A 47-year-old man had had a chronic itch on his back for 2 years. He had no history of trauma to the site, nor did he recall applying topical products to that area.

He was otherwise healthy. He worked as an electrician and said he occasionally experienced cervical and back pain while working.

An examination revealed two grayish-brown ovoid patches on the upper back, each 5 cm to 7 cm in diameter (Figure 1).

DIAGNOSIS: NOTALGIA PARESTHETICA

Chronic, brown-gray, itching patches on the back in an adult patient are characteristic of notalgia paresthetica.

Conditions that may be included in the differential diagnosis but that do not match the presentation in this patient include the following:

• Cutaneous sarcoidosis, which may exhibit several morphologies, but itching would be unusual
• Chronic discoid lupus erythematosus, characterized by scarring and atrophic plaques, but mainly on the face and scalp
• Contact dermatitis, an itchy eczematous condition, characterized by scaly erythematous plaques
• Lichen amyloidosis, a variant of cutaneous amyloidosis characterized by the deposition of amyloid or amyloid-like proteins in the dermis, resulting in red-brown hyperkeratotic lichenoid papules, usually on the pretibial surfaces.

CAUSES AND MANAGEMENT

Notalgia paresthetica is a neuropathic syndrome of the skin of the middle of the back characterized by localized pruritus.^1–3 Although common, it often goes undiagnosed.^1,3,4 It tends to be chronic, with periodic remissions and exacerbations.

Notalgia paresthetica is thought to be a sensory neuropathy and may result from compression of the posterior rami of spinal nerve segments T2 to T6. Slight degenerative changes are often but not always observed, and their clinical significance is uncertain.^1,2,4 The condition affects people of all races and both sexes, usually adults ages 40 to 80.

Clinically, it presents as localized pruritus on the back, usually within the dermatomes T2 to T6.⁵ Examination reveals a hyperpigmented patch, sometimes with excoriations.⁵

Diagnosis is based on clinical findings. Laboratory tests are not useful. Imaging is not needed, but magnetic resonance imaging and evaluation by an orthopedic surgeon are appropriate when there is chronic focal pain. Skin biopsy is usually not necessary, although it may be useful in some patients to exclude other conditions. When biopsy is done, macular amyloidosis or postinflammatory hyperpigmentation is seen.

Treatment is difficult. Topical steroids and oral antihistamines are usually ineffective,⁵ but topical capsaicin may provide temporary relief.³ The most recommended treatment in patients with notalgia paresthetica and underlying spinal disease is evaluation and conservative management of the spinal disease, including progressive exercise and rehabilitation.² Other therapies include oxcarbazepine, gabapentin, transcutaneous electrical nerve stimulation, phototherapy,⁶ and botulinum toxin injection.

TREATMENT OF OUR PATIENT

In our patient, an orthopedic evaluation revealed cervicothoracic scoliosis. He underwent 6 months of conservative treatment under the care of his family physician and a dermatologist. Treatment consisted of exercise and rehabilitation for his scoliosis, and daily application of topical mometasone. The pain and itch gradual improved.

A 47-year-old man had had a chronic itch on his back for 2 years. He had no history of trauma to the site, nor did he recall applying topical products to that area.

He was otherwise healthy. He worked as an electrician and said he occasionally experienced cervical and back pain while working.

An examination revealed two grayish-brown ovoid patches on the upper back, each 5 cm to 7 cm in diameter (Figure 1).

DIAGNOSIS: NOTALGIA PARESTHETICA

Chronic, brown-gray, itching patches on the back in an adult patient are characteristic of notalgia paresthetica.

Conditions that may be included in the differential diagnosis but that do not match the presentation in this patient include the following:

• Cutaneous sarcoidosis, which may exhibit several morphologies, but itching would be unusual
• Chronic discoid lupus erythematosus, characterized by scarring and atrophic plaques, but mainly on the face and scalp
• Contact dermatitis, an itchy eczematous condition, characterized by scaly erythematous plaques
• Lichen amyloidosis, a variant of cutaneous amyloidosis characterized by the deposition of amyloid or amyloid-like proteins in the dermis, resulting in red-brown hyperkeratotic lichenoid papules, usually on the pretibial surfaces.

CAUSES AND MANAGEMENT

Notalgia paresthetica is a neuropathic syndrome of the skin of the middle of the back characterized by localized pruritus.^1–3 Although common, it often goes undiagnosed.^1,3,4 It tends to be chronic, with periodic remissions and exacerbations.

Notalgia paresthetica is thought to be a sensory neuropathy and may result from compression of the posterior rami of spinal nerve segments T2 to T6. Slight degenerative changes are often but not always observed, and their clinical significance is uncertain.^1,2,4 The condition affects people of all races and both sexes, usually adults ages 40 to 80.

Clinically, it presents as localized pruritus on the back, usually within the dermatomes T2 to T6.⁵ Examination reveals a hyperpigmented patch, sometimes with excoriations.⁵

Diagnosis is based on clinical findings. Laboratory tests are not useful. Imaging is not needed, but magnetic resonance imaging and evaluation by an orthopedic surgeon are appropriate when there is chronic focal pain. Skin biopsy is usually not necessary, although it may be useful in some patients to exclude other conditions. When biopsy is done, macular amyloidosis or postinflammatory hyperpigmentation is seen.

Treatment is difficult. Topical steroids and oral antihistamines are usually ineffective,⁵ but topical capsaicin may provide temporary relief.³ The most recommended treatment in patients with notalgia paresthetica and underlying spinal disease is evaluation and conservative management of the spinal disease, including progressive exercise and rehabilitation.² Other therapies include oxcarbazepine, gabapentin, transcutaneous electrical nerve stimulation, phototherapy,⁶ and botulinum toxin injection.

TREATMENT OF OUR PATIENT

In our patient, an orthopedic evaluation revealed cervicothoracic scoliosis. He underwent 6 months of conservative treatment under the care of his family physician and a dermatologist. Treatment consisted of exercise and rehabilitation for his scoliosis, and daily application of topical mometasone. The pain and itch gradual improved.

A 47-year-old man had had a chronic itch on his back for 2 years. He had no history of trauma to the site, nor did he recall applying topical products to that area.

He was otherwise healthy. He worked as an electrician and said he occasionally experienced cervical and back pain while working.

An examination revealed two grayish-brown ovoid patches on the upper back, each 5 cm to 7 cm in diameter (Figure 1).

DIAGNOSIS: NOTALGIA PARESTHETICA

Chronic, brown-gray, itching patches on the back in an adult patient are characteristic of notalgia paresthetica.

Conditions that may be included in the differential diagnosis but that do not match the presentation in this patient include the following:

• Cutaneous sarcoidosis, which may exhibit several morphologies, but itching would be unusual
• Chronic discoid lupus erythematosus, characterized by scarring and atrophic plaques, but mainly on the face and scalp
• Contact dermatitis, an itchy eczematous condition, characterized by scaly erythematous plaques
• Lichen amyloidosis, a variant of cutaneous amyloidosis characterized by the deposition of amyloid or amyloid-like proteins in the dermis, resulting in red-brown hyperkeratotic lichenoid papules, usually on the pretibial surfaces.

CAUSES AND MANAGEMENT

Notalgia paresthetica is a neuropathic syndrome of the skin of the middle of the back characterized by localized pruritus.^1–3 Although common, it often goes undiagnosed.^1,3,4 It tends to be chronic, with periodic remissions and exacerbations.

Notalgia paresthetica is thought to be a sensory neuropathy and may result from compression of the posterior rami of spinal nerve segments T2 to T6. Slight degenerative changes are often but not always observed, and their clinical significance is uncertain.^1,2,4 The condition affects people of all races and both sexes, usually adults ages 40 to 80.

Clinically, it presents as localized pruritus on the back, usually within the dermatomes T2 to T6.⁵ Examination reveals a hyperpigmented patch, sometimes with excoriations.⁵

Diagnosis is based on clinical findings. Laboratory tests are not useful. Imaging is not needed, but magnetic resonance imaging and evaluation by an orthopedic surgeon are appropriate when there is chronic focal pain. Skin biopsy is usually not necessary, although it may be useful in some patients to exclude other conditions. When biopsy is done, macular amyloidosis or postinflammatory hyperpigmentation is seen.

Treatment is difficult. Topical steroids and oral antihistamines are usually ineffective,⁵ but topical capsaicin may provide temporary relief.³ The most recommended treatment in patients with notalgia paresthetica and underlying spinal disease is evaluation and conservative management of the spinal disease, including progressive exercise and rehabilitation.² Other therapies include oxcarbazepine, gabapentin, transcutaneous electrical nerve stimulation, phototherapy,⁶ and botulinum toxin injection.

TREATMENT OF OUR PATIENT

In our patient, an orthopedic evaluation revealed cervicothoracic scoliosis. He underwent 6 months of conservative treatment under the care of his family physician and a dermatologist. Treatment consisted of exercise and rehabilitation for his scoliosis, and daily application of topical mometasone. The pain and itch gradual improved.

Early thrombus removal for lower-extremity deep venous thrombosis (DVT) is at present only modestly supported by evidence and so remains controversial. It is largely aimed at preventing postthrombotic syndrome.

The decision to pursue early thrombus removal demands weighing the patient’s risk of postthrombotic syndrome against the risks and costs associated with thrombolysis and thrombectomy, such as bleeding complications. In the final analysis, this remains a subjective decision.

With these caveats in mind, the best candidate for early thrombus removal is a young patient with iliofemoral DVT with symptoms lasting fewer than 14 days.

POSTTHROMBOTIC SYNDROME IS COMMON

Anticoagulation with heparin and warfarin is the mainstay of DVT therapy. Indeed, the safety of this therapy and its effectiveness in reducing thrombus propagation and DVT recurrence are well established. Neither heparin nor warfarin, however, actively reduces the thrombus burden. Rather, both prevent the clot from propagating while it is, hopefully, gradually reabsorbed through endogenous mechanisms.

Up to 50% of DVT patients develop postthrombotic syndrome. A variety of mechanisms are involved, including persistent obstructive thrombosis and valvular injury.¹ But much remains unknown about the etiology, and some patients develop the condition in the absence of abnormalities on objective testing.

Symptoms of postthrombotic syndrome can range from mild heaviness, edema, erythema, and cramping in the affected limb to debilitating pain with classic signs of venous hypertension (eg, venous ectasia and ulcers). It accounts for significant health care costs and has a detrimental effect on quality of life.¹ Thus, there has been interest in early thrombus removal as initial therapy for DVT.

THROMBUS REMOVAL

Venous clots can be removed with open surgery or, more typically, with percutaneous catheter-based thrombolysis and thrombectomy devices that use high-velocity saline jets, ultrasonic energy, or wire oscillation to mechanically fragment the venous clot. All of these mechanisms help with drug delivery and pose a minimal risk of pulmonary embolism.

Evidence is weak

Patients with DVT of the iliac venous system or common femoral vein are at highest risk of postthrombotic syndrome. Therefore, the Society for Vascular Surgery and the American Venous Forum have issued a grade 2C (ie, weak) recommendation in favor of early thrombus removal in patients with a first-time episode of iliofemoral DVT with fewer than 14 days of symptoms.² Moreover, patients must have a low risk of bleeding complications, be ambulatory, and have reasonable life expectancy.

The recommendation is buttressed by a Cochrane meta-analysis that included 101 patients.³ It concluded that there was a significant decrement in the development of postthrombotic syndrome with thrombolysis (but without mechanical thrombectomy) compared with standard therapy: the rate was 48% (29/61) with thrombolysis, and 65% (26/40) with standard therapy.³

More recently, the Catheter-Directed Thrombolysis Versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (CaVenT) study, a randomized prospective trial in 189 patients, demonstrated a lower rate of postthrombotic syndrome at 24 months and increased iliofemoral patency at 6 months with catheter-directed thrombolysis with alteplase (41.1% and 65.9%) vs anticoagulation with heparin and warfarin alone (55.6% and 47.4%).⁴

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial is an ongoing prospective randomized multicenter trial of the effect of thrombolysis on postthrombotic syndrome that also hopes to clarify the relative benefits of different methods of pharmacomechanical clot removal.

While CaVenT has not been criticized extensively in the literature, other studies supporting early intervention for iliofemoral venous thrombosis generally have been noted to have a number of shortcomings, including a lack of randomization, and consequent bias, and the use of surrogate end points instead of a direct assessment of postthrombotic syndrome.

Reflecting the weakness of the evidence, the American College of Chest Physicians has issued a grade 2C recommendation against catheter-directed thrombolysis and against thrombectomy in favor of anticoagulant therapy.⁵

A subjective, case-by-case decision

The decision on standard vs interventional therapy must be made case by case. For example, thrombus removal may be more appropriate for a physically active young patient who is more likely to be impaired by postthrombotic syndrome, whereas standard warfarin therapy may be preferable for a sedentary patient. We are also more inclined to offer thrombus removal to patients who have worse symptoms.

Complicating the issue, many patients present with a mix of variables that support and oppose intervention—eg, a moderately active elderly patient with an unclear life expectancy and a history of gastrointestinal bleeding. At present, there is no way to quantitatively evaluate the risks and rewards of thrombus removal, and the final decision is essentially subjective.

Additional facts warranting consideration include the possibility that thrombolysis may require several days of therapy with daily venography for evaluation. Monitoring in the intensive care unit is normally required during the period of thrombolysis. Patients should be apprised of these elements of therapy beforehand; obviously, those who are unwilling to comply are not candidates.

Not a substitute for anticoagulation

It is important to recognize that thrombus removal is not a substitute for standard heparin-warfarin anticoagulation, which must also be prescribed.⁵ Thus, patients who cannot tolerate standard post-DVT anticoagulation should not undergo thrombus removal. Furthermore, the current evidence supports the use of standard anticoagulation over early thrombus removal of DVTs that are more distal in the lower extremity, such as those in the popliteal vein.⁵

PHLEGMASIA CERULEA DOLENS IS A SPECIAL CASE

Phlegmasia cerulea dolens—acute venous outflow obstruction associated with edema, cyanosis, and pain that in the worst cases may lead to shock, limb loss, and death—constitutes a special case. Although we lack robust supporting evidence, phlegmasia is a commonly accepted indication for early thrombus removal as a means of limb salvage.^2,6

Early thrombus removal for lower-extremity deep venous thrombosis (DVT) is at present only modestly supported by evidence and so remains controversial. It is largely aimed at preventing postthrombotic syndrome.

The decision to pursue early thrombus removal demands weighing the patient’s risk of postthrombotic syndrome against the risks and costs associated with thrombolysis and thrombectomy, such as bleeding complications. In the final analysis, this remains a subjective decision.

With these caveats in mind, the best candidate for early thrombus removal is a young patient with iliofemoral DVT with symptoms lasting fewer than 14 days.

POSTTHROMBOTIC SYNDROME IS COMMON

Anticoagulation with heparin and warfarin is the mainstay of DVT therapy. Indeed, the safety of this therapy and its effectiveness in reducing thrombus propagation and DVT recurrence are well established. Neither heparin nor warfarin, however, actively reduces the thrombus burden. Rather, both prevent the clot from propagating while it is, hopefully, gradually reabsorbed through endogenous mechanisms.

Up to 50% of DVT patients develop postthrombotic syndrome. A variety of mechanisms are involved, including persistent obstructive thrombosis and valvular injury.¹ But much remains unknown about the etiology, and some patients develop the condition in the absence of abnormalities on objective testing.

Symptoms of postthrombotic syndrome can range from mild heaviness, edema, erythema, and cramping in the affected limb to debilitating pain with classic signs of venous hypertension (eg, venous ectasia and ulcers). It accounts for significant health care costs and has a detrimental effect on quality of life.¹ Thus, there has been interest in early thrombus removal as initial therapy for DVT.

THROMBUS REMOVAL

Venous clots can be removed with open surgery or, more typically, with percutaneous catheter-based thrombolysis and thrombectomy devices that use high-velocity saline jets, ultrasonic energy, or wire oscillation to mechanically fragment the venous clot. All of these mechanisms help with drug delivery and pose a minimal risk of pulmonary embolism.

Evidence is weak

Patients with DVT of the iliac venous system or common femoral vein are at highest risk of postthrombotic syndrome. Therefore, the Society for Vascular Surgery and the American Venous Forum have issued a grade 2C (ie, weak) recommendation in favor of early thrombus removal in patients with a first-time episode of iliofemoral DVT with fewer than 14 days of symptoms.² Moreover, patients must have a low risk of bleeding complications, be ambulatory, and have reasonable life expectancy.

The recommendation is buttressed by a Cochrane meta-analysis that included 101 patients.³ It concluded that there was a significant decrement in the development of postthrombotic syndrome with thrombolysis (but without mechanical thrombectomy) compared with standard therapy: the rate was 48% (29/61) with thrombolysis, and 65% (26/40) with standard therapy.³

More recently, the Catheter-Directed Thrombolysis Versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (CaVenT) study, a randomized prospective trial in 189 patients, demonstrated a lower rate of postthrombotic syndrome at 24 months and increased iliofemoral patency at 6 months with catheter-directed thrombolysis with alteplase (41.1% and 65.9%) vs anticoagulation with heparin and warfarin alone (55.6% and 47.4%).⁴

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial is an ongoing prospective randomized multicenter trial of the effect of thrombolysis on postthrombotic syndrome that also hopes to clarify the relative benefits of different methods of pharmacomechanical clot removal.

While CaVenT has not been criticized extensively in the literature, other studies supporting early intervention for iliofemoral venous thrombosis generally have been noted to have a number of shortcomings, including a lack of randomization, and consequent bias, and the use of surrogate end points instead of a direct assessment of postthrombotic syndrome.

Reflecting the weakness of the evidence, the American College of Chest Physicians has issued a grade 2C recommendation against catheter-directed thrombolysis and against thrombectomy in favor of anticoagulant therapy.⁵

A subjective, case-by-case decision

The decision on standard vs interventional therapy must be made case by case. For example, thrombus removal may be more appropriate for a physically active young patient who is more likely to be impaired by postthrombotic syndrome, whereas standard warfarin therapy may be preferable for a sedentary patient. We are also more inclined to offer thrombus removal to patients who have worse symptoms.

Complicating the issue, many patients present with a mix of variables that support and oppose intervention—eg, a moderately active elderly patient with an unclear life expectancy and a history of gastrointestinal bleeding. At present, there is no way to quantitatively evaluate the risks and rewards of thrombus removal, and the final decision is essentially subjective.

Additional facts warranting consideration include the possibility that thrombolysis may require several days of therapy with daily venography for evaluation. Monitoring in the intensive care unit is normally required during the period of thrombolysis. Patients should be apprised of these elements of therapy beforehand; obviously, those who are unwilling to comply are not candidates.

Not a substitute for anticoagulation

It is important to recognize that thrombus removal is not a substitute for standard heparin-warfarin anticoagulation, which must also be prescribed.⁵ Thus, patients who cannot tolerate standard post-DVT anticoagulation should not undergo thrombus removal. Furthermore, the current evidence supports the use of standard anticoagulation over early thrombus removal of DVTs that are more distal in the lower extremity, such as those in the popliteal vein.⁵

PHLEGMASIA CERULEA DOLENS IS A SPECIAL CASE

Phlegmasia cerulea dolens—acute venous outflow obstruction associated with edema, cyanosis, and pain that in the worst cases may lead to shock, limb loss, and death—constitutes a special case. Although we lack robust supporting evidence, phlegmasia is a commonly accepted indication for early thrombus removal as a means of limb salvage.^2,6

Early thrombus removal for lower-extremity deep venous thrombosis (DVT) is at present only modestly supported by evidence and so remains controversial. It is largely aimed at preventing postthrombotic syndrome.

The decision to pursue early thrombus removal demands weighing the patient’s risk of postthrombotic syndrome against the risks and costs associated with thrombolysis and thrombectomy, such as bleeding complications. In the final analysis, this remains a subjective decision.

With these caveats in mind, the best candidate for early thrombus removal is a young patient with iliofemoral DVT with symptoms lasting fewer than 14 days.

POSTTHROMBOTIC SYNDROME IS COMMON

Anticoagulation with heparin and warfarin is the mainstay of DVT therapy. Indeed, the safety of this therapy and its effectiveness in reducing thrombus propagation and DVT recurrence are well established. Neither heparin nor warfarin, however, actively reduces the thrombus burden. Rather, both prevent the clot from propagating while it is, hopefully, gradually reabsorbed through endogenous mechanisms.

Up to 50% of DVT patients develop postthrombotic syndrome. A variety of mechanisms are involved, including persistent obstructive thrombosis and valvular injury.¹ But much remains unknown about the etiology, and some patients develop the condition in the absence of abnormalities on objective testing.

Symptoms of postthrombotic syndrome can range from mild heaviness, edema, erythema, and cramping in the affected limb to debilitating pain with classic signs of venous hypertension (eg, venous ectasia and ulcers). It accounts for significant health care costs and has a detrimental effect on quality of life.¹ Thus, there has been interest in early thrombus removal as initial therapy for DVT.

THROMBUS REMOVAL

Venous clots can be removed with open surgery or, more typically, with percutaneous catheter-based thrombolysis and thrombectomy devices that use high-velocity saline jets, ultrasonic energy, or wire oscillation to mechanically fragment the venous clot. All of these mechanisms help with drug delivery and pose a minimal risk of pulmonary embolism.

Evidence is weak

Patients with DVT of the iliac venous system or common femoral vein are at highest risk of postthrombotic syndrome. Therefore, the Society for Vascular Surgery and the American Venous Forum have issued a grade 2C (ie, weak) recommendation in favor of early thrombus removal in patients with a first-time episode of iliofemoral DVT with fewer than 14 days of symptoms.² Moreover, patients must have a low risk of bleeding complications, be ambulatory, and have reasonable life expectancy.

The recommendation is buttressed by a Cochrane meta-analysis that included 101 patients.³ It concluded that there was a significant decrement in the development of postthrombotic syndrome with thrombolysis (but without mechanical thrombectomy) compared with standard therapy: the rate was 48% (29/61) with thrombolysis, and 65% (26/40) with standard therapy.³

More recently, the Catheter-Directed Thrombolysis Versus Standard Treatment for Acute Iliofemoral Deep Vein Thrombosis (CaVenT) study, a randomized prospective trial in 189 patients, demonstrated a lower rate of postthrombotic syndrome at 24 months and increased iliofemoral patency at 6 months with catheter-directed thrombolysis with alteplase (41.1% and 65.9%) vs anticoagulation with heparin and warfarin alone (55.6% and 47.4%).⁴

The Acute Venous Thrombosis: Thrombus Removal With Adjunctive Catheter-directed Thrombolysis (ATTRACT) trial is an ongoing prospective randomized multicenter trial of the effect of thrombolysis on postthrombotic syndrome that also hopes to clarify the relative benefits of different methods of pharmacomechanical clot removal.

While CaVenT has not been criticized extensively in the literature, other studies supporting early intervention for iliofemoral venous thrombosis generally have been noted to have a number of shortcomings, including a lack of randomization, and consequent bias, and the use of surrogate end points instead of a direct assessment of postthrombotic syndrome.

Reflecting the weakness of the evidence, the American College of Chest Physicians has issued a grade 2C recommendation against catheter-directed thrombolysis and against thrombectomy in favor of anticoagulant therapy.⁵

A subjective, case-by-case decision

The decision on standard vs interventional therapy must be made case by case. For example, thrombus removal may be more appropriate for a physically active young patient who is more likely to be impaired by postthrombotic syndrome, whereas standard warfarin therapy may be preferable for a sedentary patient. We are also more inclined to offer thrombus removal to patients who have worse symptoms.

Complicating the issue, many patients present with a mix of variables that support and oppose intervention—eg, a moderately active elderly patient with an unclear life expectancy and a history of gastrointestinal bleeding. At present, there is no way to quantitatively evaluate the risks and rewards of thrombus removal, and the final decision is essentially subjective.

Additional facts warranting consideration include the possibility that thrombolysis may require several days of therapy with daily venography for evaluation. Monitoring in the intensive care unit is normally required during the period of thrombolysis. Patients should be apprised of these elements of therapy beforehand; obviously, those who are unwilling to comply are not candidates.

Not a substitute for anticoagulation

It is important to recognize that thrombus removal is not a substitute for standard heparin-warfarin anticoagulation, which must also be prescribed.⁵ Thus, patients who cannot tolerate standard post-DVT anticoagulation should not undergo thrombus removal. Furthermore, the current evidence supports the use of standard anticoagulation over early thrombus removal of DVTs that are more distal in the lower extremity, such as those in the popliteal vein.⁵

PHLEGMASIA CERULEA DOLENS IS A SPECIAL CASE

Phlegmasia cerulea dolens—acute venous outflow obstruction associated with edema, cyanosis, and pain that in the worst cases may lead to shock, limb loss, and death—constitutes a special case. Although we lack robust supporting evidence, phlegmasia is a commonly accepted indication for early thrombus removal as a means of limb salvage.^2,6

A March 2013 warning by the US Food and Drug Administration that azithromycin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however, try to determine if our patients have cardiovascular risk factors for this extreme side effect and take appropriate precautions.

AZITHROMYCIN: THE SAFEST OF THE MACROLIDES?

Azithromycin, a broad-spectrum macrolide antibiotic, is used to treat or prevent a range of common bacterial infections, including upper and lower respiratory tract infections and certain sexually transmitted diseases.

In terms of overall toxicity, azithromycin has been considered the safest of the macrolides, as it neither undergoes CYP3A4 metabolism nor inhibits CYP3A4 to any clinically meaningful degree, and therefore does not interfere with the array of commonly used medications that undergo CYP3A4 metabolism.

Also, in vitro, azithromycin shows only limited blockade of the potassium channel hERG. This channel is critically involved in cardiomyocyte repolarization, and if it is blocked or otherwise malfunctioning, the result can be a prolonged QT interval, ventricular arrhythmias, and even sudden cardiac death.^1–4 Therefore, lack of blockade, as reflected by a high inhibitory concentration (Table 1), boded well for the safety of azithromycin in terms of QT liability. However, we should be cautious in interpreting in vitro data.

With its broad antibiotic spectrum and perceived favorable safety profile, azithromycin has become one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012, according to the IMS Institute for Healthcare Informatics.

THE FDA RECEIVES 203 REPORTS OF ADVERSE EVENTS IN 8 YEARS

However, beginning with a report of azithromycin-triggered torsades de pointes in 2001,⁵ a growing body of evidence, derived from postmarketing surveillance, has linked azithromycin to cardiac arrhythmias such as pronounced QT interval prolongation and associated torsades de pointes (which can progress to life-threatening ventricular fibrillation). Other, closely related macrolides such as clarithromycin and erythromycin are also linked to these effects.

Furthermore, in the 8-year period from 2004 to 2011, the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) received a total of 203 reports of azithromycin-associated QT prolongation, torsades de pointes, ventricular arrhythmia, or, in 65 cases, sudden cardiac death (Table 1).⁶

At face value, the number of FAERS reports appears to be similar between the various macrolide antibiotics. However, it is important to remember that these drugs differ substantially in the number of prescriptions written for them, with azithromycin being prescribed more often. Also, the FAERS numbers are subject to a number of well-known limitations such as confounding variables, uneven quality and completeness of reports, duplication, and underreporting. These limitations preclude the use of such adverse reporting databases in calculating and thereby comparing the true incidence of adverse events associated with the various macrolide antibiotics.^6–9

RAY ET AL FIND A HIGHER RISK OF CARDIOVASCULAR DEATH

Despite these inherent flaws, initial postmarketing surveillance reports cast enough doubt on the long-standing notion that azithromycin is the safest macrolide antibiotic to prompt Ray et al¹⁰ to assess its safety in an observational, nonrandomized study of people enrolled in the Tennessee Medicaid program.

They found that, over the typical 5 days of therapy, people taking azithromycin had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin (Table 2).

However, the absolute excess risk compared with amoxicillin varied considerably according to baseline risk score for cardiovascular disease, with 1 excess cardiovascular death per 4,100 in the highest-risk decile compared with 1 excess cardiovascular death per 100,000 in the lowest-risk decile.^10,11

Moreover, the increase in deaths did not persist after the 5 days of therapy. This time-limited pattern directly correlated with expected peak azithromycin plasma levels during a standard 5-day course.

Ray et al used appropriate analytic methods to attempt to correct for any confounding bias intrinsic to the observational, nonrandomized study design. Nevertheless, the patients were Medicaid beneficiaries, who have a higher prevalence of comorbid conditions and higher mortality rates than the general population. Therefore, legitimate questions were raised about whether the results of the study could be generalized to populations with substantially lower baseline risk of cardiovascular disease and if differences in the baseline characteristics of the treatment groups were adequately controlled.^12,13

THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS

The striking observations by Ray et al,¹⁰ coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.

Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.

SVANSTRÖM ET AL FIND NO INCREASED RISK

However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).¹⁴

The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.

Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.¹⁴ Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.¹⁴

ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK

Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).^10,14

These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.¹⁵

AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS

On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.¹⁶ Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.

This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).¹⁶ We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.¹⁶

These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.

CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN

For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:

• Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
• In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
• For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.

With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.

A March 2013 warning by the US Food and Drug Administration that azithromycin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however, try to determine if our patients have cardiovascular risk factors for this extreme side effect and take appropriate precautions.

AZITHROMYCIN: THE SAFEST OF THE MACROLIDES?

Azithromycin, a broad-spectrum macrolide antibiotic, is used to treat or prevent a range of common bacterial infections, including upper and lower respiratory tract infections and certain sexually transmitted diseases.

In terms of overall toxicity, azithromycin has been considered the safest of the macrolides, as it neither undergoes CYP3A4 metabolism nor inhibits CYP3A4 to any clinically meaningful degree, and therefore does not interfere with the array of commonly used medications that undergo CYP3A4 metabolism.

Also, in vitro, azithromycin shows only limited blockade of the potassium channel hERG. This channel is critically involved in cardiomyocyte repolarization, and if it is blocked or otherwise malfunctioning, the result can be a prolonged QT interval, ventricular arrhythmias, and even sudden cardiac death.^1–4 Therefore, lack of blockade, as reflected by a high inhibitory concentration (Table 1), boded well for the safety of azithromycin in terms of QT liability. However, we should be cautious in interpreting in vitro data.

With its broad antibiotic spectrum and perceived favorable safety profile, azithromycin has become one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012, according to the IMS Institute for Healthcare Informatics.

THE FDA RECEIVES 203 REPORTS OF ADVERSE EVENTS IN 8 YEARS

However, beginning with a report of azithromycin-triggered torsades de pointes in 2001,⁵ a growing body of evidence, derived from postmarketing surveillance, has linked azithromycin to cardiac arrhythmias such as pronounced QT interval prolongation and associated torsades de pointes (which can progress to life-threatening ventricular fibrillation). Other, closely related macrolides such as clarithromycin and erythromycin are also linked to these effects.

Furthermore, in the 8-year period from 2004 to 2011, the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) received a total of 203 reports of azithromycin-associated QT prolongation, torsades de pointes, ventricular arrhythmia, or, in 65 cases, sudden cardiac death (Table 1).⁶

At face value, the number of FAERS reports appears to be similar between the various macrolide antibiotics. However, it is important to remember that these drugs differ substantially in the number of prescriptions written for them, with azithromycin being prescribed more often. Also, the FAERS numbers are subject to a number of well-known limitations such as confounding variables, uneven quality and completeness of reports, duplication, and underreporting. These limitations preclude the use of such adverse reporting databases in calculating and thereby comparing the true incidence of adverse events associated with the various macrolide antibiotics.^6–9

RAY ET AL FIND A HIGHER RISK OF CARDIOVASCULAR DEATH

Despite these inherent flaws, initial postmarketing surveillance reports cast enough doubt on the long-standing notion that azithromycin is the safest macrolide antibiotic to prompt Ray et al¹⁰ to assess its safety in an observational, nonrandomized study of people enrolled in the Tennessee Medicaid program.

They found that, over the typical 5 days of therapy, people taking azithromycin had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin (Table 2).

However, the absolute excess risk compared with amoxicillin varied considerably according to baseline risk score for cardiovascular disease, with 1 excess cardiovascular death per 4,100 in the highest-risk decile compared with 1 excess cardiovascular death per 100,000 in the lowest-risk decile.^10,11

Moreover, the increase in deaths did not persist after the 5 days of therapy. This time-limited pattern directly correlated with expected peak azithromycin plasma levels during a standard 5-day course.

Ray et al used appropriate analytic methods to attempt to correct for any confounding bias intrinsic to the observational, nonrandomized study design. Nevertheless, the patients were Medicaid beneficiaries, who have a higher prevalence of comorbid conditions and higher mortality rates than the general population. Therefore, legitimate questions were raised about whether the results of the study could be generalized to populations with substantially lower baseline risk of cardiovascular disease and if differences in the baseline characteristics of the treatment groups were adequately controlled.^12,13

THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS

The striking observations by Ray et al,¹⁰ coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.

Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.

SVANSTRÖM ET AL FIND NO INCREASED RISK

However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).¹⁴

The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.

Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.¹⁴ Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.¹⁴

ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK

Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).^10,14

These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.¹⁵

AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS

On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.¹⁶ Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.

This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).¹⁶ We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.¹⁶

These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.

CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN

For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:

• Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
• In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
• For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.

With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.

A March 2013 warning by the US Food and Drug Administration that azithromycin (Zithromax, Zmax, Z-pak) may increase the risk of sudden cardiac death does not mean we must abandon using it. We should, however, try to determine if our patients have cardiovascular risk factors for this extreme side effect and take appropriate precautions.

AZITHROMYCIN: THE SAFEST OF THE MACROLIDES?

Azithromycin, a broad-spectrum macrolide antibiotic, is used to treat or prevent a range of common bacterial infections, including upper and lower respiratory tract infections and certain sexually transmitted diseases.

In terms of overall toxicity, azithromycin has been considered the safest of the macrolides, as it neither undergoes CYP3A4 metabolism nor inhibits CYP3A4 to any clinically meaningful degree, and therefore does not interfere with the array of commonly used medications that undergo CYP3A4 metabolism.

Also, in vitro, azithromycin shows only limited blockade of the potassium channel hERG. This channel is critically involved in cardiomyocyte repolarization, and if it is blocked or otherwise malfunctioning, the result can be a prolonged QT interval, ventricular arrhythmias, and even sudden cardiac death.^1–4 Therefore, lack of blockade, as reflected by a high inhibitory concentration (Table 1), boded well for the safety of azithromycin in terms of QT liability. However, we should be cautious in interpreting in vitro data.

With its broad antibiotic spectrum and perceived favorable safety profile, azithromycin has become one of the top 15 most prescribed drugs and the best-selling antibiotic in the United States, accounting for 55.4 million prescriptions in 2012, according to the IMS Institute for Healthcare Informatics.

THE FDA RECEIVES 203 REPORTS OF ADVERSE EVENTS IN 8 YEARS

However, beginning with a report of azithromycin-triggered torsades de pointes in 2001,⁵ a growing body of evidence, derived from postmarketing surveillance, has linked azithromycin to cardiac arrhythmias such as pronounced QT interval prolongation and associated torsades de pointes (which can progress to life-threatening ventricular fibrillation). Other, closely related macrolides such as clarithromycin and erythromycin are also linked to these effects.

Furthermore, in the 8-year period from 2004 to 2011, the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) received a total of 203 reports of azithromycin-associated QT prolongation, torsades de pointes, ventricular arrhythmia, or, in 65 cases, sudden cardiac death (Table 1).⁶

At face value, the number of FAERS reports appears to be similar between the various macrolide antibiotics. However, it is important to remember that these drugs differ substantially in the number of prescriptions written for them, with azithromycin being prescribed more often. Also, the FAERS numbers are subject to a number of well-known limitations such as confounding variables, uneven quality and completeness of reports, duplication, and underreporting. These limitations preclude the use of such adverse reporting databases in calculating and thereby comparing the true incidence of adverse events associated with the various macrolide antibiotics.^6–9

RAY ET AL FIND A HIGHER RISK OF CARDIOVASCULAR DEATH

Despite these inherent flaws, initial postmarketing surveillance reports cast enough doubt on the long-standing notion that azithromycin is the safest macrolide antibiotic to prompt Ray et al¹⁰ to assess its safety in an observational, nonrandomized study of people enrolled in the Tennessee Medicaid program.

They found that, over the typical 5 days of therapy, people taking azithromycin had a rate of cardiovascular death 2.88 times higher than in people taking no antibiotic, and 2.49 times higher than in people taking amoxicillin (Table 2).

However, the absolute excess risk compared with amoxicillin varied considerably according to baseline risk score for cardiovascular disease, with 1 excess cardiovascular death per 4,100 in the highest-risk decile compared with 1 excess cardiovascular death per 100,000 in the lowest-risk decile.^10,11

Moreover, the increase in deaths did not persist after the 5 days of therapy. This time-limited pattern directly correlated with expected peak azithromycin plasma levels during a standard 5-day course.

Ray et al used appropriate analytic methods to attempt to correct for any confounding bias intrinsic to the observational, nonrandomized study design. Nevertheless, the patients were Medicaid beneficiaries, who have a higher prevalence of comorbid conditions and higher mortality rates than the general population. Therefore, legitimate questions were raised about whether the results of the study could be generalized to populations with substantially lower baseline risk of cardiovascular disease and if differences in the baseline characteristics of the treatment groups were adequately controlled.^12,13

THE FDA REVISES AZITHROMYCIN’S WARNINGS AND PRECAUTIONS

The striking observations by Ray et al,¹⁰ coupled with the concerns raised by postmarketing surveillance reports, compelled the FDA to review the labels of azithromycin and other macrolide antibiotics.

Ultimately, the FDA opted to revise the “warning and precautions” section of the azithromycin drug label to include a warning about the potential risk of fatal arrhythmias, specifically QT interval prolongation and torsades de pointes. In a March 2013 safety announcement, it also urged health care professionals to use caution when prescribing azithromycin to patients known to have risk factors for drug-related arrhythmias, including congenital long QT syndrome, acquired QT interval prolongation, hypokalemia, hypomagnesia, bradycardia, and concurrent use of other medications known to prolong the QT interval, specifically the class IA (eg, quinidine and procainamide) and class III (eg, amiodarone, sotalol, and dofetilide) antiarrhythmics.

SVANSTRÖM ET AL FIND NO INCREASED RISK

However, just when the medical community appeared ready to accept that azithromycin may not be as safe as we thought it was, a large prospective study by Svanström et al, published in early May 2013, found no increased risk of cardiovascular death associated with azithromycin (Table 2).¹⁴

The patients were a representative population of young to middle-aged Danish adults at low baseline risk of underlying cardiovascular disease.

Interestingly, Svanström et al were careful to point out that their study was only powered to rule out a moderate-to-high (> 55%) increase in the relative risk of cardiovascular death. Furthermore, profound differences existed in the baseline risk of death and cardiovascular risk factors between their patients and the Tennessee Medicaid patients studied by Ray et al.¹⁴ Therefore, the authors suggested that their study complements rather than contradicts the study by Ray et al. They attributed the differences in the findings to treatment-effect heterogeneity, in which the risk of azithromycin-associated cardiovascular mortality is largely limited to high-risk patients, namely those with multiple preexisting cardiovascular risk factors.¹⁴

ACC/AHA RECOMMENDATION: IDENTIFY THOSE AT RISK

Collectively, the data reviewed above provide compelling evidence that azithromycin is not completely free of the QT-prolonging and torsadogenic effects that have long been associated with other macrolide antibiotics. However, the findings from both the study by Ray et al and that of Svanström et al suggest that preexisting cardiovascular risk factors play a prominent role in determining the incidence of azithromycin-associated cardiovascular death in a given population (Table 2).^10,14

These findings should prompt physicians to carefully reassess the risks and benefits of azithromycin use in their clinical practices. They also reinforce a recent call by the American Heart Association (AHA) and American College of Cardiology (ACC) to better identify, early on, patients at risk of drug-induced ventricular arrhythmias and sudden death and to subsequently improve how these patients are monitored when the use of QT-prolonging and torsadogenic drugs is medically necessary.¹⁵

AN ELECTRONIC MEDICAL RECORD FLAGS QTc ≥ 500 MS

On the heels of these AHA/ACC suggestions, our hospital has adopted an institution-wide QT alert system. Here, the electronic medical record system (Centricity EMR; GE Healthcare) uses a proprietary algorithm to detect and electronically alert ordering physicians when a patient has a prolonged QT interval, and gives information about the potential clinical significance of this electrocardiographic finding.¹⁶ Physicians also receive a warning when ordering QT-prolonging drugs in patients at risk.

This system is still in its infancy, but it has already confirmed that a prolonged QT interval (QTc ≥ 500 ms) is a powerful predictor of death from any cause and has demonstrated that mortality rates in those with prolonged QT intervals increase in a dose-dependent fashion with the patient’s number of modifiable risk factors (eg, electrolyte disturbances or QT-prolonging medications) and nonmodifiable risk factors (eg, genetic disposition, female sex, structural heart disease, diabetes mellitus).¹⁶ We have also found evidence that modifiable risk factors may have a more pronounced effect on mortality risk than non-modifiable risk factors.¹⁶

These findings suggest that information technology-based QT alert systems may one day provide physicians with an important tool to efficiently identify and possibly even modify the risk of cardiovascular death in patients at high risk, for example, by correcting electrolyte abnormalities or reducing the burden of QT-prolonging medications.

CONSIDER RISK OF QT PROLONGATION WHEN PRESCRIBING AZITHROMYCIN

For most institutions and clinical practices, such electronic QT alert systems are still years if not decades away. However, in light of the information summarized above, all physicians should begin considering risk factors for QT prolongation and torsades de pointes (summarized in Table 3) and weighing the risks and benefits of prescribing azithromycin vs alternative antibiotics with minimal QT liability. This should be relatively simple to do. Things to keep in mind:

• Although azithromycin may increase the relative risk of a cardiovascular event, for most otherwise-healthy patients, the absolute risk is miniscule.
• In a patient at risk (eg, with baseline QT prolongation or multiple risk factors for it), if azithromycin or another QT-prolonging antibiotic such as a macrolide or fluoroquinolone is medically necessary due to preferential bacterial susceptibility or patient allergies, every effort should be made to correct modifiable risk factors (eg, electrolyte abnormalities) and, if possible, to avoid polypharmacy with multiple QT-prolonging drugs.
• For patients who have multiple risk factors for QT prolongation in whom treatment with a known QT-prolonging medication is still deemed in the patient’s best interest, strong consideration should be given to inpatient administration and monitoring until the treatment has been completed.

With careful consideration of modifiable and nonmodifiable risk factors as well as a little extra caution when prescribing potential QT-prolonging medications such as azithromycin, the clinical benefit of these often-advantageous medications can be maximized and the incidence of these tragic but rare drug-induced sudden cardiac deaths can be reduced.

When a patient tells a physician about a sudden episode of weakness, loss of vision, or loss of sensation that occurred but then quickly resolved, both the patient and the physician may feel a sense of relief. In many cases, the patient may not even seek medical evaluation. These events, when vascular in origin and not seizures or migraines, have been termed transient ischemic attacks (TIAs) by physicians, and are often called “mini-strokes” by patients. But as discussed by Drs. Shruti Sonni and David Thaler in this issue of the Journal, there is nothing “mini” about their significance.

In some ways, the perception of TIA (as opposed to stroke) has paralleled our understanding and initial misperception of non-ST-segment elevation myocardial infarction (NSTEMI). This type of acute coronary event was thought to be less severe than acute ST-elevation MI (STEMI), and patients with NSTEMI and unstable angina have historically not received the aggressive acute and preventive therapy received by patients with STEMI. But with the advent of more sensitive markers of myocardial necrosis, we now know that NSTEMI and unstable angina can be associated with significant tissue injury, and that the outcome after a year or so can be the same as or worse than if the initial injury was associated with ST-segment elevation.

A similar story has evolved with TIA. With sensitive diffusion-weighted magnetic resonance imaging, brain injury can often be detected even when it is not seen on computed tomography. Patients are often not evaluated as completely for reversible vascular lesions and may not receive aggressive secondary prevention. Yet shortly after suffering a TIA, a patient is even more likely to have another neurologic event than if the initial event had been a small stroke. And the neurologic event will more likely be a stroke with residual neurologic deficit.

All are reasons to educate our older patients—particularly those with diabetes, atrial fibrillation, peripheral vascular disease, and hypertension—about the significance of even apparently self-limited neurologic events. A TIA is a major warning signal.

When a patient tells a physician about a sudden episode of weakness, loss of vision, or loss of sensation that occurred but then quickly resolved, both the patient and the physician may feel a sense of relief. In many cases, the patient may not even seek medical evaluation. These events, when vascular in origin and not seizures or migraines, have been termed transient ischemic attacks (TIAs) by physicians, and are often called “mini-strokes” by patients. But as discussed by Drs. Shruti Sonni and David Thaler in this issue of the Journal, there is nothing “mini” about their significance.

In some ways, the perception of TIA (as opposed to stroke) has paralleled our understanding and initial misperception of non-ST-segment elevation myocardial infarction (NSTEMI). This type of acute coronary event was thought to be less severe than acute ST-elevation MI (STEMI), and patients with NSTEMI and unstable angina have historically not received the aggressive acute and preventive therapy received by patients with STEMI. But with the advent of more sensitive markers of myocardial necrosis, we now know that NSTEMI and unstable angina can be associated with significant tissue injury, and that the outcome after a year or so can be the same as or worse than if the initial injury was associated with ST-segment elevation.

A similar story has evolved with TIA. With sensitive diffusion-weighted magnetic resonance imaging, brain injury can often be detected even when it is not seen on computed tomography. Patients are often not evaluated as completely for reversible vascular lesions and may not receive aggressive secondary prevention. Yet shortly after suffering a TIA, a patient is even more likely to have another neurologic event than if the initial event had been a small stroke. And the neurologic event will more likely be a stroke with residual neurologic deficit.

All are reasons to educate our older patients—particularly those with diabetes, atrial fibrillation, peripheral vascular disease, and hypertension—about the significance of even apparently self-limited neurologic events. A TIA is a major warning signal.

When a patient tells a physician about a sudden episode of weakness, loss of vision, or loss of sensation that occurred but then quickly resolved, both the patient and the physician may feel a sense of relief. In many cases, the patient may not even seek medical evaluation. These events, when vascular in origin and not seizures or migraines, have been termed transient ischemic attacks (TIAs) by physicians, and are often called “mini-strokes” by patients. But as discussed by Drs. Shruti Sonni and David Thaler in this issue of the Journal, there is nothing “mini” about their significance.

In some ways, the perception of TIA (as opposed to stroke) has paralleled our understanding and initial misperception of non-ST-segment elevation myocardial infarction (NSTEMI). This type of acute coronary event was thought to be less severe than acute ST-elevation MI (STEMI), and patients with NSTEMI and unstable angina have historically not received the aggressive acute and preventive therapy received by patients with STEMI. But with the advent of more sensitive markers of myocardial necrosis, we now know that NSTEMI and unstable angina can be associated with significant tissue injury, and that the outcome after a year or so can be the same as or worse than if the initial injury was associated with ST-segment elevation.

A similar story has evolved with TIA. With sensitive diffusion-weighted magnetic resonance imaging, brain injury can often be detected even when it is not seen on computed tomography. Patients are often not evaluated as completely for reversible vascular lesions and may not receive aggressive secondary prevention. Yet shortly after suffering a TIA, a patient is even more likely to have another neurologic event than if the initial event had been a small stroke. And the neurologic event will more likely be a stroke with residual neurologic deficit.

All are reasons to educate our older patients—particularly those with diabetes, atrial fibrillation, peripheral vascular disease, and hypertension—about the significance of even apparently self-limited neurologic events. A TIA is a major warning signal.

A transient ischemic attack (TIA), like an episode of unstable angina, is an ominous portent of future morbidity and death even though, by definition, the event leaves no residual neurologic deficit.

But there is a positive side. When a patient presents with a TIA, the physician has the rare opportunity to reduce the risk of a disabling outcome—in this case, stroke. Therefore, patients deserve a rapid and thorough evaluation and appropriate stroke-preventive treatment.

MANY ‘TIAs’ ARE ACTUALLY STROKES

TIA has traditionally been described as a sudden focal neurologic deficit that lasts less than 24 hours, is presumed to be of vascular origin, and is confined to an area of the brain, spinal cord, or eye perfused by a specific artery. This symptom-based definition was based on the arbitrary and inaccurate assumption that brief symptoms would not be associated with damage to brain parenchyma.

The definition has since been updated and made more rational based on new concepts of brain ischemia informed by imaging, especially diffusion-weighted magnetic resonance imaging (MRI).¹ One-third of episodes characterized as a TIA according to the classic definition would be considered an infarction on the basis of diffusion-weighted MRI.² The new tissue-based definition characterizes TIA as a brief episode of neurologic dysfunction caused by focal ischemia of the brain, spinal cord, or retina, with clinical symptoms lasting less than 24 hours and without evidence of acute infarction.³

AN OPPORTUNITY TO INTERVENE

Most TIAs resolve in less than 30 minutes. The US National Institute of Neurological Disorders and Stroke trial of tissue plasminogen activator found that if symptoms of cerebral ischemia had not resolved by 1 hour or had not rapidly improved within 3 hours, complete resolution was rare (only 2% at 24 hours).⁴ Hence, physicians evaluating and treating patients with TIAs should treat these episodes with the urgency they deserve.

Moreover, half of the strokes that follow TIAs occur within 48 hours.⁵ A rapid and thorough evaluation and the initiation of secondary preventive treatments have been shown to reduce the early occurrence of stroke by up to 80%.⁶ Hence, the correct diagnosis of TIA gives the clinician the best opportunity to prevent stroke and its personal, social, and sometimes fatal consequences.

STROKES OUTNUMBER TIAs, BUT TIAs ARE UNDERREPORTED

According to 2012 statistics, nearly 795,000 strokes occur in the United States each year, 610,000 of which are first attacks and 185,000 are recurrences. Every 40 seconds, someone in the United States has a stroke.⁷

In comparison, the incidence of TIA in the United States is estimated at 200,000 to 500,000 per year, though the true number is difficult to know because of underreporting.^8,9 About half of patients who experience a TIA fail to report it to their health care provider—a lost opportunity for intervention and stroke prevention.^10,11

A meta-analysis showed that the risk of stroke after TIA was 9.9% at 2 days, 13.4% at 30 days, and 17.3% at 90 days.¹²

Interestingly, the risk of stroke after TIA exceeds the risk of recurrent stroke after a first stroke. This was shown in a study that found that patients who had made a substantial recovery within 24 hours (ie, patients with a TIA) were more likely to suffer neurologic deterioration in the next 3 months than were those who did not have significant early improvement.¹³

RISK FACTORS FOR TIA ARE THE SAME AS FOR STROKE

The risk of cerebrovascular disease increases with age and is higher in men¹⁴ and in blacks and Hispanics.¹⁵

The risk factors and clinical presentation do not differ between TIA and stroke, so the evaluation and treatment should not differ either. These two events represent a continuum of the same disease entity.

Some risk factors for TIA are modifiable, others are not.

Nonmodifiable risk factors

Nonmodifiable risk factors for TIA include older age, male sex, African American race, low birth weight, Hispanic ethnicity, and family history. If the patient has nonmodifiable risk factors, we should try all the harder to correct the modifiable ones.

Older age. The risk of ischemic stroke and intracranial hemorrhage doubles with each decade after age 55 in both sexes.¹⁶

Sex. Men have a significantly higher incidence of TIA than women,¹¹ whereas the opposite is true for stroke: women have a higher lifetime risk of stroke than men.¹⁷

African Americans have an incidence of stroke (all types) 38% higher than that of whites,¹⁸ and an incidence of TIA (inpatient and out-of-hospital) 40% higher than the overall age- and sex-adjusted rate in the white population.¹¹

Low birth weight. The odds of stroke are more than twice as high in people who weighed less than 2,500 g at birth compared with those who weighed 4,000 g or more, probably because of a correlation between low birth weight and hypertension.¹⁹

A family history of stroke increases the risk of stroke by nearly 30%, the association being stronger with large-vessel and smallvessel stroke than with cardioembolic stroke.²⁰

Modifiable risk factors

Modifiable risk factors include cigarette smoking, hypertension, diabetes, lipid abnormalities, atrial fibrillation, carotid stenosis, and dietary and hormonal factors. Detecting these factors, which often coexist, is the first step in trying to modify them and reduce the patient’s risk.

Cigarette smoking approximately doubles the risk of ischemic stroke.^21–23

Hypertension has a relationship with stroke risk that is strong, continuous, graded, consistent, and significant.²⁴

Diabetes increases stroke risk nearly six times.²⁵

Lipid abnormalities. Most studies have found an association between lipid levels (total cholesterol and low-density lipoprotein cholesterol) and the risk of death from ischemic stroke,^26–28 and an inverse relationship between high-density lipoprotein cholesterol levels and stroke risk.²⁹

Atrial fibrillation increases the risk of ischemic stroke up to fivefold, even in the absence of cardiac valvular disease. The mechanism is embolism of stasis-induced thrombi that form in the left atrial appendage.³⁰

Carotid stenosis. Asymptomatic carotid atherosclerotic stenotic lesions in the extracranial internal carotid artery or carotid bulb are associated with a higher risk of stroke.^24,31

Lifestyle factors. Diets that lower blood pressure have been found to decrease stroke risk.²⁴ Exercise in men and women reduces the risk of stroke or death by 25% to 30% compared with inactive people.³² Weight reduction has been found to lower blood pressure and reduce stroke risk.²⁴

Other potentially modifiable risk factors include migraine with aura, metabolic syndrome, excess alcohol consumption (and, paradoxically, complete abstinence from alcohol), drug abuse, sleep-disordered breathing, hyperhomocysteinemia, high lipoprotein (a) levels, hypercoagulability, infection with organisms such as Chlamydia pneumoniae, cytomegalovirus, and Helicobacter pylori, and acute infections such as respiratory and urinary infections.²⁶

Conditions in certain demographic groups

Patients in certain demographic groups present with rarer conditions associated with stroke and TIA.

Sickle cell disease. Eleven percent of patients with sickle cell disease have clinical strokes, and a substantial number have “silent” infarcts identified on neuroimaging.^33,34

Postmenopausal hormone replacement therapy with any product containing conjugated equine estrogen carries a risk of cerebrovascular events,³⁵ and the higher the dose, the higher the risk.³⁶ Also, oral contraceptives may be harmful in women who have additional risk factors such as cigarette smoking, prior thromboembolic events, or migraine with aura.^37,38

THREE CAUSES OF STROKE AND TIA

Stroke and TIA should not be considered diagnoses in themselves, but rather the end point of many other diseases. The diagnosis lies in identifying the mechanism of the cerebrovascular event. The three main mechanisms are thrombosis, embolism, and decreased perfusion.

Thrombosis is caused by obstruction of blood flow within one or more blood vessels, the most common cause being atherosclerosis. Large-artery atherosclerosis, such as in the carotid bifurcation or extracranial internal carotid, causes TIAs that occur over a period of weeks or months with a variety of presentations in that vascular territory, from years of gradual accumulation of atherosclerotic plaque.³⁹

In patients with small-artery or penetrating artery disease, hypertension is the primary risk factor and the pathology, specific to small arterioles, is lipohyalinosis rather than atherosclerosis. These patients may present with a stuttering clinical course, and episodes are more stereotypical.

Less common obstructive vascular pathologies include fibromuscular dysplasia, arteritides, and dissection.

Embolism can occur from a proximal source such as the heart or from proximal vessels such as the aorta, carotid, or vertebral arteries. The embolic particle may form on heart valves or lesions within the heart (eg, clot, tumor), or in the venous circulation and paradoxically cross over to the arterial side through an intracardiac or transpulmonary shunt. Embolism may also be due to a hypercoagulable state.⁴⁰ Embolic stroke is suspected when multiple vascular territories within the brain are clinically or radiographically affected.

Decreased systemic perfusion caused by severe heart failure or systemic hypotension can cause ischemia to the brain diffusely and bilaterally, limiting the ability of the blood-stream to wash out microemboli, especially in the border zones (also known as “watershed areas”), thus leading to ischemia or infarction.⁴¹ Decreased perfusion can also be local, due to a fixed vessel stenosis.

Using another classification system, a study in Rochester, MN, found the following incident rates of stroke subtypes, adjusted for age and sex, per 100,000 population⁴²:

• Large-vessel cervical or intracranial atherosclerosis with more than 50% stenosis—27
• Cardioembolism—40
• Lacunar, small-vessel disease—25
• Uncertain cause—52
• Other identifiable cause—4.

THREE CLINICAL FEATURES SUGGEST TIA

TIAs can be hard to distinguish from nonischemic neurologic events in the acute setting such as an emergency room. Up to 60% of patients suspected of having a TIA actually have a nonischemic cause of their symptoms.⁴³

Three clinical features suggest a TIA during the emergency room evaluation:

• Rapid onset of symptoms—“like lightning” or “in seconds,” in contrast to migraine and seizures, which develop over minutes
• No history of similar episodes in the past
• Absence of nonspecific symptoms—eg, stomach upset or tightness in the chest.

CLINICAL DIAGNOSIS

Because most TIA symptoms and signs have already resolved by the time of evaluation, the diagnosis depends on a careful history with special attention to the pace of onset and resolution, the duration and nature of the symptoms, circumstances at the time of symptom onset, previous similar episodes, associated features, vascular risk factors, and family history (Table 1).^44,45

A detailed neurologic examination is imperative and should include fundoscopy. A cardiovascular assessment should include cardiac rhythm, bruits in the neck, orbits, and groin, peripheral pulses, and electrocardiography.

Do neurologists do a better job at diagnosing TIA and stroke?

Primary care physicians, internists, and emergency department physicians are often the ones to carry out the clinical assessment of possible TIA.

Determining if transient neurologic symptoms are caused by ischemia can be a challenge. When in doubt, referral to a neurologist with subspecialty training in cerebrovascular disease should be considered.

But do neurologists really do a better job? A recent study sought to compare the accuracy of diagnosis of TIA made by general practitioners, emergency physicians, and neurologists. The nonneurologists considered “confusion” and “unexplained fall” suggestive of TIA and “lower facial palsy” and “monocular blindness” less suggestive of TIA—whereas the opposite is true. This shows that nonneurologists often label minor strokes and several nonvascular transient neurologic disturbances as TIAs, and up to half of patients could be mislabeled as a result.⁴⁶

Differences in diagnosing cerebrovascular events between emergency room physicians and attending neurologists have been tested,⁴⁷ with an accuracy of diagnosis as low as 38% by emergency department physicians in one study.⁴⁸ However, other studies did not show such a trend.^49,50

A study at a university-based teaching hospital found the sensitivity of emergency room physician diagnosis to be 98.6% with a positive predictive value of 94.8%,⁴⁹ showing that at a large teaching hospital with a comprehensive stroke intervention program, emergency physicians could identify patients with stroke, particularly hemorrhagic stroke, very accurately.

Improving the diagnosis of stroke and TIA

Routine use of imaging and involvement of a neurologist increase the sensitivity and accuracy of diagnosis. Education and written guidelines for acute stroke treatment both in the emergency department and in out-of-hospital settings seem to dramatically improve the rates of diagnostic accuracy and appropriate treatment.⁵⁰

Emergency medical service personnel use two screening tools in the field to identify TIA and stroke symptoms:

• The Cincinnati Prehospital Stroke Scale, a three-item scale based on three signs: facial droop, arm drift, and slurring of speech⁵¹
• The Los Angeles Prehospital Stroke Screen, which uses screening questions and asymmetry in the face, hand grip strength, and arm drift.⁵²

Knowing that the patient is having a minor stroke or TIA is important. Urgent treatment of these conditions decreases the risk of stroke in the next 90 days, which was 10.5% in one study.⁵ Urgent assessment and early intervention could reduce this risk of subsequent stroke down to 2%.⁶

ASSESSING RISK OF STROKE AFTER TIA

There is a practical need for prediction of stroke during the first few days after the event. The ABCD and ABCD2 scores were developed to stratify the short-term risk of stroke in patients with recent TIA.

The ABCD score

The ABCD score⁵³ was derived to allow primary care physicians and other physicians to identify which patients with a suspected diagnosis of TIA should be referred for emergency assessment, to allow secondary-care physicians to determine which patients with probable or definite TIA need emergency investigation and treatment, to allow public education about the need for medical attention after a TIA, and to identify people at high risk.

The ABCD2 score

The ABCD2 score predicts the short-term risk of stroke following a TIA.⁵⁴ Points are assigned as follows:

• Age > 60 years: 1 point
• Blood pressure (systolic) > 140 mm Hg or diastolic blood pressure > 90 mm Hg: 1 point
• Clinical factors: unilateral weakness with or without speech impairment: 2 points (1 point for speech impairment without weakness)
• Duration of symptoms > 60 minutes: 2 points (1 point for 10–59 minutes)
• Diabetes: 1 point.

Thus, the possible total ranges from 0 to 7 points. Higher scores indicate a greater risk of stroke at 2, 7, 30, and 90 days:

• Total score 0, 1, 2, or 3: 2-day stroke risk 1.0% (low risk)
• Total score 4 or 5: 2-day stroke risk 4.1% (moderate risk)
• Total score 6 or 7: 2-day stroke risk 8.1% (high risk).

WHO SHOULD BE HOSPITALIZED?

It has been suggested that the ABCD2 score can help in triaging patients to hospital admission or outpatient care, though no randomized trial has actually evaluated the utility of the ABCD2 score in this way.³

A study of consecutive TIA patients admitted over 12 months⁵⁵ found that patients with an ABCD2 score of 3 or less had the same chance of requiring hospitalization (based on positive diffusion-weighted MRI studies, risk factor identification, and treatment initiation) as those with a score of 4 to 7. Hence, admitting TIA patients on the basis of the ABCD2 score alone requires further study. However, such decisions, though informed by clinical data, depend heavily on societal input (eg, from insurance companies, national health protocols) and may be outside the purview of clinical investigation.

The benefits of hospitalization include the ability to rapidly carry out tests such as cardiac monitoring for atrial fibrillation; to detect atherosclerosis, aortic arch atheroma, and paradoxical emboli; and to quickly start secondary prevention treatments and education about the importance of adhering to them. Early endarterectomy in the case of carotid stenosis can be offered. Additionally, if stroke symptoms recur, thrombolytic drug therapy can be started quickly.

Nguyen-Huynh et al⁵⁶ analyzed the cost utility of 24-hour hospitalization for patients diagnosed with a recent TIA who were candidates for tissue plasminogen activator if a stroke occurred. They found hospitalization to be borderline cost-effective on the whole, with definite cost-effectiveness found in patients with higher stroke risk.

If patients come to medical attention several days after the TIA, then assessing risk with the ABCD2 score may no longer be reliable.⁵⁷

INVESTIGATIONS

Parenchymal neuroimaging

Computed tomography (CT) without contrast is the most widely used neuroimaging test in the acute setting, since it is widely available, fast, and relatively low-cost. It will not show any abnormality in TIA or early ischemic stroke. However, it is helpful as a screening tool to rule out intracranial lesions such as hemorrhage or tumor. It may also show evidence of established infarction, which would indicate that the ischemia probably had been present for at least 6 to 12 hours.

MRI is clearly superior to noncontrast CT for detecting small areas of ischemia in patients with TIA, and it should be used unless the patient has a contraindication to it. Roughly one-third of TIA patients have lesions detectable on diffusion-weighted imaging, which helps to confirm that the episode was caused by cerebral ischemia, but nearly half of the diffusion MRI changes may be fully reversible.⁵⁸ Evidence of prior stroke, leukoaraiosis, or white matter disease on fluid-attenuated inversion recovery and T2 sequences and microhemorrhages (on gradient echo sequences) help to determine a mechanistic diagnosis.

Subcategorizing TIA patients on the basis of the findings on diffusion-weighted MRI and the ABCD² score is prognostically helpful.⁵⁹ It can help to determine which patients need hospitalization and aggressive treatment, and in the case of identified diffusion-weighted MRI-positive stroke, it helps to localize and elucidate the mechanism of stroke. Hence, MRI is the preferred neuroimaging study for evaluating patients with TIA.³

Vascular imaging

Establishing the status of both intracranial and extracranial vessels is important for understanding the etiology, estimating the risk of future ischemic events, and formulating a treatment plan—eg, carotid endarterectomy in cases of significant stenosis (70% to 99%), which reduces the risk of ipsilateral stroke.⁶⁰ Imaging studies include CT angiography, magnetic resonance angiography, extracranial and transcranial ultrasonography, and conventional catheter-based angiography.

CT angiography has higher spatial resolution, but vessels may be obscured by calcification associated with atherosclerotic plaque. It has the advantage of wide availability, low cost, short scanning time, and excellent patient tolerability.

Magnetic resonance angiography with gadolinium enhancement offers good quality imaging from the great vessels in the chest to the medium-sized vessels distal to the circle of Willis.

The contrast agents used in MRI and CT can have negative consequences in patients with renal disease. MRI contrast has been associated with nephrogenic fibrosing dermopathy, ⁶¹ and CT contrast can cause contrast-induced nephropathy.⁶²

Carotid ultrasonography and transcranial Doppler ultrasonography are noninvasive and are not associated with significant adverse events. They can be used safely in patients with renal dysfunction, and they provide physiologic information that cannot be obtained with MRI and CT, which are static imaging techniques. Detecting microemboli on transcranial Doppler is an independent predictor of recurrent ischemic events.^63,64

Catheter-based angiography is occasionally needed in confusing or more complicated cases, but it is invasive and occasionally is associated with iatrogenic stroke and other vascular complications.

Cardiac and aortic imaging

Echocardiography is used to detect lesions that can be sources of embolism such as regional wall-motion abnormalities, cardiac thrombus or mass, endocarditis, aortic arch atheroma, and patent foramen ovale. In patients with cryptogenic TIA or stroke, those with patent foramen ovale alone were found to have a lower risk of recurrent stroke than those who had both atrial septal aneurysm and patent foramen ovale.⁶⁵

Transesophageal echocardiography is more sensitive than transthoracic echocardiography for detecting cardioembolic lesions, especially patent foramen ovale.⁶⁶ In patients with cerebral ischemia and normal transthoracic findings, cardiac sources of embolism may be detected in about 40% of patients with transesophageal echocardiography.⁶⁷

Cardiac rhythm monitoring

Electrocardiography and prolonged telemetry are recommended in patients with cryptogenic TIA to detect cardiac ischemia and paroxysmal atrial fibrillation. In one study, Holter monitoring detected atrial fibrillation in 6% of patients hospitalized with ischemic stroke or TIA.⁶⁸ In another study, atrial fibrillation was detected after a median of 21 days of outpatient cardiac monitoring in 23% of patients.⁶⁹

The optimal duration of outpatient telemetry has not yet been established, but studies have found significant increases in detection of paroxysms of atrial fibrillation with monitoring for 7 or longer.⁷⁰

Laboratory tests in the acute setting

These include lipid profile, hemoglobin A_1c, and cardiac enzymes. The advantages of hospitalization are early detection of these modifiable risk factors and early initiation of treatment.

Tests for rarer disorders

Tests for rarer disorders are sometimes indicated in unusual cases, such as ischemic symptoms occurring in young patients without other common risk factors. This includes testing for prothrombotic states, toxicology, blood cultures, inflammatory markers, hemoglobin electrophoresis, and lumbar puncture. The benefit of routine testing for thrombophilic disorders in cerebrovascular disease remains uncertain, with no clear association demonstrated with arterial stroke, but testing is more relevant in the case of venous (and paradoxical) thromboembolism.⁷¹

TREAT THE UNDERLYING DISORDER

Treatment depends on the mechanism that is thought to be responsible for the ischemic event. Vascular risk factors are important to identify and modify for all stroke subtypes.

Illustrating the importance of treating TIA and minor stroke, one study⁷² found that for antiplatelet therapy (aspirin, dipyridamole, or aspirin plus dipyridamole), the number needed to treat for 2 years was around 18.

Anticoagulation for cardioembolism

Atrial fibrillation, especially following a cerebrovascular ischemic event, should be treated with long-term anticoagulation with warfarin (Coumadin), dabigatran (Pradaxa), rivaroxaban (Xarelto), or apixaban (Eliquis).⁷³ If the patient cannot tolerate anticoagulation, aspirin is recommended, and if he or she cannot tolerate aspirin, clopidogrel (Plavix) is recommended.

Antiplatelet therapy for large-vessel atherosclerosis and small-vessel disease

In the acute phase, aspirin 81 mg to 325 mg orally can be given. If the patient is allergic to aspirin, a loading dose of clopidogrel 300 mg and then 75 mg daily may be given.

A pilot study of loading with aspirin 325 mg or clopidogrel 375 mg in acute ischemic stroke and TIA patients showed that these treatments were safe when given within 36 hours and decreased the risk of neurologic deterioration.⁷⁴ The patient should continue on aspirin 81 mg or clopidogrel 75 mg, as suggested by the Fast Assessment of Stroke and Transient Ischaemic Attack to Prevent Early Recurrence (FASTER) trial.⁷⁵ In the long term, an antiplatelet drug such as aspirin or clopidogrel or the combination of aspirin and extended-release dipyridamole is reasonable.⁷⁶

Cilostazol (Pletal) is not inferior and is possibly superior to aspirin in preventing noncardioembolic ischemic stroke. It is used off-label for secondary prevention of stroke of noncardioembolic origin.⁷⁷

Statins

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, high-dose atorvastatin (Lipitor)—80 mg daily—was found to reduce the risk of subsequent stroke and other cardiovascular events in patients with recent stroke irrespective of low-density lipoprotein cholesterol (LDL-C) level, but there was a small increase in the risk of hemorrhagic stroke.⁷⁸

In patients with hyperlipidemia, current recommendations suggest a target LDL-C level lower than 100 mg/dL in patients with atherosclerotic stroke or TIA, and lower than 70 mg/dL in those with concomitant diabetes.⁷⁹

Antihypertensive therapy

In the acute period, ie, the first 24 hours after symptoms, guidelines have advocated allowing high blood pressure to remain high (“permissive hypertension”) unless the systolic pressure is greater than 200 mm Hg or the diastolic pressure is greater than 120 mm Hg or the patient is receiving thrombolytic therapy.⁸⁰ However, this has recently been challenged by findings in randomized trials.⁸¹ Permissive hypertension and avoidance of dehydration with intravenous normal saline may improve cerebral perfusion, which is especially important in patients with high-grade intracranial or extracranial stenosis. Within the parameters outlined above, we recommend against aggressively treating high blood pressure in the acute phase.

In the long term, antihypertensive therapy reduces the risk of recurrent stroke or TIA.⁸² The goal is to keep blood pressure lower than 140/90 mm Hg, or lower than 130/80 mm Hg in patients with diabetes. A study of patients with ischemic noncardioembolic stroke showed a higher risk of recurrent stroke if the systolic blood pressure was lower than 120 or higher than 140 mm Hg.⁸³

Some classes of antihypertensive medication may be more beneficial than others. There is some evidence that angiotensin-converting enzyme (ACE) inhibitors alone or in combination with a diuretic or an angiotensin receptor blocker are superior to other regimens, possibly because of neuroprotective mechanisms.⁸⁴ A recent meta-analysis found angiotensin receptor blockers to be more effective than either ACE inhibitors or beta-blockers in stroke prevention; however, calcium channel blockers were superior to renin-angiotensin system blockers (ACE inhibitors and angiotensin receptor blockers).⁸⁵

Lifestyle modifications

Smoking cessation and cardiovascular exercise for more than 10 minutes more than 3 times per week is strongly recommended.

For patients with diabetes, the goal is to keep the fasting blood glucose level lower than 126 mg/dL.

Moderate alcohol intake has been shown to decrease stroke risk compared with excessive intake or none at all.⁸⁶

Carotid endarterectomy

Carotid endarterectomy has been recommended within 2 weeks of cerebral or retinal TIA in those cases attributable to high-grade internal carotid artery stenosis in patients who have low surgical risk.⁸⁷ This risk can be estimated on the basis of patient factors, surgeon factors, and hospital volume. The specific recommendations are as follows:

• 70% to 99% carotid stenosis: carotid endarterectomy recommended
• 50% to 69% carotid stenosis: carotid endarterectomy recommended in select patients with a perioperative complication rate < 6%
• < 50% carotid stenosis: carotid endarterectomy not routinely recommended.

Carotid artery angioplasty and stenting with distal embolic protection device

Data from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and European stenting trials indicate that in patients over age 70, carotid endarterectomy appears to be superior to carotid artery stenting, whereas in younger patients the periprocedural risks of stroke and death are similar. Hence, carotid artery stenting performed by an interventionist with a low complication rate is a reasonable alternative to carotid endarterectomy.^88,89

A transient ischemic attack (TIA), like an episode of unstable angina, is an ominous portent of future morbidity and death even though, by definition, the event leaves no residual neurologic deficit.

But there is a positive side. When a patient presents with a TIA, the physician has the rare opportunity to reduce the risk of a disabling outcome—in this case, stroke. Therefore, patients deserve a rapid and thorough evaluation and appropriate stroke-preventive treatment.

MANY ‘TIAs’ ARE ACTUALLY STROKES

TIA has traditionally been described as a sudden focal neurologic deficit that lasts less than 24 hours, is presumed to be of vascular origin, and is confined to an area of the brain, spinal cord, or eye perfused by a specific artery. This symptom-based definition was based on the arbitrary and inaccurate assumption that brief symptoms would not be associated with damage to brain parenchyma.

The definition has since been updated and made more rational based on new concepts of brain ischemia informed by imaging, especially diffusion-weighted magnetic resonance imaging (MRI).¹ One-third of episodes characterized as a TIA according to the classic definition would be considered an infarction on the basis of diffusion-weighted MRI.² The new tissue-based definition characterizes TIA as a brief episode of neurologic dysfunction caused by focal ischemia of the brain, spinal cord, or retina, with clinical symptoms lasting less than 24 hours and without evidence of acute infarction.³

AN OPPORTUNITY TO INTERVENE

Most TIAs resolve in less than 30 minutes. The US National Institute of Neurological Disorders and Stroke trial of tissue plasminogen activator found that if symptoms of cerebral ischemia had not resolved by 1 hour or had not rapidly improved within 3 hours, complete resolution was rare (only 2% at 24 hours).⁴ Hence, physicians evaluating and treating patients with TIAs should treat these episodes with the urgency they deserve.

Moreover, half of the strokes that follow TIAs occur within 48 hours.⁵ A rapid and thorough evaluation and the initiation of secondary preventive treatments have been shown to reduce the early occurrence of stroke by up to 80%.⁶ Hence, the correct diagnosis of TIA gives the clinician the best opportunity to prevent stroke and its personal, social, and sometimes fatal consequences.

STROKES OUTNUMBER TIAs, BUT TIAs ARE UNDERREPORTED

According to 2012 statistics, nearly 795,000 strokes occur in the United States each year, 610,000 of which are first attacks and 185,000 are recurrences. Every 40 seconds, someone in the United States has a stroke.⁷

In comparison, the incidence of TIA in the United States is estimated at 200,000 to 500,000 per year, though the true number is difficult to know because of underreporting.^8,9 About half of patients who experience a TIA fail to report it to their health care provider—a lost opportunity for intervention and stroke prevention.^10,11

A meta-analysis showed that the risk of stroke after TIA was 9.9% at 2 days, 13.4% at 30 days, and 17.3% at 90 days.¹²

Interestingly, the risk of stroke after TIA exceeds the risk of recurrent stroke after a first stroke. This was shown in a study that found that patients who had made a substantial recovery within 24 hours (ie, patients with a TIA) were more likely to suffer neurologic deterioration in the next 3 months than were those who did not have significant early improvement.¹³

RISK FACTORS FOR TIA ARE THE SAME AS FOR STROKE

The risk of cerebrovascular disease increases with age and is higher in men¹⁴ and in blacks and Hispanics.¹⁵

The risk factors and clinical presentation do not differ between TIA and stroke, so the evaluation and treatment should not differ either. These two events represent a continuum of the same disease entity.

Some risk factors for TIA are modifiable, others are not.

Nonmodifiable risk factors

Nonmodifiable risk factors for TIA include older age, male sex, African American race, low birth weight, Hispanic ethnicity, and family history. If the patient has nonmodifiable risk factors, we should try all the harder to correct the modifiable ones.

Older age. The risk of ischemic stroke and intracranial hemorrhage doubles with each decade after age 55 in both sexes.¹⁶

Sex. Men have a significantly higher incidence of TIA than women,¹¹ whereas the opposite is true for stroke: women have a higher lifetime risk of stroke than men.¹⁷

African Americans have an incidence of stroke (all types) 38% higher than that of whites,¹⁸ and an incidence of TIA (inpatient and out-of-hospital) 40% higher than the overall age- and sex-adjusted rate in the white population.¹¹

Low birth weight. The odds of stroke are more than twice as high in people who weighed less than 2,500 g at birth compared with those who weighed 4,000 g or more, probably because of a correlation between low birth weight and hypertension.¹⁹

A family history of stroke increases the risk of stroke by nearly 30%, the association being stronger with large-vessel and smallvessel stroke than with cardioembolic stroke.²⁰

Modifiable risk factors

Modifiable risk factors include cigarette smoking, hypertension, diabetes, lipid abnormalities, atrial fibrillation, carotid stenosis, and dietary and hormonal factors. Detecting these factors, which often coexist, is the first step in trying to modify them and reduce the patient’s risk.

Cigarette smoking approximately doubles the risk of ischemic stroke.^21–23

Hypertension has a relationship with stroke risk that is strong, continuous, graded, consistent, and significant.²⁴

Diabetes increases stroke risk nearly six times.²⁵

Lipid abnormalities. Most studies have found an association between lipid levels (total cholesterol and low-density lipoprotein cholesterol) and the risk of death from ischemic stroke,^26–28 and an inverse relationship between high-density lipoprotein cholesterol levels and stroke risk.²⁹

Atrial fibrillation increases the risk of ischemic stroke up to fivefold, even in the absence of cardiac valvular disease. The mechanism is embolism of stasis-induced thrombi that form in the left atrial appendage.³⁰

Carotid stenosis. Asymptomatic carotid atherosclerotic stenotic lesions in the extracranial internal carotid artery or carotid bulb are associated with a higher risk of stroke.^24,31

Lifestyle factors. Diets that lower blood pressure have been found to decrease stroke risk.²⁴ Exercise in men and women reduces the risk of stroke or death by 25% to 30% compared with inactive people.³² Weight reduction has been found to lower blood pressure and reduce stroke risk.²⁴

Other potentially modifiable risk factors include migraine with aura, metabolic syndrome, excess alcohol consumption (and, paradoxically, complete abstinence from alcohol), drug abuse, sleep-disordered breathing, hyperhomocysteinemia, high lipoprotein (a) levels, hypercoagulability, infection with organisms such as Chlamydia pneumoniae, cytomegalovirus, and Helicobacter pylori, and acute infections such as respiratory and urinary infections.²⁶

Conditions in certain demographic groups

Patients in certain demographic groups present with rarer conditions associated with stroke and TIA.

Sickle cell disease. Eleven percent of patients with sickle cell disease have clinical strokes, and a substantial number have “silent” infarcts identified on neuroimaging.^33,34

Postmenopausal hormone replacement therapy with any product containing conjugated equine estrogen carries a risk of cerebrovascular events,³⁵ and the higher the dose, the higher the risk.³⁶ Also, oral contraceptives may be harmful in women who have additional risk factors such as cigarette smoking, prior thromboembolic events, or migraine with aura.^37,38

THREE CAUSES OF STROKE AND TIA

Stroke and TIA should not be considered diagnoses in themselves, but rather the end point of many other diseases. The diagnosis lies in identifying the mechanism of the cerebrovascular event. The three main mechanisms are thrombosis, embolism, and decreased perfusion.

Thrombosis is caused by obstruction of blood flow within one or more blood vessels, the most common cause being atherosclerosis. Large-artery atherosclerosis, such as in the carotid bifurcation or extracranial internal carotid, causes TIAs that occur over a period of weeks or months with a variety of presentations in that vascular territory, from years of gradual accumulation of atherosclerotic plaque.³⁹

In patients with small-artery or penetrating artery disease, hypertension is the primary risk factor and the pathology, specific to small arterioles, is lipohyalinosis rather than atherosclerosis. These patients may present with a stuttering clinical course, and episodes are more stereotypical.

Less common obstructive vascular pathologies include fibromuscular dysplasia, arteritides, and dissection.

Embolism can occur from a proximal source such as the heart or from proximal vessels such as the aorta, carotid, or vertebral arteries. The embolic particle may form on heart valves or lesions within the heart (eg, clot, tumor), or in the venous circulation and paradoxically cross over to the arterial side through an intracardiac or transpulmonary shunt. Embolism may also be due to a hypercoagulable state.⁴⁰ Embolic stroke is suspected when multiple vascular territories within the brain are clinically or radiographically affected.

Decreased systemic perfusion caused by severe heart failure or systemic hypotension can cause ischemia to the brain diffusely and bilaterally, limiting the ability of the blood-stream to wash out microemboli, especially in the border zones (also known as “watershed areas”), thus leading to ischemia or infarction.⁴¹ Decreased perfusion can also be local, due to a fixed vessel stenosis.

Using another classification system, a study in Rochester, MN, found the following incident rates of stroke subtypes, adjusted for age and sex, per 100,000 population⁴²:

• Large-vessel cervical or intracranial atherosclerosis with more than 50% stenosis—27
• Cardioembolism—40
• Lacunar, small-vessel disease—25
• Uncertain cause—52
• Other identifiable cause—4.

THREE CLINICAL FEATURES SUGGEST TIA

TIAs can be hard to distinguish from nonischemic neurologic events in the acute setting such as an emergency room. Up to 60% of patients suspected of having a TIA actually have a nonischemic cause of their symptoms.⁴³

Three clinical features suggest a TIA during the emergency room evaluation:

• Rapid onset of symptoms—“like lightning” or “in seconds,” in contrast to migraine and seizures, which develop over minutes
• No history of similar episodes in the past
• Absence of nonspecific symptoms—eg, stomach upset or tightness in the chest.

CLINICAL DIAGNOSIS

Because most TIA symptoms and signs have already resolved by the time of evaluation, the diagnosis depends on a careful history with special attention to the pace of onset and resolution, the duration and nature of the symptoms, circumstances at the time of symptom onset, previous similar episodes, associated features, vascular risk factors, and family history (Table 1).^44,45

A detailed neurologic examination is imperative and should include fundoscopy. A cardiovascular assessment should include cardiac rhythm, bruits in the neck, orbits, and groin, peripheral pulses, and electrocardiography.

Do neurologists do a better job at diagnosing TIA and stroke?

Primary care physicians, internists, and emergency department physicians are often the ones to carry out the clinical assessment of possible TIA.

Determining if transient neurologic symptoms are caused by ischemia can be a challenge. When in doubt, referral to a neurologist with subspecialty training in cerebrovascular disease should be considered.

But do neurologists really do a better job? A recent study sought to compare the accuracy of diagnosis of TIA made by general practitioners, emergency physicians, and neurologists. The nonneurologists considered “confusion” and “unexplained fall” suggestive of TIA and “lower facial palsy” and “monocular blindness” less suggestive of TIA—whereas the opposite is true. This shows that nonneurologists often label minor strokes and several nonvascular transient neurologic disturbances as TIAs, and up to half of patients could be mislabeled as a result.⁴⁶

Differences in diagnosing cerebrovascular events between emergency room physicians and attending neurologists have been tested,⁴⁷ with an accuracy of diagnosis as low as 38% by emergency department physicians in one study.⁴⁸ However, other studies did not show such a trend.^49,50

A study at a university-based teaching hospital found the sensitivity of emergency room physician diagnosis to be 98.6% with a positive predictive value of 94.8%,⁴⁹ showing that at a large teaching hospital with a comprehensive stroke intervention program, emergency physicians could identify patients with stroke, particularly hemorrhagic stroke, very accurately.

Improving the diagnosis of stroke and TIA

Routine use of imaging and involvement of a neurologist increase the sensitivity and accuracy of diagnosis. Education and written guidelines for acute stroke treatment both in the emergency department and in out-of-hospital settings seem to dramatically improve the rates of diagnostic accuracy and appropriate treatment.⁵⁰

Emergency medical service personnel use two screening tools in the field to identify TIA and stroke symptoms:

• The Cincinnati Prehospital Stroke Scale, a three-item scale based on three signs: facial droop, arm drift, and slurring of speech⁵¹
• The Los Angeles Prehospital Stroke Screen, which uses screening questions and asymmetry in the face, hand grip strength, and arm drift.⁵²

Knowing that the patient is having a minor stroke or TIA is important. Urgent treatment of these conditions decreases the risk of stroke in the next 90 days, which was 10.5% in one study.⁵ Urgent assessment and early intervention could reduce this risk of subsequent stroke down to 2%.⁶

ASSESSING RISK OF STROKE AFTER TIA

There is a practical need for prediction of stroke during the first few days after the event. The ABCD and ABCD2 scores were developed to stratify the short-term risk of stroke in patients with recent TIA.

The ABCD score

The ABCD score⁵³ was derived to allow primary care physicians and other physicians to identify which patients with a suspected diagnosis of TIA should be referred for emergency assessment, to allow secondary-care physicians to determine which patients with probable or definite TIA need emergency investigation and treatment, to allow public education about the need for medical attention after a TIA, and to identify people at high risk.

The ABCD2 score

The ABCD2 score predicts the short-term risk of stroke following a TIA.⁵⁴ Points are assigned as follows:

• Age > 60 years: 1 point
• Blood pressure (systolic) > 140 mm Hg or diastolic blood pressure > 90 mm Hg: 1 point
• Clinical factors: unilateral weakness with or without speech impairment: 2 points (1 point for speech impairment without weakness)
• Duration of symptoms > 60 minutes: 2 points (1 point for 10–59 minutes)
• Diabetes: 1 point.

Thus, the possible total ranges from 0 to 7 points. Higher scores indicate a greater risk of stroke at 2, 7, 30, and 90 days:

• Total score 0, 1, 2, or 3: 2-day stroke risk 1.0% (low risk)
• Total score 4 or 5: 2-day stroke risk 4.1% (moderate risk)
• Total score 6 or 7: 2-day stroke risk 8.1% (high risk).

WHO SHOULD BE HOSPITALIZED?

It has been suggested that the ABCD2 score can help in triaging patients to hospital admission or outpatient care, though no randomized trial has actually evaluated the utility of the ABCD2 score in this way.³

A study of consecutive TIA patients admitted over 12 months⁵⁵ found that patients with an ABCD2 score of 3 or less had the same chance of requiring hospitalization (based on positive diffusion-weighted MRI studies, risk factor identification, and treatment initiation) as those with a score of 4 to 7. Hence, admitting TIA patients on the basis of the ABCD2 score alone requires further study. However, such decisions, though informed by clinical data, depend heavily on societal input (eg, from insurance companies, national health protocols) and may be outside the purview of clinical investigation.

The benefits of hospitalization include the ability to rapidly carry out tests such as cardiac monitoring for atrial fibrillation; to detect atherosclerosis, aortic arch atheroma, and paradoxical emboli; and to quickly start secondary prevention treatments and education about the importance of adhering to them. Early endarterectomy in the case of carotid stenosis can be offered. Additionally, if stroke symptoms recur, thrombolytic drug therapy can be started quickly.

Nguyen-Huynh et al⁵⁶ analyzed the cost utility of 24-hour hospitalization for patients diagnosed with a recent TIA who were candidates for tissue plasminogen activator if a stroke occurred. They found hospitalization to be borderline cost-effective on the whole, with definite cost-effectiveness found in patients with higher stroke risk.

If patients come to medical attention several days after the TIA, then assessing risk with the ABCD2 score may no longer be reliable.⁵⁷

INVESTIGATIONS

Parenchymal neuroimaging

Computed tomography (CT) without contrast is the most widely used neuroimaging test in the acute setting, since it is widely available, fast, and relatively low-cost. It will not show any abnormality in TIA or early ischemic stroke. However, it is helpful as a screening tool to rule out intracranial lesions such as hemorrhage or tumor. It may also show evidence of established infarction, which would indicate that the ischemia probably had been present for at least 6 to 12 hours.

MRI is clearly superior to noncontrast CT for detecting small areas of ischemia in patients with TIA, and it should be used unless the patient has a contraindication to it. Roughly one-third of TIA patients have lesions detectable on diffusion-weighted imaging, which helps to confirm that the episode was caused by cerebral ischemia, but nearly half of the diffusion MRI changes may be fully reversible.⁵⁸ Evidence of prior stroke, leukoaraiosis, or white matter disease on fluid-attenuated inversion recovery and T2 sequences and microhemorrhages (on gradient echo sequences) help to determine a mechanistic diagnosis.

Subcategorizing TIA patients on the basis of the findings on diffusion-weighted MRI and the ABCD² score is prognostically helpful.⁵⁹ It can help to determine which patients need hospitalization and aggressive treatment, and in the case of identified diffusion-weighted MRI-positive stroke, it helps to localize and elucidate the mechanism of stroke. Hence, MRI is the preferred neuroimaging study for evaluating patients with TIA.³

Vascular imaging

Establishing the status of both intracranial and extracranial vessels is important for understanding the etiology, estimating the risk of future ischemic events, and formulating a treatment plan—eg, carotid endarterectomy in cases of significant stenosis (70% to 99%), which reduces the risk of ipsilateral stroke.⁶⁰ Imaging studies include CT angiography, magnetic resonance angiography, extracranial and transcranial ultrasonography, and conventional catheter-based angiography.

CT angiography has higher spatial resolution, but vessels may be obscured by calcification associated with atherosclerotic plaque. It has the advantage of wide availability, low cost, short scanning time, and excellent patient tolerability.

Magnetic resonance angiography with gadolinium enhancement offers good quality imaging from the great vessels in the chest to the medium-sized vessels distal to the circle of Willis.

The contrast agents used in MRI and CT can have negative consequences in patients with renal disease. MRI contrast has been associated with nephrogenic fibrosing dermopathy, ⁶¹ and CT contrast can cause contrast-induced nephropathy.⁶²

Carotid ultrasonography and transcranial Doppler ultrasonography are noninvasive and are not associated with significant adverse events. They can be used safely in patients with renal dysfunction, and they provide physiologic information that cannot be obtained with MRI and CT, which are static imaging techniques. Detecting microemboli on transcranial Doppler is an independent predictor of recurrent ischemic events.^63,64

Catheter-based angiography is occasionally needed in confusing or more complicated cases, but it is invasive and occasionally is associated with iatrogenic stroke and other vascular complications.

Cardiac and aortic imaging

Echocardiography is used to detect lesions that can be sources of embolism such as regional wall-motion abnormalities, cardiac thrombus or mass, endocarditis, aortic arch atheroma, and patent foramen ovale. In patients with cryptogenic TIA or stroke, those with patent foramen ovale alone were found to have a lower risk of recurrent stroke than those who had both atrial septal aneurysm and patent foramen ovale.⁶⁵

Transesophageal echocardiography is more sensitive than transthoracic echocardiography for detecting cardioembolic lesions, especially patent foramen ovale.⁶⁶ In patients with cerebral ischemia and normal transthoracic findings, cardiac sources of embolism may be detected in about 40% of patients with transesophageal echocardiography.⁶⁷

Cardiac rhythm monitoring

Electrocardiography and prolonged telemetry are recommended in patients with cryptogenic TIA to detect cardiac ischemia and paroxysmal atrial fibrillation. In one study, Holter monitoring detected atrial fibrillation in 6% of patients hospitalized with ischemic stroke or TIA.⁶⁸ In another study, atrial fibrillation was detected after a median of 21 days of outpatient cardiac monitoring in 23% of patients.⁶⁹

The optimal duration of outpatient telemetry has not yet been established, but studies have found significant increases in detection of paroxysms of atrial fibrillation with monitoring for 7 or longer.⁷⁰

Laboratory tests in the acute setting

These include lipid profile, hemoglobin A_1c, and cardiac enzymes. The advantages of hospitalization are early detection of these modifiable risk factors and early initiation of treatment.

Tests for rarer disorders

Tests for rarer disorders are sometimes indicated in unusual cases, such as ischemic symptoms occurring in young patients without other common risk factors. This includes testing for prothrombotic states, toxicology, blood cultures, inflammatory markers, hemoglobin electrophoresis, and lumbar puncture. The benefit of routine testing for thrombophilic disorders in cerebrovascular disease remains uncertain, with no clear association demonstrated with arterial stroke, but testing is more relevant in the case of venous (and paradoxical) thromboembolism.⁷¹

TREAT THE UNDERLYING DISORDER

Treatment depends on the mechanism that is thought to be responsible for the ischemic event. Vascular risk factors are important to identify and modify for all stroke subtypes.

Illustrating the importance of treating TIA and minor stroke, one study⁷² found that for antiplatelet therapy (aspirin, dipyridamole, or aspirin plus dipyridamole), the number needed to treat for 2 years was around 18.

Anticoagulation for cardioembolism

Atrial fibrillation, especially following a cerebrovascular ischemic event, should be treated with long-term anticoagulation with warfarin (Coumadin), dabigatran (Pradaxa), rivaroxaban (Xarelto), or apixaban (Eliquis).⁷³ If the patient cannot tolerate anticoagulation, aspirin is recommended, and if he or she cannot tolerate aspirin, clopidogrel (Plavix) is recommended.

Antiplatelet therapy for large-vessel atherosclerosis and small-vessel disease

In the acute phase, aspirin 81 mg to 325 mg orally can be given. If the patient is allergic to aspirin, a loading dose of clopidogrel 300 mg and then 75 mg daily may be given.

A pilot study of loading with aspirin 325 mg or clopidogrel 375 mg in acute ischemic stroke and TIA patients showed that these treatments were safe when given within 36 hours and decreased the risk of neurologic deterioration.⁷⁴ The patient should continue on aspirin 81 mg or clopidogrel 75 mg, as suggested by the Fast Assessment of Stroke and Transient Ischaemic Attack to Prevent Early Recurrence (FASTER) trial.⁷⁵ In the long term, an antiplatelet drug such as aspirin or clopidogrel or the combination of aspirin and extended-release dipyridamole is reasonable.⁷⁶

Cilostazol (Pletal) is not inferior and is possibly superior to aspirin in preventing noncardioembolic ischemic stroke. It is used off-label for secondary prevention of stroke of noncardioembolic origin.⁷⁷

Statins

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, high-dose atorvastatin (Lipitor)—80 mg daily—was found to reduce the risk of subsequent stroke and other cardiovascular events in patients with recent stroke irrespective of low-density lipoprotein cholesterol (LDL-C) level, but there was a small increase in the risk of hemorrhagic stroke.⁷⁸

In patients with hyperlipidemia, current recommendations suggest a target LDL-C level lower than 100 mg/dL in patients with atherosclerotic stroke or TIA, and lower than 70 mg/dL in those with concomitant diabetes.⁷⁹

Antihypertensive therapy

In the acute period, ie, the first 24 hours after symptoms, guidelines have advocated allowing high blood pressure to remain high (“permissive hypertension”) unless the systolic pressure is greater than 200 mm Hg or the diastolic pressure is greater than 120 mm Hg or the patient is receiving thrombolytic therapy.⁸⁰ However, this has recently been challenged by findings in randomized trials.⁸¹ Permissive hypertension and avoidance of dehydration with intravenous normal saline may improve cerebral perfusion, which is especially important in patients with high-grade intracranial or extracranial stenosis. Within the parameters outlined above, we recommend against aggressively treating high blood pressure in the acute phase.

In the long term, antihypertensive therapy reduces the risk of recurrent stroke or TIA.⁸² The goal is to keep blood pressure lower than 140/90 mm Hg, or lower than 130/80 mm Hg in patients with diabetes. A study of patients with ischemic noncardioembolic stroke showed a higher risk of recurrent stroke if the systolic blood pressure was lower than 120 or higher than 140 mm Hg.⁸³

Some classes of antihypertensive medication may be more beneficial than others. There is some evidence that angiotensin-converting enzyme (ACE) inhibitors alone or in combination with a diuretic or an angiotensin receptor blocker are superior to other regimens, possibly because of neuroprotective mechanisms.⁸⁴ A recent meta-analysis found angiotensin receptor blockers to be more effective than either ACE inhibitors or beta-blockers in stroke prevention; however, calcium channel blockers were superior to renin-angiotensin system blockers (ACE inhibitors and angiotensin receptor blockers).⁸⁵

Lifestyle modifications

Smoking cessation and cardiovascular exercise for more than 10 minutes more than 3 times per week is strongly recommended.

For patients with diabetes, the goal is to keep the fasting blood glucose level lower than 126 mg/dL.

Moderate alcohol intake has been shown to decrease stroke risk compared with excessive intake or none at all.⁸⁶

Carotid endarterectomy

Carotid endarterectomy has been recommended within 2 weeks of cerebral or retinal TIA in those cases attributable to high-grade internal carotid artery stenosis in patients who have low surgical risk.⁸⁷ This risk can be estimated on the basis of patient factors, surgeon factors, and hospital volume. The specific recommendations are as follows:

• 70% to 99% carotid stenosis: carotid endarterectomy recommended
• 50% to 69% carotid stenosis: carotid endarterectomy recommended in select patients with a perioperative complication rate < 6%
• < 50% carotid stenosis: carotid endarterectomy not routinely recommended.

Carotid artery angioplasty and stenting with distal embolic protection device

Data from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and European stenting trials indicate that in patients over age 70, carotid endarterectomy appears to be superior to carotid artery stenting, whereas in younger patients the periprocedural risks of stroke and death are similar. Hence, carotid artery stenting performed by an interventionist with a low complication rate is a reasonable alternative to carotid endarterectomy.^88,89

A transient ischemic attack (TIA), like an episode of unstable angina, is an ominous portent of future morbidity and death even though, by definition, the event leaves no residual neurologic deficit.

But there is a positive side. When a patient presents with a TIA, the physician has the rare opportunity to reduce the risk of a disabling outcome—in this case, stroke. Therefore, patients deserve a rapid and thorough evaluation and appropriate stroke-preventive treatment.

MANY ‘TIAs’ ARE ACTUALLY STROKES

TIA has traditionally been described as a sudden focal neurologic deficit that lasts less than 24 hours, is presumed to be of vascular origin, and is confined to an area of the brain, spinal cord, or eye perfused by a specific artery. This symptom-based definition was based on the arbitrary and inaccurate assumption that brief symptoms would not be associated with damage to brain parenchyma.

The definition has since been updated and made more rational based on new concepts of brain ischemia informed by imaging, especially diffusion-weighted magnetic resonance imaging (MRI).¹ One-third of episodes characterized as a TIA according to the classic definition would be considered an infarction on the basis of diffusion-weighted MRI.² The new tissue-based definition characterizes TIA as a brief episode of neurologic dysfunction caused by focal ischemia of the brain, spinal cord, or retina, with clinical symptoms lasting less than 24 hours and without evidence of acute infarction.³

AN OPPORTUNITY TO INTERVENE

Most TIAs resolve in less than 30 minutes. The US National Institute of Neurological Disorders and Stroke trial of tissue plasminogen activator found that if symptoms of cerebral ischemia had not resolved by 1 hour or had not rapidly improved within 3 hours, complete resolution was rare (only 2% at 24 hours).⁴ Hence, physicians evaluating and treating patients with TIAs should treat these episodes with the urgency they deserve.

Moreover, half of the strokes that follow TIAs occur within 48 hours.⁵ A rapid and thorough evaluation and the initiation of secondary preventive treatments have been shown to reduce the early occurrence of stroke by up to 80%.⁶ Hence, the correct diagnosis of TIA gives the clinician the best opportunity to prevent stroke and its personal, social, and sometimes fatal consequences.

STROKES OUTNUMBER TIAs, BUT TIAs ARE UNDERREPORTED

According to 2012 statistics, nearly 795,000 strokes occur in the United States each year, 610,000 of which are first attacks and 185,000 are recurrences. Every 40 seconds, someone in the United States has a stroke.⁷

In comparison, the incidence of TIA in the United States is estimated at 200,000 to 500,000 per year, though the true number is difficult to know because of underreporting.^8,9 About half of patients who experience a TIA fail to report it to their health care provider—a lost opportunity for intervention and stroke prevention.^10,11

A meta-analysis showed that the risk of stroke after TIA was 9.9% at 2 days, 13.4% at 30 days, and 17.3% at 90 days.¹²

Interestingly, the risk of stroke after TIA exceeds the risk of recurrent stroke after a first stroke. This was shown in a study that found that patients who had made a substantial recovery within 24 hours (ie, patients with a TIA) were more likely to suffer neurologic deterioration in the next 3 months than were those who did not have significant early improvement.¹³

RISK FACTORS FOR TIA ARE THE SAME AS FOR STROKE

The risk of cerebrovascular disease increases with age and is higher in men¹⁴ and in blacks and Hispanics.¹⁵

The risk factors and clinical presentation do not differ between TIA and stroke, so the evaluation and treatment should not differ either. These two events represent a continuum of the same disease entity.

Some risk factors for TIA are modifiable, others are not.

Nonmodifiable risk factors

Nonmodifiable risk factors for TIA include older age, male sex, African American race, low birth weight, Hispanic ethnicity, and family history. If the patient has nonmodifiable risk factors, we should try all the harder to correct the modifiable ones.

Older age. The risk of ischemic stroke and intracranial hemorrhage doubles with each decade after age 55 in both sexes.¹⁶

Sex. Men have a significantly higher incidence of TIA than women,¹¹ whereas the opposite is true for stroke: women have a higher lifetime risk of stroke than men.¹⁷

African Americans have an incidence of stroke (all types) 38% higher than that of whites,¹⁸ and an incidence of TIA (inpatient and out-of-hospital) 40% higher than the overall age- and sex-adjusted rate in the white population.¹¹

Low birth weight. The odds of stroke are more than twice as high in people who weighed less than 2,500 g at birth compared with those who weighed 4,000 g or more, probably because of a correlation between low birth weight and hypertension.¹⁹

A family history of stroke increases the risk of stroke by nearly 30%, the association being stronger with large-vessel and smallvessel stroke than with cardioembolic stroke.²⁰

Modifiable risk factors

Modifiable risk factors include cigarette smoking, hypertension, diabetes, lipid abnormalities, atrial fibrillation, carotid stenosis, and dietary and hormonal factors. Detecting these factors, which often coexist, is the first step in trying to modify them and reduce the patient’s risk.

Cigarette smoking approximately doubles the risk of ischemic stroke.^21–23

Hypertension has a relationship with stroke risk that is strong, continuous, graded, consistent, and significant.²⁴

Diabetes increases stroke risk nearly six times.²⁵

Lipid abnormalities. Most studies have found an association between lipid levels (total cholesterol and low-density lipoprotein cholesterol) and the risk of death from ischemic stroke,^26–28 and an inverse relationship between high-density lipoprotein cholesterol levels and stroke risk.²⁹

Atrial fibrillation increases the risk of ischemic stroke up to fivefold, even in the absence of cardiac valvular disease. The mechanism is embolism of stasis-induced thrombi that form in the left atrial appendage.³⁰

Carotid stenosis. Asymptomatic carotid atherosclerotic stenotic lesions in the extracranial internal carotid artery or carotid bulb are associated with a higher risk of stroke.^24,31

Lifestyle factors. Diets that lower blood pressure have been found to decrease stroke risk.²⁴ Exercise in men and women reduces the risk of stroke or death by 25% to 30% compared with inactive people.³² Weight reduction has been found to lower blood pressure and reduce stroke risk.²⁴

Other potentially modifiable risk factors include migraine with aura, metabolic syndrome, excess alcohol consumption (and, paradoxically, complete abstinence from alcohol), drug abuse, sleep-disordered breathing, hyperhomocysteinemia, high lipoprotein (a) levels, hypercoagulability, infection with organisms such as Chlamydia pneumoniae, cytomegalovirus, and Helicobacter pylori, and acute infections such as respiratory and urinary infections.²⁶

Conditions in certain demographic groups

Patients in certain demographic groups present with rarer conditions associated with stroke and TIA.

Sickle cell disease. Eleven percent of patients with sickle cell disease have clinical strokes, and a substantial number have “silent” infarcts identified on neuroimaging.^33,34

Postmenopausal hormone replacement therapy with any product containing conjugated equine estrogen carries a risk of cerebrovascular events,³⁵ and the higher the dose, the higher the risk.³⁶ Also, oral contraceptives may be harmful in women who have additional risk factors such as cigarette smoking, prior thromboembolic events, or migraine with aura.^37,38

THREE CAUSES OF STROKE AND TIA

Stroke and TIA should not be considered diagnoses in themselves, but rather the end point of many other diseases. The diagnosis lies in identifying the mechanism of the cerebrovascular event. The three main mechanisms are thrombosis, embolism, and decreased perfusion.

Thrombosis is caused by obstruction of blood flow within one or more blood vessels, the most common cause being atherosclerosis. Large-artery atherosclerosis, such as in the carotid bifurcation or extracranial internal carotid, causes TIAs that occur over a period of weeks or months with a variety of presentations in that vascular territory, from years of gradual accumulation of atherosclerotic plaque.³⁹

In patients with small-artery or penetrating artery disease, hypertension is the primary risk factor and the pathology, specific to small arterioles, is lipohyalinosis rather than atherosclerosis. These patients may present with a stuttering clinical course, and episodes are more stereotypical.

Less common obstructive vascular pathologies include fibromuscular dysplasia, arteritides, and dissection.

Embolism can occur from a proximal source such as the heart or from proximal vessels such as the aorta, carotid, or vertebral arteries. The embolic particle may form on heart valves or lesions within the heart (eg, clot, tumor), or in the venous circulation and paradoxically cross over to the arterial side through an intracardiac or transpulmonary shunt. Embolism may also be due to a hypercoagulable state.⁴⁰ Embolic stroke is suspected when multiple vascular territories within the brain are clinically or radiographically affected.

Decreased systemic perfusion caused by severe heart failure or systemic hypotension can cause ischemia to the brain diffusely and bilaterally, limiting the ability of the blood-stream to wash out microemboli, especially in the border zones (also known as “watershed areas”), thus leading to ischemia or infarction.⁴¹ Decreased perfusion can also be local, due to a fixed vessel stenosis.

Using another classification system, a study in Rochester, MN, found the following incident rates of stroke subtypes, adjusted for age and sex, per 100,000 population⁴²:

• Large-vessel cervical or intracranial atherosclerosis with more than 50% stenosis—27
• Cardioembolism—40
• Lacunar, small-vessel disease—25
• Uncertain cause—52
• Other identifiable cause—4.

THREE CLINICAL FEATURES SUGGEST TIA

TIAs can be hard to distinguish from nonischemic neurologic events in the acute setting such as an emergency room. Up to 60% of patients suspected of having a TIA actually have a nonischemic cause of their symptoms.⁴³

Three clinical features suggest a TIA during the emergency room evaluation:

• Rapid onset of symptoms—“like lightning” or “in seconds,” in contrast to migraine and seizures, which develop over minutes
• No history of similar episodes in the past
• Absence of nonspecific symptoms—eg, stomach upset or tightness in the chest.

CLINICAL DIAGNOSIS

Because most TIA symptoms and signs have already resolved by the time of evaluation, the diagnosis depends on a careful history with special attention to the pace of onset and resolution, the duration and nature of the symptoms, circumstances at the time of symptom onset, previous similar episodes, associated features, vascular risk factors, and family history (Table 1).^44,45

A detailed neurologic examination is imperative and should include fundoscopy. A cardiovascular assessment should include cardiac rhythm, bruits in the neck, orbits, and groin, peripheral pulses, and electrocardiography.

Do neurologists do a better job at diagnosing TIA and stroke?

Primary care physicians, internists, and emergency department physicians are often the ones to carry out the clinical assessment of possible TIA.

Determining if transient neurologic symptoms are caused by ischemia can be a challenge. When in doubt, referral to a neurologist with subspecialty training in cerebrovascular disease should be considered.

But do neurologists really do a better job? A recent study sought to compare the accuracy of diagnosis of TIA made by general practitioners, emergency physicians, and neurologists. The nonneurologists considered “confusion” and “unexplained fall” suggestive of TIA and “lower facial palsy” and “monocular blindness” less suggestive of TIA—whereas the opposite is true. This shows that nonneurologists often label minor strokes and several nonvascular transient neurologic disturbances as TIAs, and up to half of patients could be mislabeled as a result.⁴⁶

Differences in diagnosing cerebrovascular events between emergency room physicians and attending neurologists have been tested,⁴⁷ with an accuracy of diagnosis as low as 38% by emergency department physicians in one study.⁴⁸ However, other studies did not show such a trend.^49,50

A study at a university-based teaching hospital found the sensitivity of emergency room physician diagnosis to be 98.6% with a positive predictive value of 94.8%,⁴⁹ showing that at a large teaching hospital with a comprehensive stroke intervention program, emergency physicians could identify patients with stroke, particularly hemorrhagic stroke, very accurately.

Improving the diagnosis of stroke and TIA

Routine use of imaging and involvement of a neurologist increase the sensitivity and accuracy of diagnosis. Education and written guidelines for acute stroke treatment both in the emergency department and in out-of-hospital settings seem to dramatically improve the rates of diagnostic accuracy and appropriate treatment.⁵⁰

Emergency medical service personnel use two screening tools in the field to identify TIA and stroke symptoms:

• The Cincinnati Prehospital Stroke Scale, a three-item scale based on three signs: facial droop, arm drift, and slurring of speech⁵¹
• The Los Angeles Prehospital Stroke Screen, which uses screening questions and asymmetry in the face, hand grip strength, and arm drift.⁵²

Knowing that the patient is having a minor stroke or TIA is important. Urgent treatment of these conditions decreases the risk of stroke in the next 90 days, which was 10.5% in one study.⁵ Urgent assessment and early intervention could reduce this risk of subsequent stroke down to 2%.⁶

ASSESSING RISK OF STROKE AFTER TIA

There is a practical need for prediction of stroke during the first few days after the event. The ABCD and ABCD2 scores were developed to stratify the short-term risk of stroke in patients with recent TIA.

The ABCD score

The ABCD score⁵³ was derived to allow primary care physicians and other physicians to identify which patients with a suspected diagnosis of TIA should be referred for emergency assessment, to allow secondary-care physicians to determine which patients with probable or definite TIA need emergency investigation and treatment, to allow public education about the need for medical attention after a TIA, and to identify people at high risk.

The ABCD2 score

The ABCD2 score predicts the short-term risk of stroke following a TIA.⁵⁴ Points are assigned as follows:

• Age > 60 years: 1 point
• Blood pressure (systolic) > 140 mm Hg or diastolic blood pressure > 90 mm Hg: 1 point
• Clinical factors: unilateral weakness with or without speech impairment: 2 points (1 point for speech impairment without weakness)
• Duration of symptoms > 60 minutes: 2 points (1 point for 10–59 minutes)
• Diabetes: 1 point.

Thus, the possible total ranges from 0 to 7 points. Higher scores indicate a greater risk of stroke at 2, 7, 30, and 90 days:

• Total score 0, 1, 2, or 3: 2-day stroke risk 1.0% (low risk)
• Total score 4 or 5: 2-day stroke risk 4.1% (moderate risk)
• Total score 6 or 7: 2-day stroke risk 8.1% (high risk).

WHO SHOULD BE HOSPITALIZED?

It has been suggested that the ABCD2 score can help in triaging patients to hospital admission or outpatient care, though no randomized trial has actually evaluated the utility of the ABCD2 score in this way.³

A study of consecutive TIA patients admitted over 12 months⁵⁵ found that patients with an ABCD2 score of 3 or less had the same chance of requiring hospitalization (based on positive diffusion-weighted MRI studies, risk factor identification, and treatment initiation) as those with a score of 4 to 7. Hence, admitting TIA patients on the basis of the ABCD2 score alone requires further study. However, such decisions, though informed by clinical data, depend heavily on societal input (eg, from insurance companies, national health protocols) and may be outside the purview of clinical investigation.

The benefits of hospitalization include the ability to rapidly carry out tests such as cardiac monitoring for atrial fibrillation; to detect atherosclerosis, aortic arch atheroma, and paradoxical emboli; and to quickly start secondary prevention treatments and education about the importance of adhering to them. Early endarterectomy in the case of carotid stenosis can be offered. Additionally, if stroke symptoms recur, thrombolytic drug therapy can be started quickly.

Nguyen-Huynh et al⁵⁶ analyzed the cost utility of 24-hour hospitalization for patients diagnosed with a recent TIA who were candidates for tissue plasminogen activator if a stroke occurred. They found hospitalization to be borderline cost-effective on the whole, with definite cost-effectiveness found in patients with higher stroke risk.

If patients come to medical attention several days after the TIA, then assessing risk with the ABCD2 score may no longer be reliable.⁵⁷

INVESTIGATIONS

Parenchymal neuroimaging

Computed tomography (CT) without contrast is the most widely used neuroimaging test in the acute setting, since it is widely available, fast, and relatively low-cost. It will not show any abnormality in TIA or early ischemic stroke. However, it is helpful as a screening tool to rule out intracranial lesions such as hemorrhage or tumor. It may also show evidence of established infarction, which would indicate that the ischemia probably had been present for at least 6 to 12 hours.

MRI is clearly superior to noncontrast CT for detecting small areas of ischemia in patients with TIA, and it should be used unless the patient has a contraindication to it. Roughly one-third of TIA patients have lesions detectable on diffusion-weighted imaging, which helps to confirm that the episode was caused by cerebral ischemia, but nearly half of the diffusion MRI changes may be fully reversible.⁵⁸ Evidence of prior stroke, leukoaraiosis, or white matter disease on fluid-attenuated inversion recovery and T2 sequences and microhemorrhages (on gradient echo sequences) help to determine a mechanistic diagnosis.

Subcategorizing TIA patients on the basis of the findings on diffusion-weighted MRI and the ABCD² score is prognostically helpful.⁵⁹ It can help to determine which patients need hospitalization and aggressive treatment, and in the case of identified diffusion-weighted MRI-positive stroke, it helps to localize and elucidate the mechanism of stroke. Hence, MRI is the preferred neuroimaging study for evaluating patients with TIA.³

Vascular imaging

Establishing the status of both intracranial and extracranial vessels is important for understanding the etiology, estimating the risk of future ischemic events, and formulating a treatment plan—eg, carotid endarterectomy in cases of significant stenosis (70% to 99%), which reduces the risk of ipsilateral stroke.⁶⁰ Imaging studies include CT angiography, magnetic resonance angiography, extracranial and transcranial ultrasonography, and conventional catheter-based angiography.

CT angiography has higher spatial resolution, but vessels may be obscured by calcification associated with atherosclerotic plaque. It has the advantage of wide availability, low cost, short scanning time, and excellent patient tolerability.

Magnetic resonance angiography with gadolinium enhancement offers good quality imaging from the great vessels in the chest to the medium-sized vessels distal to the circle of Willis.

The contrast agents used in MRI and CT can have negative consequences in patients with renal disease. MRI contrast has been associated with nephrogenic fibrosing dermopathy, ⁶¹ and CT contrast can cause contrast-induced nephropathy.⁶²

Carotid ultrasonography and transcranial Doppler ultrasonography are noninvasive and are not associated with significant adverse events. They can be used safely in patients with renal dysfunction, and they provide physiologic information that cannot be obtained with MRI and CT, which are static imaging techniques. Detecting microemboli on transcranial Doppler is an independent predictor of recurrent ischemic events.^63,64

Catheter-based angiography is occasionally needed in confusing or more complicated cases, but it is invasive and occasionally is associated with iatrogenic stroke and other vascular complications.

Cardiac and aortic imaging

Echocardiography is used to detect lesions that can be sources of embolism such as regional wall-motion abnormalities, cardiac thrombus or mass, endocarditis, aortic arch atheroma, and patent foramen ovale. In patients with cryptogenic TIA or stroke, those with patent foramen ovale alone were found to have a lower risk of recurrent stroke than those who had both atrial septal aneurysm and patent foramen ovale.⁶⁵

Transesophageal echocardiography is more sensitive than transthoracic echocardiography for detecting cardioembolic lesions, especially patent foramen ovale.⁶⁶ In patients with cerebral ischemia and normal transthoracic findings, cardiac sources of embolism may be detected in about 40% of patients with transesophageal echocardiography.⁶⁷

Cardiac rhythm monitoring

Electrocardiography and prolonged telemetry are recommended in patients with cryptogenic TIA to detect cardiac ischemia and paroxysmal atrial fibrillation. In one study, Holter monitoring detected atrial fibrillation in 6% of patients hospitalized with ischemic stroke or TIA.⁶⁸ In another study, atrial fibrillation was detected after a median of 21 days of outpatient cardiac monitoring in 23% of patients.⁶⁹

The optimal duration of outpatient telemetry has not yet been established, but studies have found significant increases in detection of paroxysms of atrial fibrillation with monitoring for 7 or longer.⁷⁰

Laboratory tests in the acute setting

These include lipid profile, hemoglobin A_1c, and cardiac enzymes. The advantages of hospitalization are early detection of these modifiable risk factors and early initiation of treatment.

Tests for rarer disorders

Tests for rarer disorders are sometimes indicated in unusual cases, such as ischemic symptoms occurring in young patients without other common risk factors. This includes testing for prothrombotic states, toxicology, blood cultures, inflammatory markers, hemoglobin electrophoresis, and lumbar puncture. The benefit of routine testing for thrombophilic disorders in cerebrovascular disease remains uncertain, with no clear association demonstrated with arterial stroke, but testing is more relevant in the case of venous (and paradoxical) thromboembolism.⁷¹

TREAT THE UNDERLYING DISORDER

Treatment depends on the mechanism that is thought to be responsible for the ischemic event. Vascular risk factors are important to identify and modify for all stroke subtypes.

Illustrating the importance of treating TIA and minor stroke, one study⁷² found that for antiplatelet therapy (aspirin, dipyridamole, or aspirin plus dipyridamole), the number needed to treat for 2 years was around 18.

Anticoagulation for cardioembolism

Atrial fibrillation, especially following a cerebrovascular ischemic event, should be treated with long-term anticoagulation with warfarin (Coumadin), dabigatran (Pradaxa), rivaroxaban (Xarelto), or apixaban (Eliquis).⁷³ If the patient cannot tolerate anticoagulation, aspirin is recommended, and if he or she cannot tolerate aspirin, clopidogrel (Plavix) is recommended.

Antiplatelet therapy for large-vessel atherosclerosis and small-vessel disease

In the acute phase, aspirin 81 mg to 325 mg orally can be given. If the patient is allergic to aspirin, a loading dose of clopidogrel 300 mg and then 75 mg daily may be given.

A pilot study of loading with aspirin 325 mg or clopidogrel 375 mg in acute ischemic stroke and TIA patients showed that these treatments were safe when given within 36 hours and decreased the risk of neurologic deterioration.⁷⁴ The patient should continue on aspirin 81 mg or clopidogrel 75 mg, as suggested by the Fast Assessment of Stroke and Transient Ischaemic Attack to Prevent Early Recurrence (FASTER) trial.⁷⁵ In the long term, an antiplatelet drug such as aspirin or clopidogrel or the combination of aspirin and extended-release dipyridamole is reasonable.⁷⁶

Cilostazol (Pletal) is not inferior and is possibly superior to aspirin in preventing noncardioembolic ischemic stroke. It is used off-label for secondary prevention of stroke of noncardioembolic origin.⁷⁷

Statins

In the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, high-dose atorvastatin (Lipitor)—80 mg daily—was found to reduce the risk of subsequent stroke and other cardiovascular events in patients with recent stroke irrespective of low-density lipoprotein cholesterol (LDL-C) level, but there was a small increase in the risk of hemorrhagic stroke.⁷⁸

In patients with hyperlipidemia, current recommendations suggest a target LDL-C level lower than 100 mg/dL in patients with atherosclerotic stroke or TIA, and lower than 70 mg/dL in those with concomitant diabetes.⁷⁹

Antihypertensive therapy

In the acute period, ie, the first 24 hours after symptoms, guidelines have advocated allowing high blood pressure to remain high (“permissive hypertension”) unless the systolic pressure is greater than 200 mm Hg or the diastolic pressure is greater than 120 mm Hg or the patient is receiving thrombolytic therapy.⁸⁰ However, this has recently been challenged by findings in randomized trials.⁸¹ Permissive hypertension and avoidance of dehydration with intravenous normal saline may improve cerebral perfusion, which is especially important in patients with high-grade intracranial or extracranial stenosis. Within the parameters outlined above, we recommend against aggressively treating high blood pressure in the acute phase.

In the long term, antihypertensive therapy reduces the risk of recurrent stroke or TIA.⁸² The goal is to keep blood pressure lower than 140/90 mm Hg, or lower than 130/80 mm Hg in patients with diabetes. A study of patients with ischemic noncardioembolic stroke showed a higher risk of recurrent stroke if the systolic blood pressure was lower than 120 or higher than 140 mm Hg.⁸³

Some classes of antihypertensive medication may be more beneficial than others. There is some evidence that angiotensin-converting enzyme (ACE) inhibitors alone or in combination with a diuretic or an angiotensin receptor blocker are superior to other regimens, possibly because of neuroprotective mechanisms.⁸⁴ A recent meta-analysis found angiotensin receptor blockers to be more effective than either ACE inhibitors or beta-blockers in stroke prevention; however, calcium channel blockers were superior to renin-angiotensin system blockers (ACE inhibitors and angiotensin receptor blockers).⁸⁵

Lifestyle modifications

Smoking cessation and cardiovascular exercise for more than 10 minutes more than 3 times per week is strongly recommended.

For patients with diabetes, the goal is to keep the fasting blood glucose level lower than 126 mg/dL.

Moderate alcohol intake has been shown to decrease stroke risk compared with excessive intake or none at all.⁸⁶

Carotid endarterectomy

Carotid endarterectomy has been recommended within 2 weeks of cerebral or retinal TIA in those cases attributable to high-grade internal carotid artery stenosis in patients who have low surgical risk.⁸⁷ This risk can be estimated on the basis of patient factors, surgeon factors, and hospital volume. The specific recommendations are as follows:

• 70% to 99% carotid stenosis: carotid endarterectomy recommended
• 50% to 69% carotid stenosis: carotid endarterectomy recommended in select patients with a perioperative complication rate < 6%
• < 50% carotid stenosis: carotid endarterectomy not routinely recommended.

Carotid artery angioplasty and stenting with distal embolic protection device

Data from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) and European stenting trials indicate that in patients over age 70, carotid endarterectomy appears to be superior to carotid artery stenting, whereas in younger patients the periprocedural risks of stroke and death are similar. Hence, carotid artery stenting performed by an interventionist with a low complication rate is a reasonable alternative to carotid endarterectomy.^88,89

Dear Dr. Mossman:

My patient, Ms. X, returned to see me after she had spent 3 months in jail. When I accessed her medication history in our state’s prescription registry, I discovered that, during her incarceration, a local pharmacy continued to fill her prescription for clonazepam. After anxiously explaining that her roommate had filled the prescriptions, Ms. X pleaded with me not to tell anyone. Do I have to report this to legal authorities? If I do, will I be breaching confidentiality?

Submitted by Dr. L

Preserving the confidentiality of patient encounters is an ethical responsibility as old as the Hippocratic Oath,¹ but protecting privacy is not an absolute duty. As psychiatrists familiar with the Tarasoff case² know, clinical events sometimes create moral and legal obligations that outweigh our confidentiality obligations.

What Dr. L should do may hinge on specific details of Ms. X’s previous and current treatment, but in this article, we’ll examine some general issues that affect Dr. L’s choices. These include:

Monitoring controlled substances

Dr. L’s clinical situation probably would not have arisen 10 years ago because until recently, she would have had no easy way to learn that Ms. X’s prescription had been filled. In 2002, Congress responded to increasing concern about “epidemic” abuse of controlled substances—especially opioids—by authorizing state grants for prescription drug monitoring programs (PDMPs).³

PDMPs are internet-based registries that let physicians quickly find out when and where their patients have filled prescriptions for controlled substances (defined in the Table).^4,5 As the rate of opioid-related deaths has risen,⁶ at least 43 states have initiated PDMPs; soon, all U.S. jurisdictions likely will have such programs.⁷ Data about the impact of PDMPs, although limited, suggest that PDMPs reduce “doctor shopping” and prescription drug abuse.⁸

The U.S. Department of Health and Human Services is promoting the development of electronic architecture standards to facilitate information exchange across jurisdictions,⁹ but states currently run their own PDMPs independently and have varying regulations about how physicians should use PDMPs.¹⁰ Excerpts from the rules used in Ohio’s prescription reporting system appear in the Box.¹¹

Reporting past crimes

What Ms. X told Dr. L implies that someone—the patient, her roommate, or both—misused a prescription to obtain a controlled substance. Simple improper possession of a scheduled drug is a federal misdemeanor offense,¹² and deception and conspiracy to obtain a scheduled drug are federal-level felonies.¹³ Such actions also violate state laws. Dr. L therefore knows that a crime has occurred.

Are doctors obligated or legally required to breach confidentiality and tell authorities about a patient’s past criminal acts? Writing several years ago, Appelbaum and Meisel¹⁴ and Goldman and Gutheil¹⁵ said the answer, in general, is “no.”

In recent years, state legislatures have modified criminal codes to encourage people to disclose their knowledge of certain crimes to police. For example, failures to report environmental offenses and financial misdealings have become criminal acts.¹⁶ A minority of states now punish failure to report other kinds of illegal behavior, but these laws focus mainly on violent crimes (often involving harm to vulnerable persons).¹⁷ Although Ohio has a law that obligates everyone to report knowledge of any felony, it makes exceptions when the information is learned during a customarily confidential relationship—including a physician’s treatment of a patient.¹⁸ Unless Dr. L herself has aided or concealed a crime (both illegal acts¹⁹), concerns about possible prosecution should not affect her decision to report what she has learned thus far.¹⁴

Deciding how to proceed

If Dr. L still feels inclined to do something about the misused prescription, what are her options? What clinical, legal, and moral obligations to act should she consider?

Obtain the facts. First, Dr. L should try to learn more about what happened. Jails are reluctant to give inmates benzodiazepines²⁰; did Ms. X receive clonazepam while in jail? When and how did Ms. X learn about her roommate’s actions? Did Ms. X obtain previous prescriptions from Dr. L with the intention of letting her roommate use them? Answers to these questions can help Dr. L determine whether her patient participated in prescription misuse, an important factor in deciding what clinical or legal actions to take.

Should the patient take the lead? Learning more about the situation might suggest that Ms. X should report what has happened herself. If, for example, the roommate has coerced Ms. X to engage in illegal conduct, Dr. L might help Ms. X figure out how to tell police what has happened—preferably after Ms. X has obtained legal advice.¹⁴

Consider implications for treatment. Last, what Ms. X reveals might significantly alter her future interactions with Dr. L. This is particularly true if Dr. L concluded that Ms. X would likely divert drugs in the future, or that the patient had established her relationship with Dr. L for purposes of improperly obtaining drugs. Federal regulations require that doctors prescribe drugs only for “legitimate medical purposes,” and issuing prescriptions to a patient who is known to be delivering the drugs to others violates this law.²²

Bottom Line

Growing concern about prescription drug misuse has led to nationwide implementation of systems for monitoring patients’ access to, and receipt of, controlled substances. Psychiatrists are expected to be more vigilant about patients’ use of scheduled drugs and, when they believe that a prescription has been misused, to take appropriate clinical or legal action.

Related Resources

• Office of National Drug Control Policy. Epidemic: responding to America’s prescription drug abuse crisis. www.whitehouse.gov/sites/default/files/ondcp/issues-content/ prescription-drugs/rx_abuse_plan.pdf.
• California Department of Alcohol and Drug Misuse. Preventing prescription drug misuse. www.prescriptiondrugmisuse.org.
• U.S. Food and Drug Administration. Combating misuse and abuse of prescription drugs: Q&A with Michael Klein, PhD. www.fda.gov/ForConsumers/ConsumerUpdates/ ucm220112.htm.

Drug Brand Names

Clonazepam • Klonopin             Hydrocodone/acetaminophen • Vicodin

Methylphenidate • Ritalin          Hydromorphone • Dilaudid

Disclosure

Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman:

My patient, Ms. X, returned to see me after she had spent 3 months in jail. When I accessed her medication history in our state’s prescription registry, I discovered that, during her incarceration, a local pharmacy continued to fill her prescription for clonazepam. After anxiously explaining that her roommate had filled the prescriptions, Ms. X pleaded with me not to tell anyone. Do I have to report this to legal authorities? If I do, will I be breaching confidentiality?

Submitted by Dr. L

Preserving the confidentiality of patient encounters is an ethical responsibility as old as the Hippocratic Oath,¹ but protecting privacy is not an absolute duty. As psychiatrists familiar with the Tarasoff case² know, clinical events sometimes create moral and legal obligations that outweigh our confidentiality obligations.

What Dr. L should do may hinge on specific details of Ms. X’s previous and current treatment, but in this article, we’ll examine some general issues that affect Dr. L’s choices. These include:

Monitoring controlled substances

Dr. L’s clinical situation probably would not have arisen 10 years ago because until recently, she would have had no easy way to learn that Ms. X’s prescription had been filled. In 2002, Congress responded to increasing concern about “epidemic” abuse of controlled substances—especially opioids—by authorizing state grants for prescription drug monitoring programs (PDMPs).³

PDMPs are internet-based registries that let physicians quickly find out when and where their patients have filled prescriptions for controlled substances (defined in the Table).^4,5 As the rate of opioid-related deaths has risen,⁶ at least 43 states have initiated PDMPs; soon, all U.S. jurisdictions likely will have such programs.⁷ Data about the impact of PDMPs, although limited, suggest that PDMPs reduce “doctor shopping” and prescription drug abuse.⁸

The U.S. Department of Health and Human Services is promoting the development of electronic architecture standards to facilitate information exchange across jurisdictions,⁹ but states currently run their own PDMPs independently and have varying regulations about how physicians should use PDMPs.¹⁰ Excerpts from the rules used in Ohio’s prescription reporting system appear in the Box.¹¹

Reporting past crimes

What Ms. X told Dr. L implies that someone—the patient, her roommate, or both—misused a prescription to obtain a controlled substance. Simple improper possession of a scheduled drug is a federal misdemeanor offense,¹² and deception and conspiracy to obtain a scheduled drug are federal-level felonies.¹³ Such actions also violate state laws. Dr. L therefore knows that a crime has occurred.

Are doctors obligated or legally required to breach confidentiality and tell authorities about a patient’s past criminal acts? Writing several years ago, Appelbaum and Meisel¹⁴ and Goldman and Gutheil¹⁵ said the answer, in general, is “no.”

In recent years, state legislatures have modified criminal codes to encourage people to disclose their knowledge of certain crimes to police. For example, failures to report environmental offenses and financial misdealings have become criminal acts.¹⁶ A minority of states now punish failure to report other kinds of illegal behavior, but these laws focus mainly on violent crimes (often involving harm to vulnerable persons).¹⁷ Although Ohio has a law that obligates everyone to report knowledge of any felony, it makes exceptions when the information is learned during a customarily confidential relationship—including a physician’s treatment of a patient.¹⁸ Unless Dr. L herself has aided or concealed a crime (both illegal acts¹⁹), concerns about possible prosecution should not affect her decision to report what she has learned thus far.¹⁴

Deciding how to proceed

If Dr. L still feels inclined to do something about the misused prescription, what are her options? What clinical, legal, and moral obligations to act should she consider?

Obtain the facts. First, Dr. L should try to learn more about what happened. Jails are reluctant to give inmates benzodiazepines²⁰; did Ms. X receive clonazepam while in jail? When and how did Ms. X learn about her roommate’s actions? Did Ms. X obtain previous prescriptions from Dr. L with the intention of letting her roommate use them? Answers to these questions can help Dr. L determine whether her patient participated in prescription misuse, an important factor in deciding what clinical or legal actions to take.

Should the patient take the lead? Learning more about the situation might suggest that Ms. X should report what has happened herself. If, for example, the roommate has coerced Ms. X to engage in illegal conduct, Dr. L might help Ms. X figure out how to tell police what has happened—preferably after Ms. X has obtained legal advice.¹⁴

Consider implications for treatment. Last, what Ms. X reveals might significantly alter her future interactions with Dr. L. This is particularly true if Dr. L concluded that Ms. X would likely divert drugs in the future, or that the patient had established her relationship with Dr. L for purposes of improperly obtaining drugs. Federal regulations require that doctors prescribe drugs only for “legitimate medical purposes,” and issuing prescriptions to a patient who is known to be delivering the drugs to others violates this law.²²

Bottom Line

Growing concern about prescription drug misuse has led to nationwide implementation of systems for monitoring patients’ access to, and receipt of, controlled substances. Psychiatrists are expected to be more vigilant about patients’ use of scheduled drugs and, when they believe that a prescription has been misused, to take appropriate clinical or legal action.

Related Resources

• Office of National Drug Control Policy. Epidemic: responding to America’s prescription drug abuse crisis. www.whitehouse.gov/sites/default/files/ondcp/issues-content/ prescription-drugs/rx_abuse_plan.pdf.
• California Department of Alcohol and Drug Misuse. Preventing prescription drug misuse. www.prescriptiondrugmisuse.org.
• U.S. Food and Drug Administration. Combating misuse and abuse of prescription drugs: Q&A with Michael Klein, PhD. www.fda.gov/ForConsumers/ConsumerUpdates/ ucm220112.htm.

Drug Brand Names

Clonazepam • Klonopin             Hydrocodone/acetaminophen • Vicodin

Methylphenidate • Ritalin          Hydromorphone • Dilaudid

Disclosure

Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dear Dr. Mossman:

My patient, Ms. X, returned to see me after she had spent 3 months in jail. When I accessed her medication history in our state’s prescription registry, I discovered that, during her incarceration, a local pharmacy continued to fill her prescription for clonazepam. After anxiously explaining that her roommate had filled the prescriptions, Ms. X pleaded with me not to tell anyone. Do I have to report this to legal authorities? If I do, will I be breaching confidentiality?

Submitted by Dr. L

Preserving the confidentiality of patient encounters is an ethical responsibility as old as the Hippocratic Oath,¹ but protecting privacy is not an absolute duty. As psychiatrists familiar with the Tarasoff case² know, clinical events sometimes create moral and legal obligations that outweigh our confidentiality obligations.

What Dr. L should do may hinge on specific details of Ms. X’s previous and current treatment, but in this article, we’ll examine some general issues that affect Dr. L’s choices. These include:

Monitoring controlled substances

Dr. L’s clinical situation probably would not have arisen 10 years ago because until recently, she would have had no easy way to learn that Ms. X’s prescription had been filled. In 2002, Congress responded to increasing concern about “epidemic” abuse of controlled substances—especially opioids—by authorizing state grants for prescription drug monitoring programs (PDMPs).³

PDMPs are internet-based registries that let physicians quickly find out when and where their patients have filled prescriptions for controlled substances (defined in the Table).^4,5 As the rate of opioid-related deaths has risen,⁶ at least 43 states have initiated PDMPs; soon, all U.S. jurisdictions likely will have such programs.⁷ Data about the impact of PDMPs, although limited, suggest that PDMPs reduce “doctor shopping” and prescription drug abuse.⁸

The U.S. Department of Health and Human Services is promoting the development of electronic architecture standards to facilitate information exchange across jurisdictions,⁹ but states currently run their own PDMPs independently and have varying regulations about how physicians should use PDMPs.¹⁰ Excerpts from the rules used in Ohio’s prescription reporting system appear in the Box.¹¹

Reporting past crimes

What Ms. X told Dr. L implies that someone—the patient, her roommate, or both—misused a prescription to obtain a controlled substance. Simple improper possession of a scheduled drug is a federal misdemeanor offense,¹² and deception and conspiracy to obtain a scheduled drug are federal-level felonies.¹³ Such actions also violate state laws. Dr. L therefore knows that a crime has occurred.

Are doctors obligated or legally required to breach confidentiality and tell authorities about a patient’s past criminal acts? Writing several years ago, Appelbaum and Meisel¹⁴ and Goldman and Gutheil¹⁵ said the answer, in general, is “no.”

In recent years, state legislatures have modified criminal codes to encourage people to disclose their knowledge of certain crimes to police. For example, failures to report environmental offenses and financial misdealings have become criminal acts.¹⁶ A minority of states now punish failure to report other kinds of illegal behavior, but these laws focus mainly on violent crimes (often involving harm to vulnerable persons).¹⁷ Although Ohio has a law that obligates everyone to report knowledge of any felony, it makes exceptions when the information is learned during a customarily confidential relationship—including a physician’s treatment of a patient.¹⁸ Unless Dr. L herself has aided or concealed a crime (both illegal acts¹⁹), concerns about possible prosecution should not affect her decision to report what she has learned thus far.¹⁴

Deciding how to proceed

If Dr. L still feels inclined to do something about the misused prescription, what are her options? What clinical, legal, and moral obligations to act should she consider?

Obtain the facts. First, Dr. L should try to learn more about what happened. Jails are reluctant to give inmates benzodiazepines²⁰; did Ms. X receive clonazepam while in jail? When and how did Ms. X learn about her roommate’s actions? Did Ms. X obtain previous prescriptions from Dr. L with the intention of letting her roommate use them? Answers to these questions can help Dr. L determine whether her patient participated in prescription misuse, an important factor in deciding what clinical or legal actions to take.

Should the patient take the lead? Learning more about the situation might suggest that Ms. X should report what has happened herself. If, for example, the roommate has coerced Ms. X to engage in illegal conduct, Dr. L might help Ms. X figure out how to tell police what has happened—preferably after Ms. X has obtained legal advice.¹⁴

Consider implications for treatment. Last, what Ms. X reveals might significantly alter her future interactions with Dr. L. This is particularly true if Dr. L concluded that Ms. X would likely divert drugs in the future, or that the patient had established her relationship with Dr. L for purposes of improperly obtaining drugs. Federal regulations require that doctors prescribe drugs only for “legitimate medical purposes,” and issuing prescriptions to a patient who is known to be delivering the drugs to others violates this law.²²

Bottom Line

Growing concern about prescription drug misuse has led to nationwide implementation of systems for monitoring patients’ access to, and receipt of, controlled substances. Psychiatrists are expected to be more vigilant about patients’ use of scheduled drugs and, when they believe that a prescription has been misused, to take appropriate clinical or legal action.

Related Resources

• Office of National Drug Control Policy. Epidemic: responding to America’s prescription drug abuse crisis. www.whitehouse.gov/sites/default/files/ondcp/issues-content/ prescription-drugs/rx_abuse_plan.pdf.
• California Department of Alcohol and Drug Misuse. Preventing prescription drug misuse. www.prescriptiondrugmisuse.org.
• U.S. Food and Drug Administration. Combating misuse and abuse of prescription drugs: Q&A with Michael Klein, PhD. www.fda.gov/ForConsumers/ConsumerUpdates/ ucm220112.htm.

Drug Brand Names

Clonazepam • Klonopin             Hydrocodone/acetaminophen • Vicodin

Methylphenidate • Ritalin          Hydromorphone • Dilaudid

Disclosure

Dr. Mossman reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

A mother had given birth to two children with thalamic abnormalities that resulted in seizures, developmental delays, and death. Before getting pregnant again, the parents sought genetic counseling and were told that identifying the specific defective gene would be impossible. The geneticist advised them that a child conceived with a donor egg and father’s sperm would have essentially the same risk as the general population. The parents asked in writing if it would be safer to
use both donor egg and donor sperm; the geneticist responded that the difference in risk was negligible.

The mother gave birth in June 2007 to a child conceived with a donated egg and the father’s sperm. After the child began to show the same symptoms as the others, an MRI of the child’s brain revealed a thalamic abnormality, and testing revealed Alpers syndrome caused by POLG gene mutations. The third child died in September 2008.

PARENTS’ CLAIM The chances of having a child with Alpers syndrome are
about 1:200,000 in the general population; if one parent is a known carrier, the chance is 1:1,000. If the parents had known this risk, they would have used donor egg and donor sperm to conceive or adopted. They were not told about Alpers syndrome and its relationship to the POLG gene until after their third child was born. The geneticist was negligent in failing to provide this information.

PHYSICIAN’S DEFENSE The parents received appropriate and accurate genetic counseling.

VERDICT A $1 million Florida verdict was returned.

What caused a delay in breast cancer diagnosis?
A 39-year-old woman underwent mammography in October 2004. After recommending a spotcompression film of a left-breast lesion, and then ultrasonography, the radiologist concluded that the lesion was benign, and suggested a 1-year follow-up. Reports were sent to the patient and her primary care physician.

In August 2006, when mammography was suspicious for breast cancer, a biopsy diagnosed infiltrating ductal carcinoma of the left breast. After undergoing a mastectomy, radiation therapy, and chemotherapy, the patient was cancer-free at the time of the trial.

patient’s CLAIM The radiologist failed to properly interpret the 2004 mammography.

physician’s DEFENSE The radiologist’s interpretations of the 2004 tests were correct. The patient failed to follow up in 1 year, as recommended, and this delayed the cancer diagnosis. The patient’s survival indicated that she had been cured of her breast cancer.

VERDICT A confidential settlement was reached with the hospital before the trial. An Illinois defense verdict was returned for the radiologist.


Heparin overdose for preemie
At 27 weeks' gestation, a woman went to a clinic with preeclampsia. After she was stabilized, the baby was born by emergency cesarean delivery.

At birth, the baby was thrombocytopenic (platelet count, 37,000/mL) with a heart rate of 60 bpm. The child’s cord blood pH was 7.27, indicating no significant hypoxia. At 1 minute of life, the child’s heart rate had not improved. After trying three times to place an endotracheal tube, chest compressions were begun at 10 minutes of life. An umbilical vein catheter (UVC) was placed at 22 minutes. Heparin was used to flush the UVC. After 40 minutes, the baby’s pH was 6.88, indicating severe acidosis. The infant was transferred to another hospital 3 hours after birth.

Head ultrasonography at 5 days of life revealed hemorrhagic and ischemic changes in the baby’s brain. The child suffered massive brain damage, is ventilator-dependent, and has a G-tube for feeding. She cannot sit up, walk, or speak, and will require specialized care for life.

Parent's claim Emergency resuscitation was not performed at birth: the low heart rate and thrombocytopenia were not treated; the UVC was not immediately placed. Twice, adult doses of heparin were used instead of normal saline to flush the UVC; heparin caused bleeding in the baby’s brain. 

Defendant's Defense The case was settled during trial.

Verdict A $3 million Maryland settlement was reached.

Uterine rupture: $130M verdict

After a woman's first child was born by cesarean delivery, vaginal birth after cesarean (VBAC) was planned for her second pregnancy. When a nurse recognized a ruptured uterus, the ObGyn ordered a cesarean delivery. The newborn suffered severe brain damage, with seizures. She has cerebral palsy with near-normal intelligence, but cannot talk or walk and continues to have seizures.

 Parents' claim The baby’s injuries occurred due to a failure to respond to fetal distress. When the intrauterine pressure catheter (IUPC) stopped working for 27 minutes, the nurse did not notify the ObGyn or apply an external monitor. Fetal heart decelerations occurred, including a prolonged deceleration for 3 minutes; the nurse did not notify the ObGyn, reposition the mother, provide oxygen and extra fluids, or discontinue oxytocin. A cesarean delivery should have occurred 30 to 60 minutes earlier.

Defendants' defense The fetal heart rates were what typically occur during the second stage of labor. The hospital’s accepted practices were followed. When the IUPC failed, the nurse measured contractions by hand and analyzed the fetal heartbeat from audible sounds; therefore, it was not necessary to notify the ObGyn. The physician was promptly called when uterine rupture was suspected. Uterine rupture and placental abruption caused the child’s injury. Uterine rupture cannot be predicted or prevented and is a known complication of VBAC.

Verdict After the parents declined an $8 million settlement, the matter was tried to a defense verdict. That decision was overturned on appeal, and, at a second trial, a $130 million New York verdict was returned against the hospital that employed the ObGyn and nurse.

Uterus, small bowel injured during D&C

A 65-year-old woman underwent dilation and curettage (D&C) to screen for uterine cancer performed by an ObGyn and a general surgeon. Her uterus and small intestine were perforated during the procedure, and a second operation was required to repair the damage.

Patient's claim Both physicians were negligent in performing D&C.

Physician's defense The ObGyn denied negligence and countered that the injuries are known complications of the procedure.

Verdict The surgeon settled for a confidential amount before trial. A New Jersey defense verdict was returned for the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

A mother had given birth to two children with thalamic abnormalities that resulted in seizures, developmental delays, and death. Before getting pregnant again, the parents sought genetic counseling and were told that identifying the specific defective gene would be impossible. The geneticist advised them that a child conceived with a donor egg and father’s sperm would have essentially the same risk as the general population. The parents asked in writing if it would be safer to
use both donor egg and donor sperm; the geneticist responded that the difference in risk was negligible.

The mother gave birth in June 2007 to a child conceived with a donated egg and the father’s sperm. After the child began to show the same symptoms as the others, an MRI of the child’s brain revealed a thalamic abnormality, and testing revealed Alpers syndrome caused by POLG gene mutations. The third child died in September 2008.

PARENTS’ CLAIM The chances of having a child with Alpers syndrome are
about 1:200,000 in the general population; if one parent is a known carrier, the chance is 1:1,000. If the parents had known this risk, they would have used donor egg and donor sperm to conceive or adopted. They were not told about Alpers syndrome and its relationship to the POLG gene until after their third child was born. The geneticist was negligent in failing to provide this information.

PHYSICIAN’S DEFENSE The parents received appropriate and accurate genetic counseling.

VERDICT A $1 million Florida verdict was returned.

What caused a delay in breast cancer diagnosis?
A 39-year-old woman underwent mammography in October 2004. After recommending a spotcompression film of a left-breast lesion, and then ultrasonography, the radiologist concluded that the lesion was benign, and suggested a 1-year follow-up. Reports were sent to the patient and her primary care physician.

In August 2006, when mammography was suspicious for breast cancer, a biopsy diagnosed infiltrating ductal carcinoma of the left breast. After undergoing a mastectomy, radiation therapy, and chemotherapy, the patient was cancer-free at the time of the trial.

patient’s CLAIM The radiologist failed to properly interpret the 2004 mammography.

physician’s DEFENSE The radiologist’s interpretations of the 2004 tests were correct. The patient failed to follow up in 1 year, as recommended, and this delayed the cancer diagnosis. The patient’s survival indicated that she had been cured of her breast cancer.

VERDICT A confidential settlement was reached with the hospital before the trial. An Illinois defense verdict was returned for the radiologist.


Heparin overdose for preemie
At 27 weeks' gestation, a woman went to a clinic with preeclampsia. After she was stabilized, the baby was born by emergency cesarean delivery.

At birth, the baby was thrombocytopenic (platelet count, 37,000/mL) with a heart rate of 60 bpm. The child’s cord blood pH was 7.27, indicating no significant hypoxia. At 1 minute of life, the child’s heart rate had not improved. After trying three times to place an endotracheal tube, chest compressions were begun at 10 minutes of life. An umbilical vein catheter (UVC) was placed at 22 minutes. Heparin was used to flush the UVC. After 40 minutes, the baby’s pH was 6.88, indicating severe acidosis. The infant was transferred to another hospital 3 hours after birth.

Head ultrasonography at 5 days of life revealed hemorrhagic and ischemic changes in the baby’s brain. The child suffered massive brain damage, is ventilator-dependent, and has a G-tube for feeding. She cannot sit up, walk, or speak, and will require specialized care for life.

Parent's claim Emergency resuscitation was not performed at birth: the low heart rate and thrombocytopenia were not treated; the UVC was not immediately placed. Twice, adult doses of heparin were used instead of normal saline to flush the UVC; heparin caused bleeding in the baby’s brain. 

Defendant's Defense The case was settled during trial.

Verdict A $3 million Maryland settlement was reached.

Uterine rupture: $130M verdict

After a woman's first child was born by cesarean delivery, vaginal birth after cesarean (VBAC) was planned for her second pregnancy. When a nurse recognized a ruptured uterus, the ObGyn ordered a cesarean delivery. The newborn suffered severe brain damage, with seizures. She has cerebral palsy with near-normal intelligence, but cannot talk or walk and continues to have seizures.

 Parents' claim The baby’s injuries occurred due to a failure to respond to fetal distress. When the intrauterine pressure catheter (IUPC) stopped working for 27 minutes, the nurse did not notify the ObGyn or apply an external monitor. Fetal heart decelerations occurred, including a prolonged deceleration for 3 minutes; the nurse did not notify the ObGyn, reposition the mother, provide oxygen and extra fluids, or discontinue oxytocin. A cesarean delivery should have occurred 30 to 60 minutes earlier.

Defendants' defense The fetal heart rates were what typically occur during the second stage of labor. The hospital’s accepted practices were followed. When the IUPC failed, the nurse measured contractions by hand and analyzed the fetal heartbeat from audible sounds; therefore, it was not necessary to notify the ObGyn. The physician was promptly called when uterine rupture was suspected. Uterine rupture and placental abruption caused the child’s injury. Uterine rupture cannot be predicted or prevented and is a known complication of VBAC.

Verdict After the parents declined an $8 million settlement, the matter was tried to a defense verdict. That decision was overturned on appeal, and, at a second trial, a $130 million New York verdict was returned against the hospital that employed the ObGyn and nurse.

Uterus, small bowel injured during D&C

A 65-year-old woman underwent dilation and curettage (D&C) to screen for uterine cancer performed by an ObGyn and a general surgeon. Her uterus and small intestine were perforated during the procedure, and a second operation was required to repair the damage.

Patient's claim Both physicians were negligent in performing D&C.

Physician's defense The ObGyn denied negligence and countered that the injuries are known complications of the procedure.

Verdict The surgeon settled for a confidential amount before trial. A New Jersey defense verdict was returned for the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

A mother had given birth to two children with thalamic abnormalities that resulted in seizures, developmental delays, and death. Before getting pregnant again, the parents sought genetic counseling and were told that identifying the specific defective gene would be impossible. The geneticist advised them that a child conceived with a donor egg and father’s sperm would have essentially the same risk as the general population. The parents asked in writing if it would be safer to
use both donor egg and donor sperm; the geneticist responded that the difference in risk was negligible.

The mother gave birth in June 2007 to a child conceived with a donated egg and the father’s sperm. After the child began to show the same symptoms as the others, an MRI of the child’s brain revealed a thalamic abnormality, and testing revealed Alpers syndrome caused by POLG gene mutations. The third child died in September 2008.

PARENTS’ CLAIM The chances of having a child with Alpers syndrome are
about 1:200,000 in the general population; if one parent is a known carrier, the chance is 1:1,000. If the parents had known this risk, they would have used donor egg and donor sperm to conceive or adopted. They were not told about Alpers syndrome and its relationship to the POLG gene until after their third child was born. The geneticist was negligent in failing to provide this information.

PHYSICIAN’S DEFENSE The parents received appropriate and accurate genetic counseling.

VERDICT A $1 million Florida verdict was returned.

What caused a delay in breast cancer diagnosis?
A 39-year-old woman underwent mammography in October 2004. After recommending a spotcompression film of a left-breast lesion, and then ultrasonography, the radiologist concluded that the lesion was benign, and suggested a 1-year follow-up. Reports were sent to the patient and her primary care physician.

In August 2006, when mammography was suspicious for breast cancer, a biopsy diagnosed infiltrating ductal carcinoma of the left breast. After undergoing a mastectomy, radiation therapy, and chemotherapy, the patient was cancer-free at the time of the trial.

patient’s CLAIM The radiologist failed to properly interpret the 2004 mammography.

physician’s DEFENSE The radiologist’s interpretations of the 2004 tests were correct. The patient failed to follow up in 1 year, as recommended, and this delayed the cancer diagnosis. The patient’s survival indicated that she had been cured of her breast cancer.

VERDICT A confidential settlement was reached with the hospital before the trial. An Illinois defense verdict was returned for the radiologist.


Heparin overdose for preemie
At 27 weeks' gestation, a woman went to a clinic with preeclampsia. After she was stabilized, the baby was born by emergency cesarean delivery.

At birth, the baby was thrombocytopenic (platelet count, 37,000/mL) with a heart rate of 60 bpm. The child’s cord blood pH was 7.27, indicating no significant hypoxia. At 1 minute of life, the child’s heart rate had not improved. After trying three times to place an endotracheal tube, chest compressions were begun at 10 minutes of life. An umbilical vein catheter (UVC) was placed at 22 minutes. Heparin was used to flush the UVC. After 40 minutes, the baby’s pH was 6.88, indicating severe acidosis. The infant was transferred to another hospital 3 hours after birth.

Head ultrasonography at 5 days of life revealed hemorrhagic and ischemic changes in the baby’s brain. The child suffered massive brain damage, is ventilator-dependent, and has a G-tube for feeding. She cannot sit up, walk, or speak, and will require specialized care for life.

Parent's claim Emergency resuscitation was not performed at birth: the low heart rate and thrombocytopenia were not treated; the UVC was not immediately placed. Twice, adult doses of heparin were used instead of normal saline to flush the UVC; heparin caused bleeding in the baby’s brain. 

Defendant's Defense The case was settled during trial.

Verdict A $3 million Maryland settlement was reached.

Uterine rupture: $130M verdict

After a woman's first child was born by cesarean delivery, vaginal birth after cesarean (VBAC) was planned for her second pregnancy. When a nurse recognized a ruptured uterus, the ObGyn ordered a cesarean delivery. The newborn suffered severe brain damage, with seizures. She has cerebral palsy with near-normal intelligence, but cannot talk or walk and continues to have seizures.

 Parents' claim The baby’s injuries occurred due to a failure to respond to fetal distress. When the intrauterine pressure catheter (IUPC) stopped working for 27 minutes, the nurse did not notify the ObGyn or apply an external monitor. Fetal heart decelerations occurred, including a prolonged deceleration for 3 minutes; the nurse did not notify the ObGyn, reposition the mother, provide oxygen and extra fluids, or discontinue oxytocin. A cesarean delivery should have occurred 30 to 60 minutes earlier.

Defendants' defense The fetal heart rates were what typically occur during the second stage of labor. The hospital’s accepted practices were followed. When the IUPC failed, the nurse measured contractions by hand and analyzed the fetal heartbeat from audible sounds; therefore, it was not necessary to notify the ObGyn. The physician was promptly called when uterine rupture was suspected. Uterine rupture and placental abruption caused the child’s injury. Uterine rupture cannot be predicted or prevented and is a known complication of VBAC.

Verdict After the parents declined an $8 million settlement, the matter was tried to a defense verdict. That decision was overturned on appeal, and, at a second trial, a $130 million New York verdict was returned against the hospital that employed the ObGyn and nurse.

Uterus, small bowel injured during D&C

A 65-year-old woman underwent dilation and curettage (D&C) to screen for uterine cancer performed by an ObGyn and a general surgeon. Her uterus and small intestine were perforated during the procedure, and a second operation was required to repair the damage.

Patient's claim Both physicians were negligent in performing D&C.

Physician's defense The ObGyn denied negligence and countered that the injuries are known complications of the procedure.

Verdict The surgeon settled for a confidential amount before trial. A New Jersey defense verdict was returned for the ObGyn.

These cases were selected by the editors of OBG Management from Medical Malpractice Verdicts, Settlements & Experts, with permission of the editor, Lewis Laska (www.verdictslaska.com). The information available to the editors about the cases presented here is sometimes incomplete. Moreover, the cases may or may not have merit. Nevertheless, these cases represent the types of clinical situations that typically result in litigation and are meant to illustrate nationwide variation in jury verdicts and awards.

Ovarian cancer causes more deaths than any other cancer affecting the female reproductive system.¹ One reason it’s so deadly: It usually isn’t detected until it has reached an advanced stage. No clear-cut symptoms point definitively to ovarian malignancy, and no feasible screening strategy has been found to increase detection at an early stage.

Among the strategies that have been utilized to detect ovarian cancer are bimanual examination of the adnexae (primarily in postmenopausal women), measurement of cancer antigen (CA) 125, and transvaginal ultrasonography (TVUS) of the ovaries. The last two strategies sometimes are combined in high-risk women.

TVUS can highlight ovarian abnormalities and provide information about their structure. The question then becomes which abnormalities are likely to resolve without treatment, and which should be scrutinized more closely. In this study, Pavlik and colleagues reviewed TVUS findings from 39,337 women enrolled in the University of Kentucky Ovarian Cancer Screening Program, which involved 221,576 baseline and interval TVUS scans.

Details of the study
Women in this study were screened with annual TVUS scans between 1987 and 2002. The population included:

• asymptomatic women aged 50 or older
• asymptomatic women over age 25 who had a first- or second-degree relative with documented ovarian cancer.

The initial TVUS scan was normal in almost 90% of women, and only about 10% subsequently experienced an abnormal scan. About half (46.7%) of the ovarian abnormalities identified via TVUS were found on the very first scan. Of these, 63.2% resolved during follow-up with no treatment.

Approximately 80% of women had no abnormal TVUS findings at any time during the observation period. This is notable because participants had a high risk for ovarian cancer by virtue of advanced age or family history.

TVUS abnormalities had a higher prevalence in premenopausal women (35%) than in postmenopausal women (17%; P<.001). The incidence of ovarian cysts also was significantly higher among premenopausal women (15.3% vs 8.2%; P<.001). These differences are to be expected, owing to the functional nature of premenopausal ovaries in regard to folliculogenesis, ovulation, and endometriosis.

Positive predictive values ranged from 15.3% to 24.7%
Over the 25 years covered by this study, our understanding of the malignant potential of various ovarian masses has evolved considerably. We have long known that unilocular cysts are extremely unlikely to be malignant, but now we are aware that even septated cysts are unlikely to represent cancer.

As for the success of this ovarian cancer-screening program, which identified 85 true malignancies and 472 nonmalignancies in surgical specimens, it had an overall positive predictive value of 15.3%. After January 1, 2008, however, when serial observation expanded to include septated cysts (because published data confirmed these masses to have low malignant potential), positive predictive value improved to 24.7%.

Pavlik and colleagues also discussed findings from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which relied on a single TVUS abnormality to trigger a recommendation for surgery, with a positive predictive value of only 5.1%.²

Most cancers were diagnosed at an early stage
Of the invasive epithelial cancers identified in this study, the stage distribution at diagnosis was:

• Stage 1: 45%
• Stage 2: 23%
• Stage 3: 32%
• Stage 4: None.

This finding is notable, given statistics from the “real world,” where about 80% of ovarian cancers are diagnosed at Stage 3 or Stage 4.

Among benign findings that were managed surgically, 47% were serous cystadenomas, 13% were hemorrhagic cysts, 9% were fibromas, thecomas, or Brenner tumors, and the rest were fairly equally divided between hydrosalpinx or paratubal cysts; endometriomas; and mucinous cystadenomas, leiomyomas, and cystic teratomas.

What this evidence means for practice

In general, unilocular or septate cysts can be followed every 6 months by TVUS. Although more complex tumors may resolve spontaneously, they should be followed with serial TVUS, with caution, at intervals of 6 weeks to 3 months. The findings of each scan should determine the subsequent course of action, which could involve further monitoring or surgical extirpation.

Regrettably, this study did not utilize color flow Doppler imaging. Because malignant tumors are rich in neovascularity, and the vessels laid down by such tumors often lack a normal media layer, they often exhibit very low resistance to flow. Although neovascularity is not a perfect diagnostic indicator of malignancy, the presence of abundant blood flow and low resistance can raise the index of suspicion. In my opinion, color flow Doppler should be incorporated into ultrasonographic evaluation of potential ovarian malignancies.

—Steven R. Goldstein, MD

Tell us what you think, at [email protected]. Please include your name and city and state.

Ovarian cancer causes more deaths than any other cancer affecting the female reproductive system.¹ One reason it’s so deadly: It usually isn’t detected until it has reached an advanced stage. No clear-cut symptoms point definitively to ovarian malignancy, and no feasible screening strategy has been found to increase detection at an early stage.

Among the strategies that have been utilized to detect ovarian cancer are bimanual examination of the adnexae (primarily in postmenopausal women), measurement of cancer antigen (CA) 125, and transvaginal ultrasonography (TVUS) of the ovaries. The last two strategies sometimes are combined in high-risk women.

TVUS can highlight ovarian abnormalities and provide information about their structure. The question then becomes which abnormalities are likely to resolve without treatment, and which should be scrutinized more closely. In this study, Pavlik and colleagues reviewed TVUS findings from 39,337 women enrolled in the University of Kentucky Ovarian Cancer Screening Program, which involved 221,576 baseline and interval TVUS scans.

Details of the study
Women in this study were screened with annual TVUS scans between 1987 and 2002. The population included:

• asymptomatic women aged 50 or older
• asymptomatic women over age 25 who had a first- or second-degree relative with documented ovarian cancer.

The initial TVUS scan was normal in almost 90% of women, and only about 10% subsequently experienced an abnormal scan. About half (46.7%) of the ovarian abnormalities identified via TVUS were found on the very first scan. Of these, 63.2% resolved during follow-up with no treatment.

Approximately 80% of women had no abnormal TVUS findings at any time during the observation period. This is notable because participants had a high risk for ovarian cancer by virtue of advanced age or family history.

TVUS abnormalities had a higher prevalence in premenopausal women (35%) than in postmenopausal women (17%; P<.001). The incidence of ovarian cysts also was significantly higher among premenopausal women (15.3% vs 8.2%; P<.001). These differences are to be expected, owing to the functional nature of premenopausal ovaries in regard to folliculogenesis, ovulation, and endometriosis.

Positive predictive values ranged from 15.3% to 24.7%
Over the 25 years covered by this study, our understanding of the malignant potential of various ovarian masses has evolved considerably. We have long known that unilocular cysts are extremely unlikely to be malignant, but now we are aware that even septated cysts are unlikely to represent cancer.

As for the success of this ovarian cancer-screening program, which identified 85 true malignancies and 472 nonmalignancies in surgical specimens, it had an overall positive predictive value of 15.3%. After January 1, 2008, however, when serial observation expanded to include septated cysts (because published data confirmed these masses to have low malignant potential), positive predictive value improved to 24.7%.

Pavlik and colleagues also discussed findings from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which relied on a single TVUS abnormality to trigger a recommendation for surgery, with a positive predictive value of only 5.1%.²

Most cancers were diagnosed at an early stage
Of the invasive epithelial cancers identified in this study, the stage distribution at diagnosis was:

• Stage 1: 45%
• Stage 2: 23%
• Stage 3: 32%
• Stage 4: None.

This finding is notable, given statistics from the “real world,” where about 80% of ovarian cancers are diagnosed at Stage 3 or Stage 4.

Among benign findings that were managed surgically, 47% were serous cystadenomas, 13% were hemorrhagic cysts, 9% were fibromas, thecomas, or Brenner tumors, and the rest were fairly equally divided between hydrosalpinx or paratubal cysts; endometriomas; and mucinous cystadenomas, leiomyomas, and cystic teratomas.

What this evidence means for practice

In general, unilocular or septate cysts can be followed every 6 months by TVUS. Although more complex tumors may resolve spontaneously, they should be followed with serial TVUS, with caution, at intervals of 6 weeks to 3 months. The findings of each scan should determine the subsequent course of action, which could involve further monitoring or surgical extirpation.

Regrettably, this study did not utilize color flow Doppler imaging. Because malignant tumors are rich in neovascularity, and the vessels laid down by such tumors often lack a normal media layer, they often exhibit very low resistance to flow. Although neovascularity is not a perfect diagnostic indicator of malignancy, the presence of abundant blood flow and low resistance can raise the index of suspicion. In my opinion, color flow Doppler should be incorporated into ultrasonographic evaluation of potential ovarian malignancies.

—Steven R. Goldstein, MD

Tell us what you think, at [email protected]. Please include your name and city and state.

Ovarian cancer causes more deaths than any other cancer affecting the female reproductive system.¹ One reason it’s so deadly: It usually isn’t detected until it has reached an advanced stage. No clear-cut symptoms point definitively to ovarian malignancy, and no feasible screening strategy has been found to increase detection at an early stage.

Among the strategies that have been utilized to detect ovarian cancer are bimanual examination of the adnexae (primarily in postmenopausal women), measurement of cancer antigen (CA) 125, and transvaginal ultrasonography (TVUS) of the ovaries. The last two strategies sometimes are combined in high-risk women.

TVUS can highlight ovarian abnormalities and provide information about their structure. The question then becomes which abnormalities are likely to resolve without treatment, and which should be scrutinized more closely. In this study, Pavlik and colleagues reviewed TVUS findings from 39,337 women enrolled in the University of Kentucky Ovarian Cancer Screening Program, which involved 221,576 baseline and interval TVUS scans.

Details of the study
Women in this study were screened with annual TVUS scans between 1987 and 2002. The population included:

• asymptomatic women aged 50 or older
• asymptomatic women over age 25 who had a first- or second-degree relative with documented ovarian cancer.

The initial TVUS scan was normal in almost 90% of women, and only about 10% subsequently experienced an abnormal scan. About half (46.7%) of the ovarian abnormalities identified via TVUS were found on the very first scan. Of these, 63.2% resolved during follow-up with no treatment.

Approximately 80% of women had no abnormal TVUS findings at any time during the observation period. This is notable because participants had a high risk for ovarian cancer by virtue of advanced age or family history.

TVUS abnormalities had a higher prevalence in premenopausal women (35%) than in postmenopausal women (17%; P<.001). The incidence of ovarian cysts also was significantly higher among premenopausal women (15.3% vs 8.2%; P<.001). These differences are to be expected, owing to the functional nature of premenopausal ovaries in regard to folliculogenesis, ovulation, and endometriosis.

Positive predictive values ranged from 15.3% to 24.7%
Over the 25 years covered by this study, our understanding of the malignant potential of various ovarian masses has evolved considerably. We have long known that unilocular cysts are extremely unlikely to be malignant, but now we are aware that even septated cysts are unlikely to represent cancer.

As for the success of this ovarian cancer-screening program, which identified 85 true malignancies and 472 nonmalignancies in surgical specimens, it had an overall positive predictive value of 15.3%. After January 1, 2008, however, when serial observation expanded to include septated cysts (because published data confirmed these masses to have low malignant potential), positive predictive value improved to 24.7%.

Pavlik and colleagues also discussed findings from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, which relied on a single TVUS abnormality to trigger a recommendation for surgery, with a positive predictive value of only 5.1%.²

Most cancers were diagnosed at an early stage
Of the invasive epithelial cancers identified in this study, the stage distribution at diagnosis was:

• Stage 1: 45%
• Stage 2: 23%
• Stage 3: 32%
• Stage 4: None.

This finding is notable, given statistics from the “real world,” where about 80% of ovarian cancers are diagnosed at Stage 3 or Stage 4.

Among benign findings that were managed surgically, 47% were serous cystadenomas, 13% were hemorrhagic cysts, 9% were fibromas, thecomas, or Brenner tumors, and the rest were fairly equally divided between hydrosalpinx or paratubal cysts; endometriomas; and mucinous cystadenomas, leiomyomas, and cystic teratomas.

What this evidence means for practice

In general, unilocular or septate cysts can be followed every 6 months by TVUS. Although more complex tumors may resolve spontaneously, they should be followed with serial TVUS, with caution, at intervals of 6 weeks to 3 months. The findings of each scan should determine the subsequent course of action, which could involve further monitoring or surgical extirpation.

Regrettably, this study did not utilize color flow Doppler imaging. Because malignant tumors are rich in neovascularity, and the vessels laid down by such tumors often lack a normal media layer, they often exhibit very low resistance to flow. Although neovascularity is not a perfect diagnostic indicator of malignancy, the presence of abundant blood flow and low resistance can raise the index of suspicion. In my opinion, color flow Doppler should be incorporated into ultrasonographic evaluation of potential ovarian malignancies.

—Steven R. Goldstein, MD

Tell us what you think, at [email protected]. Please include your name and city and state.