and active malignancy, anticoagulation is recommended for at least 6 to 12 months and as long as there is evidence of active malignancy.

A 43-year-old woman presents to the emergency department with substernal chest pressure of moderate intensity that started approximately 6 hours ago. The pressure radiates to both arms and is accompanied by nausea. She says she has had no emesis, diaphoresis, fevers, chills, shortness of breath, abdominal pain, melena, dysuria, weight loss, headaches, change in vision, seizures, joint pain, or skin rashes. She also says she has had no prior similar episodes and has no history of myocardial infarction (MI) or stroke.

The patient has a history of gastroesophageal reflux disease and uterine fibroids. She has had three pregnancies, one ending in spontaneous abortion at 12 weeks and two ending with healthy children delivered by cesarean section. She does not take any daily medications. She has smoked one pack per day over the last 25 years. She denies using alcohol or illicit drugs.

The patient’s mother had idiopathic deep vein thrombosis (DVT) at age 46, her father had an MI at age 65, and her sister had an MI at age 43.

On examination, she is in mild distress but is alert and oriented. Her temperature is 99.0°F (37.2°C), blood pressure 98/66 mm Hg, heart rate 65 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 99% on room air. Her body mass index is 19.5 (normal range 18.5–24.9). Her skin appears normal. Her head and neck show no obvious abnormalities, lymphadenopathy, thyromegaly, or bruits. Her heart, lungs, and abdomen are normal, as are her strength, sensation, reflexes, and gait.

Laboratory values at the time of admission:

• White blood cell count 12.58 × 10⁹/L (reference range 4.0–11.0)
• Hemoglobin 15.4 g/dL (12.0–16.0)
• Platelet count 122 × 10⁹/L (150–400)
• International normalized ratio (INR) 1.1 (0.9–1.1)
• Activated partial thromboplastin time 29.1 seconds (24.6–34).

A heart attack, and then a stroke

An initial electrocardiogram shows normal sinus rhythm, left anterior hemiblock, and nonspecific T-wave abnormalities. Cardiac enzymes are measured at intervals: her troponin T level is less than 0.01 ng/mL at the time of admission but rises to 0.75 ng/mL 3 hours later (normal range 0.0–0.1 ng/mL). Similarly, her creatine kinase-MB level is 3.3 ng/mL at admission but rises to 71.9 ng/mL 3 hours later (normal range 0.0–8.0 ng/mL).

The patient is diagnosed with non-ST-elevation MI. An intravenous heparin drip is started, and she is sent for urgent cardiac catheterization, which shows a total occlusion in a lateral obtuse marginal branch of the left circumflex artery due to a thrombus in the vessel. Otherwise, her coronary arteries are angiographically free of disease. The heparin drip is continued, and treatment is started with abciximab (ReoPro) and tissue plasminogen activator (Alteplase). She is sent to the cardiac intensive care unit for recovery, where she is placed on continuous cardiac monitoring, with no evidence of arrhythmia.

One day later, the left side of her face is drooping, her left arm is weak, and her speech is slurred. Magnetic resonance imaging of the brain shows an acute ischemic infarct in the right temporoparietal area and multiple areas of subacute to chronic ischemia. Magnetic resonance angiography of the brain indicates patent vessels. Both transthoracic and transesophageal echocardiography are performed and indicate normal left ventricular size, ejection fraction of 55%, valves without thrombus or vegetations, aorta with mild atheroma, and no patent foramen ovale by Doppler flow or agitated saline contrast study. Carotid artery Doppler ultrasonography shows 40% to 59% stenosis bilaterally.

ARTERIAL THROMBOSIS

1. Which of the following is a risk factor for arterial thrombosis?

• Atherosclerosis
• Protein C deficiency
• Use of oral contraceptive pills
• The factor V Leiden mutation

Protein C deficiency, the use of oral contraceptives, and the factor V Leiden mutation are typically associated with venous thrombosis¹; they have been documented as a cause of arterial thrombosis only in some case reports. In contrast, atherosclerosis is a well-established risk factor for arterial thrombosis.

Arterial occlusion can be due to thrombosis, embolism, or trauma

The causes of arterial occlusion can be categorized as thrombotic, embolic, or traumatic (Table 1).

Atherosclerosis is a risk factor for thrombosis and can be a source of emboli. Atherosclerotic plaque rupture may release inflammatory mediators, which also predispose to thrombosis.² This patient’s coronary arteries are essentially free of atherosclerotic disease per angiography. However, studies of intravascular ultrasonography have shown that coronary angiography may not detect all atherosclerotic plaques, as angiography can show only the lumen of the artery and not the plaque itself.³ For that reason, atherosclerosis has not been ruled out completely, and further workup is needed to evaluate other possible causes of her thrombotic events.

Embolism is the most likely cause of her stroke, however. Cases of arterial embolism can be classified on the basis of the origin of the thrombus, ie, the heart, an artery, or the venous system via a patent foramen ovale (paradoxical embolism). This patient’s echocardiogram reveals mild aortic atheroma, which can be a source of emboli, especially soon after intervention.

Case continues: Acute and recurrent DVT

While recovering from her MI and stroke, the patient develops edema and pain in both legs. Doppler ultrasonography is performed, which reveals acute DVT in the right gastrocnemius and posterior tibial veins and left soleal vein, despite her continued heparin therapy.

Her platelet count is 189 × 10⁹/L, so heparin-induced thrombocytopenia is not suspected; the new DVT is thought to be due to her hospitalization. Several days later, oral warfarin (Coumadin) is started and titrated to an INR of 2.0 to 3.0, the heparin is phased out, and the patient is sent home.

In the first few months after discharge, the patient presents to the emergency department three times with severe leg pain, and each time she is found to have extensive DVT in various leg veins even though she is complying with her warfarin therapy. At each visit, her INR is in the range of 2.5 to 3.1.

Comment. Her recurrent DVT warrants further evaluation for risk factors for venous thrombosis, which can be divided into hereditary and acquired factors.

Hereditary risk factors include the factor V Leiden mutation, the prothrombin gene mutation, hyperhomocysteinemia, dysfibrinogenemia, and deficiencies of protein C, protein S, and antithrombin.

Acquired risk factors include the antiphospholipid antibody syndrome, cancer, immobilization, surgery, congestive heart failure, pregnancy, use of hormonal contraceptives, hormone replacement therapy, nephrotic syndrome, trauma, and infection.^1,4

TESTING FOR HYPERCOAGULABLE STATES

2. In view of our patient’s recurrent thrombotic episodes, should she be tested for hypercoagulable states?

• Yes
• No

Testing for hypercoagulable conditions is warranted if it will affect the patient’s management or outcome. Some authorities recommend testing patients who are clinically characterized as “strongly” thrombophilic,⁵ ie, those who present with DVT and are younger than age 50, have recurrent thrombotic episodes, have a first-degree relative with documented thromboembolism before age 50, or have thrombotic episodes despite warfarin therapy.

This patient should be tested for hypercoagulable conditions because her initial DVT occurred before age 50 (at age 43), she has had recurrent, apparently idiopathic thrombotic episodes, she has a family history of thromboembolism, and she had clots while on therapeutic warfarin therapy, all of which suggest a hypercoagulable state. Furthermore, the confirmation of her diagnosis may affect her medical management, as it may determine if further testing and therapies are needed.

Case continues: Tests are negative

Laboratory tests for hypercoagulable conditions are performed and are negative for the factor V Leiden mutation, the prothrombin gene mutation, antithrombin deficiency, and protein C and S deficiencies. A screen for antiphospholipid antibodies is indeterminate.

TREATMENT AFFECTS TEST RESULTS

3. If a patient is on warfarin therapy, which test results may be affected?

• Antithrombin levels
• Protein C and S levels
• Factor V Leiden mutation

Warfarin decreases the levels of proteins C and S; therefore, the levels of these substances cannot be accurately interpreted in a patient taking warfarin.

All anticoagulants prolong the clotting time and may affect the results of assays based on the clotting time, such as the prothrombin time, the partial thromboplastin time, the dilute Russell’s viper venom time (DRVVT), the hexagonal phase phospholipid neutralization assay, the thrombin time, and clottable protein C and protein S. Heparin reduces the level of antithrombin; however, laboratories now have heparin-binding agents that reduce the effect of heparin in clotting studies.

Acute thrombotic states lower the levels of antithrombin and proteins C and S.

Assays not based on the clotting time (immunogenic or genetic tests such as those for anticardiolipin antibodies and the factor V Leiden and prothrombin gene mutations) are not affected by anticoagulant use.⁵

However, the presence or absence of a hypercoagulable state should not affect the treatment of acute DVT, and a full 6- to 12-month course of anticoagulation should be completed.^6,7 If possible, lupus anticoagulant testing should be repeated 2 weeks after anticoagulation is stopped.⁸

This patient needs lifelong anticoagulation because of her repeated thrombotic episodes. Stopping the medication for 2 weeks for testing would increase the risk of rethrombosis in this patient, and most experts would not advise it.

In summary, testing for hypercoagulable conditions is not recommended during an acute thrombotic episode and is preferably performed while the patient is not on anticoagulation therapy. If the patient is already on anticoagulation, the results of tests for hypercoagulable conditions should be interpreted with caution.

Case continues: Another stroke

During the subsequent year, the patient’s primary care physician monitors her warfarin use and sends her for age-appropriate cancer screening, including a breast examination, Papanicolaou smear, and mammography. Also, given her history of smoking, a chest radiograph is ordered. All of these studies are normal. In addition, evaluations for hematologic disorders such as myelodysplastic syndrome, polycythemia vera, and Waldenström macroglobulinema reveal normal complete blood counts and normal results on serum and urine protein electrophoresis.

Later that year, she returns to the emergency department with complete aphasia and total right-sided paralysis. Magnetic resonance imaging shows an acute infarct in the left frontal operculum, a subacute infarct in the right cerebellum, and multiple chronic cortical and subcortical infarcts throughout the brain. Ultrasonography shows an extensive new DVT in her right leg. Her INR at this time is 3.1.

WHAT CONDITIONS CAUSE BOTH ARTERIAL AND VENOUS THROMBOSIS?

4. Given that the patient has evidence of both recurrent arterial and venous thromboses, which of the following conditions is likely?

• Antiphospholipid antibody syndrome
• Heparin-induced thrombocytopenia
• Malignancy
• All of the above

Conditions associated with both arterial and venous thrombosis include antiphospholipid antibody syndrome, heparin-induced thrombocytopenia, malignancy, paradoxical embolism, hyperhomocysteinemia, myeloproliferative disorders, myelodysplastic disorder, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.^1,4

At present, the exact mechanism that causes Trousseau syndrome is unknown. Some hypotheses implicate mucin (produced by the cancer),¹⁰ tissue factor,¹¹ tumor-associated cysteine proteinase,¹² tumor hypoxia,¹³ and oncogene activation as plausible triggers for this syndrome.

DOES SHE HAVE ANTIPHOSPHOLIPID ANTIBODY SYNDROME?

5. The patient is positive for lupus anticoagulant. Does she have antiphospholipid antibody syndrome?

• Yes
• No
• Repeat testing is needed to meet the diagnostic criteria

The Sapporo criteria¹⁵ indicate that antiphospholipid antibody syndrome is present if at least one clinical criterion and one laboratory criterion are met. The clinical criteria are one or more episodes of arterial or venous thrombosis or pregnancy-related morbidity, ie:

• Unexplained intrauterine fetal death at 10 weeks gestation or later with no apparent fetal abnormality
• Premature births of a morphologically normal fetus at less than 34 weeks of gestation due to preeclampsia, eclampsia, or placental insufficiency
• Three or more spontaneous abortions at 10 weeks of gestation or earlier, with no known paternal chromosomal abnormalities or maternal hormonal abnormalities and normal maternal anatomy.

The laboratory criteria are:

• Lupus anticoagulant present
• Anticardiolipin antibody (IgG or IgM) titer greater than 40 IgG antiphospholipid units (GPL) or IgM antiphospholipid units (MPL) or higher than the 99th percentile of the testing laboratory normal reference range
• Anti-beta-2 glycoprotein-I antibody (IgG or IgM) titer greater than 20 GPL or MPL or higher than the 99th percentile of the testing laboratory normal reference range.

The patient likely has antiphospholipid antibody syndrome because her lupus anticoagulant screen is positive and she meets the clinical criteria of thrombosis, and she should continue to be treated accordingly. However, to officially meet the revised Sapporo criteria, she would need to have laboratory tests that are positive on two or more occasions at least 12 weeks apart.

Case continues: Lung cancer is found

The patient reports that she has lost 10 pounds in 4 months. Since age-appropriate cancer testing was previously performed, a more extensive evaluation for weight loss is undertaken, with computed tomography of the chest, abdomen, and pelvis. These tests reveal a nodule in the right upper lobe of the lung, scarring in the right middle and left lower lung lobes, and hilar lymphadenopathy. Bronchoscopy with transbronchial biopsy confirms that she has adenocarcinoma of the lung.

6. What is suggested as a sufficient workup for malignancy in patients with idiopathic venous thromboembolism?

• Computed tomography of the chest, abdomen, and pelvis for every patient with idiopathic venous thromboembolism
• Positron emission tomography and tumor marker levels
• A comprehensive history and physical examination, routine laboratory tests, chest radiography, age- and sex-specific cancer screening, and patient-specific testing as indicated clinically

To date, there is no evidence to support a cancer evaluation beyond a comprehensive medical history and physical examination, routine laboratory testing, chest radiography, and age- and sex-specific cancer screening unless it is dictated by the patient’s clinical presentation. A study by Cornuz et al¹⁶ suggested that this approach is appropriate for detecting cancer in patients with idiopathic venous thromboembolism.

A 2004 study¹⁷ attempted to answer the question of what to do about patients who have idiopathic venous thromboembolism but no other signs or symptoms that raise any clinical suspicion of cancer. This study randomized patients with idiopathic venous thromboembolism to undergo either routine medical management or an extensive malignancy evaluation. The evaluation included ultrasonography of the abdomen and pelvis, computed tomography of the abdomen and pelvis, gastroscopy or a double-contrast barium swallow study, colonoscopy or sigmoidoscopy followed by a barium enema, stool occult blood testing, and sputum cytology. Women were also tested for the tumor markers carcinoembryonic antigen, alpha-fetoprotein, and CA-125, and they underwent mammography and Papanicolaou testing; men were tested for prostate-specific antigen and underwent ultrasonography of the prostate. The results of the study did not reveal a statistically significant survival benefit in the group that underwent extensive cancer evaluation.

These studies indicate that the decision to test for cancer should be guided by clinical suspicion. Our patient lost 10 pounds in 4 months, smokes, and has had recurrent venous thromboembolism, so testing was appropriate.

After her diagnosis with adenocarcinoma of the lung, the patient has yet another DVT despite an INR of 3.1 and treatment with warfarin and aspirin.

LOW-MOLECULAR-WEIGHT HEPARIN FOR PATIENTS WITH CANCER?

7. True or false? Low-molecular-weight heparin is more effective than warfarin in preventing DVT in cancer patients without increasing the bleeding risk.

• True
• False

This statement is true. The American College of Chest Physicians (ACCP) recommends immediate treatment of DVT with low-molecular-weight heparin for 6 to 12 months after a thrombotic event in a patient with malignancy.^6,18

Two major studies provide evidence for these recommendations: the Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer (CLOT)¹⁹ and the Trial of the Effect of Low-Molecular-Weight Heparin Versus Warfarin on Mortality in the Long-Term Treatment of Proximal Deep Vein Thrombosis (LITE)²⁰ studies.

The CLOT¹⁹ study showed that dalteparin (Fragmin) 200 IU/kg subcutaneously once daily for l month and then 150 IU/kg once daily was more effective than oral warfarin titrated to an INR of 2.5 and did not increase the risk of bleeding.

The LITE trial²⁰ showed the efficacy of tinzaparin (Innohep) 175 IU/kg subcutaneously daily, which can be used as an alternative.

Enoxaparin sodium (Lovenox) 1.5 mg/kg once daily has also been used. However, if low-molecular-weight heparin is not available, warfarin titrated to an INR of 2 to 3 is also acceptable.¹⁸

The ACCP consensus panel recommends giving anticoagulation for an initial 6 to 12 months and continuing it as long as there is evidence of active malignancy.⁶ The American Society for Clinical Oncology also recommends placement of an inferior vena cava filter for patients who have contraindications to anticoagulation or for whom low-molecular-weight heparin fails.¹⁸

Case continues: Summing up

In conclusion, our patient had an underlying malignancy, causing Trousseau syndrome. Before her cancer was diagnosed, she also had test results that suggested antiphospholipid antibody syndrome. Both of these conditions likely contributed to her hypercoagulable state, increasing her propensity for clotting and causing her recurrent thrombosis. The patient is currently on low-molecular-weight heparin and is undergoing palliative chemotherapy for metastatic adenocarcinoma of the lung. To this date, she has not had any new thrombotic events.

TAKE-HOME POINTS

• Risk factors for arterial occlusion can be divided into thrombotic, embolic, and traumatic categories.
• Risk factors for venous thrombosis can be divided into hereditary and acquired categories.
• Evaluation for hypercoagulable conditions is recommended if it will affect patient management or outcome. Patients to be considered for testing include those with idiopathic DVT and who are under age 50, those with a history of recurrent thrombosis, and those with a first-degree relative with documented venous thromboembolism before age 50.
• Evaluation for hypercoagulable conditions should ideally be performed either before starting anticoagulation therapy or 2 weeks after completing it.
• Potential causes of both arterial and venous thrombosis include antiphospholipid antibody syndrome, cancer, hyperhomocysteinemia, heparin-induced thrombocytopenia, paradoxical emboli, myeloproliferative disorders, myelodysplastic syndrome, paraproteinemia, vasculitis, and paroxysmal nocturnal hemoglobinuria.
• Current evidence does not support an extensive cancer evaluation in patients with idiopathic venous thromboembolism, unless dictated by the patient’s clinical condition.
• In patients with venous thromboembolism and active malignancy, anticoagulation is recommended for at least 6 to 12 months and as long as there is evidence of active malignancy.

A 28-year-old woman comes in for her annual checkup. Her physician notices a palpable, painless, 1-cm, well-demarcated mass in the left breast at the 3 o’clock position 2 cm from the nipple, with no associated skin changes, nipple retraction, or discharge. The patient has no personal or family history of breast cancer.

Given the patient’s age, physical findings, and medical history, the clinician believes it unlikely that the patient has cancer. How should she proceed with the workup of this patient?

PHYSICAL FINDINGS OF A BREAST MASS ARE NOT EXCLUSIVE

Benign lesions tend to have discrete, well-defined margins and are typically mobile. Malignant lesions may be firm, may have indistinct borders, and are often immobile.² Although most breast masses found by palpation are benign, imaging is the critical next step in the workup to help determine if the mass is benign or malignant.

Benign palpable masses include:

• 

  Cysts (Figure 1)
• Fibroadenomas (Figure 2)
• Prominent fat lobules
• Lymph nodes
• Oil cysts
• Lipomas
• Hamartomas (Figure 3)
• Hematomas
• Fat necrosis
• Galactoceles.

Malignant palpable masses include:

• 

  Invasive ductal and lobular carcinoma (Figure 4)
• Ductal carcinoma in situ (which rarely presents as a palpable mass.)

HISTORY AND PHYSICAL EXAMINATION

To ensure that imaging provides the most useful information about a palpable breast lump, it is important to first do a careful history and physical examination. Important aspects of the history include family history, personal history of breast cancer, and any previous breast biopsies. The onset and duration of the palpable mass, changes in its size, the relationship of these changes to the menstrual cycle, and the presence or lack of tenderness are additional important elements of the history.

IMAGING TECHNIQUES

Mammography and ultrasonography are the primary imaging studies for evaluating palpable breast masses. Typically, in women under age 30, ultrasonography is the first or the only test ordered to evaluate the abnormality.⁴ In women age 30 or older, diagnostic mammography is typically the first test ordered. If mammography indicates that the palpable mass is not benign, then ultrasonography is the next study to be done.³ Although a powerful tool, magnetic resonance imaging of the breast does not currently have a role in the workup of a palpable abnormality and should not be used as a decision-delaying tactic or in place of biopsy.

Screening or diagnostic mammography?

Mammography is used in both screening and diagnosis. Screening mammography consists of two standard views of each breast—craniocaudal and mediolateral oblique—and is appropriate for asymptomatic women.

Women age 30 or older who present with a palpable breast mass require diagnostic mammography, in which standard mammographic views are obtained, as well as additional views (eg, tangential or spot-compression views) to better define the area of clinical concern. In a tangential view, a metallic skin marker is placed on the skin overlying the site of the palpable abnormality.

On mammography, a suspicious palpable mass has an irregular shape with spiculated margins. A benign mass typically has a round shape with well-circumscribed margins. If the palpable abnormality is not mammographically benign (eg, if it does not look like a lymph node, lipoma, or degenerating fibroadenoma), then ultrasonography is performed.

Mammography is less sensitive in younger women (ie, under age 30) because their breast tissue tends to be dense and glandular, whereas the tissue becomes more “fat-replaced” with age.³

Ultrasonography plays a complementary role

Ultrasonography complements diagnostic mammography and can be used as a first imaging study to evaluate a palpable breast mass in a young woman (ie, under age 30) with dense breast tissue. Ultrasonography is helpful in distinguishing cystic lesions from solid masses. It helps the radiologist delineate the shape, borders, and acoustic properties of the mass. It is also performed when a palpable mass is mammographically occult. When a mass appears suspicious on either mammography or ultrasonography, ultrasonography can be used to guide biopsy.

A suspicious mass on ultrasonography classically appears “taller than wide” and has posterior acoustic shadowing. Microlobulations and a spiculated margin also raise concern for malignancy. A benign sonographic appearance of a palpable mass includes a “wider than tall” (ellipsoid) shape, with homogeneous echogenicity, and four or fewer gentle lobulations. A thin, echogenic capsule also suggests the mass is benign.

Core-needle biopsy with ultrasonographic guidance

Core-needle biopsy is performed with a large-diameter (14-gauge to 18-gauge) needle to obtain tissue cores for histologic analysis. It has gained popularity over fine-needle aspiration because it includes surrounding tissue architecture, thus providing a more definitive histologic diagnosis.

Pathologic information obtained from core-needle biopsy allows the radiologist and surgeon to counsel the patient and determine the best surgical management or follow-up imaging study. If a clinician performs fine-needle biopsy in the office, it should be preceded by an imaging workup of the palpable finding.

WHAT IS APPROPRIATE FOR OUR 28-YEAR-OLD PATIENT?

Because she is under age 30, ultrasonography is the initial study of choice to evaluate the mass. If a simple cyst is detected, she can be reassured that the lesion is benign, and no subsequent follow-up is required. If the lesion is a solid mass with benign features, mammography may be considered, the patient may be followed with short-interval imaging (every 6 months) depending on patient-specific factors such as family history, or the mass can be biopsied. If the lesion is a solid mass with suspicious or malignant features, mammography with spot-compression views should be performed, and the patient should undergo core-needle biopsy with ultrasonographic guidance.

In a patient age 30 or older, diagnostic mammography is the imaging study of first choice.³ If the mass is clearly benign on mammography, no additional imaging would be necessary. If mammography fails to image the mass or shows it to have benign features such as fat, then the patient can undergo ultrasonography for further evaluation and confirmation of the clinical and mammographic findings. If the mass appears suspicious or malignant on mammography, ultrasonography is the next step, as it can help characterize the lesion and be used to guide core-needle biopsy.

IF A PREGNANT WOMAN HAS A PALPABLE BREAST MASS

Most publications on breast cancer in pregnancy report a prevalence of 3 per 10,000 pregnancies, accounting for 3% of all breast cancers diagnosed.⁵ Therefore, imaging evaluation of a palpable mass should not be postponed.

Hormonal changes throughout pregnancy may increase the nodularity of breast tissue, raising the concern of palpable masses. Additionally, there is a higher prevalence of galactoceles and lactating adenomas in these patients. Because contrasting fatty breast tissue is lost during pregnancy and because of the need to minimize radiation exposure, ultrasonography is often the imaging test of first choice. If mammography is required, the radiation dose is very low and the patient’s abdomen and pelvis can be shielded.⁶ In this situation, the patient can be reassured that the imaging test is not jeopardizing her fetus.

WHAT WORKUP IS REQUIRED IN MEN?

Breast cancer in men is rare, accounting for less than 0.5% of all cases.⁷ Most often, a palpable breast mass in a man presents as unilateral gynecomastia. Gynecomastia occurs in a bimodal age distribution (in the 2nd and 7th decades) and has a variety of hormonal and drug-related causes. Despite the low prevalence of breast cancer in men, the combination of mammography and ultrasonography is recommended for evaluation at all ages.

A 28-year-old woman comes in for her annual checkup. Her physician notices a palpable, painless, 1-cm, well-demarcated mass in the left breast at the 3 o’clock position 2 cm from the nipple, with no associated skin changes, nipple retraction, or discharge. The patient has no personal or family history of breast cancer.

Given the patient’s age, physical findings, and medical history, the clinician believes it unlikely that the patient has cancer. How should she proceed with the workup of this patient?

PHYSICAL FINDINGS OF A BREAST MASS ARE NOT EXCLUSIVE

Benign lesions tend to have discrete, well-defined margins and are typically mobile. Malignant lesions may be firm, may have indistinct borders, and are often immobile.² Although most breast masses found by palpation are benign, imaging is the critical next step in the workup to help determine if the mass is benign or malignant.

Benign palpable masses include:

• 

  Cysts (Figure 1)
• Fibroadenomas (Figure 2)
• Prominent fat lobules
• Lymph nodes
• Oil cysts
• Lipomas
• Hamartomas (Figure 3)
• Hematomas
• Fat necrosis
• Galactoceles.

Malignant palpable masses include:

• 

  Invasive ductal and lobular carcinoma (Figure 4)
• Ductal carcinoma in situ (which rarely presents as a palpable mass.)

HISTORY AND PHYSICAL EXAMINATION

To ensure that imaging provides the most useful information about a palpable breast lump, it is important to first do a careful history and physical examination. Important aspects of the history include family history, personal history of breast cancer, and any previous breast biopsies. The onset and duration of the palpable mass, changes in its size, the relationship of these changes to the menstrual cycle, and the presence or lack of tenderness are additional important elements of the history.

IMAGING TECHNIQUES

Mammography and ultrasonography are the primary imaging studies for evaluating palpable breast masses. Typically, in women under age 30, ultrasonography is the first or the only test ordered to evaluate the abnormality.⁴ In women age 30 or older, diagnostic mammography is typically the first test ordered. If mammography indicates that the palpable mass is not benign, then ultrasonography is the next study to be done.³ Although a powerful tool, magnetic resonance imaging of the breast does not currently have a role in the workup of a palpable abnormality and should not be used as a decision-delaying tactic or in place of biopsy.

Screening or diagnostic mammography?

Mammography is used in both screening and diagnosis. Screening mammography consists of two standard views of each breast—craniocaudal and mediolateral oblique—and is appropriate for asymptomatic women.

Women age 30 or older who present with a palpable breast mass require diagnostic mammography, in which standard mammographic views are obtained, as well as additional views (eg, tangential or spot-compression views) to better define the area of clinical concern. In a tangential view, a metallic skin marker is placed on the skin overlying the site of the palpable abnormality.

On mammography, a suspicious palpable mass has an irregular shape with spiculated margins. A benign mass typically has a round shape with well-circumscribed margins. If the palpable abnormality is not mammographically benign (eg, if it does not look like a lymph node, lipoma, or degenerating fibroadenoma), then ultrasonography is performed.

Mammography is less sensitive in younger women (ie, under age 30) because their breast tissue tends to be dense and glandular, whereas the tissue becomes more “fat-replaced” with age.³

Ultrasonography plays a complementary role

Ultrasonography complements diagnostic mammography and can be used as a first imaging study to evaluate a palpable breast mass in a young woman (ie, under age 30) with dense breast tissue. Ultrasonography is helpful in distinguishing cystic lesions from solid masses. It helps the radiologist delineate the shape, borders, and acoustic properties of the mass. It is also performed when a palpable mass is mammographically occult. When a mass appears suspicious on either mammography or ultrasonography, ultrasonography can be used to guide biopsy.

A suspicious mass on ultrasonography classically appears “taller than wide” and has posterior acoustic shadowing. Microlobulations and a spiculated margin also raise concern for malignancy. A benign sonographic appearance of a palpable mass includes a “wider than tall” (ellipsoid) shape, with homogeneous echogenicity, and four or fewer gentle lobulations. A thin, echogenic capsule also suggests the mass is benign.

Core-needle biopsy with ultrasonographic guidance

Core-needle biopsy is performed with a large-diameter (14-gauge to 18-gauge) needle to obtain tissue cores for histologic analysis. It has gained popularity over fine-needle aspiration because it includes surrounding tissue architecture, thus providing a more definitive histologic diagnosis.

Pathologic information obtained from core-needle biopsy allows the radiologist and surgeon to counsel the patient and determine the best surgical management or follow-up imaging study. If a clinician performs fine-needle biopsy in the office, it should be preceded by an imaging workup of the palpable finding.

WHAT IS APPROPRIATE FOR OUR 28-YEAR-OLD PATIENT?

Because she is under age 30, ultrasonography is the initial study of choice to evaluate the mass. If a simple cyst is detected, she can be reassured that the lesion is benign, and no subsequent follow-up is required. If the lesion is a solid mass with benign features, mammography may be considered, the patient may be followed with short-interval imaging (every 6 months) depending on patient-specific factors such as family history, or the mass can be biopsied. If the lesion is a solid mass with suspicious or malignant features, mammography with spot-compression views should be performed, and the patient should undergo core-needle biopsy with ultrasonographic guidance.

In a patient age 30 or older, diagnostic mammography is the imaging study of first choice.³ If the mass is clearly benign on mammography, no additional imaging would be necessary. If mammography fails to image the mass or shows it to have benign features such as fat, then the patient can undergo ultrasonography for further evaluation and confirmation of the clinical and mammographic findings. If the mass appears suspicious or malignant on mammography, ultrasonography is the next step, as it can help characterize the lesion and be used to guide core-needle biopsy.

IF A PREGNANT WOMAN HAS A PALPABLE BREAST MASS

Most publications on breast cancer in pregnancy report a prevalence of 3 per 10,000 pregnancies, accounting for 3% of all breast cancers diagnosed.⁵ Therefore, imaging evaluation of a palpable mass should not be postponed.

Hormonal changes throughout pregnancy may increase the nodularity of breast tissue, raising the concern of palpable masses. Additionally, there is a higher prevalence of galactoceles and lactating adenomas in these patients. Because contrasting fatty breast tissue is lost during pregnancy and because of the need to minimize radiation exposure, ultrasonography is often the imaging test of first choice. If mammography is required, the radiation dose is very low and the patient’s abdomen and pelvis can be shielded.⁶ In this situation, the patient can be reassured that the imaging test is not jeopardizing her fetus.

WHAT WORKUP IS REQUIRED IN MEN?

Breast cancer in men is rare, accounting for less than 0.5% of all cases.⁷ Most often, a palpable breast mass in a man presents as unilateral gynecomastia. Gynecomastia occurs in a bimodal age distribution (in the 2nd and 7th decades) and has a variety of hormonal and drug-related causes. Despite the low prevalence of breast cancer in men, the combination of mammography and ultrasonography is recommended for evaluation at all ages.

A 28-year-old woman comes in for her annual checkup. Her physician notices a palpable, painless, 1-cm, well-demarcated mass in the left breast at the 3 o’clock position 2 cm from the nipple, with no associated skin changes, nipple retraction, or discharge. The patient has no personal or family history of breast cancer.

Given the patient’s age, physical findings, and medical history, the clinician believes it unlikely that the patient has cancer. How should she proceed with the workup of this patient?

PHYSICAL FINDINGS OF A BREAST MASS ARE NOT EXCLUSIVE

Benign lesions tend to have discrete, well-defined margins and are typically mobile. Malignant lesions may be firm, may have indistinct borders, and are often immobile.² Although most breast masses found by palpation are benign, imaging is the critical next step in the workup to help determine if the mass is benign or malignant.

Benign palpable masses include:

• 

  Cysts (Figure 1)
• Fibroadenomas (Figure 2)
• Prominent fat lobules
• Lymph nodes
• Oil cysts
• Lipomas
• Hamartomas (Figure 3)
• Hematomas
• Fat necrosis
• Galactoceles.

Malignant palpable masses include:

• 

  Invasive ductal and lobular carcinoma (Figure 4)
• Ductal carcinoma in situ (which rarely presents as a palpable mass.)

HISTORY AND PHYSICAL EXAMINATION

To ensure that imaging provides the most useful information about a palpable breast lump, it is important to first do a careful history and physical examination. Important aspects of the history include family history, personal history of breast cancer, and any previous breast biopsies. The onset and duration of the palpable mass, changes in its size, the relationship of these changes to the menstrual cycle, and the presence or lack of tenderness are additional important elements of the history.

IMAGING TECHNIQUES

Mammography and ultrasonography are the primary imaging studies for evaluating palpable breast masses. Typically, in women under age 30, ultrasonography is the first or the only test ordered to evaluate the abnormality.⁴ In women age 30 or older, diagnostic mammography is typically the first test ordered. If mammography indicates that the palpable mass is not benign, then ultrasonography is the next study to be done.³ Although a powerful tool, magnetic resonance imaging of the breast does not currently have a role in the workup of a palpable abnormality and should not be used as a decision-delaying tactic or in place of biopsy.

Screening or diagnostic mammography?

Mammography is used in both screening and diagnosis. Screening mammography consists of two standard views of each breast—craniocaudal and mediolateral oblique—and is appropriate for asymptomatic women.

Women age 30 or older who present with a palpable breast mass require diagnostic mammography, in which standard mammographic views are obtained, as well as additional views (eg, tangential or spot-compression views) to better define the area of clinical concern. In a tangential view, a metallic skin marker is placed on the skin overlying the site of the palpable abnormality.

On mammography, a suspicious palpable mass has an irregular shape with spiculated margins. A benign mass typically has a round shape with well-circumscribed margins. If the palpable abnormality is not mammographically benign (eg, if it does not look like a lymph node, lipoma, or degenerating fibroadenoma), then ultrasonography is performed.

Mammography is less sensitive in younger women (ie, under age 30) because their breast tissue tends to be dense and glandular, whereas the tissue becomes more “fat-replaced” with age.³

Ultrasonography plays a complementary role

Ultrasonography complements diagnostic mammography and can be used as a first imaging study to evaluate a palpable breast mass in a young woman (ie, under age 30) with dense breast tissue. Ultrasonography is helpful in distinguishing cystic lesions from solid masses. It helps the radiologist delineate the shape, borders, and acoustic properties of the mass. It is also performed when a palpable mass is mammographically occult. When a mass appears suspicious on either mammography or ultrasonography, ultrasonography can be used to guide biopsy.

A suspicious mass on ultrasonography classically appears “taller than wide” and has posterior acoustic shadowing. Microlobulations and a spiculated margin also raise concern for malignancy. A benign sonographic appearance of a palpable mass includes a “wider than tall” (ellipsoid) shape, with homogeneous echogenicity, and four or fewer gentle lobulations. A thin, echogenic capsule also suggests the mass is benign.

Core-needle biopsy with ultrasonographic guidance

Core-needle biopsy is performed with a large-diameter (14-gauge to 18-gauge) needle to obtain tissue cores for histologic analysis. It has gained popularity over fine-needle aspiration because it includes surrounding tissue architecture, thus providing a more definitive histologic diagnosis.

Pathologic information obtained from core-needle biopsy allows the radiologist and surgeon to counsel the patient and determine the best surgical management or follow-up imaging study. If a clinician performs fine-needle biopsy in the office, it should be preceded by an imaging workup of the palpable finding.

WHAT IS APPROPRIATE FOR OUR 28-YEAR-OLD PATIENT?

Because she is under age 30, ultrasonography is the initial study of choice to evaluate the mass. If a simple cyst is detected, she can be reassured that the lesion is benign, and no subsequent follow-up is required. If the lesion is a solid mass with benign features, mammography may be considered, the patient may be followed with short-interval imaging (every 6 months) depending on patient-specific factors such as family history, or the mass can be biopsied. If the lesion is a solid mass with suspicious or malignant features, mammography with spot-compression views should be performed, and the patient should undergo core-needle biopsy with ultrasonographic guidance.

In a patient age 30 or older, diagnostic mammography is the imaging study of first choice.³ If the mass is clearly benign on mammography, no additional imaging would be necessary. If mammography fails to image the mass or shows it to have benign features such as fat, then the patient can undergo ultrasonography for further evaluation and confirmation of the clinical and mammographic findings. If the mass appears suspicious or malignant on mammography, ultrasonography is the next step, as it can help characterize the lesion and be used to guide core-needle biopsy.

IF A PREGNANT WOMAN HAS A PALPABLE BREAST MASS

Most publications on breast cancer in pregnancy report a prevalence of 3 per 10,000 pregnancies, accounting for 3% of all breast cancers diagnosed.⁵ Therefore, imaging evaluation of a palpable mass should not be postponed.

Hormonal changes throughout pregnancy may increase the nodularity of breast tissue, raising the concern of palpable masses. Additionally, there is a higher prevalence of galactoceles and lactating adenomas in these patients. Because contrasting fatty breast tissue is lost during pregnancy and because of the need to minimize radiation exposure, ultrasonography is often the imaging test of first choice. If mammography is required, the radiation dose is very low and the patient’s abdomen and pelvis can be shielded.⁶ In this situation, the patient can be reassured that the imaging test is not jeopardizing her fetus.

WHAT WORKUP IS REQUIRED IN MEN?

Breast cancer in men is rare, accounting for less than 0.5% of all cases.⁷ Most often, a palpable breast mass in a man presents as unilateral gynecomastia. Gynecomastia occurs in a bimodal age distribution (in the 2nd and 7th decades) and has a variety of hormonal and drug-related causes. Despite the low prevalence of breast cancer in men, the combination of mammography and ultrasonography is recommended for evaluation at all ages.

A 54-year-old man presents with sudden visual loss in the left eye. The left eye and left periorbital area have been painful for the past 5 days.

Duplex ultrasonography of the carotid arteries shows total occlusion of the left internal carotid artery. Fluorescein angiography of the fundus reveals focal hyperfluorescence with delayed arteriovenous transit time in the left eye.

Q: Which of the following diagnoses is the most likely at this point in the evaluation?

• Hypertensive retinopathy
• Diabetic retinopathy
• Human immunodeficiency virus (HIV) retinopathy
• Retinal involvement of systemic autoimmune disease
• Ocular ischemic syndrome

A: The ocular symptoms of hypertension, diabetes mellitus, HIV infection, and other autoimmune diseases usually present bilaterally, and funduscopic examination often reveals other signs such as vessel tortuosity, venous dilation, microaneurysms, retinal hemorrhages, hard exudates, and new vessel formation, in addition to cotton wool spots. In this patient, the lack of these signs and the unilateral cotton wool spots combined with the delay in arteriovenous transit time on fluorescein angiography point to ocular ischemic syndrome.

Ocular ischemic syndrome is the result of hypoperfusion of the globe caused by obstruction of the carotid or the ophthalmic artery,¹ most commonly from atherosclerosis. Retinal hypoperfusion is also caused by arteritis, external compression, dissection of the artery,² and, rarely, cardiac failure.

USUAL SIGNS AND SYMPTOMS

Usually, the patient presents with visual loss that has progressed gradually over a period of weeks or months and is associated with dull aching in the eye or orbit (“ocular angina”).³ Cotton wool spots on funduscopic examination represent retinal nerve fiber layer infarcts, a sign of retinal hypoperfusion. Delays in the choroidal filling time and the arteriole-to-venule transit time on fluorescein angiography confirm the diagnosis.

Strong clue to underlying disease

Ocular ischemic syndrome is an important clue to underlying macrovascular atherosclerotic disease: 50% of patients with ocular ischemic syndrome have ischemic heart disease, 25% have a history of stroke, and 20% have severe peripheral vascular disease. Ocular complications of the syndrome are rubeosis iridis, neovascular glaucoma, and neovascularization of the optic disc and retina. Prompt diagnosis is very important because the death rate at 5 years is 40%.⁴

Recommended workup

The recommended workup is a thorough history and physical examination to identify underlying systemic disease such as diabetes, hypertension, or collagen vascular disease. When carotid artery disease is suspected, a noninvasive vascular workup with carotid duplex ultrasonography is mandatory to confirm carotid arterial disease, to establish its cause, and to assess the severity of the lesion.

CURRENT TREATMENT OPTIONS

Treatment focuses on the control of systemic risk factors and follow-up to monitor for systemic and ocular complications. The combination of aspirin and extended-release dipyridamole (Aggrenox) is currently considered the most effective antiplatelet strategy, as it reduces the risk of stroke by 37% compared with 25% with aspirin alone.⁵

Carotid endarterectomy has been shown to benefit symptomatic patients with nondisabling stroke, amaurosis fugax, and a hemispheric transient ischemic attack and who have carotid stenosis of 70% to 99%. The North American Symptomatic Carotid Endarterectomy Trial found a 2-year stroke rate of 9% in such patients who underwent endarterectomy vs 26% in those treated with antiplatelet therapy alone.^6,7 Some improvement in visual outcomes was also noted, but the data so far are not conclusive.⁶

Bypass procedures such as anastomosis of the superficial temporal artery to the middle cerebral artery have been tried in patients with 100% obstruction of the carotid artery in whom a thrombus has propagated distally, thus precluding endarterectomy.

We continue to monitor our patient for the development of ocular complications. The development of retinal neovascularization may warrant panretinal photocoagulation with or without anterior retinal cryoablation. Panretinal photocoagulation decreases the retinal demand for oxygen and decreases the release of angiogenic factors, thereby arresting the growth of neovascularization and preventing complications such as vitreous hemorrhage and tractional retinal detachment. Although no studies have analyzed the benefit of panretinal photocoagulation in patients with ocular ischemia, its long-term benefit has been well documented in diabetic patients.⁸

A 54-year-old man presents with sudden visual loss in the left eye. The left eye and left periorbital area have been painful for the past 5 days.

Duplex ultrasonography of the carotid arteries shows total occlusion of the left internal carotid artery. Fluorescein angiography of the fundus reveals focal hyperfluorescence with delayed arteriovenous transit time in the left eye.

Q: Which of the following diagnoses is the most likely at this point in the evaluation?

• Hypertensive retinopathy
• Diabetic retinopathy
• Human immunodeficiency virus (HIV) retinopathy
• Retinal involvement of systemic autoimmune disease
• Ocular ischemic syndrome

A: The ocular symptoms of hypertension, diabetes mellitus, HIV infection, and other autoimmune diseases usually present bilaterally, and funduscopic examination often reveals other signs such as vessel tortuosity, venous dilation, microaneurysms, retinal hemorrhages, hard exudates, and new vessel formation, in addition to cotton wool spots. In this patient, the lack of these signs and the unilateral cotton wool spots combined with the delay in arteriovenous transit time on fluorescein angiography point to ocular ischemic syndrome.

Ocular ischemic syndrome is the result of hypoperfusion of the globe caused by obstruction of the carotid or the ophthalmic artery,¹ most commonly from atherosclerosis. Retinal hypoperfusion is also caused by arteritis, external compression, dissection of the artery,² and, rarely, cardiac failure.

USUAL SIGNS AND SYMPTOMS

Usually, the patient presents with visual loss that has progressed gradually over a period of weeks or months and is associated with dull aching in the eye or orbit (“ocular angina”).³ Cotton wool spots on funduscopic examination represent retinal nerve fiber layer infarcts, a sign of retinal hypoperfusion. Delays in the choroidal filling time and the arteriole-to-venule transit time on fluorescein angiography confirm the diagnosis.

Strong clue to underlying disease

Ocular ischemic syndrome is an important clue to underlying macrovascular atherosclerotic disease: 50% of patients with ocular ischemic syndrome have ischemic heart disease, 25% have a history of stroke, and 20% have severe peripheral vascular disease. Ocular complications of the syndrome are rubeosis iridis, neovascular glaucoma, and neovascularization of the optic disc and retina. Prompt diagnosis is very important because the death rate at 5 years is 40%.⁴

Recommended workup

The recommended workup is a thorough history and physical examination to identify underlying systemic disease such as diabetes, hypertension, or collagen vascular disease. When carotid artery disease is suspected, a noninvasive vascular workup with carotid duplex ultrasonography is mandatory to confirm carotid arterial disease, to establish its cause, and to assess the severity of the lesion.

CURRENT TREATMENT OPTIONS

Treatment focuses on the control of systemic risk factors and follow-up to monitor for systemic and ocular complications. The combination of aspirin and extended-release dipyridamole (Aggrenox) is currently considered the most effective antiplatelet strategy, as it reduces the risk of stroke by 37% compared with 25% with aspirin alone.⁵

Carotid endarterectomy has been shown to benefit symptomatic patients with nondisabling stroke, amaurosis fugax, and a hemispheric transient ischemic attack and who have carotid stenosis of 70% to 99%. The North American Symptomatic Carotid Endarterectomy Trial found a 2-year stroke rate of 9% in such patients who underwent endarterectomy vs 26% in those treated with antiplatelet therapy alone.^6,7 Some improvement in visual outcomes was also noted, but the data so far are not conclusive.⁶

Bypass procedures such as anastomosis of the superficial temporal artery to the middle cerebral artery have been tried in patients with 100% obstruction of the carotid artery in whom a thrombus has propagated distally, thus precluding endarterectomy.

We continue to monitor our patient for the development of ocular complications. The development of retinal neovascularization may warrant panretinal photocoagulation with or without anterior retinal cryoablation. Panretinal photocoagulation decreases the retinal demand for oxygen and decreases the release of angiogenic factors, thereby arresting the growth of neovascularization and preventing complications such as vitreous hemorrhage and tractional retinal detachment. Although no studies have analyzed the benefit of panretinal photocoagulation in patients with ocular ischemia, its long-term benefit has been well documented in diabetic patients.⁸

A 54-year-old man presents with sudden visual loss in the left eye. The left eye and left periorbital area have been painful for the past 5 days.

Duplex ultrasonography of the carotid arteries shows total occlusion of the left internal carotid artery. Fluorescein angiography of the fundus reveals focal hyperfluorescence with delayed arteriovenous transit time in the left eye.

Q: Which of the following diagnoses is the most likely at this point in the evaluation?

• Hypertensive retinopathy
• Diabetic retinopathy
• Human immunodeficiency virus (HIV) retinopathy
• Retinal involvement of systemic autoimmune disease
• Ocular ischemic syndrome

A: The ocular symptoms of hypertension, diabetes mellitus, HIV infection, and other autoimmune diseases usually present bilaterally, and funduscopic examination often reveals other signs such as vessel tortuosity, venous dilation, microaneurysms, retinal hemorrhages, hard exudates, and new vessel formation, in addition to cotton wool spots. In this patient, the lack of these signs and the unilateral cotton wool spots combined with the delay in arteriovenous transit time on fluorescein angiography point to ocular ischemic syndrome.

Ocular ischemic syndrome is the result of hypoperfusion of the globe caused by obstruction of the carotid or the ophthalmic artery,¹ most commonly from atherosclerosis. Retinal hypoperfusion is also caused by arteritis, external compression, dissection of the artery,² and, rarely, cardiac failure.

USUAL SIGNS AND SYMPTOMS

Usually, the patient presents with visual loss that has progressed gradually over a period of weeks or months and is associated with dull aching in the eye or orbit (“ocular angina”).³ Cotton wool spots on funduscopic examination represent retinal nerve fiber layer infarcts, a sign of retinal hypoperfusion. Delays in the choroidal filling time and the arteriole-to-venule transit time on fluorescein angiography confirm the diagnosis.

Strong clue to underlying disease

Ocular ischemic syndrome is an important clue to underlying macrovascular atherosclerotic disease: 50% of patients with ocular ischemic syndrome have ischemic heart disease, 25% have a history of stroke, and 20% have severe peripheral vascular disease. Ocular complications of the syndrome are rubeosis iridis, neovascular glaucoma, and neovascularization of the optic disc and retina. Prompt diagnosis is very important because the death rate at 5 years is 40%.⁴

Recommended workup

The recommended workup is a thorough history and physical examination to identify underlying systemic disease such as diabetes, hypertension, or collagen vascular disease. When carotid artery disease is suspected, a noninvasive vascular workup with carotid duplex ultrasonography is mandatory to confirm carotid arterial disease, to establish its cause, and to assess the severity of the lesion.

CURRENT TREATMENT OPTIONS

Treatment focuses on the control of systemic risk factors and follow-up to monitor for systemic and ocular complications. The combination of aspirin and extended-release dipyridamole (Aggrenox) is currently considered the most effective antiplatelet strategy, as it reduces the risk of stroke by 37% compared with 25% with aspirin alone.⁵

Carotid endarterectomy has been shown to benefit symptomatic patients with nondisabling stroke, amaurosis fugax, and a hemispheric transient ischemic attack and who have carotid stenosis of 70% to 99%. The North American Symptomatic Carotid Endarterectomy Trial found a 2-year stroke rate of 9% in such patients who underwent endarterectomy vs 26% in those treated with antiplatelet therapy alone.^6,7 Some improvement in visual outcomes was also noted, but the data so far are not conclusive.⁶

Bypass procedures such as anastomosis of the superficial temporal artery to the middle cerebral artery have been tried in patients with 100% obstruction of the carotid artery in whom a thrombus has propagated distally, thus precluding endarterectomy.

We continue to monitor our patient for the development of ocular complications. The development of retinal neovascularization may warrant panretinal photocoagulation with or without anterior retinal cryoablation. Panretinal photocoagulation decreases the retinal demand for oxygen and decreases the release of angiogenic factors, thereby arresting the growth of neovascularization and preventing complications such as vitreous hemorrhage and tractional retinal detachment. Although no studies have analyzed the benefit of panretinal photocoagulation in patients with ocular ischemia, its long-term benefit has been well documented in diabetic patients.⁸

Highlights of the 2008 recommendations of the CDC’s Advisory Committee on Immunization Practices (ACIP), detailed in the child and adult immunization schedules in the MMWR in January,^1,2 include:

• an expansion of the age groups for whom an annual influenza vaccine is recommended;
• expanded indications for the pneumococcal polysaccharide vaccine;
• 2 new combination vaccines for children; and
• a second rotavirus vaccine, with revised recommendations to accommodate both vaccine products.

School-age children should get flu vaccine

Children and adolescents ages 5 through 18 years are now among those who should receive an annual flu vaccine. Previously, routine vaccination was recommended only for adults and children ages 6 months through 59 months.³

Because of the timing of vaccine purchase, ACIP recognizes that routine vaccination of 5- to 18-year-olds may not be possible in some settings until next year. Family physicians who are unable to fully incorporate this new recommendation in the 2008-2009 flu season should immunize children and adolescents who are at high risk for complications of the flu. Included in that group are 5- to 18-year-olds who are on long-term aspirin therapy; have a chronic pulmonary disease, including asthma, or a cardiovascular, renal, hepatic, hematologic, or metabolic disorder; are immunosuppressed; or have a neurological or musculoskeletal disorder that alters respiratory function or the clearance of respiratory secretions. Children and adolescents who live with others at elevated risk—kids younger than 5 years, adults older than 50 years, or individuals with medical conditions that place them at high risk for severe influenza complications—should also be vaccinated.

Pneumococcal vaccine: New indications, clarifications

Two new groups have been added to the list of people for whom the 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended: asthma patients and smokers. Smoking poses as great a risk for pneumococcal pneumonia as diabetes and other chronic illnesses that had already been noted as indications for the vaccine. The number needed to vaccinate to prevent 1 case of pneumonia in smokers is 10,000 for those between the ages of 18 to 44 years, and 4000 for those ages 45 to 64 years.

A second dose. Also in 2008, ACIP clarified its dosing recommendations for PPV23: A second dose, given 5 years after the first, is recommended for those with immune suppression, sickle cell disease, or asplenia. Individuals who are 65 years of age or older should receive a second dose if they were vaccinated 5 or more years ago and were younger than 65 at the time of primary vaccination.

Not for all Native Americans. The recommendation for the use of PPV23 among the Native American population has changed, too.

Research showing high rates of invasive pneumococcal disease in Native American communities has been performed in only a few locations and cannot be generalized to all Native Americans. Therefore, ACIP has gone from recommending routine use of the vaccine among all Native Americans to a recommendation based on the same risks and age recommendations as the general population and, in communities with high rates of disease, on public health recommendations based on the incidence and epidemiology of disease.

Combination products may mean fewer injections

Two new combination vaccine products—Pentacel⁴ and Kinrix⁵—were approved last year. Both can reduce the number of injections required to complete the child immunization recommendations.

Pentacel combines 5 vaccines—diphtheria, tetanus, and pertussis (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib)—and is licensed for children 6 weeks through 4 years of age. Pentacel has a 4-dose schedule, with vaccine administration at 2, 4, 6, and 15 to 18 months of age. Technically, this 4-dose schedule would fulfill requirements for 4 doses of IPV. However, this could conflict with a state school immunization schedule that requires the last dose of IPV vaccine to be administered when the child is between the ages of 4 and 6 years.⁶

TABLE
Rotavirus vaccines: An administration guide

Kinrix contains DTaP and IPV. The vaccine is indicated for use as the fifth dose of DTaP and the fourth dose of IPV in children 4 through 6 years of age, following a primary series using Infanrix (DTaP) and Pediarix (DTaP, hepatitis B, and IPV).

Rotavirus vaccines: Now there are 2

There are now 2 licensed rotavirus vaccines: RotaTeq was approved in 2006,⁷ and Rotarix in 2008.⁸ ACIP does not express a preference for either product, but has revised its recommendations for rotavirus vaccination to accommodate the new release. Both RotaTeq and Rotarix are live oral vaccines, but they differ in composition and schedule of administration. Rotarix should not be given to infants who are allergic to latex, as its oral applicator contains latex rubber.

Dosing requirements. RotaTeq is administered in a 3-dose series at ages 2, 4, and 6 months; Rotarix is given in a 2-dose series at 2 and 4 months of age (TABLE). The first dose of either vaccine should be administered to children between the ages of 6 weeks and 14 weeks, 6 days. (Previously, 12 weeks was the maximum age for the first dose of rotavirus vaccine.) Neither vaccine series should be initiated in infants who are 15 weeks of age or older. The minimum interval between doses is 4 weeks, and the final dose should be administered by the age of 8 months.

It is best to complete the vaccine series with the same product. If the vaccine used initially is not available, the series can be completed with the other product, but the different number of doses required must be considered. If any dose in the series was RotaTeq or you are unable to determine which rotavirus vaccine was administered previously, a total of 3 doses should be given.

HPV and meningococcal vaccine clarification

Human papilloma virus vaccine. The HPV vaccine is recommended for all females ages 11 through 26 years, but ACIP has indicated that girls as young as 9 years may be vaccinated.¹

Three doses are required, with the second and third doses administered 2 and 6 months after the first. Because some providers had been administering the third dose at month 4, ACIP issued a clarification in 2008, noting that there should be a minimum of 24 weeks between the first and third dose.

MCV and MPSV. Meningococcal conjugate vaccine (MCV) is preferred over meningococcal polysaccharide vaccine (MPSV) for those 55 years of age or younger, although MPSV is an acceptable alternative. ACIP clarified recommendations for revaccination, as follows:

Individuals ages 11 to 55 years who were vaccinated with MPSV should consider revaccination with MCV after 5 years, if the risk of meningococcal meningitis persists. Children ages 2 to 10 years should be revaccinated with MCV 3 years after receiving MPSV.

Highlights of the 2008 recommendations of the CDC’s Advisory Committee on Immunization Practices (ACIP), detailed in the child and adult immunization schedules in the MMWR in January,^1,2 include:

• an expansion of the age groups for whom an annual influenza vaccine is recommended;
• expanded indications for the pneumococcal polysaccharide vaccine;
• 2 new combination vaccines for children; and
• a second rotavirus vaccine, with revised recommendations to accommodate both vaccine products.

School-age children should get flu vaccine

Children and adolescents ages 5 through 18 years are now among those who should receive an annual flu vaccine. Previously, routine vaccination was recommended only for adults and children ages 6 months through 59 months.³

Because of the timing of vaccine purchase, ACIP recognizes that routine vaccination of 5- to 18-year-olds may not be possible in some settings until next year. Family physicians who are unable to fully incorporate this new recommendation in the 2008-2009 flu season should immunize children and adolescents who are at high risk for complications of the flu. Included in that group are 5- to 18-year-olds who are on long-term aspirin therapy; have a chronic pulmonary disease, including asthma, or a cardiovascular, renal, hepatic, hematologic, or metabolic disorder; are immunosuppressed; or have a neurological or musculoskeletal disorder that alters respiratory function or the clearance of respiratory secretions. Children and adolescents who live with others at elevated risk—kids younger than 5 years, adults older than 50 years, or individuals with medical conditions that place them at high risk for severe influenza complications—should also be vaccinated.

Pneumococcal vaccine: New indications, clarifications

Two new groups have been added to the list of people for whom the 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended: asthma patients and smokers. Smoking poses as great a risk for pneumococcal pneumonia as diabetes and other chronic illnesses that had already been noted as indications for the vaccine. The number needed to vaccinate to prevent 1 case of pneumonia in smokers is 10,000 for those between the ages of 18 to 44 years, and 4000 for those ages 45 to 64 years.

A second dose. Also in 2008, ACIP clarified its dosing recommendations for PPV23: A second dose, given 5 years after the first, is recommended for those with immune suppression, sickle cell disease, or asplenia. Individuals who are 65 years of age or older should receive a second dose if they were vaccinated 5 or more years ago and were younger than 65 at the time of primary vaccination.

Not for all Native Americans. The recommendation for the use of PPV23 among the Native American population has changed, too.

Research showing high rates of invasive pneumococcal disease in Native American communities has been performed in only a few locations and cannot be generalized to all Native Americans. Therefore, ACIP has gone from recommending routine use of the vaccine among all Native Americans to a recommendation based on the same risks and age recommendations as the general population and, in communities with high rates of disease, on public health recommendations based on the incidence and epidemiology of disease.

Combination products may mean fewer injections

Two new combination vaccine products—Pentacel⁴ and Kinrix⁵—were approved last year. Both can reduce the number of injections required to complete the child immunization recommendations.

Pentacel combines 5 vaccines—diphtheria, tetanus, and pertussis (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib)—and is licensed for children 6 weeks through 4 years of age. Pentacel has a 4-dose schedule, with vaccine administration at 2, 4, 6, and 15 to 18 months of age. Technically, this 4-dose schedule would fulfill requirements for 4 doses of IPV. However, this could conflict with a state school immunization schedule that requires the last dose of IPV vaccine to be administered when the child is between the ages of 4 and 6 years.⁶

TABLE
Rotavirus vaccines: An administration guide

Kinrix contains DTaP and IPV. The vaccine is indicated for use as the fifth dose of DTaP and the fourth dose of IPV in children 4 through 6 years of age, following a primary series using Infanrix (DTaP) and Pediarix (DTaP, hepatitis B, and IPV).

Rotavirus vaccines: Now there are 2

There are now 2 licensed rotavirus vaccines: RotaTeq was approved in 2006,⁷ and Rotarix in 2008.⁸ ACIP does not express a preference for either product, but has revised its recommendations for rotavirus vaccination to accommodate the new release. Both RotaTeq and Rotarix are live oral vaccines, but they differ in composition and schedule of administration. Rotarix should not be given to infants who are allergic to latex, as its oral applicator contains latex rubber.

Dosing requirements. RotaTeq is administered in a 3-dose series at ages 2, 4, and 6 months; Rotarix is given in a 2-dose series at 2 and 4 months of age (TABLE). The first dose of either vaccine should be administered to children between the ages of 6 weeks and 14 weeks, 6 days. (Previously, 12 weeks was the maximum age for the first dose of rotavirus vaccine.) Neither vaccine series should be initiated in infants who are 15 weeks of age or older. The minimum interval between doses is 4 weeks, and the final dose should be administered by the age of 8 months.

It is best to complete the vaccine series with the same product. If the vaccine used initially is not available, the series can be completed with the other product, but the different number of doses required must be considered. If any dose in the series was RotaTeq or you are unable to determine which rotavirus vaccine was administered previously, a total of 3 doses should be given.

HPV and meningococcal vaccine clarification

Human papilloma virus vaccine. The HPV vaccine is recommended for all females ages 11 through 26 years, but ACIP has indicated that girls as young as 9 years may be vaccinated.¹

Three doses are required, with the second and third doses administered 2 and 6 months after the first. Because some providers had been administering the third dose at month 4, ACIP issued a clarification in 2008, noting that there should be a minimum of 24 weeks between the first and third dose.

MCV and MPSV. Meningococcal conjugate vaccine (MCV) is preferred over meningococcal polysaccharide vaccine (MPSV) for those 55 years of age or younger, although MPSV is an acceptable alternative. ACIP clarified recommendations for revaccination, as follows:

Individuals ages 11 to 55 years who were vaccinated with MPSV should consider revaccination with MCV after 5 years, if the risk of meningococcal meningitis persists. Children ages 2 to 10 years should be revaccinated with MCV 3 years after receiving MPSV.

Highlights of the 2008 recommendations of the CDC’s Advisory Committee on Immunization Practices (ACIP), detailed in the child and adult immunization schedules in the MMWR in January,^1,2 include:

• an expansion of the age groups for whom an annual influenza vaccine is recommended;
• expanded indications for the pneumococcal polysaccharide vaccine;
• 2 new combination vaccines for children; and
• a second rotavirus vaccine, with revised recommendations to accommodate both vaccine products.

School-age children should get flu vaccine

Children and adolescents ages 5 through 18 years are now among those who should receive an annual flu vaccine. Previously, routine vaccination was recommended only for adults and children ages 6 months through 59 months.³

Because of the timing of vaccine purchase, ACIP recognizes that routine vaccination of 5- to 18-year-olds may not be possible in some settings until next year. Family physicians who are unable to fully incorporate this new recommendation in the 2008-2009 flu season should immunize children and adolescents who are at high risk for complications of the flu. Included in that group are 5- to 18-year-olds who are on long-term aspirin therapy; have a chronic pulmonary disease, including asthma, or a cardiovascular, renal, hepatic, hematologic, or metabolic disorder; are immunosuppressed; or have a neurological or musculoskeletal disorder that alters respiratory function or the clearance of respiratory secretions. Children and adolescents who live with others at elevated risk—kids younger than 5 years, adults older than 50 years, or individuals with medical conditions that place them at high risk for severe influenza complications—should also be vaccinated.

Pneumococcal vaccine: New indications, clarifications

Two new groups have been added to the list of people for whom the 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended: asthma patients and smokers. Smoking poses as great a risk for pneumococcal pneumonia as diabetes and other chronic illnesses that had already been noted as indications for the vaccine. The number needed to vaccinate to prevent 1 case of pneumonia in smokers is 10,000 for those between the ages of 18 to 44 years, and 4000 for those ages 45 to 64 years.

A second dose. Also in 2008, ACIP clarified its dosing recommendations for PPV23: A second dose, given 5 years after the first, is recommended for those with immune suppression, sickle cell disease, or asplenia. Individuals who are 65 years of age or older should receive a second dose if they were vaccinated 5 or more years ago and were younger than 65 at the time of primary vaccination.

Not for all Native Americans. The recommendation for the use of PPV23 among the Native American population has changed, too.

Research showing high rates of invasive pneumococcal disease in Native American communities has been performed in only a few locations and cannot be generalized to all Native Americans. Therefore, ACIP has gone from recommending routine use of the vaccine among all Native Americans to a recommendation based on the same risks and age recommendations as the general population and, in communities with high rates of disease, on public health recommendations based on the incidence and epidemiology of disease.

Combination products may mean fewer injections

Two new combination vaccine products—Pentacel⁴ and Kinrix⁵—were approved last year. Both can reduce the number of injections required to complete the child immunization recommendations.

Pentacel combines 5 vaccines—diphtheria, tetanus, and pertussis (DTaP), inactivated poliovirus (IPV), and Haemophilus influenzae type b (Hib)—and is licensed for children 6 weeks through 4 years of age. Pentacel has a 4-dose schedule, with vaccine administration at 2, 4, 6, and 15 to 18 months of age. Technically, this 4-dose schedule would fulfill requirements for 4 doses of IPV. However, this could conflict with a state school immunization schedule that requires the last dose of IPV vaccine to be administered when the child is between the ages of 4 and 6 years.⁶

TABLE
Rotavirus vaccines: An administration guide

Kinrix contains DTaP and IPV. The vaccine is indicated for use as the fifth dose of DTaP and the fourth dose of IPV in children 4 through 6 years of age, following a primary series using Infanrix (DTaP) and Pediarix (DTaP, hepatitis B, and IPV).

Rotavirus vaccines: Now there are 2

There are now 2 licensed rotavirus vaccines: RotaTeq was approved in 2006,⁷ and Rotarix in 2008.⁸ ACIP does not express a preference for either product, but has revised its recommendations for rotavirus vaccination to accommodate the new release. Both RotaTeq and Rotarix are live oral vaccines, but they differ in composition and schedule of administration. Rotarix should not be given to infants who are allergic to latex, as its oral applicator contains latex rubber.

Dosing requirements. RotaTeq is administered in a 3-dose series at ages 2, 4, and 6 months; Rotarix is given in a 2-dose series at 2 and 4 months of age (TABLE). The first dose of either vaccine should be administered to children between the ages of 6 weeks and 14 weeks, 6 days. (Previously, 12 weeks was the maximum age for the first dose of rotavirus vaccine.) Neither vaccine series should be initiated in infants who are 15 weeks of age or older. The minimum interval between doses is 4 weeks, and the final dose should be administered by the age of 8 months.

It is best to complete the vaccine series with the same product. If the vaccine used initially is not available, the series can be completed with the other product, but the different number of doses required must be considered. If any dose in the series was RotaTeq or you are unable to determine which rotavirus vaccine was administered previously, a total of 3 doses should be given.

HPV and meningococcal vaccine clarification

Human papilloma virus vaccine. The HPV vaccine is recommended for all females ages 11 through 26 years, but ACIP has indicated that girls as young as 9 years may be vaccinated.¹

Three doses are required, with the second and third doses administered 2 and 6 months after the first. Because some providers had been administering the third dose at month 4, ACIP issued a clarification in 2008, noting that there should be a minimum of 24 weeks between the first and third dose.

MCV and MPSV. Meningococcal conjugate vaccine (MCV) is preferred over meningococcal polysaccharide vaccine (MPSV) for those 55 years of age or younger, although MPSV is an acceptable alternative. ACIP clarified recommendations for revaccination, as follows:

Individuals ages 11 to 55 years who were vaccinated with MPSV should consider revaccination with MCV after 5 years, if the risk of meningococcal meningitis persists. Children ages 2 to 10 years should be revaccinated with MCV 3 years after receiving MPSV.

When L.O., an African American boy, was 13 months old, he was taken to the emergency room by his mother for an episode of diffuse expiratory wheezing. The family had a history of asthma. L.O.’s wheezing was effectively treated with albuterol, which was prescribed for use at home. At 17 months, L.O. was diagnosed with eczema and allergy to eggs.

When the boy was 3 years old, his mother brought him to St. Dominic’s Health Clinic in Jamaica, NY, for a well-child visit. She reported that L.O. had experienced only 2 asthma attacks in the past year. We diagnosed mild intermittent asthma and advised the mother to continue using albuterol as needed. The patient returned to the clinic at age 4, with redness and swelling of both eyes typical of allergic conjunctivitis. Four months later L.O. returned with rhinorrhea, which, in conjunction with asthma, eczema, and allergic conjunctivitis, led us to diagnose atopic syndrome. This time, we prescribed 4 mg Singulair (montelukast sodium), to be taken once daily.

Immediately after taking a single Singulair tablet in the afternoon, L.O. developed pruritus. That evening he awoke from his sleep screaming; he had prominent lip, facial, and pedal edema. He also had trouble breathing and had red, blotchy hives over his entire back. His mother was unable to administer epinephrine (EpiPen), which had been prescribed for L.O.’s egg allergy. She called 911 and L.O. was taken to an emergency room. He had tachycardia and a low-grade fever. Epinephrine and diphenhydramine (Benadryl) began to lower his temperature and gradually lessened his edema and urticaria. Upon L.O.’s discharge, his mother was cautioned not to give him any more Singulair.

How common is L.O.’s experience? In a review of the literature, we found just 4 mentions of an anaphylactic response to Singulair treatment. We describe these reports here and discuss the implications.

A drug with few reported side effects

Singulair is a leukotriene receptor antagonist commonly prescribed for the prevention and treatment of asthma and for the treatment of allergic rhinitis. It is an orally active compound that binds with high affinity to the CysLT type-1 receptor, a leukotriene receptor found in a variety of human airway cells, including smooth muscle cells, macrophages, and eosinophils.¹ At this receptor, Singulair inhibits the physiologic action of LTD4, a leukotriene released by various inflammatory cells that normally initiates the symptoms of asthma.

Singulair has been shown to dramatically increase forced expiratory volume, decrease usage of inhaled beta-agonists, and improve other asthma-related outcomes in both adults and children. In clinical studies, Singulair has proven safe, with few reported side effects. Some benign adverse events have been associated with this drug when compared with placebo, but causality between these events and Singulair is uncertain. Anaphylaxis was not reported in any of the premarketing clinical studies of Singulair.

4 other accounts of anaphylaxis

Singulair’s package insert mentions anaphylaxis as an adverse reaction reported after the US Food and Drug Administration approved the drug in 1998.¹ Merck & Co., producer and distributor of Singulair, did not provide any specific information on reports of anaphylaxis for this review.

The Drug Safety Research Unit, an independent body associated with the University of Portsmouth in England, mentioned just one instance of anaphylaxis in a study of adverse reactions to montelukast among a cohort of more than 15,000 patients.²

A presentation given at a Healthcare Information Management Systems Society conference also briefly mentioned the case of an 8-year-old boy who experienced an anaphylactic reaction to Singulair.³

The only published description of a possible case of anaphylaxis in response to Singulair appeared in a report published by Lareb, the Dutch national pharmacovigilance system.⁴ A 4-year-old boy suffered facial edema, rash, coughing, and fatigue 2 days after starting montelukast 5 mg daily for asthma. The patient’s age and symptoms were strikingly similar to those of L.O.

Anaphylaxis: Always a possibility

Clearly, anaphylaxis as an adverse reaction to Singulair is rare, with only a handful of cases being reported worldwide. Nevertheless, anaphylaxis is life threatening, and we should be alert to its possibility when prescribing Singulair, especially for patients with a history of atopy.

Correspondence
Adriel Gerard, State University of New York at Buffalo School of Medicine, 99 Gold Street, Apt 1L, Brooklyn, NY 11201; adriel.gerard@gmail.com

When L.O., an African American boy, was 13 months old, he was taken to the emergency room by his mother for an episode of diffuse expiratory wheezing. The family had a history of asthma. L.O.’s wheezing was effectively treated with albuterol, which was prescribed for use at home. At 17 months, L.O. was diagnosed with eczema and allergy to eggs.

When the boy was 3 years old, his mother brought him to St. Dominic’s Health Clinic in Jamaica, NY, for a well-child visit. She reported that L.O. had experienced only 2 asthma attacks in the past year. We diagnosed mild intermittent asthma and advised the mother to continue using albuterol as needed. The patient returned to the clinic at age 4, with redness and swelling of both eyes typical of allergic conjunctivitis. Four months later L.O. returned with rhinorrhea, which, in conjunction with asthma, eczema, and allergic conjunctivitis, led us to diagnose atopic syndrome. This time, we prescribed 4 mg Singulair (montelukast sodium), to be taken once daily.

Immediately after taking a single Singulair tablet in the afternoon, L.O. developed pruritus. That evening he awoke from his sleep screaming; he had prominent lip, facial, and pedal edema. He also had trouble breathing and had red, blotchy hives over his entire back. His mother was unable to administer epinephrine (EpiPen), which had been prescribed for L.O.’s egg allergy. She called 911 and L.O. was taken to an emergency room. He had tachycardia and a low-grade fever. Epinephrine and diphenhydramine (Benadryl) began to lower his temperature and gradually lessened his edema and urticaria. Upon L.O.’s discharge, his mother was cautioned not to give him any more Singulair.

How common is L.O.’s experience? In a review of the literature, we found just 4 mentions of an anaphylactic response to Singulair treatment. We describe these reports here and discuss the implications.

A drug with few reported side effects

Singulair is a leukotriene receptor antagonist commonly prescribed for the prevention and treatment of asthma and for the treatment of allergic rhinitis. It is an orally active compound that binds with high affinity to the CysLT type-1 receptor, a leukotriene receptor found in a variety of human airway cells, including smooth muscle cells, macrophages, and eosinophils.¹ At this receptor, Singulair inhibits the physiologic action of LTD4, a leukotriene released by various inflammatory cells that normally initiates the symptoms of asthma.

Singulair has been shown to dramatically increase forced expiratory volume, decrease usage of inhaled beta-agonists, and improve other asthma-related outcomes in both adults and children. In clinical studies, Singulair has proven safe, with few reported side effects. Some benign adverse events have been associated with this drug when compared with placebo, but causality between these events and Singulair is uncertain. Anaphylaxis was not reported in any of the premarketing clinical studies of Singulair.

4 other accounts of anaphylaxis

Singulair’s package insert mentions anaphylaxis as an adverse reaction reported after the US Food and Drug Administration approved the drug in 1998.¹ Merck & Co., producer and distributor of Singulair, did not provide any specific information on reports of anaphylaxis for this review.

The Drug Safety Research Unit, an independent body associated with the University of Portsmouth in England, mentioned just one instance of anaphylaxis in a study of adverse reactions to montelukast among a cohort of more than 15,000 patients.²

A presentation given at a Healthcare Information Management Systems Society conference also briefly mentioned the case of an 8-year-old boy who experienced an anaphylactic reaction to Singulair.³

The only published description of a possible case of anaphylaxis in response to Singulair appeared in a report published by Lareb, the Dutch national pharmacovigilance system.⁴ A 4-year-old boy suffered facial edema, rash, coughing, and fatigue 2 days after starting montelukast 5 mg daily for asthma. The patient’s age and symptoms were strikingly similar to those of L.O.

Anaphylaxis: Always a possibility

Clearly, anaphylaxis as an adverse reaction to Singulair is rare, with only a handful of cases being reported worldwide. Nevertheless, anaphylaxis is life threatening, and we should be alert to its possibility when prescribing Singulair, especially for patients with a history of atopy.

Correspondence
Adriel Gerard, State University of New York at Buffalo School of Medicine, 99 Gold Street, Apt 1L, Brooklyn, NY 11201; adriel.gerard@gmail.com

When L.O., an African American boy, was 13 months old, he was taken to the emergency room by his mother for an episode of diffuse expiratory wheezing. The family had a history of asthma. L.O.’s wheezing was effectively treated with albuterol, which was prescribed for use at home. At 17 months, L.O. was diagnosed with eczema and allergy to eggs.

When the boy was 3 years old, his mother brought him to St. Dominic’s Health Clinic in Jamaica, NY, for a well-child visit. She reported that L.O. had experienced only 2 asthma attacks in the past year. We diagnosed mild intermittent asthma and advised the mother to continue using albuterol as needed. The patient returned to the clinic at age 4, with redness and swelling of both eyes typical of allergic conjunctivitis. Four months later L.O. returned with rhinorrhea, which, in conjunction with asthma, eczema, and allergic conjunctivitis, led us to diagnose atopic syndrome. This time, we prescribed 4 mg Singulair (montelukast sodium), to be taken once daily.

Immediately after taking a single Singulair tablet in the afternoon, L.O. developed pruritus. That evening he awoke from his sleep screaming; he had prominent lip, facial, and pedal edema. He also had trouble breathing and had red, blotchy hives over his entire back. His mother was unable to administer epinephrine (EpiPen), which had been prescribed for L.O.’s egg allergy. She called 911 and L.O. was taken to an emergency room. He had tachycardia and a low-grade fever. Epinephrine and diphenhydramine (Benadryl) began to lower his temperature and gradually lessened his edema and urticaria. Upon L.O.’s discharge, his mother was cautioned not to give him any more Singulair.

How common is L.O.’s experience? In a review of the literature, we found just 4 mentions of an anaphylactic response to Singulair treatment. We describe these reports here and discuss the implications.

A drug with few reported side effects

Singulair is a leukotriene receptor antagonist commonly prescribed for the prevention and treatment of asthma and for the treatment of allergic rhinitis. It is an orally active compound that binds with high affinity to the CysLT type-1 receptor, a leukotriene receptor found in a variety of human airway cells, including smooth muscle cells, macrophages, and eosinophils.¹ At this receptor, Singulair inhibits the physiologic action of LTD4, a leukotriene released by various inflammatory cells that normally initiates the symptoms of asthma.

Singulair has been shown to dramatically increase forced expiratory volume, decrease usage of inhaled beta-agonists, and improve other asthma-related outcomes in both adults and children. In clinical studies, Singulair has proven safe, with few reported side effects. Some benign adverse events have been associated with this drug when compared with placebo, but causality between these events and Singulair is uncertain. Anaphylaxis was not reported in any of the premarketing clinical studies of Singulair.

4 other accounts of anaphylaxis

Singulair’s package insert mentions anaphylaxis as an adverse reaction reported after the US Food and Drug Administration approved the drug in 1998.¹ Merck & Co., producer and distributor of Singulair, did not provide any specific information on reports of anaphylaxis for this review.

The Drug Safety Research Unit, an independent body associated with the University of Portsmouth in England, mentioned just one instance of anaphylaxis in a study of adverse reactions to montelukast among a cohort of more than 15,000 patients.²

A presentation given at a Healthcare Information Management Systems Society conference also briefly mentioned the case of an 8-year-old boy who experienced an anaphylactic reaction to Singulair.³

The only published description of a possible case of anaphylaxis in response to Singulair appeared in a report published by Lareb, the Dutch national pharmacovigilance system.⁴ A 4-year-old boy suffered facial edema, rash, coughing, and fatigue 2 days after starting montelukast 5 mg daily for asthma. The patient’s age and symptoms were strikingly similar to those of L.O.

Anaphylaxis: Always a possibility

Clearly, anaphylaxis as an adverse reaction to Singulair is rare, with only a handful of cases being reported worldwide. Nevertheless, anaphylaxis is life threatening, and we should be alert to its possibility when prescribing Singulair, especially for patients with a history of atopy.

Correspondence
Adriel Gerard, State University of New York at Buffalo School of Medicine, 99 Gold Street, Apt 1L, Brooklyn, NY 11201; adriel.gerard@gmail.com

The author reports that he serves on the speaker’s bureau for Novogyne, TherRx, Warner-Chilcott, and Solvay, and on the advisory board for Upsher-Smith, Novogyne, QuatRx, and Wyeth.

CASE: History of dyspareunia

At her latest visit, a 56-year-old woman who is 7 years postmenopausal relates that she has been experiencing worsening pain with intercourse to the point that she now has very little sex drive at all. This problem began approximately 1 year after she discontinued hormone therapy in the wake of reports that it causes cancer and heart attack. She has been offered both local vaginal and systemic hormone therapy, but is too frightened to use any hormones at all. Sexual lubricants no longer seem to work.

How do you counsel her about these symptoms? And what therapy do you offer?

Physicians and other health-care practitioners are seeing a large and growing number of genitourinary and sexual-related complaints among menopausal women—so much so that it has reached epidemic proportions. Yet dyspareunia is underreported and undertreated, and quality of life suffers for these women.

In this article, I focus on two interrelated causes of this epidemic:

• vaginal dryness and vulvovaginal atrophy (VVA) and the impact of these conditions on women’s sexual function and psychosocial well-being
• barriers to optimal treatment.

I also explore how ObGyns’ role in this area of care is evolving—as a way to understand how you can better serve this expanding segment of our patient population.

Dyspareunia can have many causes, including endometriosis, interstitial cystitis, surgical scarring, injury that occurs during childbirth, and psychosocial origin (such as a history of sexual abuse). Our focus here is on dyspareunia due to VVA.

Just how sizable is the postmenopausal population?

About 32% of the female population is older than 50 years.¹ That means that around 48 million women are currently menopausal, or will become so over the next few years.

Because average life expectancy approaches 80 years in the United States and other countries of the industrialized world,² many women will live approximately 40 years beyond menopause or their final menstrual period. Their quality of life during the second half of their life is dependent on both physical and psychosocial health.

Postmenopausal dyspareunia isn’t new

Sexual issues arising from physical causes—dyspareunia among them—have long accounted for a large share of medical concerns reported by postmenopausal women. In a 1985 survey, for example, dyspareunia accounted for 42.5% of their complaints.³

But epidemiologic studies to determine the prevalence of female sexual dysfunction in postmenopausal women are difficult to carry out. Why? Because researchers would need to 1) address changes over time and 2) distinguish problems of sexual function from those brought on by aging.⁴

The techniques and methodology for researching female sexual dysfunction continue to evolve, creating new definitions of the stages of menopause and new diagnostic approaches to female sexual dysfunction.

However, based on available studies, Dennerstein and Hayes concluded that:

• postmenopausal women report a high rate of sexual dysfunction (higher than men)
• psychosocial factors can ameliorate a decline in sexual function
• “vaginal dryness and dyspareunia seem to be driven primarily by declining estradiol.”⁴

The WHI and its domino effect

Millions of postmenopausal women stopped taking estrogen-based therapy in the wake of widespread media coverage after 2002 publication of data from the estrogen–progestin arm of the Women’s Health Initiative (WHI), which purported to show, among other things, an increased risk of breast cancer.⁵

For decades, many postmenopausal women achieved medical management of VVA through long-term use of systemic hormone replacement therapy (HRT), which they used primarily to control other chronic symptoms of menopause, such as hot flashes.

After the WHI data were published (and misrepresented), reduced usage of estrogen-based HRT “unmasked” vaginal symptoms, including sexual pain, due to the effects of estrogen deficiency on the vaginal epithelium and vaginal blood flow. Since then, we have been forced to examine anew the natural history of menopause.

Within days or weeks of discontinuing HRT, women may reexperience the acute vasomotor symptoms that accompany estrogen withdrawal—most commonly hot flashes, night sweats, sleeplessness, palpitations, and headaches. Over time—anywhere from 6 months to several years—the body adjusts to the loss or withdrawal of estrogen, and these vasomotor symptoms eventually diminish or resolve. Not so for the longer-term physical effects of chronic low serum levels of estrogen, which worsen over time.

Approximately 6 months after discontinuing estrogen therapy, postmenopausal women may begin to experience vaginal dryness and VVA. As the years pass, other side effects of estrogen deficiency arise: bone loss, joint pain, mood alteration (including depression), change in skin tone, hair loss, and cardiac and central nervous system changes. These side effects do not resolve spontaneously; in fact, they grow worse as a woman ages. They may have deleterious psychosocial as well as physical impacts on her life—especially on the quality of her intimate relationship.

Is 60 the new 40?

Many women and men in the large cohort known as the Baby Boomer generation continue to be sexually active into their 60s, 70s, and 80s, as demonstrated by a 2007 study of sexuality and health in older adults.⁶ In the 57- to 64-year-old age group, 61.6% of women and 83.7% of men were sexually active (defined as sexual activity with a partner within the past 12 months). In the 65- to 74-year-old group, 39.5% of women and 67% of men were sexually active; and in the 75- to 85-year-old group, 16.7% of women and 38.5% of men were sexually active (TABLE).

These findings indicate that fewer women than men remain sexually active during their later years. One reason may be the epidemic of sexual-related symptoms among postmenopausal women. In the same survey, 34.3% of women 57 to 64 years old reported avoiding sex because of:

• pain during intercourse (17.8%)
• difficulty with lubrication (35.9%).

Across all groups, the most prevalent sexual problem was low desire (43%).⁶ Around 40% of postmenopausal women reported no sexual activity in the past 12 months, as well as lack of interest in sex. This number may include women who have ceased to have sex because of vaginal dryness and dyspareunia, thereby reducing the percentage reporting these symptoms (TABLE).

TABLE

Older adults are having sex—and experiencing sexual problems

Assessing menopause-related sexual function is a challenge

Although the transition phases of menopause have been well studied and reported for decades, few of these studies have included questions about the impact of menopause on sexual function.⁷ When longitudinal studies that included the classification of female sexual dysfunction began to appear, they provided evidence of the important role that VVA and psychosocial factors play in female sexual dysfunction.⁸

In the fourth year of the Melbourne Women’s Midlife Health Project longitudinal study, six variables related to sexual function were identified. Three were determinate of sexual function:

• feelings for the partner
• problems related to the partner
• vaginal dryness/dyspareunia.

The other three variables—sexual responsiveness, frequency of sexual activity, and libido—were dependent or outcome variables.

By the sixth year of this study, two variables had increased in significance: vaginal dryness/dyspareunia and partner problems.⁷

Sexual pain and relationship problems can create a vicious cycle

The interrelationship of vaginal dryness, sexual pain, flagging desire, and psychosocial parameters can produce a vicious cycle. A woman experiencing or anticipating pain may have diminished sexual desire or avoid sex altogether. During intercourse, the brain’s awareness of vaginal pain may trigger a physiologic response that can cause the muscles of the vagina to tighten and lubrication to decrease. The result? Greater vaginal pain.

This vicious cycle can contribute to relationship issues with the sexual partner and harm a woman’s psychosocial well-being. Resentment, anger, and misunderstanding may arise when a couple is dealing with problems of sexual function, and these stressors can damage many aspects of the relationship, further exacerbating sexual difficulties.

An additional and very important dimension of these issues is their potential impact on the family unit.

VVA can diminish overall well-being

In a 2007 survey reported at the North American Menopause Society (NAMS), one third to one half of 506 respondents said that VVA had a bad effect on their sexual interest, mood, self-esteem, and the intimate relationship (FIGURE 1).⁹ Reports from in-depth interviews were consistent with survey results and offered further insight into a woman’s emotional response to the condition of vaginal dryness and its impact on her life. Women found the condition “embarrassing,” something they had to endure but didn’t talk about, and felt that it had a major impact on their self-esteem and intimate relationship.

FIGURE 1 Dyspareunia affects more than interest in sex—relationships, mood, and self-esteem suffer

Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas.

Clinicians often don’t ask about VVA, and patients are reluctant to talk

Among women of all ages, dyspareunia is underreported and undertreated. In the survey reported at NAMS, 40% of respondents said that their physician had never asked them about the problem of VVA (FIGURE 2).⁹

Women themselves may be reluctant to discuss the problem with physicians, nurse practitioners, or other health-care providers out of embarrassment or the assumption that there is nothing to be done about the problem. Nevertheless, more than 40% of respondents said they would be highly likely to seek treatment for VVA if they had a concern about urogenital complications of the condition (FIGURE 3).⁹

Another barrier may be the sense that asking the health-care provider about sex may embarrass him or her. As a result, sufferers do not anticipate help from their physician and other members of the health-care profession and fail to seek treatment or counseling for this chronic medical condition.^10,11

In a 1999 telephone survey of 500 adults 25 years of age or older, 71% said they thought that their doctor would dismiss concerns about sexual problems, but 85% said they would talk to their physician anyway if they had a problem, even though they might not get treatment.¹¹ In that survey, 91% of married men and 84% of married women rated a satisfying sex life as important to quality of life.¹¹

Another important and often overlooked limitation on this type of discussion is the time constraints that busy clinicians face, especially with the low reimbursement offered by managed care. Sexual problems can hardly be adequately discussed in 7 to 10 minutes.

FIGURE 2 Do physicians ask about dyspareunia? Most women surveyed said “rarely” or “never”

Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas.

FIGURE 3 Are these women likely to seek treatment?

Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas.

Women have performance anxiety, too

It is well known that men with even a mild degree of erectile dysfunction can suffer from performance anxiety, but the fact that women can also suffer from this phenomenon is not given as much attention. Such anxiety can be a factor in relationship difficulties. With both partners perhaps feeling anxious about sexual performance, a couple may avoid even simple acts of affection, such as holding hands, to avoid raising the other’s expectations.

Exacerbating the situation is the fact that many men use widely prescribed phosphodiesterase type 5 (PDE5) inhibitors, whereas women are contending with barriers to continued sexual activity as they age. It does not take a psychologist to understand that this imbalance often adds to emotional strain and tension between partners.

Popular media address the issue

Look beyond what our postmenopausal patients tell us directly—to the popular media and online forums—to appreciate the scope of sexual pain as a major issue among postmenopausal women. Evidence of psychosocial effects is found on numerous Web sites—some from organizations, others designed by women seeking help from each other.

Red Hot Mamas

(www.redhotmamas.org)

This organization aims to empower women through menopause education. Highlighted in the Winter 2007/2008 Red Hot Mamas Report is a survey done in conjunction with Harris Interactive exploring the impact of menopausal symptoms on a woman’s sex life, which found that 47% of women who have VVA have avoided or stopped sex completely because it was uncomfortable, compared with 23% of normal women.

Power Surge

(www.power-surge.com)

This Web site offers a list of strategies for dealing with sexual pain, including an overview of hormone-based prescription and nonprescription products, along with a variety of over-the-counter, natural, holistic, and herbal therapies for treating dyspareunia.

What is the physician’s role?

Given the epidemic of sexual pain, it is crucial that physicians and others who care for postmenopausal women increase their awareness of this issue and pay special attention to its psychosocial parameters.

Ask patients about sexual function in general and dyspareunia in particular as part of the routine annual visit. A simple opening “Yes/No” question, such as “Are you sexually active?” can lead to further questions appropriate to the patient. For example, if the answer is “No,” the follow-up question might be, “Does that bother you or your partner?” Further discussion may uncover whether the lack of sexual activity is a cause of distress and identify which variables are involved.

If, instead, the answer is “Yes,” follow-up questions can identify the presence of common postmenopausal physical issues, such as vaginal dryness and difficulty with lubrication. The visit then can turn to strategies to ameliorate those conditions.

When a patient reports dyspareunia, further diagnostic information such as precise location, degree of arousal, and reaction to pain can help determine the appropriate course of treatment. For an approach to this aspect of ascertaining patient history, see the list of sample questions above.¹²

During the physical, pay particular attention to any physical abnormalities or organic causes of sexual pain. Questions designed to characterize the location and nature of the pain can pinpoint the cause. Sexual pain arising from VVA is likely to 1) be localized at the introitus and 2) occur with penile entry.

Think female sexual function is linear? Think again

Since the mid-1990s, the availability of validated scales to measure female sexual function has increased rapidly and enabled researchers to better identify, quantify, and evaluate treatments for female sexual dysfunction.⁷ Over time, we have moved away from the somewhat mechanical sequence inherent in the linear progression of desire leading to genital stimulation followed by arousal and orgasm toward an appreciation of the multiple physical, emotional, and subjective factors that are at play in women’s sexual function.

By 1998, a classification scheme was developed to further the means to study and discuss disorders of desire, arousal, orgasm, and sexual pain.⁸ Further contextual definitions of sexual dysfunction are under consideration.¹³

Basson proposed one new model of female sexual function (see the diagram), and observed that

"…women identify many reasons they are sexual over and beyond inherent sexual drive or “hunger.” Women tell of wanting to increase emotional closeness, commitment, sharing, tenderness, and tolerance, and to show the partner that he or she has been missed (emotionally or physically). Such intimacy-based reasons motivate the woman to find a way to become sexually aroused. This arousal is not spontaneous but triggered by deliberately sought sexual stimuli."¹³

Intimacy-based model of female sexual response cycle

In this flow of physical and emotional variables involved in female sexual function, categories interact. For example, low desire can be and is frequently secondary to the anticipation of pain during sexual intercourse. Arousal can be hampered by lack of vaginal lubrication—perhaps inhibited by the anticipation of pain. Secondary orgasmic disorders can result from low desire, difficulty of arousal, and sexual pain.¹⁴ Sexual pain can affect sexual function at any point on this continuum.

Treatments in the pipeline

For decades, hormone-based treatments have been the predominant therapeutic option for vaginal dryness. Often they are a secondary benefit of hormone therapy for vasomotor symptoms and osteoporosis. Estrogen can be delivered in the form of oral tablet, transdermal patch, gel, spray, or vaginal ring for systemic use, or as vaginal cream, ring, or tablet for local use.

However, despite data to the contrary and our reassurances to the patient about overall safety, a large number of women, and many primary care providers, are no longer inclined to use short- or long-term HRT in any presentation.

Other women may have risk factors that contraindicate exogenous hormones.

Nonhormonal options for vaginal dryness and dyspareunia are limited, and there are no approved systemic or oral nonestrogen options. Over-the-counter topical lubricants can ease some of the symptoms of VVA temporarily and allow successful vaginal penetration in many cases. Some may cause vaginal warming and pleasant sensations, but overall they treat the symptom rather than the source of pain. Moreover, many patients consider local lubricants messy and inconvenient and claim they “ruin the mood.”

The use of vaginal dilators along with estrogen or lubricant therapy is an often-forgotten adjunct to therapy for dyspareunia caused by VVA (FIGURE 4).

FIGURE 4 Mechanical dilation of the vagina is a useful adjunct

Mechanical dilation is often needed to restore penetration capability in the vagina, even after hormonal treatment. The focus should be on the vaginal introitus, with the top 25% to 35% of the dilator inserted into the opening once a day for 15 minutes, increasing the dilator diameter over time.

New SERMs are in development

Preclinical and clinical research into the diverse class of selective estrogen receptor modulators (SERMs) to treat estrogen-mediated disease produced tamoxifen for breast cancer prevention and raloxifene for both vertebral osteoporosis and breast cancer prevention. Each SERM seems to have unique tissue selectivity. The antiestrogenic activity of tamoxifen and raloxifene extends to the vagina and can exacerbate vaginal dryness.

A new generation of orally active SERMs is under investigation specifically for the treatment of chronic vaginal symptoms. These new agents target the nonvaginal treatment of VVA and associated symptoms. The first oral SERM for long-term treatment of these symptoms, ospemifene (Ophena), may become available in the near future. It is a novel SERM that has both anti-estrogenic and estrogenic actions, depending on the tissue. It was shown to significantly improve both vaginal dryness and dyspareunia in a large placebo-controlled trial.¹⁵

The author reports that he serves on the speaker’s bureau for Novogyne, TherRx, Warner-Chilcott, and Solvay, and on the advisory board for Upsher-Smith, Novogyne, QuatRx, and Wyeth.

CASE: History of dyspareunia

At her latest visit, a 56-year-old woman who is 7 years postmenopausal relates that she has been experiencing worsening pain with intercourse to the point that she now has very little sex drive at all. This problem began approximately 1 year after she discontinued hormone therapy in the wake of reports that it causes cancer and heart attack. She has been offered both local vaginal and systemic hormone therapy, but is too frightened to use any hormones at all. Sexual lubricants no longer seem to work.

How do you counsel her about these symptoms? And what therapy do you offer?

Physicians and other health-care practitioners are seeing a large and growing number of genitourinary and sexual-related complaints among menopausal women—so much so that it has reached epidemic proportions. Yet dyspareunia is underreported and undertreated, and quality of life suffers for these women.

In this article, I focus on two interrelated causes of this epidemic:

• vaginal dryness and vulvovaginal atrophy (VVA) and the impact of these conditions on women’s sexual function and psychosocial well-being
• barriers to optimal treatment.

I also explore how ObGyns’ role in this area of care is evolving—as a way to understand how you can better serve this expanding segment of our patient population.

Dyspareunia can have many causes, including endometriosis, interstitial cystitis, surgical scarring, injury that occurs during childbirth, and psychosocial origin (such as a history of sexual abuse). Our focus here is on dyspareunia due to VVA.

Just how sizable is the postmenopausal population?

About 32% of the female population is older than 50 years.¹ That means that around 48 million women are currently menopausal, or will become so over the next few years.

Because average life expectancy approaches 80 years in the United States and other countries of the industrialized world,² many women will live approximately 40 years beyond menopause or their final menstrual period. Their quality of life during the second half of their life is dependent on both physical and psychosocial health.

Postmenopausal dyspareunia isn’t new

Sexual issues arising from physical causes—dyspareunia among them—have long accounted for a large share of medical concerns reported by postmenopausal women. In a 1985 survey, for example, dyspareunia accounted for 42.5% of their complaints.³

But epidemiologic studies to determine the prevalence of female sexual dysfunction in postmenopausal women are difficult to carry out. Why? Because researchers would need to 1) address changes over time and 2) distinguish problems of sexual function from those brought on by aging.⁴

The techniques and methodology for researching female sexual dysfunction continue to evolve, creating new definitions of the stages of menopause and new diagnostic approaches to female sexual dysfunction.

However, based on available studies, Dennerstein and Hayes concluded that:

• postmenopausal women report a high rate of sexual dysfunction (higher than men)
• psychosocial factors can ameliorate a decline in sexual function
• “vaginal dryness and dyspareunia seem to be driven primarily by declining estradiol.”⁴

The WHI and its domino effect

Millions of postmenopausal women stopped taking estrogen-based therapy in the wake of widespread media coverage after 2002 publication of data from the estrogen–progestin arm of the Women’s Health Initiative (WHI), which purported to show, among other things, an increased risk of breast cancer.⁵

For decades, many postmenopausal women achieved medical management of VVA through long-term use of systemic hormone replacement therapy (HRT), which they used primarily to control other chronic symptoms of menopause, such as hot flashes.

After the WHI data were published (and misrepresented), reduced usage of estrogen-based HRT “unmasked” vaginal symptoms, including sexual pain, due to the effects of estrogen deficiency on the vaginal epithelium and vaginal blood flow. Since then, we have been forced to examine anew the natural history of menopause.

Within days or weeks of discontinuing HRT, women may reexperience the acute vasomotor symptoms that accompany estrogen withdrawal—most commonly hot flashes, night sweats, sleeplessness, palpitations, and headaches. Over time—anywhere from 6 months to several years—the body adjusts to the loss or withdrawal of estrogen, and these vasomotor symptoms eventually diminish or resolve. Not so for the longer-term physical effects of chronic low serum levels of estrogen, which worsen over time.

Approximately 6 months after discontinuing estrogen therapy, postmenopausal women may begin to experience vaginal dryness and VVA. As the years pass, other side effects of estrogen deficiency arise: bone loss, joint pain, mood alteration (including depression), change in skin tone, hair loss, and cardiac and central nervous system changes. These side effects do not resolve spontaneously; in fact, they grow worse as a woman ages. They may have deleterious psychosocial as well as physical impacts on her life—especially on the quality of her intimate relationship.

Is 60 the new 40?

Many women and men in the large cohort known as the Baby Boomer generation continue to be sexually active into their 60s, 70s, and 80s, as demonstrated by a 2007 study of sexuality and health in older adults.⁶ In the 57- to 64-year-old age group, 61.6% of women and 83.7% of men were sexually active (defined as sexual activity with a partner within the past 12 months). In the 65- to 74-year-old group, 39.5% of women and 67% of men were sexually active; and in the 75- to 85-year-old group, 16.7% of women and 38.5% of men were sexually active (TABLE).

These findings indicate that fewer women than men remain sexually active during their later years. One reason may be the epidemic of sexual-related symptoms among postmenopausal women. In the same survey, 34.3% of women 57 to 64 years old reported avoiding sex because of:

• pain during intercourse (17.8%)
• difficulty with lubrication (35.9%).

Across all groups, the most prevalent sexual problem was low desire (43%).⁶ Around 40% of postmenopausal women reported no sexual activity in the past 12 months, as well as lack of interest in sex. This number may include women who have ceased to have sex because of vaginal dryness and dyspareunia, thereby reducing the percentage reporting these symptoms (TABLE).

TABLE

Older adults are having sex—and experiencing sexual problems

Assessing menopause-related sexual function is a challenge

Although the transition phases of menopause have been well studied and reported for decades, few of these studies have included questions about the impact of menopause on sexual function.⁷ When longitudinal studies that included the classification of female sexual dysfunction began to appear, they provided evidence of the important role that VVA and psychosocial factors play in female sexual dysfunction.⁸

In the fourth year of the Melbourne Women’s Midlife Health Project longitudinal study, six variables related to sexual function were identified. Three were determinate of sexual function:

• feelings for the partner
• problems related to the partner
• vaginal dryness/dyspareunia.

The other three variables—sexual responsiveness, frequency of sexual activity, and libido—were dependent or outcome variables.

By the sixth year of this study, two variables had increased in significance: vaginal dryness/dyspareunia and partner problems.⁷

Sexual pain and relationship problems can create a vicious cycle

The interrelationship of vaginal dryness, sexual pain, flagging desire, and psychosocial parameters can produce a vicious cycle. A woman experiencing or anticipating pain may have diminished sexual desire or avoid sex altogether. During intercourse, the brain’s awareness of vaginal pain may trigger a physiologic response that can cause the muscles of the vagina to tighten and lubrication to decrease. The result? Greater vaginal pain.

This vicious cycle can contribute to relationship issues with the sexual partner and harm a woman’s psychosocial well-being. Resentment, anger, and misunderstanding may arise when a couple is dealing with problems of sexual function, and these stressors can damage many aspects of the relationship, further exacerbating sexual difficulties.

An additional and very important dimension of these issues is their potential impact on the family unit.

VVA can diminish overall well-being

In a 2007 survey reported at the North American Menopause Society (NAMS), one third to one half of 506 respondents said that VVA had a bad effect on their sexual interest, mood, self-esteem, and the intimate relationship (FIGURE 1).⁹ Reports from in-depth interviews were consistent with survey results and offered further insight into a woman’s emotional response to the condition of vaginal dryness and its impact on her life. Women found the condition “embarrassing,” something they had to endure but didn’t talk about, and felt that it had a major impact on their self-esteem and intimate relationship.

FIGURE 1 Dyspareunia affects more than interest in sex—relationships, mood, and self-esteem suffer

Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas.

Clinicians often don’t ask about VVA, and patients are reluctant to talk

Among women of all ages, dyspareunia is underreported and undertreated. In the survey reported at NAMS, 40% of respondents said that their physician had never asked them about the problem of VVA (FIGURE 2).⁹

Women themselves may be reluctant to discuss the problem with physicians, nurse practitioners, or other health-care providers out of embarrassment or the assumption that there is nothing to be done about the problem. Nevertheless, more than 40% of respondents said they would be highly likely to seek treatment for VVA if they had a concern about urogenital complications of the condition (FIGURE 3).⁹

Another barrier may be the sense that asking the health-care provider about sex may embarrass him or her. As a result, sufferers do not anticipate help from their physician and other members of the health-care profession and fail to seek treatment or counseling for this chronic medical condition.^10,11

In a 1999 telephone survey of 500 adults 25 years of age or older, 71% said they thought that their doctor would dismiss concerns about sexual problems, but 85% said they would talk to their physician anyway if they had a problem, even though they might not get treatment.¹¹ In that survey, 91% of married men and 84% of married women rated a satisfying sex life as important to quality of life.¹¹

Another important and often overlooked limitation on this type of discussion is the time constraints that busy clinicians face, especially with the low reimbursement offered by managed care. Sexual problems can hardly be adequately discussed in 7 to 10 minutes.

FIGURE 2 Do physicians ask about dyspareunia? Most women surveyed said “rarely” or “never”

Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas.

FIGURE 3 Are these women likely to seek treatment?

Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas.

Women have performance anxiety, too

It is well known that men with even a mild degree of erectile dysfunction can suffer from performance anxiety, but the fact that women can also suffer from this phenomenon is not given as much attention. Such anxiety can be a factor in relationship difficulties. With both partners perhaps feeling anxious about sexual performance, a couple may avoid even simple acts of affection, such as holding hands, to avoid raising the other’s expectations.

Exacerbating the situation is the fact that many men use widely prescribed phosphodiesterase type 5 (PDE5) inhibitors, whereas women are contending with barriers to continued sexual activity as they age. It does not take a psychologist to understand that this imbalance often adds to emotional strain and tension between partners.

Popular media address the issue

Look beyond what our postmenopausal patients tell us directly—to the popular media and online forums—to appreciate the scope of sexual pain as a major issue among postmenopausal women. Evidence of psychosocial effects is found on numerous Web sites—some from organizations, others designed by women seeking help from each other.

Red Hot Mamas

(www.redhotmamas.org)

This organization aims to empower women through menopause education. Highlighted in the Winter 2007/2008 Red Hot Mamas Report is a survey done in conjunction with Harris Interactive exploring the impact of menopausal symptoms on a woman’s sex life, which found that 47% of women who have VVA have avoided or stopped sex completely because it was uncomfortable, compared with 23% of normal women.

Power Surge

(www.power-surge.com)

This Web site offers a list of strategies for dealing with sexual pain, including an overview of hormone-based prescription and nonprescription products, along with a variety of over-the-counter, natural, holistic, and herbal therapies for treating dyspareunia.

What is the physician’s role?

Given the epidemic of sexual pain, it is crucial that physicians and others who care for postmenopausal women increase their awareness of this issue and pay special attention to its psychosocial parameters.

Ask patients about sexual function in general and dyspareunia in particular as part of the routine annual visit. A simple opening “Yes/No” question, such as “Are you sexually active?” can lead to further questions appropriate to the patient. For example, if the answer is “No,” the follow-up question might be, “Does that bother you or your partner?” Further discussion may uncover whether the lack of sexual activity is a cause of distress and identify which variables are involved.

If, instead, the answer is “Yes,” follow-up questions can identify the presence of common postmenopausal physical issues, such as vaginal dryness and difficulty with lubrication. The visit then can turn to strategies to ameliorate those conditions.

When a patient reports dyspareunia, further diagnostic information such as precise location, degree of arousal, and reaction to pain can help determine the appropriate course of treatment. For an approach to this aspect of ascertaining patient history, see the list of sample questions above.¹²

During the physical, pay particular attention to any physical abnormalities or organic causes of sexual pain. Questions designed to characterize the location and nature of the pain can pinpoint the cause. Sexual pain arising from VVA is likely to 1) be localized at the introitus and 2) occur with penile entry.

Think female sexual function is linear? Think again

Since the mid-1990s, the availability of validated scales to measure female sexual function has increased rapidly and enabled researchers to better identify, quantify, and evaluate treatments for female sexual dysfunction.⁷ Over time, we have moved away from the somewhat mechanical sequence inherent in the linear progression of desire leading to genital stimulation followed by arousal and orgasm toward an appreciation of the multiple physical, emotional, and subjective factors that are at play in women’s sexual function.

By 1998, a classification scheme was developed to further the means to study and discuss disorders of desire, arousal, orgasm, and sexual pain.⁸ Further contextual definitions of sexual dysfunction are under consideration.¹³

Basson proposed one new model of female sexual function (see the diagram), and observed that

"…women identify many reasons they are sexual over and beyond inherent sexual drive or “hunger.” Women tell of wanting to increase emotional closeness, commitment, sharing, tenderness, and tolerance, and to show the partner that he or she has been missed (emotionally or physically). Such intimacy-based reasons motivate the woman to find a way to become sexually aroused. This arousal is not spontaneous but triggered by deliberately sought sexual stimuli."¹³

Intimacy-based model of female sexual response cycle

In this flow of physical and emotional variables involved in female sexual function, categories interact. For example, low desire can be and is frequently secondary to the anticipation of pain during sexual intercourse. Arousal can be hampered by lack of vaginal lubrication—perhaps inhibited by the anticipation of pain. Secondary orgasmic disorders can result from low desire, difficulty of arousal, and sexual pain.¹⁴ Sexual pain can affect sexual function at any point on this continuum.

Treatments in the pipeline

For decades, hormone-based treatments have been the predominant therapeutic option for vaginal dryness. Often they are a secondary benefit of hormone therapy for vasomotor symptoms and osteoporosis. Estrogen can be delivered in the form of oral tablet, transdermal patch, gel, spray, or vaginal ring for systemic use, or as vaginal cream, ring, or tablet for local use.

However, despite data to the contrary and our reassurances to the patient about overall safety, a large number of women, and many primary care providers, are no longer inclined to use short- or long-term HRT in any presentation.

Other women may have risk factors that contraindicate exogenous hormones.

Nonhormonal options for vaginal dryness and dyspareunia are limited, and there are no approved systemic or oral nonestrogen options. Over-the-counter topical lubricants can ease some of the symptoms of VVA temporarily and allow successful vaginal penetration in many cases. Some may cause vaginal warming and pleasant sensations, but overall they treat the symptom rather than the source of pain. Moreover, many patients consider local lubricants messy and inconvenient and claim they “ruin the mood.”

The use of vaginal dilators along with estrogen or lubricant therapy is an often-forgotten adjunct to therapy for dyspareunia caused by VVA (FIGURE 4).

FIGURE 4 Mechanical dilation of the vagina is a useful adjunct

Mechanical dilation is often needed to restore penetration capability in the vagina, even after hormonal treatment. The focus should be on the vaginal introitus, with the top 25% to 35% of the dilator inserted into the opening once a day for 15 minutes, increasing the dilator diameter over time.

New SERMs are in development

Preclinical and clinical research into the diverse class of selective estrogen receptor modulators (SERMs) to treat estrogen-mediated disease produced tamoxifen for breast cancer prevention and raloxifene for both vertebral osteoporosis and breast cancer prevention. Each SERM seems to have unique tissue selectivity. The antiestrogenic activity of tamoxifen and raloxifene extends to the vagina and can exacerbate vaginal dryness.

A new generation of orally active SERMs is under investigation specifically for the treatment of chronic vaginal symptoms. These new agents target the nonvaginal treatment of VVA and associated symptoms. The first oral SERM for long-term treatment of these symptoms, ospemifene (Ophena), may become available in the near future. It is a novel SERM that has both anti-estrogenic and estrogenic actions, depending on the tissue. It was shown to significantly improve both vaginal dryness and dyspareunia in a large placebo-controlled trial.¹⁵

The author reports that he serves on the speaker’s bureau for Novogyne, TherRx, Warner-Chilcott, and Solvay, and on the advisory board for Upsher-Smith, Novogyne, QuatRx, and Wyeth.

CASE: History of dyspareunia

At her latest visit, a 56-year-old woman who is 7 years postmenopausal relates that she has been experiencing worsening pain with intercourse to the point that she now has very little sex drive at all. This problem began approximately 1 year after she discontinued hormone therapy in the wake of reports that it causes cancer and heart attack. She has been offered both local vaginal and systemic hormone therapy, but is too frightened to use any hormones at all. Sexual lubricants no longer seem to work.

How do you counsel her about these symptoms? And what therapy do you offer?

Physicians and other health-care practitioners are seeing a large and growing number of genitourinary and sexual-related complaints among menopausal women—so much so that it has reached epidemic proportions. Yet dyspareunia is underreported and undertreated, and quality of life suffers for these women.

In this article, I focus on two interrelated causes of this epidemic:

• vaginal dryness and vulvovaginal atrophy (VVA) and the impact of these conditions on women’s sexual function and psychosocial well-being
• barriers to optimal treatment.

I also explore how ObGyns’ role in this area of care is evolving—as a way to understand how you can better serve this expanding segment of our patient population.

Dyspareunia can have many causes, including endometriosis, interstitial cystitis, surgical scarring, injury that occurs during childbirth, and psychosocial origin (such as a history of sexual abuse). Our focus here is on dyspareunia due to VVA.

Just how sizable is the postmenopausal population?

About 32% of the female population is older than 50 years.¹ That means that around 48 million women are currently menopausal, or will become so over the next few years.

Because average life expectancy approaches 80 years in the United States and other countries of the industrialized world,² many women will live approximately 40 years beyond menopause or their final menstrual period. Their quality of life during the second half of their life is dependent on both physical and psychosocial health.

Postmenopausal dyspareunia isn’t new

Sexual issues arising from physical causes—dyspareunia among them—have long accounted for a large share of medical concerns reported by postmenopausal women. In a 1985 survey, for example, dyspareunia accounted for 42.5% of their complaints.³

But epidemiologic studies to determine the prevalence of female sexual dysfunction in postmenopausal women are difficult to carry out. Why? Because researchers would need to 1) address changes over time and 2) distinguish problems of sexual function from those brought on by aging.⁴

The techniques and methodology for researching female sexual dysfunction continue to evolve, creating new definitions of the stages of menopause and new diagnostic approaches to female sexual dysfunction.

However, based on available studies, Dennerstein and Hayes concluded that:

• postmenopausal women report a high rate of sexual dysfunction (higher than men)
• psychosocial factors can ameliorate a decline in sexual function
• “vaginal dryness and dyspareunia seem to be driven primarily by declining estradiol.”⁴

The WHI and its domino effect

Millions of postmenopausal women stopped taking estrogen-based therapy in the wake of widespread media coverage after 2002 publication of data from the estrogen–progestin arm of the Women’s Health Initiative (WHI), which purported to show, among other things, an increased risk of breast cancer.⁵

For decades, many postmenopausal women achieved medical management of VVA through long-term use of systemic hormone replacement therapy (HRT), which they used primarily to control other chronic symptoms of menopause, such as hot flashes.

After the WHI data were published (and misrepresented), reduced usage of estrogen-based HRT “unmasked” vaginal symptoms, including sexual pain, due to the effects of estrogen deficiency on the vaginal epithelium and vaginal blood flow. Since then, we have been forced to examine anew the natural history of menopause.

Within days or weeks of discontinuing HRT, women may reexperience the acute vasomotor symptoms that accompany estrogen withdrawal—most commonly hot flashes, night sweats, sleeplessness, palpitations, and headaches. Over time—anywhere from 6 months to several years—the body adjusts to the loss or withdrawal of estrogen, and these vasomotor symptoms eventually diminish or resolve. Not so for the longer-term physical effects of chronic low serum levels of estrogen, which worsen over time.

Approximately 6 months after discontinuing estrogen therapy, postmenopausal women may begin to experience vaginal dryness and VVA. As the years pass, other side effects of estrogen deficiency arise: bone loss, joint pain, mood alteration (including depression), change in skin tone, hair loss, and cardiac and central nervous system changes. These side effects do not resolve spontaneously; in fact, they grow worse as a woman ages. They may have deleterious psychosocial as well as physical impacts on her life—especially on the quality of her intimate relationship.

Is 60 the new 40?

Many women and men in the large cohort known as the Baby Boomer generation continue to be sexually active into their 60s, 70s, and 80s, as demonstrated by a 2007 study of sexuality and health in older adults.⁶ In the 57- to 64-year-old age group, 61.6% of women and 83.7% of men were sexually active (defined as sexual activity with a partner within the past 12 months). In the 65- to 74-year-old group, 39.5% of women and 67% of men were sexually active; and in the 75- to 85-year-old group, 16.7% of women and 38.5% of men were sexually active (TABLE).

These findings indicate that fewer women than men remain sexually active during their later years. One reason may be the epidemic of sexual-related symptoms among postmenopausal women. In the same survey, 34.3% of women 57 to 64 years old reported avoiding sex because of:

• pain during intercourse (17.8%)
• difficulty with lubrication (35.9%).

Across all groups, the most prevalent sexual problem was low desire (43%).⁶ Around 40% of postmenopausal women reported no sexual activity in the past 12 months, as well as lack of interest in sex. This number may include women who have ceased to have sex because of vaginal dryness and dyspareunia, thereby reducing the percentage reporting these symptoms (TABLE).

TABLE

Older adults are having sex—and experiencing sexual problems

Assessing menopause-related sexual function is a challenge

Although the transition phases of menopause have been well studied and reported for decades, few of these studies have included questions about the impact of menopause on sexual function.⁷ When longitudinal studies that included the classification of female sexual dysfunction began to appear, they provided evidence of the important role that VVA and psychosocial factors play in female sexual dysfunction.⁸

In the fourth year of the Melbourne Women’s Midlife Health Project longitudinal study, six variables related to sexual function were identified. Three were determinate of sexual function:

• feelings for the partner
• problems related to the partner
• vaginal dryness/dyspareunia.

The other three variables—sexual responsiveness, frequency of sexual activity, and libido—were dependent or outcome variables.

By the sixth year of this study, two variables had increased in significance: vaginal dryness/dyspareunia and partner problems.⁷

Sexual pain and relationship problems can create a vicious cycle

The interrelationship of vaginal dryness, sexual pain, flagging desire, and psychosocial parameters can produce a vicious cycle. A woman experiencing or anticipating pain may have diminished sexual desire or avoid sex altogether. During intercourse, the brain’s awareness of vaginal pain may trigger a physiologic response that can cause the muscles of the vagina to tighten and lubrication to decrease. The result? Greater vaginal pain.

This vicious cycle can contribute to relationship issues with the sexual partner and harm a woman’s psychosocial well-being. Resentment, anger, and misunderstanding may arise when a couple is dealing with problems of sexual function, and these stressors can damage many aspects of the relationship, further exacerbating sexual difficulties.

An additional and very important dimension of these issues is their potential impact on the family unit.

VVA can diminish overall well-being

In a 2007 survey reported at the North American Menopause Society (NAMS), one third to one half of 506 respondents said that VVA had a bad effect on their sexual interest, mood, self-esteem, and the intimate relationship (FIGURE 1).⁹ Reports from in-depth interviews were consistent with survey results and offered further insight into a woman’s emotional response to the condition of vaginal dryness and its impact on her life. Women found the condition “embarrassing,” something they had to endure but didn’t talk about, and felt that it had a major impact on their self-esteem and intimate relationship.

FIGURE 1 Dyspareunia affects more than interest in sex—relationships, mood, and self-esteem suffer

Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas.

Clinicians often don’t ask about VVA, and patients are reluctant to talk

Among women of all ages, dyspareunia is underreported and undertreated. In the survey reported at NAMS, 40% of respondents said that their physician had never asked them about the problem of VVA (FIGURE 2).⁹

Women themselves may be reluctant to discuss the problem with physicians, nurse practitioners, or other health-care providers out of embarrassment or the assumption that there is nothing to be done about the problem. Nevertheless, more than 40% of respondents said they would be highly likely to seek treatment for VVA if they had a concern about urogenital complications of the condition (FIGURE 3).⁹

Another barrier may be the sense that asking the health-care provider about sex may embarrass him or her. As a result, sufferers do not anticipate help from their physician and other members of the health-care profession and fail to seek treatment or counseling for this chronic medical condition.^10,11

In a 1999 telephone survey of 500 adults 25 years of age or older, 71% said they thought that their doctor would dismiss concerns about sexual problems, but 85% said they would talk to their physician anyway if they had a problem, even though they might not get treatment.¹¹ In that survey, 91% of married men and 84% of married women rated a satisfying sex life as important to quality of life.¹¹

Another important and often overlooked limitation on this type of discussion is the time constraints that busy clinicians face, especially with the low reimbursement offered by managed care. Sexual problems can hardly be adequately discussed in 7 to 10 minutes.

FIGURE 2 Do physicians ask about dyspareunia? Most women surveyed said “rarely” or “never”

Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas.

FIGURE 3 Are these women likely to seek treatment?

Simon JA, Komi J. Vulvovaginal atrophy (VVA) negatively impacts sexual function, psychosocial well-being, and partner relationships. Poster presented at North American Menopause Association Annual Meeting; October 3-6, 2007; Dallas, Texas.

Women have performance anxiety, too

It is well known that men with even a mild degree of erectile dysfunction can suffer from performance anxiety, but the fact that women can also suffer from this phenomenon is not given as much attention. Such anxiety can be a factor in relationship difficulties. With both partners perhaps feeling anxious about sexual performance, a couple may avoid even simple acts of affection, such as holding hands, to avoid raising the other’s expectations.

Exacerbating the situation is the fact that many men use widely prescribed phosphodiesterase type 5 (PDE5) inhibitors, whereas women are contending with barriers to continued sexual activity as they age. It does not take a psychologist to understand that this imbalance often adds to emotional strain and tension between partners.

Popular media address the issue

Look beyond what our postmenopausal patients tell us directly—to the popular media and online forums—to appreciate the scope of sexual pain as a major issue among postmenopausal women. Evidence of psychosocial effects is found on numerous Web sites—some from organizations, others designed by women seeking help from each other.

Red Hot Mamas

(www.redhotmamas.org)

This organization aims to empower women through menopause education. Highlighted in the Winter 2007/2008 Red Hot Mamas Report is a survey done in conjunction with Harris Interactive exploring the impact of menopausal symptoms on a woman’s sex life, which found that 47% of women who have VVA have avoided or stopped sex completely because it was uncomfortable, compared with 23% of normal women.

Power Surge

(www.power-surge.com)

This Web site offers a list of strategies for dealing with sexual pain, including an overview of hormone-based prescription and nonprescription products, along with a variety of over-the-counter, natural, holistic, and herbal therapies for treating dyspareunia.

What is the physician’s role?

Given the epidemic of sexual pain, it is crucial that physicians and others who care for postmenopausal women increase their awareness of this issue and pay special attention to its psychosocial parameters.

Ask patients about sexual function in general and dyspareunia in particular as part of the routine annual visit. A simple opening “Yes/No” question, such as “Are you sexually active?” can lead to further questions appropriate to the patient. For example, if the answer is “No,” the follow-up question might be, “Does that bother you or your partner?” Further discussion may uncover whether the lack of sexual activity is a cause of distress and identify which variables are involved.

If, instead, the answer is “Yes,” follow-up questions can identify the presence of common postmenopausal physical issues, such as vaginal dryness and difficulty with lubrication. The visit then can turn to strategies to ameliorate those conditions.

When a patient reports dyspareunia, further diagnostic information such as precise location, degree of arousal, and reaction to pain can help determine the appropriate course of treatment. For an approach to this aspect of ascertaining patient history, see the list of sample questions above.¹²

During the physical, pay particular attention to any physical abnormalities or organic causes of sexual pain. Questions designed to characterize the location and nature of the pain can pinpoint the cause. Sexual pain arising from VVA is likely to 1) be localized at the introitus and 2) occur with penile entry.

Think female sexual function is linear? Think again

Since the mid-1990s, the availability of validated scales to measure female sexual function has increased rapidly and enabled researchers to better identify, quantify, and evaluate treatments for female sexual dysfunction.⁷ Over time, we have moved away from the somewhat mechanical sequence inherent in the linear progression of desire leading to genital stimulation followed by arousal and orgasm toward an appreciation of the multiple physical, emotional, and subjective factors that are at play in women’s sexual function.

By 1998, a classification scheme was developed to further the means to study and discuss disorders of desire, arousal, orgasm, and sexual pain.⁸ Further contextual definitions of sexual dysfunction are under consideration.¹³

Basson proposed one new model of female sexual function (see the diagram), and observed that

"…women identify many reasons they are sexual over and beyond inherent sexual drive or “hunger.” Women tell of wanting to increase emotional closeness, commitment, sharing, tenderness, and tolerance, and to show the partner that he or she has been missed (emotionally or physically). Such intimacy-based reasons motivate the woman to find a way to become sexually aroused. This arousal is not spontaneous but triggered by deliberately sought sexual stimuli."¹³

Intimacy-based model of female sexual response cycle

In this flow of physical and emotional variables involved in female sexual function, categories interact. For example, low desire can be and is frequently secondary to the anticipation of pain during sexual intercourse. Arousal can be hampered by lack of vaginal lubrication—perhaps inhibited by the anticipation of pain. Secondary orgasmic disorders can result from low desire, difficulty of arousal, and sexual pain.¹⁴ Sexual pain can affect sexual function at any point on this continuum.

Treatments in the pipeline

For decades, hormone-based treatments have been the predominant therapeutic option for vaginal dryness. Often they are a secondary benefit of hormone therapy for vasomotor symptoms and osteoporosis. Estrogen can be delivered in the form of oral tablet, transdermal patch, gel, spray, or vaginal ring for systemic use, or as vaginal cream, ring, or tablet for local use.

However, despite data to the contrary and our reassurances to the patient about overall safety, a large number of women, and many primary care providers, are no longer inclined to use short- or long-term HRT in any presentation.

Other women may have risk factors that contraindicate exogenous hormones.

Nonhormonal options for vaginal dryness and dyspareunia are limited, and there are no approved systemic or oral nonestrogen options. Over-the-counter topical lubricants can ease some of the symptoms of VVA temporarily and allow successful vaginal penetration in many cases. Some may cause vaginal warming and pleasant sensations, but overall they treat the symptom rather than the source of pain. Moreover, many patients consider local lubricants messy and inconvenient and claim they “ruin the mood.”

The use of vaginal dilators along with estrogen or lubricant therapy is an often-forgotten adjunct to therapy for dyspareunia caused by VVA (FIGURE 4).

FIGURE 4 Mechanical dilation of the vagina is a useful adjunct

Mechanical dilation is often needed to restore penetration capability in the vagina, even after hormonal treatment. The focus should be on the vaginal introitus, with the top 25% to 35% of the dilator inserted into the opening once a day for 15 minutes, increasing the dilator diameter over time.

New SERMs are in development

Preclinical and clinical research into the diverse class of selective estrogen receptor modulators (SERMs) to treat estrogen-mediated disease produced tamoxifen for breast cancer prevention and raloxifene for both vertebral osteoporosis and breast cancer prevention. Each SERM seems to have unique tissue selectivity. The antiestrogenic activity of tamoxifen and raloxifene extends to the vagina and can exacerbate vaginal dryness.

A new generation of orally active SERMs is under investigation specifically for the treatment of chronic vaginal symptoms. These new agents target the nonvaginal treatment of VVA and associated symptoms. The first oral SERM for long-term treatment of these symptoms, ospemifene (Ophena), may become available in the near future. It is a novel SERM that has both anti-estrogenic and estrogenic actions, depending on the tissue. It was shown to significantly improve both vaginal dryness and dyspareunia in a large placebo-controlled trial.¹⁵