Imaging

A 55-year-old man with a 20-year history of type 2 diabetes mellitus was admitted to the hospital after presenting to the emergency department with an acute change in mental status. Three days earlier, he had begun to feel abdominal discomfort and dizziness, which gradually worsened.

On presentation, his Glasgow Coma Scale score was 13 out of 15 (eye-opening response 3 of 4, verbal response 4 of 5, motor response 6 of 6), his blood pressure was 221/114 mm Hg, and other vital signs were normal. Physical examination including a neurologic examination was normal. No gait abnormality or ataxia was noted.

When asked about current medications, he said that 2 years earlier he had missed an appointment with his primary care physician and so had never obtained refills of his diabetes medications.

Results of laboratory testing were as follows:

• Blood glucose 1,011 mg/dL (reference range 65–110)
• Hemoglobin A_1c 17.8% (4%–5.6%)
• Sodium 126 mmol/L (135–145)
• Sodium corrected for serum glucose 141 mmol/L
• Potassium 3.2 mmol/L (3.5–5.0)
• Blood urea nitrogen 43.8 mg/dL (8–21)
• Calculated serum osmolality 324 mosm/kg (275–295).

Blood gas analysis showed no acidosis. Tests for urinary and serum ketones were negative. Computed tomography (CT) of the head without contrast was normal.

Based on the results of the evaluation, the patient’s condition was diagnosed as a hyperosmolar hyperglycemic state, presumably from dehydration and noncompliance with diabetes medications. His altered mental status was also attributed to this diagnosis. He was started on aggressive hydration and insulin infusion to correct the blood glucose level. Repeat laboratory testing 7 hours after admission revealed a blood glucose of 49 mg/dL, sodium 148 mmol/L, blood urea nitrogen 43 mg/dL, and calculated serum osmolality 290 mosm/kg.

The insulin infusion was suspended, and glucose infusion was started. With this treatment, his blood glucose level stabilized, but his Glasgow Coma Scale score was unchanged from the time of presentation. A neurologic examination at this time showed bilateral dysmetria. Cranial nerves were normal. Motor examination showed normal tone with a Medical Research Council score of 5 of 5 in all extremities. Sensory examination revealed a glove-and-stocking pattern of loss of vibratory sensation. Tendon reflexes were normal except for diminished bilateral knee-jerk and ankle-jerk responses.

OSMOTIC DEMYELINATION SYNDROME

Central pontine myelinolysis is a pivotal manifestation of the syndrome and is characterized by progressive lethargy, quadriparesis, dysarthria, ophthalmoplegia, dysphasia, ataxia, and reflex changes. Clinical symptoms of extrapontine myelinolysis are variable.⁴

Although CT may underestimate osmotic demyelination syndrome, the typical radiologic findings on brain MRI are hyperintense lesions in the central pons or associated extrapontine structures on T2-weighted and fluid-attenuated inversion recovery sequences.⁴

A precise definition of hyperosmolar hyperglycemia does not exist. The Joint British Diabetes Societies for Inpatient Care suggested the following features: a measured osmolality of 320 mosm/kg or higher, a blood glucose level of 541 mg/dL or higher, severe dehydration, and feeling unwell.⁵

Our patient’s clinical course and high hemoglobin A_1c suggested prolonged hyperglycemia and high serum osmolality before his admission. After his admission, aggressive hydration and insulin therapy corrected the hyperglycemia and serum osmolality too rapidly for his brain cells to adjust to the change. It was reasonable to suspect a hyperosmolar hyperglycemic state as one of the main causes of his mental status change and ataxia. This, along with lack of improvement in his impaired metal status and new-onset ataxia despite treatment, led to suspicion of osmotic demyelination syndrome. His diminished bilateral knee-jerk and ankle-jerk responses more likely represented diabetic neuropathy rather than osmotic demyelination syndrome.

Osmotic demyelination syndrome has seldom been reported as a complication of hyperosmolar hyperglycemia.^6–13 And extrapontine myelinolysis with hyperosmolar hyperglycemia is extremely rare, with only 2 reports to date to the best of our knowledge.^6,10

There is no specific treatment for osmotic demyelination syndrome except for supportive care and treatment of coexisting conditions. Once an osmotic derangement is identified, we recommend correcting chronically elevated serum glucose values gradually to avoid overtreatment, just as we would do with elevated serum sodium levels. Changes in neurologic findings, serum blood glucose level, and serum osmolality should be followed closely. A review showed that a favorable recovery from osmotic demyelination syndrome is possible even with severe neurologic deficits.⁴

TAKE-AWAY POINTS

• Osmotic demyelination syndrome is a rare but severe complication of a hyperosmolar hyperglycemic state.
• Physicians should be aware not only of changes in serum sodium, but also of changes in serum osmolality and serum glucose.
• When a new-onset neurologic deficit is found during treatment of a hyperosmolar hyperglycemic state, suspect osmotic demyelination syndrome, monitor changes in serum osmolality, and consider brain MRI.

A 55-year-old man with a 20-year history of type 2 diabetes mellitus was admitted to the hospital after presenting to the emergency department with an acute change in mental status. Three days earlier, he had begun to feel abdominal discomfort and dizziness, which gradually worsened.

On presentation, his Glasgow Coma Scale score was 13 out of 15 (eye-opening response 3 of 4, verbal response 4 of 5, motor response 6 of 6), his blood pressure was 221/114 mm Hg, and other vital signs were normal. Physical examination including a neurologic examination was normal. No gait abnormality or ataxia was noted.

When asked about current medications, he said that 2 years earlier he had missed an appointment with his primary care physician and so had never obtained refills of his diabetes medications.

Results of laboratory testing were as follows:

• Blood glucose 1,011 mg/dL (reference range 65–110)
• Hemoglobin A_1c 17.8% (4%–5.6%)
• Sodium 126 mmol/L (135–145)
• Sodium corrected for serum glucose 141 mmol/L
• Potassium 3.2 mmol/L (3.5–5.0)
• Blood urea nitrogen 43.8 mg/dL (8–21)
• Calculated serum osmolality 324 mosm/kg (275–295).

Blood gas analysis showed no acidosis. Tests for urinary and serum ketones were negative. Computed tomography (CT) of the head without contrast was normal.

Based on the results of the evaluation, the patient’s condition was diagnosed as a hyperosmolar hyperglycemic state, presumably from dehydration and noncompliance with diabetes medications. His altered mental status was also attributed to this diagnosis. He was started on aggressive hydration and insulin infusion to correct the blood glucose level. Repeat laboratory testing 7 hours after admission revealed a blood glucose of 49 mg/dL, sodium 148 mmol/L, blood urea nitrogen 43 mg/dL, and calculated serum osmolality 290 mosm/kg.

The insulin infusion was suspended, and glucose infusion was started. With this treatment, his blood glucose level stabilized, but his Glasgow Coma Scale score was unchanged from the time of presentation. A neurologic examination at this time showed bilateral dysmetria. Cranial nerves were normal. Motor examination showed normal tone with a Medical Research Council score of 5 of 5 in all extremities. Sensory examination revealed a glove-and-stocking pattern of loss of vibratory sensation. Tendon reflexes were normal except for diminished bilateral knee-jerk and ankle-jerk responses.

OSMOTIC DEMYELINATION SYNDROME

Central pontine myelinolysis is a pivotal manifestation of the syndrome and is characterized by progressive lethargy, quadriparesis, dysarthria, ophthalmoplegia, dysphasia, ataxia, and reflex changes. Clinical symptoms of extrapontine myelinolysis are variable.⁴

Although CT may underestimate osmotic demyelination syndrome, the typical radiologic findings on brain MRI are hyperintense lesions in the central pons or associated extrapontine structures on T2-weighted and fluid-attenuated inversion recovery sequences.⁴

A precise definition of hyperosmolar hyperglycemia does not exist. The Joint British Diabetes Societies for Inpatient Care suggested the following features: a measured osmolality of 320 mosm/kg or higher, a blood glucose level of 541 mg/dL or higher, severe dehydration, and feeling unwell.⁵

Our patient’s clinical course and high hemoglobin A_1c suggested prolonged hyperglycemia and high serum osmolality before his admission. After his admission, aggressive hydration and insulin therapy corrected the hyperglycemia and serum osmolality too rapidly for his brain cells to adjust to the change. It was reasonable to suspect a hyperosmolar hyperglycemic state as one of the main causes of his mental status change and ataxia. This, along with lack of improvement in his impaired metal status and new-onset ataxia despite treatment, led to suspicion of osmotic demyelination syndrome. His diminished bilateral knee-jerk and ankle-jerk responses more likely represented diabetic neuropathy rather than osmotic demyelination syndrome.

Osmotic demyelination syndrome has seldom been reported as a complication of hyperosmolar hyperglycemia.^6–13 And extrapontine myelinolysis with hyperosmolar hyperglycemia is extremely rare, with only 2 reports to date to the best of our knowledge.^6,10

There is no specific treatment for osmotic demyelination syndrome except for supportive care and treatment of coexisting conditions. Once an osmotic derangement is identified, we recommend correcting chronically elevated serum glucose values gradually to avoid overtreatment, just as we would do with elevated serum sodium levels. Changes in neurologic findings, serum blood glucose level, and serum osmolality should be followed closely. A review showed that a favorable recovery from osmotic demyelination syndrome is possible even with severe neurologic deficits.⁴

TAKE-AWAY POINTS

• Osmotic demyelination syndrome is a rare but severe complication of a hyperosmolar hyperglycemic state.
• Physicians should be aware not only of changes in serum sodium, but also of changes in serum osmolality and serum glucose.
• When a new-onset neurologic deficit is found during treatment of a hyperosmolar hyperglycemic state, suspect osmotic demyelination syndrome, monitor changes in serum osmolality, and consider brain MRI.

A 55-year-old man with a 20-year history of type 2 diabetes mellitus was admitted to the hospital after presenting to the emergency department with an acute change in mental status. Three days earlier, he had begun to feel abdominal discomfort and dizziness, which gradually worsened.

On presentation, his Glasgow Coma Scale score was 13 out of 15 (eye-opening response 3 of 4, verbal response 4 of 5, motor response 6 of 6), his blood pressure was 221/114 mm Hg, and other vital signs were normal. Physical examination including a neurologic examination was normal. No gait abnormality or ataxia was noted.

When asked about current medications, he said that 2 years earlier he had missed an appointment with his primary care physician and so had never obtained refills of his diabetes medications.

Results of laboratory testing were as follows:

• Blood glucose 1,011 mg/dL (reference range 65–110)
• Hemoglobin A_1c 17.8% (4%–5.6%)
• Sodium 126 mmol/L (135–145)
• Sodium corrected for serum glucose 141 mmol/L
• Potassium 3.2 mmol/L (3.5–5.0)
• Blood urea nitrogen 43.8 mg/dL (8–21)
• Calculated serum osmolality 324 mosm/kg (275–295).

Blood gas analysis showed no acidosis. Tests for urinary and serum ketones were negative. Computed tomography (CT) of the head without contrast was normal.

Based on the results of the evaluation, the patient’s condition was diagnosed as a hyperosmolar hyperglycemic state, presumably from dehydration and noncompliance with diabetes medications. His altered mental status was also attributed to this diagnosis. He was started on aggressive hydration and insulin infusion to correct the blood glucose level. Repeat laboratory testing 7 hours after admission revealed a blood glucose of 49 mg/dL, sodium 148 mmol/L, blood urea nitrogen 43 mg/dL, and calculated serum osmolality 290 mosm/kg.

The insulin infusion was suspended, and glucose infusion was started. With this treatment, his blood glucose level stabilized, but his Glasgow Coma Scale score was unchanged from the time of presentation. A neurologic examination at this time showed bilateral dysmetria. Cranial nerves were normal. Motor examination showed normal tone with a Medical Research Council score of 5 of 5 in all extremities. Sensory examination revealed a glove-and-stocking pattern of loss of vibratory sensation. Tendon reflexes were normal except for diminished bilateral knee-jerk and ankle-jerk responses.

OSMOTIC DEMYELINATION SYNDROME

Central pontine myelinolysis is a pivotal manifestation of the syndrome and is characterized by progressive lethargy, quadriparesis, dysarthria, ophthalmoplegia, dysphasia, ataxia, and reflex changes. Clinical symptoms of extrapontine myelinolysis are variable.⁴

Although CT may underestimate osmotic demyelination syndrome, the typical radiologic findings on brain MRI are hyperintense lesions in the central pons or associated extrapontine structures on T2-weighted and fluid-attenuated inversion recovery sequences.⁴

A precise definition of hyperosmolar hyperglycemia does not exist. The Joint British Diabetes Societies for Inpatient Care suggested the following features: a measured osmolality of 320 mosm/kg or higher, a blood glucose level of 541 mg/dL or higher, severe dehydration, and feeling unwell.⁵

Our patient’s clinical course and high hemoglobin A_1c suggested prolonged hyperglycemia and high serum osmolality before his admission. After his admission, aggressive hydration and insulin therapy corrected the hyperglycemia and serum osmolality too rapidly for his brain cells to adjust to the change. It was reasonable to suspect a hyperosmolar hyperglycemic state as one of the main causes of his mental status change and ataxia. This, along with lack of improvement in his impaired metal status and new-onset ataxia despite treatment, led to suspicion of osmotic demyelination syndrome. His diminished bilateral knee-jerk and ankle-jerk responses more likely represented diabetic neuropathy rather than osmotic demyelination syndrome.

Osmotic demyelination syndrome has seldom been reported as a complication of hyperosmolar hyperglycemia.^6–13 And extrapontine myelinolysis with hyperosmolar hyperglycemia is extremely rare, with only 2 reports to date to the best of our knowledge.^6,10

There is no specific treatment for osmotic demyelination syndrome except for supportive care and treatment of coexisting conditions. Once an osmotic derangement is identified, we recommend correcting chronically elevated serum glucose values gradually to avoid overtreatment, just as we would do with elevated serum sodium levels. Changes in neurologic findings, serum blood glucose level, and serum osmolality should be followed closely. A review showed that a favorable recovery from osmotic demyelination syndrome is possible even with severe neurologic deficits.⁴

TAKE-AWAY POINTS

• Osmotic demyelination syndrome is a rare but severe complication of a hyperosmolar hyperglycemic state.
• Physicians should be aware not only of changes in serum sodium, but also of changes in serum osmolality and serum glucose.
• When a new-onset neurologic deficit is found during treatment of a hyperosmolar hyperglycemic state, suspect osmotic demyelination syndrome, monitor changes in serum osmolality, and consider brain MRI.

Staphylococcus aureus is the most common infective agent in native and prosthetic valve endocarditis, and 13% to 22% of patients with S aureus bacteremia have infective endocarditis.¹

See related editorial

Transthoracic echocardiography (TTE) is a good starting point in the workup of suspected infective endocarditis, but transesophageal echocardiography (TEE) plays a key role in diagnosis and is indicated in patients with a high pretest probability of infective endocarditis, as in the following scenarios:

• Clinical picture consistent with infective endocarditis
• Presence of previously placed port or other indwelling vascular device
• Presence of a prosthetic valve or other prosthetic material 
• Presence of a pacemaker
• History of valve disease
• Injection drug use
• Positive blood cultures after 72 hours despite appropriate antibiotic treatment
• Abnormal TTE result requiring better visualization of valvular anatomy and function and confirmation of local complications
• Absence of another reasonable explanation for S aureus bacteremia.

Forgoing TEE is reasonable in patients with normal results on TTE, no predisposing risk factors, a reasonable alternative explanation for S aureus bacteremia, and a low pretest probability of infective endocarditis.¹ TEE may also be unnecessary if there is another disease focus requiring extended treatment (eg, vertebral infection) and there are no findings suggesting complicated infective endocarditis, eg, persistent bacteremia, symptoms of heart failure, and conduction abnormality.¹

TEE also may be unnecessary in patients at low risk who have identifiable foci of bacteremia due to soft-tissue infection or a newly placed vascular catheter and whose bacteremia clears within 72 hours of the start of antibiotic therapy. These patients may be followed clinically for the development of new findings such as metastatic foci of infection (eg, septic pulmonary emboli, renal infarction, splenic abscess or infarction), the new onset of heart failure or cardiac conduction abnormality, or recurrence of previously cleared S aureus bacteremia. If these should develop, then a more invasive study such as TEE may be warranted.

INFECTIVE ENDOCARDITIS: EPIDEMIOLOGY AND MICROBIOLOGY

The US incidence rate of infective endocarditis has steadily increased, with an estimated 457,052 hospitalizations from 2000 to 2011. During that period, from 2000 to 2007, there was a marked increase in valve replacement surgeries.² This trend is likely explained by an increase in the at-risk population—eg, elderly patients, patients with opiate dependence or diabetes, and patients on hemodialysis.

Although S aureus is the predominant pathogen in infective endocarditis,^2–5S aureus bacteremia is often observed in patients with skin or soft-tissue infection, prosthetic device infection, vascular graft or catheter infection, and bone and joint infections. S aureus bacteremia necessitates a search for the source of infection.

S aureus is a major pathogen in bloodstream infections, and up to 14% of patients with S aureus bacteremia have infective endocarditis as the primary source of infection.³ The pathogenesis of S aureus infective endocarditis is thought to be mediated by cell-wall factors that promote adhesion to the extracellular matrix of intravascular structures.³

A new localizing symptom such as back pain, joint pain, or swelling in a patient with S aureus bacteremia should trigger an investigation for metastatic infection.

Infectious disease consultation in patients with S aureus bacteremia is associated with improved outcomes and, thus, should be pursued.³

A cardiac surgery consult is recommended early on in cases of infective endocarditis caused by vancomycin-resistant enterococci, Pseudomonas aeruginosa, and fungi, as well as in patients with complications such as valvular insufficiency, perivalvular abscess, conduction abnormalities, persistent bacteremia, and metastatic foci of infection.⁶

Risk factors for infective endocarditis include injection drug abuse, valvular heart disease, congenital heart disease (unrepaired, repaired with residual defects, or fully repaired within the past 6 months), previous infective endocarditis, prosthetic heart valve, and cardiac transplant.^2–4,6 Other risk factors are poor dentition, hemodialysis, ventriculoatrial shunts, intravascular devices including vascular grafts, and pacemakers.^2,3 Many risk factors for infective endocarditis and S aureus bacteremia overlap.³

DIAGNOSTIC PRINCIPLES

The clinical presentation of infective endocarditis can vary from a nonspecific infectious syndrome, to overt organ failure (heart failure, kidney failure), to an acute vascular catastrophe (arterial ischemia, cerebrovascular accidents, myocardial infarction). Patients may present with indolent symptoms such as fever, fatigue, and weight loss,⁶ or they may present at an advanced stage, with fulminant acute heart failure due to valvular insufficiency or with arrhythmias due to a perivalvular abscess infiltrating the conduction system. Extracardiac clinical manifestations may be related to direct infective metastatic foci such as septic emboli or to immunologic phenomena such as glomerulonephritis or Osler nodes.

ECHOCARDIOGRAPHY’S ROLE IN DIAGNOSIS

TTE plays an important role in diagnosis and risk stratification of infective endocarditis.⁶ TTE is usually done first because of its low cost, wide availability, and safety; it has a sensitivity of 70% and a specificity over 95%.⁸ While a normal result on TTE does not completely rule out infective endocarditis, completely normal valvular morphology and function on TTE make the diagnosis less likely.^8,9

If suspicion remains high despite a normal study, repeating TTE at a later time may result in a higher diagnostic yield because of growth of the suspected vegetation. Otherwise, TEE should be considered.

TEE provides a higher spatial resolution and diagnostic yield than TTE, especially for detecting complex pathology such as pseudoaneurysm, valve perforation, or valvular abscess. TEE has a sensitivity and specificity of approximately 95% for infective endocarditis.⁸ It should be performed early in patients with preexisting valve disease, prosthetic cardiac material (eg, valves), or a pacemaker or implantable cardioverter-defibrillator.^6,7

Detecting valve vegetation provides answers about the cause of S aureus bacteremia with its complications (eg, septic emboli, mycotic aneurysm) and informs decisions about the duration of antibiotic therapy and the need for surgery.^3,6

As with any diagnostic test, it is important to compare the results of any recent study with those of previous studies whenever possible to differentiate new from old findings.

WHEN TO FORGO TEE IN S AUREUS BACTEREMIA

Because TEE is invasive and requires the patient to swallow an endoscopic probe,¹⁰ it is important to screen patients for esophageal disease, cervical spine conditions, and baseline respiratory insufficiency. Complications are rare but include esophageal perforation, esophageal bleeding, pharyngeal hematoma, and reactions to anesthesia.¹⁰

As with any diagnostic test, the clinician first needs to consider the patient’s pretest probability of the disease, the diagnostic accuracy, the associated risks and costs, and the implications of the results.

While TEE provides better diagnostic images than TTE, a normal TEE study does not exclude the diagnosis of infective endocarditis: small lesions and complications such as paravalvular abscess of a prosthetic aortic valve may still be missed. In such patients, a repeat TEE examination or additional imaging study (eg, gated computed tomographic angiography) should be considered.⁶

Noninfective sterile echodensities, valvular tumors such as papillary fibroelastomas, Lambl excrescences, and suture lines of prosthetic valves are among the conditions and factors that can cause a false-positive result on TEE. 

Staphylococcus aureus is the most common infective agent in native and prosthetic valve endocarditis, and 13% to 22% of patients with S aureus bacteremia have infective endocarditis.¹

See related editorial

Transthoracic echocardiography (TTE) is a good starting point in the workup of suspected infective endocarditis, but transesophageal echocardiography (TEE) plays a key role in diagnosis and is indicated in patients with a high pretest probability of infective endocarditis, as in the following scenarios:

• Clinical picture consistent with infective endocarditis
• Presence of previously placed port or other indwelling vascular device
• Presence of a prosthetic valve or other prosthetic material 
• Presence of a pacemaker
• History of valve disease
• Injection drug use
• Positive blood cultures after 72 hours despite appropriate antibiotic treatment
• Abnormal TTE result requiring better visualization of valvular anatomy and function and confirmation of local complications
• Absence of another reasonable explanation for S aureus bacteremia.

Forgoing TEE is reasonable in patients with normal results on TTE, no predisposing risk factors, a reasonable alternative explanation for S aureus bacteremia, and a low pretest probability of infective endocarditis.¹ TEE may also be unnecessary if there is another disease focus requiring extended treatment (eg, vertebral infection) and there are no findings suggesting complicated infective endocarditis, eg, persistent bacteremia, symptoms of heart failure, and conduction abnormality.¹

TEE also may be unnecessary in patients at low risk who have identifiable foci of bacteremia due to soft-tissue infection or a newly placed vascular catheter and whose bacteremia clears within 72 hours of the start of antibiotic therapy. These patients may be followed clinically for the development of new findings such as metastatic foci of infection (eg, septic pulmonary emboli, renal infarction, splenic abscess or infarction), the new onset of heart failure or cardiac conduction abnormality, or recurrence of previously cleared S aureus bacteremia. If these should develop, then a more invasive study such as TEE may be warranted.

INFECTIVE ENDOCARDITIS: EPIDEMIOLOGY AND MICROBIOLOGY

The US incidence rate of infective endocarditis has steadily increased, with an estimated 457,052 hospitalizations from 2000 to 2011. During that period, from 2000 to 2007, there was a marked increase in valve replacement surgeries.² This trend is likely explained by an increase in the at-risk population—eg, elderly patients, patients with opiate dependence or diabetes, and patients on hemodialysis.

Although S aureus is the predominant pathogen in infective endocarditis,^2–5S aureus bacteremia is often observed in patients with skin or soft-tissue infection, prosthetic device infection, vascular graft or catheter infection, and bone and joint infections. S aureus bacteremia necessitates a search for the source of infection.

S aureus is a major pathogen in bloodstream infections, and up to 14% of patients with S aureus bacteremia have infective endocarditis as the primary source of infection.³ The pathogenesis of S aureus infective endocarditis is thought to be mediated by cell-wall factors that promote adhesion to the extracellular matrix of intravascular structures.³

A new localizing symptom such as back pain, joint pain, or swelling in a patient with S aureus bacteremia should trigger an investigation for metastatic infection.

Infectious disease consultation in patients with S aureus bacteremia is associated with improved outcomes and, thus, should be pursued.³

A cardiac surgery consult is recommended early on in cases of infective endocarditis caused by vancomycin-resistant enterococci, Pseudomonas aeruginosa, and fungi, as well as in patients with complications such as valvular insufficiency, perivalvular abscess, conduction abnormalities, persistent bacteremia, and metastatic foci of infection.⁶

Risk factors for infective endocarditis include injection drug abuse, valvular heart disease, congenital heart disease (unrepaired, repaired with residual defects, or fully repaired within the past 6 months), previous infective endocarditis, prosthetic heart valve, and cardiac transplant.^2–4,6 Other risk factors are poor dentition, hemodialysis, ventriculoatrial shunts, intravascular devices including vascular grafts, and pacemakers.^2,3 Many risk factors for infective endocarditis and S aureus bacteremia overlap.³

DIAGNOSTIC PRINCIPLES

The clinical presentation of infective endocarditis can vary from a nonspecific infectious syndrome, to overt organ failure (heart failure, kidney failure), to an acute vascular catastrophe (arterial ischemia, cerebrovascular accidents, myocardial infarction). Patients may present with indolent symptoms such as fever, fatigue, and weight loss,⁶ or they may present at an advanced stage, with fulminant acute heart failure due to valvular insufficiency or with arrhythmias due to a perivalvular abscess infiltrating the conduction system. Extracardiac clinical manifestations may be related to direct infective metastatic foci such as septic emboli or to immunologic phenomena such as glomerulonephritis or Osler nodes.

ECHOCARDIOGRAPHY’S ROLE IN DIAGNOSIS

TTE plays an important role in diagnosis and risk stratification of infective endocarditis.⁶ TTE is usually done first because of its low cost, wide availability, and safety; it has a sensitivity of 70% and a specificity over 95%.⁸ While a normal result on TTE does not completely rule out infective endocarditis, completely normal valvular morphology and function on TTE make the diagnosis less likely.^8,9

If suspicion remains high despite a normal study, repeating TTE at a later time may result in a higher diagnostic yield because of growth of the suspected vegetation. Otherwise, TEE should be considered.

TEE provides a higher spatial resolution and diagnostic yield than TTE, especially for detecting complex pathology such as pseudoaneurysm, valve perforation, or valvular abscess. TEE has a sensitivity and specificity of approximately 95% for infective endocarditis.⁸ It should be performed early in patients with preexisting valve disease, prosthetic cardiac material (eg, valves), or a pacemaker or implantable cardioverter-defibrillator.^6,7

Detecting valve vegetation provides answers about the cause of S aureus bacteremia with its complications (eg, septic emboli, mycotic aneurysm) and informs decisions about the duration of antibiotic therapy and the need for surgery.^3,6

As with any diagnostic test, it is important to compare the results of any recent study with those of previous studies whenever possible to differentiate new from old findings.

WHEN TO FORGO TEE IN S AUREUS BACTEREMIA

Because TEE is invasive and requires the patient to swallow an endoscopic probe,¹⁰ it is important to screen patients for esophageal disease, cervical spine conditions, and baseline respiratory insufficiency. Complications are rare but include esophageal perforation, esophageal bleeding, pharyngeal hematoma, and reactions to anesthesia.¹⁰

As with any diagnostic test, the clinician first needs to consider the patient’s pretest probability of the disease, the diagnostic accuracy, the associated risks and costs, and the implications of the results.

While TEE provides better diagnostic images than TTE, a normal TEE study does not exclude the diagnosis of infective endocarditis: small lesions and complications such as paravalvular abscess of a prosthetic aortic valve may still be missed. In such patients, a repeat TEE examination or additional imaging study (eg, gated computed tomographic angiography) should be considered.⁶

Noninfective sterile echodensities, valvular tumors such as papillary fibroelastomas, Lambl excrescences, and suture lines of prosthetic valves are among the conditions and factors that can cause a false-positive result on TEE. 

Staphylococcus aureus is the most common infective agent in native and prosthetic valve endocarditis, and 13% to 22% of patients with S aureus bacteremia have infective endocarditis.¹

See related editorial

Transthoracic echocardiography (TTE) is a good starting point in the workup of suspected infective endocarditis, but transesophageal echocardiography (TEE) plays a key role in diagnosis and is indicated in patients with a high pretest probability of infective endocarditis, as in the following scenarios:

• Clinical picture consistent with infective endocarditis
• Presence of previously placed port or other indwelling vascular device
• Presence of a prosthetic valve or other prosthetic material 
• Presence of a pacemaker
• History of valve disease
• Injection drug use
• Positive blood cultures after 72 hours despite appropriate antibiotic treatment
• Abnormal TTE result requiring better visualization of valvular anatomy and function and confirmation of local complications
• Absence of another reasonable explanation for S aureus bacteremia.

Forgoing TEE is reasonable in patients with normal results on TTE, no predisposing risk factors, a reasonable alternative explanation for S aureus bacteremia, and a low pretest probability of infective endocarditis.¹ TEE may also be unnecessary if there is another disease focus requiring extended treatment (eg, vertebral infection) and there are no findings suggesting complicated infective endocarditis, eg, persistent bacteremia, symptoms of heart failure, and conduction abnormality.¹

TEE also may be unnecessary in patients at low risk who have identifiable foci of bacteremia due to soft-tissue infection or a newly placed vascular catheter and whose bacteremia clears within 72 hours of the start of antibiotic therapy. These patients may be followed clinically for the development of new findings such as metastatic foci of infection (eg, septic pulmonary emboli, renal infarction, splenic abscess or infarction), the new onset of heart failure or cardiac conduction abnormality, or recurrence of previously cleared S aureus bacteremia. If these should develop, then a more invasive study such as TEE may be warranted.

INFECTIVE ENDOCARDITIS: EPIDEMIOLOGY AND MICROBIOLOGY

The US incidence rate of infective endocarditis has steadily increased, with an estimated 457,052 hospitalizations from 2000 to 2011. During that period, from 2000 to 2007, there was a marked increase in valve replacement surgeries.² This trend is likely explained by an increase in the at-risk population—eg, elderly patients, patients with opiate dependence or diabetes, and patients on hemodialysis.

Although S aureus is the predominant pathogen in infective endocarditis,^2–5S aureus bacteremia is often observed in patients with skin or soft-tissue infection, prosthetic device infection, vascular graft or catheter infection, and bone and joint infections. S aureus bacteremia necessitates a search for the source of infection.

S aureus is a major pathogen in bloodstream infections, and up to 14% of patients with S aureus bacteremia have infective endocarditis as the primary source of infection.³ The pathogenesis of S aureus infective endocarditis is thought to be mediated by cell-wall factors that promote adhesion to the extracellular matrix of intravascular structures.³

A new localizing symptom such as back pain, joint pain, or swelling in a patient with S aureus bacteremia should trigger an investigation for metastatic infection.

Infectious disease consultation in patients with S aureus bacteremia is associated with improved outcomes and, thus, should be pursued.³

A cardiac surgery consult is recommended early on in cases of infective endocarditis caused by vancomycin-resistant enterococci, Pseudomonas aeruginosa, and fungi, as well as in patients with complications such as valvular insufficiency, perivalvular abscess, conduction abnormalities, persistent bacteremia, and metastatic foci of infection.⁶

Risk factors for infective endocarditis include injection drug abuse, valvular heart disease, congenital heart disease (unrepaired, repaired with residual defects, or fully repaired within the past 6 months), previous infective endocarditis, prosthetic heart valve, and cardiac transplant.^2–4,6 Other risk factors are poor dentition, hemodialysis, ventriculoatrial shunts, intravascular devices including vascular grafts, and pacemakers.^2,3 Many risk factors for infective endocarditis and S aureus bacteremia overlap.³

DIAGNOSTIC PRINCIPLES

The clinical presentation of infective endocarditis can vary from a nonspecific infectious syndrome, to overt organ failure (heart failure, kidney failure), to an acute vascular catastrophe (arterial ischemia, cerebrovascular accidents, myocardial infarction). Patients may present with indolent symptoms such as fever, fatigue, and weight loss,⁶ or they may present at an advanced stage, with fulminant acute heart failure due to valvular insufficiency or with arrhythmias due to a perivalvular abscess infiltrating the conduction system. Extracardiac clinical manifestations may be related to direct infective metastatic foci such as septic emboli or to immunologic phenomena such as glomerulonephritis or Osler nodes.

ECHOCARDIOGRAPHY’S ROLE IN DIAGNOSIS

TTE plays an important role in diagnosis and risk stratification of infective endocarditis.⁶ TTE is usually done first because of its low cost, wide availability, and safety; it has a sensitivity of 70% and a specificity over 95%.⁸ While a normal result on TTE does not completely rule out infective endocarditis, completely normal valvular morphology and function on TTE make the diagnosis less likely.^8,9

If suspicion remains high despite a normal study, repeating TTE at a later time may result in a higher diagnostic yield because of growth of the suspected vegetation. Otherwise, TEE should be considered.

TEE provides a higher spatial resolution and diagnostic yield than TTE, especially for detecting complex pathology such as pseudoaneurysm, valve perforation, or valvular abscess. TEE has a sensitivity and specificity of approximately 95% for infective endocarditis.⁸ It should be performed early in patients with preexisting valve disease, prosthetic cardiac material (eg, valves), or a pacemaker or implantable cardioverter-defibrillator.^6,7

Detecting valve vegetation provides answers about the cause of S aureus bacteremia with its complications (eg, septic emboli, mycotic aneurysm) and informs decisions about the duration of antibiotic therapy and the need for surgery.^3,6

As with any diagnostic test, it is important to compare the results of any recent study with those of previous studies whenever possible to differentiate new from old findings.

WHEN TO FORGO TEE IN S AUREUS BACTEREMIA

Because TEE is invasive and requires the patient to swallow an endoscopic probe,¹⁰ it is important to screen patients for esophageal disease, cervical spine conditions, and baseline respiratory insufficiency. Complications are rare but include esophageal perforation, esophageal bleeding, pharyngeal hematoma, and reactions to anesthesia.¹⁰

As with any diagnostic test, the clinician first needs to consider the patient’s pretest probability of the disease, the diagnostic accuracy, the associated risks and costs, and the implications of the results.

While TEE provides better diagnostic images than TTE, a normal TEE study does not exclude the diagnosis of infective endocarditis: small lesions and complications such as paravalvular abscess of a prosthetic aortic valve may still be missed. In such patients, a repeat TEE examination or additional imaging study (eg, gated computed tomographic angiography) should be considered.⁶

Noninfective sterile echodensities, valvular tumors such as papillary fibroelastomas, Lambl excrescences, and suture lines of prosthetic valves are among the conditions and factors that can cause a false-positive result on TEE. 

Morbidity and mortality rates in patients with Staphylococcus aureus bacteremia remain high even though diagnostic tests have improved and antibiotic therapy is effective. Diagnosis and management are made more complex by difficulties in finding the source of bacteremia and sites of metastatic infection.

See related article

S aureus bacteremia is a finding that demands further investigation, since up to 25% of people who have it may have endocarditis, a condition with even worse consequences.¹ The ability of S aureus to infect normal valves^2,3 adds to the challenge. In the mid-20th century, Wilson and Hamburger⁴ demonstrated that 64% of patients with S aureus bacteremia had evidence of valvular infection at autopsy. In a more recent case series of patients with S aureus endocarditis, the diagnosis was established at autopsy in 32%.⁵

Specific clinical findings in patients with complicated S aureus bacteremia—those who have a site of infection remote from or extended beyond the primary focus—may be useful in determining the need for additional diagnostic and therapeutic measures.

In a prospective cohort study, Fowler et al⁶ identified several factors that predicted complicated S aureus bacteremia (including but not limited to endocarditis):

• Prolonged bacteremia (> 48–72 hours after initiation of therapy)
• Community onset
• Fever persisting more than 72 hours
• Skin findings suggesting systemic infection.

THE ROLE OF ECHOCARDIOGRAPHY

Infective endocarditis may be difficult to detect in patients with S aureus bacteremia; experts recommend routine use of echocardiography in this process.^7,8 Transesophageal echocardiography (TEE) detects more cases of endocarditis than transthoracic echocardiography (TTE),^9,10 but access, cost, and risks lead to questions about its utility.

Guidance for the use of echocardiography in S aureus bacteremia^1,10–14 continues to evolve. Consensus seems to be emerging that the risk of endocarditis is lower in patients with S aureus bacteremia who:

• Do not have a prosthetic valve or other permanent intracardiac device
• Have sterile blood cultures within 96 hours after the initial set
• Are not hemodialysis-dependent
• Developed the bacteremia in a healthcare setting
• Have no secondary focus of infection
• Have no clinical signs of infective endocarditis.

Heriot et al¹⁴ point out that studies of risk-stratification approaches to echocardiography in patients with S aureus bacteremia are difficult to interpret, as there are questions regarding the validity of the studies and the balance of the risks and benefits.¹ The question of timing of TEE remains largely unexplored, both in initial screening and in follow-up of previously undiagnosed cases of S aureus endocarditis.

In this issue of the Journal, Mirrakhimov et al¹⁵ weigh in on use of a risk-stratification model to guide use of TEE in patients with S aureus bacteremia. Their comments about avoiding TEE in patients who have an alternative explanation for S aureus bacteremia and a low pretest probability for infectious endocarditis and in patients with a disease focus that requires extended treatment are derived from a survey of infectious disease physicians.¹⁶

ROLE OF INFECTIOUS DISEASE CONSULTATION

Infectious disease consultation reduces mortality rates and healthcare costs for a variety of infections, with endocarditis as a prime example.¹⁷ For S aureus bacteremia, a large and growing body of literature demonstrates the impact of infectious disease consultation, including improved adherence to guidelines and quality measures,^18–20 lower in-hospital mortality rates^18–21 and earlier hospital discharge.¹⁸ In the era of “curbside consults” and “e-consultation,” it is interesting to note the enduring value of bedside, in-person consultation in the management of S aureus bacteremia.²⁰

Many people with S aureus bacteremia should undergo TEE. Until the evidence becomes more robust, the decision to forgo TEE must be made with caution. The expertise of infectious disease physicians in the diagnosis and management of endocarditis can assist clinicians working with the often-complex patients who develop S aureus bacteremia. If the goal is to improve outcomes, infectious disease consultation may be at least as important as appropriate selection of patients for TEE.

Morbidity and mortality rates in patients with Staphylococcus aureus bacteremia remain high even though diagnostic tests have improved and antibiotic therapy is effective. Diagnosis and management are made more complex by difficulties in finding the source of bacteremia and sites of metastatic infection.

See related article

S aureus bacteremia is a finding that demands further investigation, since up to 25% of people who have it may have endocarditis, a condition with even worse consequences.¹ The ability of S aureus to infect normal valves^2,3 adds to the challenge. In the mid-20th century, Wilson and Hamburger⁴ demonstrated that 64% of patients with S aureus bacteremia had evidence of valvular infection at autopsy. In a more recent case series of patients with S aureus endocarditis, the diagnosis was established at autopsy in 32%.⁵

Specific clinical findings in patients with complicated S aureus bacteremia—those who have a site of infection remote from or extended beyond the primary focus—may be useful in determining the need for additional diagnostic and therapeutic measures.

In a prospective cohort study, Fowler et al⁶ identified several factors that predicted complicated S aureus bacteremia (including but not limited to endocarditis):

• Prolonged bacteremia (> 48–72 hours after initiation of therapy)
• Community onset
• Fever persisting more than 72 hours
• Skin findings suggesting systemic infection.

THE ROLE OF ECHOCARDIOGRAPHY

Infective endocarditis may be difficult to detect in patients with S aureus bacteremia; experts recommend routine use of echocardiography in this process.^7,8 Transesophageal echocardiography (TEE) detects more cases of endocarditis than transthoracic echocardiography (TTE),^9,10 but access, cost, and risks lead to questions about its utility.

Guidance for the use of echocardiography in S aureus bacteremia^1,10–14 continues to evolve. Consensus seems to be emerging that the risk of endocarditis is lower in patients with S aureus bacteremia who:

• Do not have a prosthetic valve or other permanent intracardiac device
• Have sterile blood cultures within 96 hours after the initial set
• Are not hemodialysis-dependent
• Developed the bacteremia in a healthcare setting
• Have no secondary focus of infection
• Have no clinical signs of infective endocarditis.

Heriot et al¹⁴ point out that studies of risk-stratification approaches to echocardiography in patients with S aureus bacteremia are difficult to interpret, as there are questions regarding the validity of the studies and the balance of the risks and benefits.¹ The question of timing of TEE remains largely unexplored, both in initial screening and in follow-up of previously undiagnosed cases of S aureus endocarditis.

In this issue of the Journal, Mirrakhimov et al¹⁵ weigh in on use of a risk-stratification model to guide use of TEE in patients with S aureus bacteremia. Their comments about avoiding TEE in patients who have an alternative explanation for S aureus bacteremia and a low pretest probability for infectious endocarditis and in patients with a disease focus that requires extended treatment are derived from a survey of infectious disease physicians.¹⁶

ROLE OF INFECTIOUS DISEASE CONSULTATION

Infectious disease consultation reduces mortality rates and healthcare costs for a variety of infections, with endocarditis as a prime example.¹⁷ For S aureus bacteremia, a large and growing body of literature demonstrates the impact of infectious disease consultation, including improved adherence to guidelines and quality measures,^18–20 lower in-hospital mortality rates^18–21 and earlier hospital discharge.¹⁸ In the era of “curbside consults” and “e-consultation,” it is interesting to note the enduring value of bedside, in-person consultation in the management of S aureus bacteremia.²⁰

Many people with S aureus bacteremia should undergo TEE. Until the evidence becomes more robust, the decision to forgo TEE must be made with caution. The expertise of infectious disease physicians in the diagnosis and management of endocarditis can assist clinicians working with the often-complex patients who develop S aureus bacteremia. If the goal is to improve outcomes, infectious disease consultation may be at least as important as appropriate selection of patients for TEE.

Morbidity and mortality rates in patients with Staphylococcus aureus bacteremia remain high even though diagnostic tests have improved and antibiotic therapy is effective. Diagnosis and management are made more complex by difficulties in finding the source of bacteremia and sites of metastatic infection.

See related article

S aureus bacteremia is a finding that demands further investigation, since up to 25% of people who have it may have endocarditis, a condition with even worse consequences.¹ The ability of S aureus to infect normal valves^2,3 adds to the challenge. In the mid-20th century, Wilson and Hamburger⁴ demonstrated that 64% of patients with S aureus bacteremia had evidence of valvular infection at autopsy. In a more recent case series of patients with S aureus endocarditis, the diagnosis was established at autopsy in 32%.⁵

Specific clinical findings in patients with complicated S aureus bacteremia—those who have a site of infection remote from or extended beyond the primary focus—may be useful in determining the need for additional diagnostic and therapeutic measures.

In a prospective cohort study, Fowler et al⁶ identified several factors that predicted complicated S aureus bacteremia (including but not limited to endocarditis):

• Prolonged bacteremia (> 48–72 hours after initiation of therapy)
• Community onset
• Fever persisting more than 72 hours
• Skin findings suggesting systemic infection.

THE ROLE OF ECHOCARDIOGRAPHY

Infective endocarditis may be difficult to detect in patients with S aureus bacteremia; experts recommend routine use of echocardiography in this process.^7,8 Transesophageal echocardiography (TEE) detects more cases of endocarditis than transthoracic echocardiography (TTE),^9,10 but access, cost, and risks lead to questions about its utility.

Guidance for the use of echocardiography in S aureus bacteremia^1,10–14 continues to evolve. Consensus seems to be emerging that the risk of endocarditis is lower in patients with S aureus bacteremia who:

• Do not have a prosthetic valve or other permanent intracardiac device
• Have sterile blood cultures within 96 hours after the initial set
• Are not hemodialysis-dependent
• Developed the bacteremia in a healthcare setting
• Have no secondary focus of infection
• Have no clinical signs of infective endocarditis.

Heriot et al¹⁴ point out that studies of risk-stratification approaches to echocardiography in patients with S aureus bacteremia are difficult to interpret, as there are questions regarding the validity of the studies and the balance of the risks and benefits.¹ The question of timing of TEE remains largely unexplored, both in initial screening and in follow-up of previously undiagnosed cases of S aureus endocarditis.

In this issue of the Journal, Mirrakhimov et al¹⁵ weigh in on use of a risk-stratification model to guide use of TEE in patients with S aureus bacteremia. Their comments about avoiding TEE in patients who have an alternative explanation for S aureus bacteremia and a low pretest probability for infectious endocarditis and in patients with a disease focus that requires extended treatment are derived from a survey of infectious disease physicians.¹⁶

ROLE OF INFECTIOUS DISEASE CONSULTATION

Infectious disease consultation reduces mortality rates and healthcare costs for a variety of infections, with endocarditis as a prime example.¹⁷ For S aureus bacteremia, a large and growing body of literature demonstrates the impact of infectious disease consultation, including improved adherence to guidelines and quality measures,^18–20 lower in-hospital mortality rates^18–21 and earlier hospital discharge.¹⁸ In the era of “curbside consults” and “e-consultation,” it is interesting to note the enduring value of bedside, in-person consultation in the management of S aureus bacteremia.²⁰

Many people with S aureus bacteremia should undergo TEE. Until the evidence becomes more robust, the decision to forgo TEE must be made with caution. The expertise of infectious disease physicians in the diagnosis and management of endocarditis can assist clinicians working with the often-complex patients who develop S aureus bacteremia. If the goal is to improve outcomes, infectious disease consultation may be at least as important as appropriate selection of patients for TEE.

ABSTRACT

Standard 2-dimensional (2-D) computed tomography (CT) scans of the shoulder are often aligned to the plane of the body as opposed to the plane of the scapula, which may challenge the ability to accurately measure glenoid width and glenoid bone loss (GBL). The purpose of this study is to determine the effect of sagittal rotation of the glenoid on axial anterior-posterior (AP) glenoid width measurements in the setting of anterior GBL.

Forty-three CT scans from consecutive patients with anterior GBL (minimum 10%) were reformatted utilizing open-source DICOM software (OsiriX MD). Patients were grouped according to extent of GBL: I, 10% to 14.9% (N = 12); II, 15% to 19.9% (N = 16); and III, >20% (N = 15). The uncorrected (UNCORR) and corrected (CORR) images were assessed in the axial plane at 5 standardized cuts and measured for AP glenoid width.

For groups I and III, UNCORR scans underestimated axial AP width (and thus overestimated anterior GBL) in cuts 1 and 2, while in cuts 3 to 5, the axial AP width was overestimated (GBL was underestimated). In Group II, axial AP width was underestimated (GBL was overestimated), while in cuts 2 to 5, the axial AP width was overestimated (GBL was underestimated). Overall, AP glenoid width was consistently underestimated in cut 1, the most caudal cut; while AP glenoid width was consistently overestimated in cuts 3 to 5, the more cephalad cuts.

UNCORR 2-D CT scans inaccurately estimated glenoid width and the degree of anterior GBL. This data suggests that corrected 2D CT scans or a 3-dimensional (3-D) reconstruction can help in accurately defining the anterior GBL in patients with shoulder instability.

The treatment of glenohumeral instability has substantially evolved over the past several decades. The understanding of glenoid bone loss (GBL), in particular, has advanced to such a level that we utilize the quantification of GBL for surgical decision-making. Unrecognized and/or untreated GBL is associated with recurrent instability, pain, and disability. Controversy exists, however, regarding the precise amount of anterior GBL that is significant enough to warrant surgical treatment. While historically, 25%^1,2 of anterior GBL was thought to be the critical number required to warrant osseous augmentation, studies that are more recent have highlighted the need to perform osseous glenoid reconstruction with lesser degrees of GBL, particularly in the contact athlete.^3-9 As small differences in the amount of GBL can change surgical decision-making from an all-soft tissue repair to an osseous reconstruction, it is paramount that we have accurate, valid, and reproducible methods for calculating GBL.

Continue to: Historically, plain radiographs...

Computed tomography (CT) of the shoulder has become the most commonly utilized imaging modality in the evaluation of patients with shoulder instability associated with GBL. Standard 2-dimensional (2-D) CT scans of the shoulder are often aligned to the plane of the body as opposed to the plane of the scapula/glenoid, as standard protocols often fail to account for the anterior sagittal rotation of the scapula/glenoid, similar to the disadvantage of standard radiographs. While 3-dimensional (3-D) CT reconstructions eliminate the effect of gantry angles, and thus allow for an en face view of the glenoid, 3-D reconstructions are not always available, and cannot always be measured.^12-14 Thus, improved methodology for utilizing standard 2D scans is warranted, as the ability to correctly align the axial CT scan to the axis of the glenoid may allow for more accurate GBL measurements, which will ultimately impact surgical decision-making. Recently, Gross and colleagues¹⁵ reported the effect of sagittal rotation of the glenoid on axial measurements of anterior-posterior (AP) glenoid width and glenoid version in normal glenoids, without bone loss, and found that the mean angle of correction needed to align the sagittal plane was 20.1° ± 1.2° of rotation. To the authors’ knowledge, this same methodology has not been applied to patients with clinically meaningful anterior GBL. Given that the average glenoid width in human shoulders is 24.4 mm ± 2.9 mm,¹⁶ 1 mm of glenoid bone loss (GBL) corresponds to approximately 4% of the glenoid width, and thus even subtle differences in the interpretation of GBL may have substantial clinical implications. Therefore, the purpose of this study is to determine the effect of sagittal rotation of the glenoid on axial AP glenoid width measurements in the setting of clinically significant anterior GBL.

METHODS

This study was approved by Massachusetts General Hospital Institutional Review Board. A retrospective review of consecutive patients with a diagnosis of anterior shoulder instability between 2009 and 2013 was conducted. Inclusion criteria comprised patients with a minimum of 10% anterior GBL, an available CT scan of the affected shoulder, and no history of prior ipsilateral surgeries. Exclusion criteria comprised evidence of degenerative changes to the glenoid and/or humeral head, as well as prior ipsilateral shoulder surgery. Sixty consecutive patients were originally identified as having anterior shoulder instability, and 17 were excluded based on the inclusion/exclusion criteria, leaving 43 patients (43 shoulders) available for inclusion. Shoulder CT scans from all 43 patients were reformatted utilizing open-source DICOM software (OsiriX MD, version 2.5.1 65-bit) multi-planar reconstruction (MPR).

CT PROTOCOL

All patients underwent a standard glenohumeral CT scan using a Siemens Sensation 64 Scanner (Siemens), a 64-detector scanner. Scans were acquired with 0.6 mm of collimation, 140 kV, and 300 mA-seconds. Slice thickness was set to 2 mm. All patient information was de-identified for analysis.

The uncorrected (UNCORR) scans were defined as the default orientation on the scanner. In the UNCORR scans, the axial, coronal, and sagittal views were oriented relative to the scanner gantry table, as opposed to the anatomy of the glenoid. The corrected (CORR) CT scans were aligned in all 3 planes relative to the glenoid face, and thus the cuts were perpendicular to the long axis of the glenoid.¹⁵ This resulted in sagittal cuts perpendicular to the 12-o’clock to 6-o’clock axis in the sagittal plane (Figure 1).

Continue to: In a de-identified fashion...

IMAGE ANALYSIS AND REFORMATTING

In a de-identified fashion, all CT scans were imported and analyzed using open-source Digital Imaging and Communications in Medicine (DICOM) software (OsiriX MD, version 2.5.1 64-bit). By following a previously developed method, CT scans were reformatted using OsiriX MPR. The OsiriX software has an MPR function that allows simultaneous manipulation of 2-D CT scans in 3 orthogonal planes: axial, sagittal, and coronal. In the MPR mode, the alternation of 1 plane directly affects the orientation of the remaining 2 planes. Thus, by using an MPR, one can analyze the impact that a default CT scan performed relative to the gantry of the table, UNCORR, has on the axial images.

First, the en face view was obtained via a 2-step process: alignment of the axial plane to account for the scapular angle, followed by alignment of the coronal plane to adjust for the glenoid inclination.¹⁵ These 2 adjustments provided a true en face sagittal glenoid view. The final adjustment step was a sagittal en face rotation of the glenoid such that the superior and inferior glenoid tubercles were placed on the 12-o’clock to 6-o’clock axis (CORR scan). Previous studies have identified a central longitudinal axis that was used in this method to align the supraglenoid tubercle with the 12-o’clock to 6-o’clock axis on the glenoid face.^15,17,18 The standard error of mean was 1.21^°. This new CORR view resulted in axial cuts through the glenoid that were oriented perpendicular to the 12-o’clock to 6-o’clock axis. The UNCORR and CORR images were assessed in the axial plane at 5 standardized cuts and measured for AP glenoid width by 2 independent observers in a blinded, randomized fashion. When the measured AP width of the UNCORR scan was less than that measured on the CORR scan, the AP width of the glenoid was considered underestimated, and the degree of GBL was considered overestimated (Figure 2).

SCAPULAR ANGLE

Scapular angle measurements were performed on the axial view as the angle between a line through the long axis of the body of the scapula, and a line parallel to the CT gantry table.^15,19 Subsequently, the axial plane was aligned to the glenoid surface.

CORONAL INCLINATION

Coronal inclination measurements were performed on the sagittal view as the angle between a line tangential to the face of the glenoid and a line perpendicular to the CT gantry table. Positive values represented superior inclination, while negative values represented inferior glenoid inclination.¹⁵

SAGITTAL ROTATION

Sagittal rotation measurements were performed using the built-in angle measurement tool in OsiriX in the sagittal plane since the degree of rotation required aligning the long axis of the glenoid to the 12-o’clock to 6-o’clock axis. The amount of rotation was defined as the rotation angle.¹⁵

Continue to: Similarly, as described by Gross...

GLENOID WIDTH

Similarly, as described by Gross and colleagues,¹⁵ the sagittal en face view was divided via 5 cuts, throughout a superimposed best-fit circle that closely represents the glenoid.^9,15,20 For both the UNCORR and CORR, glenoid width (AP distance) was measured on the axial image at the widest point from AP cortex across the glenoid face.

PATIENT GROUPS

Utilizing the en face 3-D CT reconstruction view of the glenoid as the gold standard, patients were placed into 1 of 3 groups according to the degree of anterior GBL measured via the surface method.^9,20 The groups were as follows:

I. 10% to 14.9% (N = 12)

II. 15% to 19.9% (N = 16)

III. >20% (N = 15)

STATISTICAL METHODS

Paired t-tests were used to compare all measurements between CORR and UNCORR scans for each of the 5 cuts. A P-value of .05 was used as the threshold for statistical significance in 2-tailed comparisons. Mean and standard errors are presented with standard deviations throughout the study. For interobserver reliability, the measurements between the observers, the intraclass correlation coefficient was calculated. All statistics were performed with SPSS (Version 22).

RESULTS

The study cohort was comprised of 19 left shoulders (44%) and 24 right shoulders (56%), including 36 male patients (84%) and 7 female patients (16%). The average age was 27.8 years (range, 21-40 years). The variability in measured difference, with respect to AP width, was 1.05 mm. The UNCORR CT scans required a mean correction for coronal inclination of 7.0° ± 5.8° (range, -8°-6°). The UNCORR CT scans required a mean correction for scapular angle of 30.2° ± 8.0° (range, 15°-49°). The mean angle of sagittal rotation required to align the glenoid face with the 12-o’clock to 6-o’clock axis was 24.2° ± 5.1 ° (range, 13°-30°). These results are summarized in Table 1. 

For all measurements, the intraclass correlation coefficient for independent observers for all cuts within the 3 groups was r >.900 in all cases.

On an optimized CT scan, over 5 standardized cuts across a best-fit circle of the inferior glenoid, there was a statistically significant absolute mean difference of 12.6% in axial AP glenoid width (2.86 mm ± 2.00 mm, P =.016) when compared with the UNCORR scan. This corresponds to a 3% to 21% error in measurement of the AP width of the glenoid.

Continue to: For the entire cohort...

For groups I (10%-14.9% GBL) and III (>20% GBL), the UNCORR scans underestimated the axial AP width (and thus overestimated anterior GBL) in cuts 1 and 2, while in cuts 3 to 5, the axial AP width was overestimated (GBL was underestimated) (Tables 2, 3). In Group II (15%-19.9% GBL), the axial AP width was underestimated (GBL was overestimated), while in cuts 2 to 5, the axial AP width was overestimated (GBL was underestimated). Overall, AP glenoid width was consistently underestimated in cut 1, the most caudal cut, while AP glenoid width was consistently overestimated in cuts 3 to 5, the more cephalad cuts.

Abbreviations: AP, anterior-posterior; GBL, glenoid bone loss.

Abbreviations: AP, anterior-posterior; CORR, corrected; UNCORR, uncorrected.

DISCUSSION

The principle findings of this study demonstrate that UNCORR conventional 2-D CT scans inaccurately estimate glenoid width as well as inaccurately quantify the degree of anterior GBL. Underestimations of GBL may lead to insufficient treatment of clinically meaningful GBL, thereby increasing the risk of instability recurrence; whereas overestimations of GBL may lead to unnecessary treatment, subjecting patients to increased surgical morbidity. Therefore, the authors recommend correcting the orientation of the scapula in cases wherein clinical decisions are entirely based on 2-D CT, or using alternative methods for quantifying GBL, specifically in the form of 3-D reconstructions.

The use of axial imaging, with CT scans and/or magnetic resonance imaging, is growing in popularity for evaluation of both glenoid anatomy and GBL. Nevertheless, despite our improved ability to critically evaluate the glenoid using these advanced imaging modalities, the images themselves require scrutiny by clinicians to determine if the images accurately depict the true anatomy of the glenoid. As demonstrated by Gross and colleagues,¹⁵ conventional 2D CT scan protocols are not optimized to the anatomy of the glenohumeral joint, even in patients without GBL. Due to the alignment of the image relative to the plane of the scapula as opposed to the plane of the glenoid, UNCORR scans result in significantly different measurements of glenoid version (2.0° ± 0.1°) and AP glenoid width (1.2 mm  ± 0.42 mm) compared with corrected scans, requiring an average 20.1° ± 1.2° of correction to align the sagittal plane. In the present study involving the patients with GBL, we also found that conventional, UNCORR 2-D CT scan protocols inaccurately estimate glenoid width and the degree of anterior GBL. In particular, AP glenoid width was consistently underestimated in the more caudal cuts, while AP glenoid width was consistently overestimated in the more cephalad cuts. Thus, anterior GBL was overestimated (AP glenoid width was underestimated) in the more caudal cuts, whereas anterior GBL was underestimated in the more cranial cuts (AP glenoid width was overestimated). Given that approximately 1 mm of glenoid bone corresponds to approximately 4% of glenoid width,¹⁶ even subtle differences in the interpretation of GBL may lead to gross overestimation/underestimation of bone loss, with significant clinical implications.

In the anterior instability patient population, clinical decision-making is often based on the degree of GBL as determined by advanced imaging modalities. In addition to other patient-specific factors, including age, gender, activity level, type of sport, and number of prior dislocations and/or prior surgeries, the quantity of GBL will often determine which surgical procedure needs to be performed. Typically, patients with >20% to 25% anterior GBL are indicated for a glenoid reconstruction procedure, most commonly via the Latarjet procedure (coracoid transfer).^21-27 The Latarjet procedure remains an excellent technique for appropriately indicated patients, with historically good clinical outcomes and low recurrence rates. Complications associated with the Latarjet procedure, however, are not uncommon, including devastating neuropraxia of the axillary and musculocutaneous nerves, and occasionally permanent neurologic deficits.²⁸ Thus, it is critical to avoid overtreating patients with recurrent instability and GBL. As demonstrated by this study, depending on the cranial-to-caudal location on the glenoid, current 2-D CT techniques may underestimate AP glenoid width, resulting in an overestimation of GBL, potentially leading to the decision to proceed with glenoid bone reconstruction when such a procedure is not required. On the contrary, overestimation of AP glenoid width, which occurs in the more cephalad cuts of the glenoid, is perhaps more worrisome, as the resulting underestimation of GBL may lead to inadequate treatment of patients with recurrent instability. Certainly, one of the main risk factors for failed soft tissue shoulder stabilization is a failure to address GBL. If clinical decisions are made based on UNCORR 2-D CT scans, which are often inaccurate with respect to AP glenoid width by an average 2.86 mm ± 2.00 mm (equivalent to 12.6% ± 6.9% GBL) as determined in this study, patients who truly require osseous glenoid reconstructions may be indicated for only soft tissue stabilization, based on the underestimation of GBL.

Continue to: The current gold standard...

LIMITATIONS

This study has limitations, such as the relatively small sample size and the selection bias by the reviewers with potential differences in interobserver reliability. Further, minor modifications during the reformatting process may be found with each attempt to manipulate the images and may result in minor, insignificant differences in AP width measurements. Performing 1 or more additional CT scans on the same cohort of patients would have been helpful; however, due to the increased risk of radiation exposure, this was not performed. Performing CT scans on cadaveric specimens with GBL and applying the study methodology would also have been helpful to provide independent verification of our clinical findings; however, specimens were not available for this study. Another limitation of this study is that we did not compare our findings with the findings of glenoid width, and bone loss, as determined using the circle method, which is commonly utilized when 3-D reconstructions are available. In this study, the purpose was to utilize only the 2-D reformatted images, with the assumption that 3-D reconstructions are not always available, and cannot always be measured. To minimize selection bias, the investigators measured the correction effects within groups of patients with similar degrees of GBL (10%-14.9%, 15%-19.9%, and >20%). In addition, not all the selected patients showed degenerative glenoid changes or irregular glenoid shape indicating previous bone augmentation.

CONCLUSIONS

UNCORR 2D CT scans inaccurately estimate glenoid width and the degree of anterior GBL. The clinical implications of these findings are profound and suggest corrected 2D CT scans or 3D reconstruction allow measurements to be taken in the axis of the glenoid to accurately define the anatomy and quantity of anterior GBL in patients with shoulder instability.

ABSTRACT

Standard 2-dimensional (2-D) computed tomography (CT) scans of the shoulder are often aligned to the plane of the body as opposed to the plane of the scapula, which may challenge the ability to accurately measure glenoid width and glenoid bone loss (GBL). The purpose of this study is to determine the effect of sagittal rotation of the glenoid on axial anterior-posterior (AP) glenoid width measurements in the setting of anterior GBL.

Forty-three CT scans from consecutive patients with anterior GBL (minimum 10%) were reformatted utilizing open-source DICOM software (OsiriX MD). Patients were grouped according to extent of GBL: I, 10% to 14.9% (N = 12); II, 15% to 19.9% (N = 16); and III, >20% (N = 15). The uncorrected (UNCORR) and corrected (CORR) images were assessed in the axial plane at 5 standardized cuts and measured for AP glenoid width.

For groups I and III, UNCORR scans underestimated axial AP width (and thus overestimated anterior GBL) in cuts 1 and 2, while in cuts 3 to 5, the axial AP width was overestimated (GBL was underestimated). In Group II, axial AP width was underestimated (GBL was overestimated), while in cuts 2 to 5, the axial AP width was overestimated (GBL was underestimated). Overall, AP glenoid width was consistently underestimated in cut 1, the most caudal cut; while AP glenoid width was consistently overestimated in cuts 3 to 5, the more cephalad cuts.

UNCORR 2-D CT scans inaccurately estimated glenoid width and the degree of anterior GBL. This data suggests that corrected 2D CT scans or a 3-dimensional (3-D) reconstruction can help in accurately defining the anterior GBL in patients with shoulder instability.

The treatment of glenohumeral instability has substantially evolved over the past several decades. The understanding of glenoid bone loss (GBL), in particular, has advanced to such a level that we utilize the quantification of GBL for surgical decision-making. Unrecognized and/or untreated GBL is associated with recurrent instability, pain, and disability. Controversy exists, however, regarding the precise amount of anterior GBL that is significant enough to warrant surgical treatment. While historically, 25%^1,2 of anterior GBL was thought to be the critical number required to warrant osseous augmentation, studies that are more recent have highlighted the need to perform osseous glenoid reconstruction with lesser degrees of GBL, particularly in the contact athlete.^3-9 As small differences in the amount of GBL can change surgical decision-making from an all-soft tissue repair to an osseous reconstruction, it is paramount that we have accurate, valid, and reproducible methods for calculating GBL.

Continue to: Historically, plain radiographs...

Computed tomography (CT) of the shoulder has become the most commonly utilized imaging modality in the evaluation of patients with shoulder instability associated with GBL. Standard 2-dimensional (2-D) CT scans of the shoulder are often aligned to the plane of the body as opposed to the plane of the scapula/glenoid, as standard protocols often fail to account for the anterior sagittal rotation of the scapula/glenoid, similar to the disadvantage of standard radiographs. While 3-dimensional (3-D) CT reconstructions eliminate the effect of gantry angles, and thus allow for an en face view of the glenoid, 3-D reconstructions are not always available, and cannot always be measured.^12-14 Thus, improved methodology for utilizing standard 2D scans is warranted, as the ability to correctly align the axial CT scan to the axis of the glenoid may allow for more accurate GBL measurements, which will ultimately impact surgical decision-making. Recently, Gross and colleagues¹⁵ reported the effect of sagittal rotation of the glenoid on axial measurements of anterior-posterior (AP) glenoid width and glenoid version in normal glenoids, without bone loss, and found that the mean angle of correction needed to align the sagittal plane was 20.1° ± 1.2° of rotation. To the authors’ knowledge, this same methodology has not been applied to patients with clinically meaningful anterior GBL. Given that the average glenoid width in human shoulders is 24.4 mm ± 2.9 mm,¹⁶ 1 mm of glenoid bone loss (GBL) corresponds to approximately 4% of the glenoid width, and thus even subtle differences in the interpretation of GBL may have substantial clinical implications. Therefore, the purpose of this study is to determine the effect of sagittal rotation of the glenoid on axial AP glenoid width measurements in the setting of clinically significant anterior GBL.

METHODS

This study was approved by Massachusetts General Hospital Institutional Review Board. A retrospective review of consecutive patients with a diagnosis of anterior shoulder instability between 2009 and 2013 was conducted. Inclusion criteria comprised patients with a minimum of 10% anterior GBL, an available CT scan of the affected shoulder, and no history of prior ipsilateral surgeries. Exclusion criteria comprised evidence of degenerative changes to the glenoid and/or humeral head, as well as prior ipsilateral shoulder surgery. Sixty consecutive patients were originally identified as having anterior shoulder instability, and 17 were excluded based on the inclusion/exclusion criteria, leaving 43 patients (43 shoulders) available for inclusion. Shoulder CT scans from all 43 patients were reformatted utilizing open-source DICOM software (OsiriX MD, version 2.5.1 65-bit) multi-planar reconstruction (MPR).

CT PROTOCOL

All patients underwent a standard glenohumeral CT scan using a Siemens Sensation 64 Scanner (Siemens), a 64-detector scanner. Scans were acquired with 0.6 mm of collimation, 140 kV, and 300 mA-seconds. Slice thickness was set to 2 mm. All patient information was de-identified for analysis.

The uncorrected (UNCORR) scans were defined as the default orientation on the scanner. In the UNCORR scans, the axial, coronal, and sagittal views were oriented relative to the scanner gantry table, as opposed to the anatomy of the glenoid. The corrected (CORR) CT scans were aligned in all 3 planes relative to the glenoid face, and thus the cuts were perpendicular to the long axis of the glenoid.¹⁵ This resulted in sagittal cuts perpendicular to the 12-o’clock to 6-o’clock axis in the sagittal plane (Figure 1).

Continue to: In a de-identified fashion...

IMAGE ANALYSIS AND REFORMATTING

In a de-identified fashion, all CT scans were imported and analyzed using open-source Digital Imaging and Communications in Medicine (DICOM) software (OsiriX MD, version 2.5.1 64-bit). By following a previously developed method, CT scans were reformatted using OsiriX MPR. The OsiriX software has an MPR function that allows simultaneous manipulation of 2-D CT scans in 3 orthogonal planes: axial, sagittal, and coronal. In the MPR mode, the alternation of 1 plane directly affects the orientation of the remaining 2 planes. Thus, by using an MPR, one can analyze the impact that a default CT scan performed relative to the gantry of the table, UNCORR, has on the axial images.

First, the en face view was obtained via a 2-step process: alignment of the axial plane to account for the scapular angle, followed by alignment of the coronal plane to adjust for the glenoid inclination.¹⁵ These 2 adjustments provided a true en face sagittal glenoid view. The final adjustment step was a sagittal en face rotation of the glenoid such that the superior and inferior glenoid tubercles were placed on the 12-o’clock to 6-o’clock axis (CORR scan). Previous studies have identified a central longitudinal axis that was used in this method to align the supraglenoid tubercle with the 12-o’clock to 6-o’clock axis on the glenoid face.^15,17,18 The standard error of mean was 1.21^°. This new CORR view resulted in axial cuts through the glenoid that were oriented perpendicular to the 12-o’clock to 6-o’clock axis. The UNCORR and CORR images were assessed in the axial plane at 5 standardized cuts and measured for AP glenoid width by 2 independent observers in a blinded, randomized fashion. When the measured AP width of the UNCORR scan was less than that measured on the CORR scan, the AP width of the glenoid was considered underestimated, and the degree of GBL was considered overestimated (Figure 2).

SCAPULAR ANGLE

Scapular angle measurements were performed on the axial view as the angle between a line through the long axis of the body of the scapula, and a line parallel to the CT gantry table.^15,19 Subsequently, the axial plane was aligned to the glenoid surface.

CORONAL INCLINATION

Coronal inclination measurements were performed on the sagittal view as the angle between a line tangential to the face of the glenoid and a line perpendicular to the CT gantry table. Positive values represented superior inclination, while negative values represented inferior glenoid inclination.¹⁵

SAGITTAL ROTATION

Sagittal rotation measurements were performed using the built-in angle measurement tool in OsiriX in the sagittal plane since the degree of rotation required aligning the long axis of the glenoid to the 12-o’clock to 6-o’clock axis. The amount of rotation was defined as the rotation angle.¹⁵

Continue to: Similarly, as described by Gross...

GLENOID WIDTH

Similarly, as described by Gross and colleagues,¹⁵ the sagittal en face view was divided via 5 cuts, throughout a superimposed best-fit circle that closely represents the glenoid.^9,15,20 For both the UNCORR and CORR, glenoid width (AP distance) was measured on the axial image at the widest point from AP cortex across the glenoid face.

PATIENT GROUPS

Utilizing the en face 3-D CT reconstruction view of the glenoid as the gold standard, patients were placed into 1 of 3 groups according to the degree of anterior GBL measured via the surface method.^9,20 The groups were as follows:

I. 10% to 14.9% (N = 12)

II. 15% to 19.9% (N = 16)

III. >20% (N = 15)

STATISTICAL METHODS

Paired t-tests were used to compare all measurements between CORR and UNCORR scans for each of the 5 cuts. A P-value of .05 was used as the threshold for statistical significance in 2-tailed comparisons. Mean and standard errors are presented with standard deviations throughout the study. For interobserver reliability, the measurements between the observers, the intraclass correlation coefficient was calculated. All statistics were performed with SPSS (Version 22).

RESULTS

The study cohort was comprised of 19 left shoulders (44%) and 24 right shoulders (56%), including 36 male patients (84%) and 7 female patients (16%). The average age was 27.8 years (range, 21-40 years). The variability in measured difference, with respect to AP width, was 1.05 mm. The UNCORR CT scans required a mean correction for coronal inclination of 7.0° ± 5.8° (range, -8°-6°). The UNCORR CT scans required a mean correction for scapular angle of 30.2° ± 8.0° (range, 15°-49°). The mean angle of sagittal rotation required to align the glenoid face with the 12-o’clock to 6-o’clock axis was 24.2° ± 5.1 ° (range, 13°-30°). These results are summarized in Table 1. 

For all measurements, the intraclass correlation coefficient for independent observers for all cuts within the 3 groups was r >.900 in all cases.

On an optimized CT scan, over 5 standardized cuts across a best-fit circle of the inferior glenoid, there was a statistically significant absolute mean difference of 12.6% in axial AP glenoid width (2.86 mm ± 2.00 mm, P =.016) when compared with the UNCORR scan. This corresponds to a 3% to 21% error in measurement of the AP width of the glenoid.

Continue to: For the entire cohort...

For groups I (10%-14.9% GBL) and III (>20% GBL), the UNCORR scans underestimated the axial AP width (and thus overestimated anterior GBL) in cuts 1 and 2, while in cuts 3 to 5, the axial AP width was overestimated (GBL was underestimated) (Tables 2, 3). In Group II (15%-19.9% GBL), the axial AP width was underestimated (GBL was overestimated), while in cuts 2 to 5, the axial AP width was overestimated (GBL was underestimated). Overall, AP glenoid width was consistently underestimated in cut 1, the most caudal cut, while AP glenoid width was consistently overestimated in cuts 3 to 5, the more cephalad cuts.

Abbreviations: AP, anterior-posterior; GBL, glenoid bone loss.

Abbreviations: AP, anterior-posterior; CORR, corrected; UNCORR, uncorrected.

DISCUSSION

The principle findings of this study demonstrate that UNCORR conventional 2-D CT scans inaccurately estimate glenoid width as well as inaccurately quantify the degree of anterior GBL. Underestimations of GBL may lead to insufficient treatment of clinically meaningful GBL, thereby increasing the risk of instability recurrence; whereas overestimations of GBL may lead to unnecessary treatment, subjecting patients to increased surgical morbidity. Therefore, the authors recommend correcting the orientation of the scapula in cases wherein clinical decisions are entirely based on 2-D CT, or using alternative methods for quantifying GBL, specifically in the form of 3-D reconstructions.

The use of axial imaging, with CT scans and/or magnetic resonance imaging, is growing in popularity for evaluation of both glenoid anatomy and GBL. Nevertheless, despite our improved ability to critically evaluate the glenoid using these advanced imaging modalities, the images themselves require scrutiny by clinicians to determine if the images accurately depict the true anatomy of the glenoid. As demonstrated by Gross and colleagues,¹⁵ conventional 2D CT scan protocols are not optimized to the anatomy of the glenohumeral joint, even in patients without GBL. Due to the alignment of the image relative to the plane of the scapula as opposed to the plane of the glenoid, UNCORR scans result in significantly different measurements of glenoid version (2.0° ± 0.1°) and AP glenoid width (1.2 mm  ± 0.42 mm) compared with corrected scans, requiring an average 20.1° ± 1.2° of correction to align the sagittal plane. In the present study involving the patients with GBL, we also found that conventional, UNCORR 2-D CT scan protocols inaccurately estimate glenoid width and the degree of anterior GBL. In particular, AP glenoid width was consistently underestimated in the more caudal cuts, while AP glenoid width was consistently overestimated in the more cephalad cuts. Thus, anterior GBL was overestimated (AP glenoid width was underestimated) in the more caudal cuts, whereas anterior GBL was underestimated in the more cranial cuts (AP glenoid width was overestimated). Given that approximately 1 mm of glenoid bone corresponds to approximately 4% of glenoid width,¹⁶ even subtle differences in the interpretation of GBL may lead to gross overestimation/underestimation of bone loss, with significant clinical implications.

In the anterior instability patient population, clinical decision-making is often based on the degree of GBL as determined by advanced imaging modalities. In addition to other patient-specific factors, including age, gender, activity level, type of sport, and number of prior dislocations and/or prior surgeries, the quantity of GBL will often determine which surgical procedure needs to be performed. Typically, patients with >20% to 25% anterior GBL are indicated for a glenoid reconstruction procedure, most commonly via the Latarjet procedure (coracoid transfer).^21-27 The Latarjet procedure remains an excellent technique for appropriately indicated patients, with historically good clinical outcomes and low recurrence rates. Complications associated with the Latarjet procedure, however, are not uncommon, including devastating neuropraxia of the axillary and musculocutaneous nerves, and occasionally permanent neurologic deficits.²⁸ Thus, it is critical to avoid overtreating patients with recurrent instability and GBL. As demonstrated by this study, depending on the cranial-to-caudal location on the glenoid, current 2-D CT techniques may underestimate AP glenoid width, resulting in an overestimation of GBL, potentially leading to the decision to proceed with glenoid bone reconstruction when such a procedure is not required. On the contrary, overestimation of AP glenoid width, which occurs in the more cephalad cuts of the glenoid, is perhaps more worrisome, as the resulting underestimation of GBL may lead to inadequate treatment of patients with recurrent instability. Certainly, one of the main risk factors for failed soft tissue shoulder stabilization is a failure to address GBL. If clinical decisions are made based on UNCORR 2-D CT scans, which are often inaccurate with respect to AP glenoid width by an average 2.86 mm ± 2.00 mm (equivalent to 12.6% ± 6.9% GBL) as determined in this study, patients who truly require osseous glenoid reconstructions may be indicated for only soft tissue stabilization, based on the underestimation of GBL.

Continue to: The current gold standard...

LIMITATIONS

This study has limitations, such as the relatively small sample size and the selection bias by the reviewers with potential differences in interobserver reliability. Further, minor modifications during the reformatting process may be found with each attempt to manipulate the images and may result in minor, insignificant differences in AP width measurements. Performing 1 or more additional CT scans on the same cohort of patients would have been helpful; however, due to the increased risk of radiation exposure, this was not performed. Performing CT scans on cadaveric specimens with GBL and applying the study methodology would also have been helpful to provide independent verification of our clinical findings; however, specimens were not available for this study. Another limitation of this study is that we did not compare our findings with the findings of glenoid width, and bone loss, as determined using the circle method, which is commonly utilized when 3-D reconstructions are available. In this study, the purpose was to utilize only the 2-D reformatted images, with the assumption that 3-D reconstructions are not always available, and cannot always be measured. To minimize selection bias, the investigators measured the correction effects within groups of patients with similar degrees of GBL (10%-14.9%, 15%-19.9%, and >20%). In addition, not all the selected patients showed degenerative glenoid changes or irregular glenoid shape indicating previous bone augmentation.

CONCLUSIONS

UNCORR 2D CT scans inaccurately estimate glenoid width and the degree of anterior GBL. The clinical implications of these findings are profound and suggest corrected 2D CT scans or 3D reconstruction allow measurements to be taken in the axis of the glenoid to accurately define the anatomy and quantity of anterior GBL in patients with shoulder instability.

ABSTRACT

Standard 2-dimensional (2-D) computed tomography (CT) scans of the shoulder are often aligned to the plane of the body as opposed to the plane of the scapula, which may challenge the ability to accurately measure glenoid width and glenoid bone loss (GBL). The purpose of this study is to determine the effect of sagittal rotation of the glenoid on axial anterior-posterior (AP) glenoid width measurements in the setting of anterior GBL.

Forty-three CT scans from consecutive patients with anterior GBL (minimum 10%) were reformatted utilizing open-source DICOM software (OsiriX MD). Patients were grouped according to extent of GBL: I, 10% to 14.9% (N = 12); II, 15% to 19.9% (N = 16); and III, >20% (N = 15). The uncorrected (UNCORR) and corrected (CORR) images were assessed in the axial plane at 5 standardized cuts and measured for AP glenoid width.

For groups I and III, UNCORR scans underestimated axial AP width (and thus overestimated anterior GBL) in cuts 1 and 2, while in cuts 3 to 5, the axial AP width was overestimated (GBL was underestimated). In Group II, axial AP width was underestimated (GBL was overestimated), while in cuts 2 to 5, the axial AP width was overestimated (GBL was underestimated). Overall, AP glenoid width was consistently underestimated in cut 1, the most caudal cut; while AP glenoid width was consistently overestimated in cuts 3 to 5, the more cephalad cuts.

UNCORR 2-D CT scans inaccurately estimated glenoid width and the degree of anterior GBL. This data suggests that corrected 2D CT scans or a 3-dimensional (3-D) reconstruction can help in accurately defining the anterior GBL in patients with shoulder instability.

The treatment of glenohumeral instability has substantially evolved over the past several decades. The understanding of glenoid bone loss (GBL), in particular, has advanced to such a level that we utilize the quantification of GBL for surgical decision-making. Unrecognized and/or untreated GBL is associated with recurrent instability, pain, and disability. Controversy exists, however, regarding the precise amount of anterior GBL that is significant enough to warrant surgical treatment. While historically, 25%^1,2 of anterior GBL was thought to be the critical number required to warrant osseous augmentation, studies that are more recent have highlighted the need to perform osseous glenoid reconstruction with lesser degrees of GBL, particularly in the contact athlete.^3-9 As small differences in the amount of GBL can change surgical decision-making from an all-soft tissue repair to an osseous reconstruction, it is paramount that we have accurate, valid, and reproducible methods for calculating GBL.

Continue to: Historically, plain radiographs...

Computed tomography (CT) of the shoulder has become the most commonly utilized imaging modality in the evaluation of patients with shoulder instability associated with GBL. Standard 2-dimensional (2-D) CT scans of the shoulder are often aligned to the plane of the body as opposed to the plane of the scapula/glenoid, as standard protocols often fail to account for the anterior sagittal rotation of the scapula/glenoid, similar to the disadvantage of standard radiographs. While 3-dimensional (3-D) CT reconstructions eliminate the effect of gantry angles, and thus allow for an en face view of the glenoid, 3-D reconstructions are not always available, and cannot always be measured.^12-14 Thus, improved methodology for utilizing standard 2D scans is warranted, as the ability to correctly align the axial CT scan to the axis of the glenoid may allow for more accurate GBL measurements, which will ultimately impact surgical decision-making. Recently, Gross and colleagues¹⁵ reported the effect of sagittal rotation of the glenoid on axial measurements of anterior-posterior (AP) glenoid width and glenoid version in normal glenoids, without bone loss, and found that the mean angle of correction needed to align the sagittal plane was 20.1° ± 1.2° of rotation. To the authors’ knowledge, this same methodology has not been applied to patients with clinically meaningful anterior GBL. Given that the average glenoid width in human shoulders is 24.4 mm ± 2.9 mm,¹⁶ 1 mm of glenoid bone loss (GBL) corresponds to approximately 4% of the glenoid width, and thus even subtle differences in the interpretation of GBL may have substantial clinical implications. Therefore, the purpose of this study is to determine the effect of sagittal rotation of the glenoid on axial AP glenoid width measurements in the setting of clinically significant anterior GBL.

METHODS

This study was approved by Massachusetts General Hospital Institutional Review Board. A retrospective review of consecutive patients with a diagnosis of anterior shoulder instability between 2009 and 2013 was conducted. Inclusion criteria comprised patients with a minimum of 10% anterior GBL, an available CT scan of the affected shoulder, and no history of prior ipsilateral surgeries. Exclusion criteria comprised evidence of degenerative changes to the glenoid and/or humeral head, as well as prior ipsilateral shoulder surgery. Sixty consecutive patients were originally identified as having anterior shoulder instability, and 17 were excluded based on the inclusion/exclusion criteria, leaving 43 patients (43 shoulders) available for inclusion. Shoulder CT scans from all 43 patients were reformatted utilizing open-source DICOM software (OsiriX MD, version 2.5.1 65-bit) multi-planar reconstruction (MPR).

CT PROTOCOL

All patients underwent a standard glenohumeral CT scan using a Siemens Sensation 64 Scanner (Siemens), a 64-detector scanner. Scans were acquired with 0.6 mm of collimation, 140 kV, and 300 mA-seconds. Slice thickness was set to 2 mm. All patient information was de-identified for analysis.

The uncorrected (UNCORR) scans were defined as the default orientation on the scanner. In the UNCORR scans, the axial, coronal, and sagittal views were oriented relative to the scanner gantry table, as opposed to the anatomy of the glenoid. The corrected (CORR) CT scans were aligned in all 3 planes relative to the glenoid face, and thus the cuts were perpendicular to the long axis of the glenoid.¹⁵ This resulted in sagittal cuts perpendicular to the 12-o’clock to 6-o’clock axis in the sagittal plane (Figure 1).

Continue to: In a de-identified fashion...

IMAGE ANALYSIS AND REFORMATTING

In a de-identified fashion, all CT scans were imported and analyzed using open-source Digital Imaging and Communications in Medicine (DICOM) software (OsiriX MD, version 2.5.1 64-bit). By following a previously developed method, CT scans were reformatted using OsiriX MPR. The OsiriX software has an MPR function that allows simultaneous manipulation of 2-D CT scans in 3 orthogonal planes: axial, sagittal, and coronal. In the MPR mode, the alternation of 1 plane directly affects the orientation of the remaining 2 planes. Thus, by using an MPR, one can analyze the impact that a default CT scan performed relative to the gantry of the table, UNCORR, has on the axial images.

First, the en face view was obtained via a 2-step process: alignment of the axial plane to account for the scapular angle, followed by alignment of the coronal plane to adjust for the glenoid inclination.¹⁵ These 2 adjustments provided a true en face sagittal glenoid view. The final adjustment step was a sagittal en face rotation of the glenoid such that the superior and inferior glenoid tubercles were placed on the 12-o’clock to 6-o’clock axis (CORR scan). Previous studies have identified a central longitudinal axis that was used in this method to align the supraglenoid tubercle with the 12-o’clock to 6-o’clock axis on the glenoid face.^15,17,18 The standard error of mean was 1.21^°. This new CORR view resulted in axial cuts through the glenoid that were oriented perpendicular to the 12-o’clock to 6-o’clock axis. The UNCORR and CORR images were assessed in the axial plane at 5 standardized cuts and measured for AP glenoid width by 2 independent observers in a blinded, randomized fashion. When the measured AP width of the UNCORR scan was less than that measured on the CORR scan, the AP width of the glenoid was considered underestimated, and the degree of GBL was considered overestimated (Figure 2).

SCAPULAR ANGLE

Scapular angle measurements were performed on the axial view as the angle between a line through the long axis of the body of the scapula, and a line parallel to the CT gantry table.^15,19 Subsequently, the axial plane was aligned to the glenoid surface.

CORONAL INCLINATION

Coronal inclination measurements were performed on the sagittal view as the angle between a line tangential to the face of the glenoid and a line perpendicular to the CT gantry table. Positive values represented superior inclination, while negative values represented inferior glenoid inclination.¹⁵

SAGITTAL ROTATION

Sagittal rotation measurements were performed using the built-in angle measurement tool in OsiriX in the sagittal plane since the degree of rotation required aligning the long axis of the glenoid to the 12-o’clock to 6-o’clock axis. The amount of rotation was defined as the rotation angle.¹⁵

Continue to: Similarly, as described by Gross...

GLENOID WIDTH

Similarly, as described by Gross and colleagues,¹⁵ the sagittal en face view was divided via 5 cuts, throughout a superimposed best-fit circle that closely represents the glenoid.^9,15,20 For both the UNCORR and CORR, glenoid width (AP distance) was measured on the axial image at the widest point from AP cortex across the glenoid face.

PATIENT GROUPS

Utilizing the en face 3-D CT reconstruction view of the glenoid as the gold standard, patients were placed into 1 of 3 groups according to the degree of anterior GBL measured via the surface method.^9,20 The groups were as follows:

I. 10% to 14.9% (N = 12)

II. 15% to 19.9% (N = 16)

III. >20% (N = 15)

STATISTICAL METHODS

Paired t-tests were used to compare all measurements between CORR and UNCORR scans for each of the 5 cuts. A P-value of .05 was used as the threshold for statistical significance in 2-tailed comparisons. Mean and standard errors are presented with standard deviations throughout the study. For interobserver reliability, the measurements between the observers, the intraclass correlation coefficient was calculated. All statistics were performed with SPSS (Version 22).

RESULTS

The study cohort was comprised of 19 left shoulders (44%) and 24 right shoulders (56%), including 36 male patients (84%) and 7 female patients (16%). The average age was 27.8 years (range, 21-40 years). The variability in measured difference, with respect to AP width, was 1.05 mm. The UNCORR CT scans required a mean correction for coronal inclination of 7.0° ± 5.8° (range, -8°-6°). The UNCORR CT scans required a mean correction for scapular angle of 30.2° ± 8.0° (range, 15°-49°). The mean angle of sagittal rotation required to align the glenoid face with the 12-o’clock to 6-o’clock axis was 24.2° ± 5.1 ° (range, 13°-30°). These results are summarized in Table 1. 

For all measurements, the intraclass correlation coefficient for independent observers for all cuts within the 3 groups was r >.900 in all cases.

On an optimized CT scan, over 5 standardized cuts across a best-fit circle of the inferior glenoid, there was a statistically significant absolute mean difference of 12.6% in axial AP glenoid width (2.86 mm ± 2.00 mm, P =.016) when compared with the UNCORR scan. This corresponds to a 3% to 21% error in measurement of the AP width of the glenoid.

Continue to: For the entire cohort...

For groups I (10%-14.9% GBL) and III (>20% GBL), the UNCORR scans underestimated the axial AP width (and thus overestimated anterior GBL) in cuts 1 and 2, while in cuts 3 to 5, the axial AP width was overestimated (GBL was underestimated) (Tables 2, 3). In Group II (15%-19.9% GBL), the axial AP width was underestimated (GBL was overestimated), while in cuts 2 to 5, the axial AP width was overestimated (GBL was underestimated). Overall, AP glenoid width was consistently underestimated in cut 1, the most caudal cut, while AP glenoid width was consistently overestimated in cuts 3 to 5, the more cephalad cuts.

Abbreviations: AP, anterior-posterior; GBL, glenoid bone loss.

Abbreviations: AP, anterior-posterior; CORR, corrected; UNCORR, uncorrected.

DISCUSSION

The principle findings of this study demonstrate that UNCORR conventional 2-D CT scans inaccurately estimate glenoid width as well as inaccurately quantify the degree of anterior GBL. Underestimations of GBL may lead to insufficient treatment of clinically meaningful GBL, thereby increasing the risk of instability recurrence; whereas overestimations of GBL may lead to unnecessary treatment, subjecting patients to increased surgical morbidity. Therefore, the authors recommend correcting the orientation of the scapula in cases wherein clinical decisions are entirely based on 2-D CT, or using alternative methods for quantifying GBL, specifically in the form of 3-D reconstructions.

The use of axial imaging, with CT scans and/or magnetic resonance imaging, is growing in popularity for evaluation of both glenoid anatomy and GBL. Nevertheless, despite our improved ability to critically evaluate the glenoid using these advanced imaging modalities, the images themselves require scrutiny by clinicians to determine if the images accurately depict the true anatomy of the glenoid. As demonstrated by Gross and colleagues,¹⁵ conventional 2D CT scan protocols are not optimized to the anatomy of the glenohumeral joint, even in patients without GBL. Due to the alignment of the image relative to the plane of the scapula as opposed to the plane of the glenoid, UNCORR scans result in significantly different measurements of glenoid version (2.0° ± 0.1°) and AP glenoid width (1.2 mm  ± 0.42 mm) compared with corrected scans, requiring an average 20.1° ± 1.2° of correction to align the sagittal plane. In the present study involving the patients with GBL, we also found that conventional, UNCORR 2-D CT scan protocols inaccurately estimate glenoid width and the degree of anterior GBL. In particular, AP glenoid width was consistently underestimated in the more caudal cuts, while AP glenoid width was consistently overestimated in the more cephalad cuts. Thus, anterior GBL was overestimated (AP glenoid width was underestimated) in the more caudal cuts, whereas anterior GBL was underestimated in the more cranial cuts (AP glenoid width was overestimated). Given that approximately 1 mm of glenoid bone corresponds to approximately 4% of glenoid width,¹⁶ even subtle differences in the interpretation of GBL may lead to gross overestimation/underestimation of bone loss, with significant clinical implications.

In the anterior instability patient population, clinical decision-making is often based on the degree of GBL as determined by advanced imaging modalities. In addition to other patient-specific factors, including age, gender, activity level, type of sport, and number of prior dislocations and/or prior surgeries, the quantity of GBL will often determine which surgical procedure needs to be performed. Typically, patients with >20% to 25% anterior GBL are indicated for a glenoid reconstruction procedure, most commonly via the Latarjet procedure (coracoid transfer).^21-27 The Latarjet procedure remains an excellent technique for appropriately indicated patients, with historically good clinical outcomes and low recurrence rates. Complications associated with the Latarjet procedure, however, are not uncommon, including devastating neuropraxia of the axillary and musculocutaneous nerves, and occasionally permanent neurologic deficits.²⁸ Thus, it is critical to avoid overtreating patients with recurrent instability and GBL. As demonstrated by this study, depending on the cranial-to-caudal location on the glenoid, current 2-D CT techniques may underestimate AP glenoid width, resulting in an overestimation of GBL, potentially leading to the decision to proceed with glenoid bone reconstruction when such a procedure is not required. On the contrary, overestimation of AP glenoid width, which occurs in the more cephalad cuts of the glenoid, is perhaps more worrisome, as the resulting underestimation of GBL may lead to inadequate treatment of patients with recurrent instability. Certainly, one of the main risk factors for failed soft tissue shoulder stabilization is a failure to address GBL. If clinical decisions are made based on UNCORR 2-D CT scans, which are often inaccurate with respect to AP glenoid width by an average 2.86 mm ± 2.00 mm (equivalent to 12.6% ± 6.9% GBL) as determined in this study, patients who truly require osseous glenoid reconstructions may be indicated for only soft tissue stabilization, based on the underestimation of GBL.

Continue to: The current gold standard...

LIMITATIONS

This study has limitations, such as the relatively small sample size and the selection bias by the reviewers with potential differences in interobserver reliability. Further, minor modifications during the reformatting process may be found with each attempt to manipulate the images and may result in minor, insignificant differences in AP width measurements. Performing 1 or more additional CT scans on the same cohort of patients would have been helpful; however, due to the increased risk of radiation exposure, this was not performed. Performing CT scans on cadaveric specimens with GBL and applying the study methodology would also have been helpful to provide independent verification of our clinical findings; however, specimens were not available for this study. Another limitation of this study is that we did not compare our findings with the findings of glenoid width, and bone loss, as determined using the circle method, which is commonly utilized when 3-D reconstructions are available. In this study, the purpose was to utilize only the 2-D reformatted images, with the assumption that 3-D reconstructions are not always available, and cannot always be measured. To minimize selection bias, the investigators measured the correction effects within groups of patients with similar degrees of GBL (10%-14.9%, 15%-19.9%, and >20%). In addition, not all the selected patients showed degenerative glenoid changes or irregular glenoid shape indicating previous bone augmentation.

CONCLUSIONS

UNCORR 2D CT scans inaccurately estimate glenoid width and the degree of anterior GBL. The clinical implications of these findings are profound and suggest corrected 2D CT scans or 3D reconstruction allow measurements to be taken in the axis of the glenoid to accurately define the anatomy and quantity of anterior GBL in patients with shoulder instability.

Thoracic aortic aneurysm (TAA) needs to be detected, monitored, and managed in a timely manner to prevent a serious consequence such as acute dissection or rupture. But only about 5% of patients experience symptoms before an acute event occurs, and for the other 95% the first “symptom” is often death.¹ Most cases are detected either incidentally with echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI) during workup for another condition. Patients may also be diagnosed during workup of a murmur or after a family member is found to have an aneurysm. Therefore, its true incidence is difficult to determine.²

With these facts in mind, how would you manage the following 2 cases?

Case 1: Bicuspid aortic valve, ascending aortic aneurysm

A 45-year-old man with stage 1 hypertension presents for evaluation of a bicuspid aortic valve and ascending aortic aneurysm. He has several first-degree relatives with similar conditions, and his brother recently underwent elective aortic repair. At the urging of his primary care physician, he underwent screening echocardiography, which demonstrated a “dilated root and ascending aorta” 4.6 cm in diameter. He presents today to discuss management options and how the aneurysm could affect his everyday life.

Case 2: Marfan syndrome in a young woman

A 24-year-old woman with Marfan syndrome diagnosed in adolescence presents for annual follow-up. She has many family members with the same condition, and several have undergone prophylactic aortic root repair. Her aortic root has been monitored annually for progression of dilation, and today it is 4.6 cm in diameter, a 3-mm increase from the last measurement. She has grade 2+ aortic insufficiency (on a scale of 1+ to 4+) based on echocardiography, but she has no symptoms. She is curious about what size her aortic root will need to reach for surgery to be considered.

LIKELY UNDERDETECTED

TAA is being detected more often than in the past thanks to better detection methods and heightened awareness among physicians and patients. While an incidence rate of 10.4 per 100,000 patient-years is often cited,³ this figure likely underestimates the true incidence of this clinically silent condition. The most robust data come from studies based on in-hospital diagnostic codes coupled with data from autopsies for out-of-hospital deaths.

Olsson et al,⁴ in a 2016 study in Sweden, found the incidence of TAA and aortic dissection to be 16.3 per 100,000 per year for men and 9.1 per 100,000 per year for women.

Clouse et al⁵ reported the incidence of thoracic aortic dissection as 3.5 per 100,000 patient-years, and the same figure for thoracic aortic rupture. 

Aneurysmal disease accounts for 52,000 deaths per year in the United States, making it the 19th most common cause of death.⁶ These figures are likely lower than the true mortality rate for this condition, given that aortic dissection is often mistaken for acute myocardial infarction or other acute event if an autopsy is not done to confirm the cause of death.⁷

RISK FACTORS FOR THORACIC AORTIC ANEURYSM

Risk factors for TAA include genetic conditions that lead to aortic medial weakness or destruction such as Loeys-Dietz syndrome and Marfan syndrome.² In addition, family history is important even in the absence of known genetic mutations. Other risk factors include conditions that increase aortic wall stress, such as hypertension, cocaine abuse, extreme weightlifting, trauma, and aortic coarctation.²

DIAMETER INCREASES WITH AGE, BODY SURFACE AREA

Normal dimensions for the aortic segments differ depending on age, sex, and body surface area.^8,44,45 The size of the aortic root may also vary depending on how it is measured, due to the root’s trefoil shape. Measured sinus to sinus, the root is larger than when measured sinus to commissure on CT angiography or cardiac MRI. It is also larger when measured leading edge to leading edge than inner edge to inner edge on echocardiography.¹⁰

TAA is defined as an aortic diameter at least 50% greater than the upper limit of normal.⁸ 

Geometric changes in the curvature of the ascending aorta, aortic arch, and descending thoracic aorta can occur as the result of hypertension, atherosclerosis, or connective tissue disease. 

Imaging tests

It is particularly important to obtain a gated CTA image in patients with aortic root aneurysm to avoid motion artifact and possible erroneous measurements. Gated CTA is done with electrocardiographic synchronization and allows for image processing to correct for cardiac motion.

TAA can be caused by a variety of inherited and sporadic conditions. These differences in pathogenesis lend themselves to classification of aneurysms into groups. Table 3 highlights the most common conditions associated with TAA.¹³

Bicuspid aortic valve aortopathy

From 1% to 2% of people have a bicuspid aortic valve, with a 3-to-1 male predominance.^14,15 Aortic dilation occurs in 35% to 80% of people who have a bicuspid aortic valve, conferring a risk of dissection 8 times higher than in the general population.^16–18

The pathogenic mechanisms that lead to this condition are widely debated, although a combination of genetic defects leading to intrinsic weakening of the aortic wall and hemodynamic effects likely contribute.¹⁹ Evidence of hemodynamic contributions to aortic dilation comes from findings that particular patterns of cusp fusion of the bicuspid aortic valve result in changes in transvalvular flow, placing more stress on specific regions of the ascending aorta.^20,21 These hemodynamic alterations result in patterns of aortic dilation that depend on cusp fusion and the presence of valvular disease.

Multiple small studies found that replacing bicuspid aortic valves reduced the rate of aortic dilation, suggesting that hemodynamic factors may play a larger role than intrinsic wall properties in genetically susceptible individuals.^22,23 However, larger studies are needed before any definitive conclusions can be made.

HOW IS ANEURYSM MANAGED ON AN OUTPATIENT BASIS?

Patients with a new diagnosis of TAA should be referred to a cardiologist with expertise in managing aortic disease or to a cardiac surgeon specializing in aortic surgery, depending on the initial size of the aneurysm.

Control blood pressure with beta-blockers

Medical management for patients with TAA has historically been limited to strict blood pressure control aimed at reducing aortic wall stress, mainly with beta-blockers.

Are angiotensin II receptor blockers (ARBs) beneficial? Studies in a mouse model of Marfan syndrome revealed that the ARB losartan attenuated aortic root growth.²⁴ The results of early, small studies in humans were promising,^25–27 but larger randomized trials have shown no advantage of losartan over beta-blockers in slowing aortic root growth.²⁸ These negative results led many to question the effectiveness of losartan, although some point out that no studies have shown even beta-blockers to be beneficial in reducing the clinical end points of death or dissection.²⁹ On the other hand, patients with certain FBN1 mutations respond more readily than others to losartan.³⁰ Additional clinical trials of ARBs in Marfan syndrome are ongoing.

Current guidelines recommend stringent blood pressure control and smoking cessation for patients with a small aneurysm not requiring surgery and for those who are considered unsuitable for surgical or percutaneous intervention (level of evidence C, the lowest).² For patients with TAA, it is considered reasonable to give beta-blockers. Angiotensin-converting enzyme inhibitors or ARBs may be used in combination with beta-blockers, titrated to the lowest tolerable blood pressure without adverse effects (level of evidence B).²

The recommended target blood pressure is less than 140/90 mm Hg, or 130/80 mm Hg in those with diabetes or chronic kidney disease (level of evidence B).² However, we recommend more stringent blood pressure control: ie, less than 130/80 mm Hg for all patients with aortic aneurysm and a heart rate goal of 70 beats per minute or less, as tolerated.

Activity restriction

Activity restrictions for patients with TAA are largely based on theory, and certain activities may require more modification than others. For example, heavy lifting should be discouraged, as it may increase blood pressure significantly for short periods of time.^2,31 The increased wall stress, in theory, could initiate dissection or rupture. However, moderate-intensity aerobic activity is rarely associated with significant elevations in blood pressure and should be encouraged. Stressful emotional states have been anecdotally associated with aortic dissection; thus, measures to reduce stress may offer some benefit.³¹

Our recommendations. While there are no published guidelines regarding activity restrictions in patients with TAA, we use a graded approach based on aortic diameter:

• 4.0 to 4.4 cm—lift no more than 75 pounds
• 4.5 to 5 cm—lift no more than 50 pounds
• 5 cm—lift no more than 25 pounds.

We also recommend not lifting anything heavier than half of one’s body weight and to avoid breath-holding or performing the Valsalva maneuver while lifting. Although these recommendations are somewhat arbitrary, based on theory and a large clinical experience at our aortic center, they seem reasonable and practical.

Activity restrictions should be stringent and individualized in patients with Marfan, Loeys-Dietz, or Ehlers-Danlos syndrome due to increased risk of dissection or rupture even if the aorta is normal in size.

We sometimes recommend exercise stress testing to assess the heart rate and blood pressure response to exercise, and we are developing research protocols to help tailor activity recommendations.

To a cardiologist at the time of diagnosis

As soon as TAA is diagnosed, the patient should be referred to a cardiologist who has special interest in aortic disease. This will allow for appropriate and timely decisions about medical management, imaging, follow-up, and referral to surgery. Additional recommendations for screening of family members and referral to clinical geneticists can be discussed at this juncture. Activity restrictions should be reviewed at the initial evaluation.

To a surgeon relatively early

Size thresholds for surgical intervention are discussed below, but one should not wait until these thresholds are reached to send the patient for surgical consultation. It is beneficial to the state of mind of a potential surgical candidate to have early discussions pertaining to the types of operations available, their outcomes, and associated risks and benefits. If a patient’s aortic size remains stable over time, he or she may be followed by the cardiologist until significant size or growth has been documented, at which time the patient and surgeon can reconvene to discuss options for definitive treatment.

To a clinical geneticist

If 1 or more first-degree relatives of a patient with TAA or dissection are found to have aneurysmal disease, referral to a clinical geneticist is very important for genetic testing of multiple genes that have been implicated in thoracic aortic aneurysm and dissection.

WHEN SHOULD TAA BE REPAIRED?

Surgery to prevent rupture or dissection remains the definitive treatment of TAA when size thresholds are reached, and symptomatic aneurysm should be operated on regardless of the size. However, rarely are thoracic aneurysms symptomatic unless they rupture or dissect. The size criteria are based on underlying genetic etiology if known and on the behavior and natural course of TAA.

Size and other factors

Treatment should be tailored to the patient’s clinical scenario, family history, and estimated risk of rupture or dissection, balanced against the individual center’s outcomes of elective aortic replacement.³² For example, young and otherwise healthy patients with TAA and a family history of aortic dissection (who may be more likely to have connective tissue disorders such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehler-Danlos syndrome) may elect to undergo repair when the aneurysm reaches or nearly reaches the diameter of that of the family member’s aorta when dissection occurred.² On the other hand, TAA of degenerative etiology (eg, related to smoking or hypertension) measuring less than 5.5 cm in an older patient with comorbidities poses a lower risk of a catastrophic event such as dissection or rupture than the risk of surgery.¹¹

Thresholds for surgery. Once the diameter of the ascending aorta reaches 6 cm, the likelihood of an acute dissection is 31%.¹¹ A similar threshold is reached for the descending aorta at a size of 7 cm.¹¹ Therefore, to avoid high-risk emergency surgery on an acutely dissected aorta, surgery on an ascending aortic aneurysm of degenerative etiology is usually suggested when the aneurysm reaches 5.5 cm or a documented growth rate greater than 0.5 cm/year.^2,33

Additionally, in patients already undergoing surgery for valvular or coronary disease, prophylactic aortic replacement is recommended if the ascending aorta is larger than 4.5 cm. The threshold for intervention is lower in patients with connective tissue disease (> 5.0 cm for Marfan syndrome, 4.4–4.6 cm for Loeys-Dietz syndrome).^2,33

Observational studies suggest that the risk of aortic complications in patients with bicuspid aortic valve aortopathy is low overall, though significantly greater than in the general population.^18,34,35 These findings led to changes in the 2014 American College of Cardiology/American Heart Association guidelines on valvular heart disease,³⁶ suggesting a surgical threshold of 5.5 cm in the absence of significant valve disease or family history of dissection of an aorta of smaller diameter.

A 2015 study of dissection risk in patients with bicuspid aortic valve aortopathy by our group found a dramatic increase in risk of aortic dissection for ascending aortic diameters greater than 5.3 cm, and a gradual increase in risk for aortic root diameters greater than 5.0 cm.³⁷ In addition, a near-constant 3% to 4% risk of dissection was present for aortic diameters ranging from 4.7 cm to 5.0 cm, revealing that watchful waiting carries its own inherent risks.³⁷ In our surgical experience with this population, the hospital mortality rate and risk of stroke from aortic surgery were 0.25% and 0.75%, respectively.³⁷ Thus, the decision to operate for aortic aneurysm in the setting of a bicuspid aortic valve should take into account patient-specific factors and institutional outcomes.

A statement of clarification in the American College of Cardiology/American Heart Association guidelines was published in 2015, recommending surgery for patients with an aortic diameter of 5.0 cm or greater if the patient is at low risk and the surgery is performed by an experienced surgical team at a center with established surgical expertise in this condition.³⁸ However, current recommendations are for surgery at 5.5 cm if the above conditions are not met.

Ratio of aortic cross-sectional area to height

Although size alone has long been used to guide surgical intervention, a recent review from the International Registry of Aortic Dissection revealed that 59% of patients suffered aortic dissection at diameters less than 5.5 cm, and that patients with certain connective tissue diseases such as Loeys-Dietz syndrome or familial thoracic aneurysm and dissection had a documented propensity for dissection at smaller diameters.^39–41

Size indices such as the aortic cross-sectional area indexed to height have been implemented in guidelines for certain patient populations (eg, 10 cm²/m in Marfan syndrome) and provide better risk stratification than size cutoffs alone.^2,42

The ratio of aortic cross-sectional area to the patient’s height has also been applied to patients with bicuspid aortic valve-associated aortopathy and to those with a dilated aorta and a tricuspid aortic valve.^43,44 Notably, a ratio greater than 10 cm²/m has been associated with aortic dissection in these groups, and this cutoff provides better stratification for prediction of death than traditional size metrics.^27,28

Initial screening and follow-up

Follow-up of TAA depends on the initial aortic size or rate of growth, or both. For patients presenting for the first time with TAA, it is reasonable to obtain definitive aortic imaging with CT or magnetic resonance angiography (MRA), then to repeat imaging at 6 months to document stability. If the aortic dimensions remain stable, then annual follow-up with CT or MRA is reasonable.²

Our flow chart of initial screening and follow-up is shown in Figure 5.

Screening of family members

In our center, we routinely recommend screening of all first-degree relatives of patients with TAA. Aortic imaging with echocardiography plus CT or MRI should be considered to detect asymptomatic disease.² In patients with a strong family history (ie, multiple relatives affected with aortic aneurysm, dissection, or sudden cardiac death), genetic screening and testing for known mutations are recommended for the patient as well as for the family members.

If a mutation is identified in a family, then first-degree relatives should undergo genetic screening for the mutation and aortic imaging.² Imaging in second-degree relatives may also be considered if one or more first-degree relatives are found to have aortic dilation.²

We recommend similar screening of first-degree family members of patients with bicuspid aortic valve aortopathy. In patients with young children, we recommend obtaining an echocardiogram of the child to look for a bicuspid aortic valve or aortic dilation. If an abnormality is detected or suspected, dedicated imaging with MRA to assess aortic dimensions is warranted.

BACK TO OUR PATIENT WITH A BICUSPID AORTIC VALVE

Our patient with a bicuspid aortic valve had a 4.6-cm root, an ascending aortic aneurysm, and several affected family members.

We would obtain dedicated aortic imaging at this patient’s initial visit with either gated CT with contrast or MRA, and we would obtain a cardioaortic surgery consult. We would repeat these studies at a follow-up visit 6 months later to detect any aortic growth compared with initial studies, and follow up annually thereafter. Echocardiography can also be done at the initial visit to determine if valvular disease is present that may influence clinical decisions.

Surgery would likely be recommended once the root reached a maximum area-to-height ratio greater than 10 cm²/m, or if the valve became severely dysfunctional during follow-up.

BACK TO OUR PATIENT WITH MARFAN SYNDROME

The young woman with Marfan syndrome has a 4.6-cm aortic root aneurysm and 2+ aortic insufficiency. Her question pertains to the threshold at which an operation would be considered. This question is complicated and is influenced by several concurrent clinical features in her presentation.

Starting with size criteria, patients with Marfan syndrome should be considered for elective aortic root repair at a diameter greater than 5 cm. However, an aortic cross-sectional area-to-height ratio greater than 10 cm²/m may provide a more robust metric for clinical decision-making than aortic diameter alone. Additional factors such as degree of aortic insufficiency and deleterious left ventricular remodeling may urge one to consider aortic root repair at a diameter of 4.5 cm.

These factors, including rate of growth and the surgeon’s assessment about his or her ability to preserve the aortic valve during repair, should be considered collectively in this scenario.

Thoracic aortic aneurysm (TAA) needs to be detected, monitored, and managed in a timely manner to prevent a serious consequence such as acute dissection or rupture. But only about 5% of patients experience symptoms before an acute event occurs, and for the other 95% the first “symptom” is often death.¹ Most cases are detected either incidentally with echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI) during workup for another condition. Patients may also be diagnosed during workup of a murmur or after a family member is found to have an aneurysm. Therefore, its true incidence is difficult to determine.²

With these facts in mind, how would you manage the following 2 cases?

Case 1: Bicuspid aortic valve, ascending aortic aneurysm

A 45-year-old man with stage 1 hypertension presents for evaluation of a bicuspid aortic valve and ascending aortic aneurysm. He has several first-degree relatives with similar conditions, and his brother recently underwent elective aortic repair. At the urging of his primary care physician, he underwent screening echocardiography, which demonstrated a “dilated root and ascending aorta” 4.6 cm in diameter. He presents today to discuss management options and how the aneurysm could affect his everyday life.

Case 2: Marfan syndrome in a young woman

A 24-year-old woman with Marfan syndrome diagnosed in adolescence presents for annual follow-up. She has many family members with the same condition, and several have undergone prophylactic aortic root repair. Her aortic root has been monitored annually for progression of dilation, and today it is 4.6 cm in diameter, a 3-mm increase from the last measurement. She has grade 2+ aortic insufficiency (on a scale of 1+ to 4+) based on echocardiography, but she has no symptoms. She is curious about what size her aortic root will need to reach for surgery to be considered.

LIKELY UNDERDETECTED

TAA is being detected more often than in the past thanks to better detection methods and heightened awareness among physicians and patients. While an incidence rate of 10.4 per 100,000 patient-years is often cited,³ this figure likely underestimates the true incidence of this clinically silent condition. The most robust data come from studies based on in-hospital diagnostic codes coupled with data from autopsies for out-of-hospital deaths.

Olsson et al,⁴ in a 2016 study in Sweden, found the incidence of TAA and aortic dissection to be 16.3 per 100,000 per year for men and 9.1 per 100,000 per year for women.

Clouse et al⁵ reported the incidence of thoracic aortic dissection as 3.5 per 100,000 patient-years, and the same figure for thoracic aortic rupture. 

Aneurysmal disease accounts for 52,000 deaths per year in the United States, making it the 19th most common cause of death.⁶ These figures are likely lower than the true mortality rate for this condition, given that aortic dissection is often mistaken for acute myocardial infarction or other acute event if an autopsy is not done to confirm the cause of death.⁷

RISK FACTORS FOR THORACIC AORTIC ANEURYSM

Risk factors for TAA include genetic conditions that lead to aortic medial weakness or destruction such as Loeys-Dietz syndrome and Marfan syndrome.² In addition, family history is important even in the absence of known genetic mutations. Other risk factors include conditions that increase aortic wall stress, such as hypertension, cocaine abuse, extreme weightlifting, trauma, and aortic coarctation.²

DIAMETER INCREASES WITH AGE, BODY SURFACE AREA

Normal dimensions for the aortic segments differ depending on age, sex, and body surface area.^8,44,45 The size of the aortic root may also vary depending on how it is measured, due to the root’s trefoil shape. Measured sinus to sinus, the root is larger than when measured sinus to commissure on CT angiography or cardiac MRI. It is also larger when measured leading edge to leading edge than inner edge to inner edge on echocardiography.¹⁰

TAA is defined as an aortic diameter at least 50% greater than the upper limit of normal.⁸ 

Geometric changes in the curvature of the ascending aorta, aortic arch, and descending thoracic aorta can occur as the result of hypertension, atherosclerosis, or connective tissue disease. 

Imaging tests

It is particularly important to obtain a gated CTA image in patients with aortic root aneurysm to avoid motion artifact and possible erroneous measurements. Gated CTA is done with electrocardiographic synchronization and allows for image processing to correct for cardiac motion.

TAA can be caused by a variety of inherited and sporadic conditions. These differences in pathogenesis lend themselves to classification of aneurysms into groups. Table 3 highlights the most common conditions associated with TAA.¹³

Bicuspid aortic valve aortopathy

From 1% to 2% of people have a bicuspid aortic valve, with a 3-to-1 male predominance.^14,15 Aortic dilation occurs in 35% to 80% of people who have a bicuspid aortic valve, conferring a risk of dissection 8 times higher than in the general population.^16–18

The pathogenic mechanisms that lead to this condition are widely debated, although a combination of genetic defects leading to intrinsic weakening of the aortic wall and hemodynamic effects likely contribute.¹⁹ Evidence of hemodynamic contributions to aortic dilation comes from findings that particular patterns of cusp fusion of the bicuspid aortic valve result in changes in transvalvular flow, placing more stress on specific regions of the ascending aorta.^20,21 These hemodynamic alterations result in patterns of aortic dilation that depend on cusp fusion and the presence of valvular disease.

Multiple small studies found that replacing bicuspid aortic valves reduced the rate of aortic dilation, suggesting that hemodynamic factors may play a larger role than intrinsic wall properties in genetically susceptible individuals.^22,23 However, larger studies are needed before any definitive conclusions can be made.

HOW IS ANEURYSM MANAGED ON AN OUTPATIENT BASIS?

Patients with a new diagnosis of TAA should be referred to a cardiologist with expertise in managing aortic disease or to a cardiac surgeon specializing in aortic surgery, depending on the initial size of the aneurysm.

Control blood pressure with beta-blockers

Medical management for patients with TAA has historically been limited to strict blood pressure control aimed at reducing aortic wall stress, mainly with beta-blockers.

Are angiotensin II receptor blockers (ARBs) beneficial? Studies in a mouse model of Marfan syndrome revealed that the ARB losartan attenuated aortic root growth.²⁴ The results of early, small studies in humans were promising,^25–27 but larger randomized trials have shown no advantage of losartan over beta-blockers in slowing aortic root growth.²⁸ These negative results led many to question the effectiveness of losartan, although some point out that no studies have shown even beta-blockers to be beneficial in reducing the clinical end points of death or dissection.²⁹ On the other hand, patients with certain FBN1 mutations respond more readily than others to losartan.³⁰ Additional clinical trials of ARBs in Marfan syndrome are ongoing.

Current guidelines recommend stringent blood pressure control and smoking cessation for patients with a small aneurysm not requiring surgery and for those who are considered unsuitable for surgical or percutaneous intervention (level of evidence C, the lowest).² For patients with TAA, it is considered reasonable to give beta-blockers. Angiotensin-converting enzyme inhibitors or ARBs may be used in combination with beta-blockers, titrated to the lowest tolerable blood pressure without adverse effects (level of evidence B).²

The recommended target blood pressure is less than 140/90 mm Hg, or 130/80 mm Hg in those with diabetes or chronic kidney disease (level of evidence B).² However, we recommend more stringent blood pressure control: ie, less than 130/80 mm Hg for all patients with aortic aneurysm and a heart rate goal of 70 beats per minute or less, as tolerated.

Activity restriction

Activity restrictions for patients with TAA are largely based on theory, and certain activities may require more modification than others. For example, heavy lifting should be discouraged, as it may increase blood pressure significantly for short periods of time.^2,31 The increased wall stress, in theory, could initiate dissection or rupture. However, moderate-intensity aerobic activity is rarely associated with significant elevations in blood pressure and should be encouraged. Stressful emotional states have been anecdotally associated with aortic dissection; thus, measures to reduce stress may offer some benefit.³¹

Our recommendations. While there are no published guidelines regarding activity restrictions in patients with TAA, we use a graded approach based on aortic diameter:

• 4.0 to 4.4 cm—lift no more than 75 pounds
• 4.5 to 5 cm—lift no more than 50 pounds
• 5 cm—lift no more than 25 pounds.

We also recommend not lifting anything heavier than half of one’s body weight and to avoid breath-holding or performing the Valsalva maneuver while lifting. Although these recommendations are somewhat arbitrary, based on theory and a large clinical experience at our aortic center, they seem reasonable and practical.

Activity restrictions should be stringent and individualized in patients with Marfan, Loeys-Dietz, or Ehlers-Danlos syndrome due to increased risk of dissection or rupture even if the aorta is normal in size.

We sometimes recommend exercise stress testing to assess the heart rate and blood pressure response to exercise, and we are developing research protocols to help tailor activity recommendations.

To a cardiologist at the time of diagnosis

As soon as TAA is diagnosed, the patient should be referred to a cardiologist who has special interest in aortic disease. This will allow for appropriate and timely decisions about medical management, imaging, follow-up, and referral to surgery. Additional recommendations for screening of family members and referral to clinical geneticists can be discussed at this juncture. Activity restrictions should be reviewed at the initial evaluation.

To a surgeon relatively early

Size thresholds for surgical intervention are discussed below, but one should not wait until these thresholds are reached to send the patient for surgical consultation. It is beneficial to the state of mind of a potential surgical candidate to have early discussions pertaining to the types of operations available, their outcomes, and associated risks and benefits. If a patient’s aortic size remains stable over time, he or she may be followed by the cardiologist until significant size or growth has been documented, at which time the patient and surgeon can reconvene to discuss options for definitive treatment.

To a clinical geneticist

If 1 or more first-degree relatives of a patient with TAA or dissection are found to have aneurysmal disease, referral to a clinical geneticist is very important for genetic testing of multiple genes that have been implicated in thoracic aortic aneurysm and dissection.

WHEN SHOULD TAA BE REPAIRED?

Surgery to prevent rupture or dissection remains the definitive treatment of TAA when size thresholds are reached, and symptomatic aneurysm should be operated on regardless of the size. However, rarely are thoracic aneurysms symptomatic unless they rupture or dissect. The size criteria are based on underlying genetic etiology if known and on the behavior and natural course of TAA.

Size and other factors

Treatment should be tailored to the patient’s clinical scenario, family history, and estimated risk of rupture or dissection, balanced against the individual center’s outcomes of elective aortic replacement.³² For example, young and otherwise healthy patients with TAA and a family history of aortic dissection (who may be more likely to have connective tissue disorders such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehler-Danlos syndrome) may elect to undergo repair when the aneurysm reaches or nearly reaches the diameter of that of the family member’s aorta when dissection occurred.² On the other hand, TAA of degenerative etiology (eg, related to smoking or hypertension) measuring less than 5.5 cm in an older patient with comorbidities poses a lower risk of a catastrophic event such as dissection or rupture than the risk of surgery.¹¹

Thresholds for surgery. Once the diameter of the ascending aorta reaches 6 cm, the likelihood of an acute dissection is 31%.¹¹ A similar threshold is reached for the descending aorta at a size of 7 cm.¹¹ Therefore, to avoid high-risk emergency surgery on an acutely dissected aorta, surgery on an ascending aortic aneurysm of degenerative etiology is usually suggested when the aneurysm reaches 5.5 cm or a documented growth rate greater than 0.5 cm/year.^2,33

Additionally, in patients already undergoing surgery for valvular or coronary disease, prophylactic aortic replacement is recommended if the ascending aorta is larger than 4.5 cm. The threshold for intervention is lower in patients with connective tissue disease (> 5.0 cm for Marfan syndrome, 4.4–4.6 cm for Loeys-Dietz syndrome).^2,33

Observational studies suggest that the risk of aortic complications in patients with bicuspid aortic valve aortopathy is low overall, though significantly greater than in the general population.^18,34,35 These findings led to changes in the 2014 American College of Cardiology/American Heart Association guidelines on valvular heart disease,³⁶ suggesting a surgical threshold of 5.5 cm in the absence of significant valve disease or family history of dissection of an aorta of smaller diameter.

A 2015 study of dissection risk in patients with bicuspid aortic valve aortopathy by our group found a dramatic increase in risk of aortic dissection for ascending aortic diameters greater than 5.3 cm, and a gradual increase in risk for aortic root diameters greater than 5.0 cm.³⁷ In addition, a near-constant 3% to 4% risk of dissection was present for aortic diameters ranging from 4.7 cm to 5.0 cm, revealing that watchful waiting carries its own inherent risks.³⁷ In our surgical experience with this population, the hospital mortality rate and risk of stroke from aortic surgery were 0.25% and 0.75%, respectively.³⁷ Thus, the decision to operate for aortic aneurysm in the setting of a bicuspid aortic valve should take into account patient-specific factors and institutional outcomes.

A statement of clarification in the American College of Cardiology/American Heart Association guidelines was published in 2015, recommending surgery for patients with an aortic diameter of 5.0 cm or greater if the patient is at low risk and the surgery is performed by an experienced surgical team at a center with established surgical expertise in this condition.³⁸ However, current recommendations are for surgery at 5.5 cm if the above conditions are not met.

Ratio of aortic cross-sectional area to height

Although size alone has long been used to guide surgical intervention, a recent review from the International Registry of Aortic Dissection revealed that 59% of patients suffered aortic dissection at diameters less than 5.5 cm, and that patients with certain connective tissue diseases such as Loeys-Dietz syndrome or familial thoracic aneurysm and dissection had a documented propensity for dissection at smaller diameters.^39–41

Size indices such as the aortic cross-sectional area indexed to height have been implemented in guidelines for certain patient populations (eg, 10 cm²/m in Marfan syndrome) and provide better risk stratification than size cutoffs alone.^2,42

The ratio of aortic cross-sectional area to the patient’s height has also been applied to patients with bicuspid aortic valve-associated aortopathy and to those with a dilated aorta and a tricuspid aortic valve.^43,44 Notably, a ratio greater than 10 cm²/m has been associated with aortic dissection in these groups, and this cutoff provides better stratification for prediction of death than traditional size metrics.^27,28

Initial screening and follow-up

Follow-up of TAA depends on the initial aortic size or rate of growth, or both. For patients presenting for the first time with TAA, it is reasonable to obtain definitive aortic imaging with CT or magnetic resonance angiography (MRA), then to repeat imaging at 6 months to document stability. If the aortic dimensions remain stable, then annual follow-up with CT or MRA is reasonable.²

Our flow chart of initial screening and follow-up is shown in Figure 5.

Screening of family members

In our center, we routinely recommend screening of all first-degree relatives of patients with TAA. Aortic imaging with echocardiography plus CT or MRI should be considered to detect asymptomatic disease.² In patients with a strong family history (ie, multiple relatives affected with aortic aneurysm, dissection, or sudden cardiac death), genetic screening and testing for known mutations are recommended for the patient as well as for the family members.

If a mutation is identified in a family, then first-degree relatives should undergo genetic screening for the mutation and aortic imaging.² Imaging in second-degree relatives may also be considered if one or more first-degree relatives are found to have aortic dilation.²

We recommend similar screening of first-degree family members of patients with bicuspid aortic valve aortopathy. In patients with young children, we recommend obtaining an echocardiogram of the child to look for a bicuspid aortic valve or aortic dilation. If an abnormality is detected or suspected, dedicated imaging with MRA to assess aortic dimensions is warranted.

BACK TO OUR PATIENT WITH A BICUSPID AORTIC VALVE

Our patient with a bicuspid aortic valve had a 4.6-cm root, an ascending aortic aneurysm, and several affected family members.

We would obtain dedicated aortic imaging at this patient’s initial visit with either gated CT with contrast or MRA, and we would obtain a cardioaortic surgery consult. We would repeat these studies at a follow-up visit 6 months later to detect any aortic growth compared with initial studies, and follow up annually thereafter. Echocardiography can also be done at the initial visit to determine if valvular disease is present that may influence clinical decisions.

Surgery would likely be recommended once the root reached a maximum area-to-height ratio greater than 10 cm²/m, or if the valve became severely dysfunctional during follow-up.

BACK TO OUR PATIENT WITH MARFAN SYNDROME

The young woman with Marfan syndrome has a 4.6-cm aortic root aneurysm and 2+ aortic insufficiency. Her question pertains to the threshold at which an operation would be considered. This question is complicated and is influenced by several concurrent clinical features in her presentation.

Starting with size criteria, patients with Marfan syndrome should be considered for elective aortic root repair at a diameter greater than 5 cm. However, an aortic cross-sectional area-to-height ratio greater than 10 cm²/m may provide a more robust metric for clinical decision-making than aortic diameter alone. Additional factors such as degree of aortic insufficiency and deleterious left ventricular remodeling may urge one to consider aortic root repair at a diameter of 4.5 cm.

These factors, including rate of growth and the surgeon’s assessment about his or her ability to preserve the aortic valve during repair, should be considered collectively in this scenario.

Thoracic aortic aneurysm (TAA) needs to be detected, monitored, and managed in a timely manner to prevent a serious consequence such as acute dissection or rupture. But only about 5% of patients experience symptoms before an acute event occurs, and for the other 95% the first “symptom” is often death.¹ Most cases are detected either incidentally with echocardiography, computed tomography (CT), or magnetic resonance imaging (MRI) during workup for another condition. Patients may also be diagnosed during workup of a murmur or after a family member is found to have an aneurysm. Therefore, its true incidence is difficult to determine.²

With these facts in mind, how would you manage the following 2 cases?

Case 1: Bicuspid aortic valve, ascending aortic aneurysm

A 45-year-old man with stage 1 hypertension presents for evaluation of a bicuspid aortic valve and ascending aortic aneurysm. He has several first-degree relatives with similar conditions, and his brother recently underwent elective aortic repair. At the urging of his primary care physician, he underwent screening echocardiography, which demonstrated a “dilated root and ascending aorta” 4.6 cm in diameter. He presents today to discuss management options and how the aneurysm could affect his everyday life.

Case 2: Marfan syndrome in a young woman

A 24-year-old woman with Marfan syndrome diagnosed in adolescence presents for annual follow-up. She has many family members with the same condition, and several have undergone prophylactic aortic root repair. Her aortic root has been monitored annually for progression of dilation, and today it is 4.6 cm in diameter, a 3-mm increase from the last measurement. She has grade 2+ aortic insufficiency (on a scale of 1+ to 4+) based on echocardiography, but she has no symptoms. She is curious about what size her aortic root will need to reach for surgery to be considered.

LIKELY UNDERDETECTED

TAA is being detected more often than in the past thanks to better detection methods and heightened awareness among physicians and patients. While an incidence rate of 10.4 per 100,000 patient-years is often cited,³ this figure likely underestimates the true incidence of this clinically silent condition. The most robust data come from studies based on in-hospital diagnostic codes coupled with data from autopsies for out-of-hospital deaths.

Olsson et al,⁴ in a 2016 study in Sweden, found the incidence of TAA and aortic dissection to be 16.3 per 100,000 per year for men and 9.1 per 100,000 per year for women.

Clouse et al⁵ reported the incidence of thoracic aortic dissection as 3.5 per 100,000 patient-years, and the same figure for thoracic aortic rupture. 

Aneurysmal disease accounts for 52,000 deaths per year in the United States, making it the 19th most common cause of death.⁶ These figures are likely lower than the true mortality rate for this condition, given that aortic dissection is often mistaken for acute myocardial infarction or other acute event if an autopsy is not done to confirm the cause of death.⁷

RISK FACTORS FOR THORACIC AORTIC ANEURYSM

Risk factors for TAA include genetic conditions that lead to aortic medial weakness or destruction such as Loeys-Dietz syndrome and Marfan syndrome.² In addition, family history is important even in the absence of known genetic mutations. Other risk factors include conditions that increase aortic wall stress, such as hypertension, cocaine abuse, extreme weightlifting, trauma, and aortic coarctation.²

DIAMETER INCREASES WITH AGE, BODY SURFACE AREA

Normal dimensions for the aortic segments differ depending on age, sex, and body surface area.^8,44,45 The size of the aortic root may also vary depending on how it is measured, due to the root’s trefoil shape. Measured sinus to sinus, the root is larger than when measured sinus to commissure on CT angiography or cardiac MRI. It is also larger when measured leading edge to leading edge than inner edge to inner edge on echocardiography.¹⁰

TAA is defined as an aortic diameter at least 50% greater than the upper limit of normal.⁸ 

Geometric changes in the curvature of the ascending aorta, aortic arch, and descending thoracic aorta can occur as the result of hypertension, atherosclerosis, or connective tissue disease. 

Imaging tests

It is particularly important to obtain a gated CTA image in patients with aortic root aneurysm to avoid motion artifact and possible erroneous measurements. Gated CTA is done with electrocardiographic synchronization and allows for image processing to correct for cardiac motion.

TAA can be caused by a variety of inherited and sporadic conditions. These differences in pathogenesis lend themselves to classification of aneurysms into groups. Table 3 highlights the most common conditions associated with TAA.¹³

Bicuspid aortic valve aortopathy

From 1% to 2% of people have a bicuspid aortic valve, with a 3-to-1 male predominance.^14,15 Aortic dilation occurs in 35% to 80% of people who have a bicuspid aortic valve, conferring a risk of dissection 8 times higher than in the general population.^16–18

The pathogenic mechanisms that lead to this condition are widely debated, although a combination of genetic defects leading to intrinsic weakening of the aortic wall and hemodynamic effects likely contribute.¹⁹ Evidence of hemodynamic contributions to aortic dilation comes from findings that particular patterns of cusp fusion of the bicuspid aortic valve result in changes in transvalvular flow, placing more stress on specific regions of the ascending aorta.^20,21 These hemodynamic alterations result in patterns of aortic dilation that depend on cusp fusion and the presence of valvular disease.

Multiple small studies found that replacing bicuspid aortic valves reduced the rate of aortic dilation, suggesting that hemodynamic factors may play a larger role than intrinsic wall properties in genetically susceptible individuals.^22,23 However, larger studies are needed before any definitive conclusions can be made.

HOW IS ANEURYSM MANAGED ON AN OUTPATIENT BASIS?

Patients with a new diagnosis of TAA should be referred to a cardiologist with expertise in managing aortic disease or to a cardiac surgeon specializing in aortic surgery, depending on the initial size of the aneurysm.

Control blood pressure with beta-blockers

Medical management for patients with TAA has historically been limited to strict blood pressure control aimed at reducing aortic wall stress, mainly with beta-blockers.

Are angiotensin II receptor blockers (ARBs) beneficial? Studies in a mouse model of Marfan syndrome revealed that the ARB losartan attenuated aortic root growth.²⁴ The results of early, small studies in humans were promising,^25–27 but larger randomized trials have shown no advantage of losartan over beta-blockers in slowing aortic root growth.²⁸ These negative results led many to question the effectiveness of losartan, although some point out that no studies have shown even beta-blockers to be beneficial in reducing the clinical end points of death or dissection.²⁹ On the other hand, patients with certain FBN1 mutations respond more readily than others to losartan.³⁰ Additional clinical trials of ARBs in Marfan syndrome are ongoing.

Current guidelines recommend stringent blood pressure control and smoking cessation for patients with a small aneurysm not requiring surgery and for those who are considered unsuitable for surgical or percutaneous intervention (level of evidence C, the lowest).² For patients with TAA, it is considered reasonable to give beta-blockers. Angiotensin-converting enzyme inhibitors or ARBs may be used in combination with beta-blockers, titrated to the lowest tolerable blood pressure without adverse effects (level of evidence B).²

The recommended target blood pressure is less than 140/90 mm Hg, or 130/80 mm Hg in those with diabetes or chronic kidney disease (level of evidence B).² However, we recommend more stringent blood pressure control: ie, less than 130/80 mm Hg for all patients with aortic aneurysm and a heart rate goal of 70 beats per minute or less, as tolerated.

Activity restriction

Activity restrictions for patients with TAA are largely based on theory, and certain activities may require more modification than others. For example, heavy lifting should be discouraged, as it may increase blood pressure significantly for short periods of time.^2,31 The increased wall stress, in theory, could initiate dissection or rupture. However, moderate-intensity aerobic activity is rarely associated with significant elevations in blood pressure and should be encouraged. Stressful emotional states have been anecdotally associated with aortic dissection; thus, measures to reduce stress may offer some benefit.³¹

Our recommendations. While there are no published guidelines regarding activity restrictions in patients with TAA, we use a graded approach based on aortic diameter:

• 4.0 to 4.4 cm—lift no more than 75 pounds
• 4.5 to 5 cm—lift no more than 50 pounds
• 5 cm—lift no more than 25 pounds.

We also recommend not lifting anything heavier than half of one’s body weight and to avoid breath-holding or performing the Valsalva maneuver while lifting. Although these recommendations are somewhat arbitrary, based on theory and a large clinical experience at our aortic center, they seem reasonable and practical.

Activity restrictions should be stringent and individualized in patients with Marfan, Loeys-Dietz, or Ehlers-Danlos syndrome due to increased risk of dissection or rupture even if the aorta is normal in size.

We sometimes recommend exercise stress testing to assess the heart rate and blood pressure response to exercise, and we are developing research protocols to help tailor activity recommendations.

To a cardiologist at the time of diagnosis

As soon as TAA is diagnosed, the patient should be referred to a cardiologist who has special interest in aortic disease. This will allow for appropriate and timely decisions about medical management, imaging, follow-up, and referral to surgery. Additional recommendations for screening of family members and referral to clinical geneticists can be discussed at this juncture. Activity restrictions should be reviewed at the initial evaluation.

To a surgeon relatively early

Size thresholds for surgical intervention are discussed below, but one should not wait until these thresholds are reached to send the patient for surgical consultation. It is beneficial to the state of mind of a potential surgical candidate to have early discussions pertaining to the types of operations available, their outcomes, and associated risks and benefits. If a patient’s aortic size remains stable over time, he or she may be followed by the cardiologist until significant size or growth has been documented, at which time the patient and surgeon can reconvene to discuss options for definitive treatment.

To a clinical geneticist

If 1 or more first-degree relatives of a patient with TAA or dissection are found to have aneurysmal disease, referral to a clinical geneticist is very important for genetic testing of multiple genes that have been implicated in thoracic aortic aneurysm and dissection.

WHEN SHOULD TAA BE REPAIRED?

Surgery to prevent rupture or dissection remains the definitive treatment of TAA when size thresholds are reached, and symptomatic aneurysm should be operated on regardless of the size. However, rarely are thoracic aneurysms symptomatic unless they rupture or dissect. The size criteria are based on underlying genetic etiology if known and on the behavior and natural course of TAA.

Size and other factors

Treatment should be tailored to the patient’s clinical scenario, family history, and estimated risk of rupture or dissection, balanced against the individual center’s outcomes of elective aortic replacement.³² For example, young and otherwise healthy patients with TAA and a family history of aortic dissection (who may be more likely to have connective tissue disorders such as Marfan syndrome, Loeys-Dietz syndrome, or vascular Ehler-Danlos syndrome) may elect to undergo repair when the aneurysm reaches or nearly reaches the diameter of that of the family member’s aorta when dissection occurred.² On the other hand, TAA of degenerative etiology (eg, related to smoking or hypertension) measuring less than 5.5 cm in an older patient with comorbidities poses a lower risk of a catastrophic event such as dissection or rupture than the risk of surgery.¹¹

Thresholds for surgery. Once the diameter of the ascending aorta reaches 6 cm, the likelihood of an acute dissection is 31%.¹¹ A similar threshold is reached for the descending aorta at a size of 7 cm.¹¹ Therefore, to avoid high-risk emergency surgery on an acutely dissected aorta, surgery on an ascending aortic aneurysm of degenerative etiology is usually suggested when the aneurysm reaches 5.5 cm or a documented growth rate greater than 0.5 cm/year.^2,33

Additionally, in patients already undergoing surgery for valvular or coronary disease, prophylactic aortic replacement is recommended if the ascending aorta is larger than 4.5 cm. The threshold for intervention is lower in patients with connective tissue disease (> 5.0 cm for Marfan syndrome, 4.4–4.6 cm for Loeys-Dietz syndrome).^2,33

Observational studies suggest that the risk of aortic complications in patients with bicuspid aortic valve aortopathy is low overall, though significantly greater than in the general population.^18,34,35 These findings led to changes in the 2014 American College of Cardiology/American Heart Association guidelines on valvular heart disease,³⁶ suggesting a surgical threshold of 5.5 cm in the absence of significant valve disease or family history of dissection of an aorta of smaller diameter.

A 2015 study of dissection risk in patients with bicuspid aortic valve aortopathy by our group found a dramatic increase in risk of aortic dissection for ascending aortic diameters greater than 5.3 cm, and a gradual increase in risk for aortic root diameters greater than 5.0 cm.³⁷ In addition, a near-constant 3% to 4% risk of dissection was present for aortic diameters ranging from 4.7 cm to 5.0 cm, revealing that watchful waiting carries its own inherent risks.³⁷ In our surgical experience with this population, the hospital mortality rate and risk of stroke from aortic surgery were 0.25% and 0.75%, respectively.³⁷ Thus, the decision to operate for aortic aneurysm in the setting of a bicuspid aortic valve should take into account patient-specific factors and institutional outcomes.

A statement of clarification in the American College of Cardiology/American Heart Association guidelines was published in 2015, recommending surgery for patients with an aortic diameter of 5.0 cm or greater if the patient is at low risk and the surgery is performed by an experienced surgical team at a center with established surgical expertise in this condition.³⁸ However, current recommendations are for surgery at 5.5 cm if the above conditions are not met.

Ratio of aortic cross-sectional area to height

Although size alone has long been used to guide surgical intervention, a recent review from the International Registry of Aortic Dissection revealed that 59% of patients suffered aortic dissection at diameters less than 5.5 cm, and that patients with certain connective tissue diseases such as Loeys-Dietz syndrome or familial thoracic aneurysm and dissection had a documented propensity for dissection at smaller diameters.^39–41

Size indices such as the aortic cross-sectional area indexed to height have been implemented in guidelines for certain patient populations (eg, 10 cm²/m in Marfan syndrome) and provide better risk stratification than size cutoffs alone.^2,42

The ratio of aortic cross-sectional area to the patient’s height has also been applied to patients with bicuspid aortic valve-associated aortopathy and to those with a dilated aorta and a tricuspid aortic valve.^43,44 Notably, a ratio greater than 10 cm²/m has been associated with aortic dissection in these groups, and this cutoff provides better stratification for prediction of death than traditional size metrics.^27,28

Initial screening and follow-up

Follow-up of TAA depends on the initial aortic size or rate of growth, or both. For patients presenting for the first time with TAA, it is reasonable to obtain definitive aortic imaging with CT or magnetic resonance angiography (MRA), then to repeat imaging at 6 months to document stability. If the aortic dimensions remain stable, then annual follow-up with CT or MRA is reasonable.²

Our flow chart of initial screening and follow-up is shown in Figure 5.

Screening of family members

In our center, we routinely recommend screening of all first-degree relatives of patients with TAA. Aortic imaging with echocardiography plus CT or MRI should be considered to detect asymptomatic disease.² In patients with a strong family history (ie, multiple relatives affected with aortic aneurysm, dissection, or sudden cardiac death), genetic screening and testing for known mutations are recommended for the patient as well as for the family members.

If a mutation is identified in a family, then first-degree relatives should undergo genetic screening for the mutation and aortic imaging.² Imaging in second-degree relatives may also be considered if one or more first-degree relatives are found to have aortic dilation.²

We recommend similar screening of first-degree family members of patients with bicuspid aortic valve aortopathy. In patients with young children, we recommend obtaining an echocardiogram of the child to look for a bicuspid aortic valve or aortic dilation. If an abnormality is detected or suspected, dedicated imaging with MRA to assess aortic dimensions is warranted.

BACK TO OUR PATIENT WITH A BICUSPID AORTIC VALVE

Our patient with a bicuspid aortic valve had a 4.6-cm root, an ascending aortic aneurysm, and several affected family members.

We would obtain dedicated aortic imaging at this patient’s initial visit with either gated CT with contrast or MRA, and we would obtain a cardioaortic surgery consult. We would repeat these studies at a follow-up visit 6 months later to detect any aortic growth compared with initial studies, and follow up annually thereafter. Echocardiography can also be done at the initial visit to determine if valvular disease is present that may influence clinical decisions.

Surgery would likely be recommended once the root reached a maximum area-to-height ratio greater than 10 cm²/m, or if the valve became severely dysfunctional during follow-up.

BACK TO OUR PATIENT WITH MARFAN SYNDROME

The young woman with Marfan syndrome has a 4.6-cm aortic root aneurysm and 2+ aortic insufficiency. Her question pertains to the threshold at which an operation would be considered. This question is complicated and is influenced by several concurrent clinical features in her presentation.

Starting with size criteria, patients with Marfan syndrome should be considered for elective aortic root repair at a diameter greater than 5 cm. However, an aortic cross-sectional area-to-height ratio greater than 10 cm²/m may provide a more robust metric for clinical decision-making than aortic diameter alone. Additional factors such as degree of aortic insufficiency and deleterious left ventricular remodeling may urge one to consider aortic root repair at a diameter of 4.5 cm.

These factors, including rate of growth and the surgeon’s assessment about his or her ability to preserve the aortic valve during repair, should be considered collectively in this scenario.

A 40-year-old man with a history of hypertension and alcohol abuse presented with acute onset of mild chest tightness, left leg pain, and increasing agitation, which prevented us from obtaining additional meaningful information from him.

On admission, his heart rate was 120 beats per minute, blood pressure 211/122 mm Hg, respiratory rate 18 per minute, and oxygen saturation 92% on room air. Given his history of alcohol abuse, we checked his blood ethanol level, which was less than 0.01%, well below the legal limit for intoxication.

We gave the patient intravenous lorazepam for possible alcohol withdrawal and started labetalol by intravenous infusion to lower his blood pressure.

On physical examination, his left lower extremity was cold and without pulses, including the femoral pulse. Suspecting acute arterial thrombosis, we ordered immediate computed tomographic (CT) angiography of the abdomen and pelvis with left lower extremity runoff. The images showed dissection of the abdominal aorta with extension to both the left and right common iliac arteries and the origin of the right external iliac artery. There was resultant occlusion of the left external iliac artery (Figure 1).

Immediate CT angiography of the chest was then performed, which revealed dissection of the thoracic aorta as well, starting superior to the aortic valve annulus and involving the ascending aorta, aortic arch, and the entire descending thoracic aorta (Figure 2).

The patient underwent emergency surgical repair of the aortic root, ascending aorta, and aortic arch. Residual dissection of the descending aorta was managed conservatively with blood pressure control using intravenous labetalol initially, which was then switched to oral carvedilol, and the pulses returned in his left lower extremity. He had an unremarkable postoperative recovery and was discharged after 1 week.

AORTIC DISSECTION AND MALPERFUSION SYNDROME

Aortic dissection is most often associated with acute onset of sharp chest pain and upper back pain. On rare occasions, it can have an atypical presentation such as stroke, paraplegia, mesenteric ischemia, or lower limb malperfusion.¹

Extension of aortic dissection into the iliac and femoral arteries can cause impaired or absent blood flow to the lower extremity. These pulse deficits are a part of limb mal­perfusion syndrome. Symptoms of malperfusion syndrome vary greatly and depend on the vessels involved. Malperfusion of the branches of the aortic arch can result in stroke or altered sensorium. Compromise of intra-abdominal vessels due to dissection can involve the mesenteric bed, the renal arteries, or both, resulting in laboratory derangements such as lactic acidosis and renal failure.

How aortic dissection and malperfusion syndrome occur

Over time, shear forces on the aortic wall result in degeneration of the tunica intima and media. Dissection occurs when deterioration of the intima causes propagation of blood through a cleavage plane into the outer portion of the diseased media, forming a false lumen.

Anterograde or retrograde progression of dissection depends on the balance of the pressure gradient between true and false lumens.² With every systolic ventricular contraction, a fluid and pressure wave travels down both lumens (true and false). However, the pressure gradient between the false and true lumens allows the more pliable intimal flap to bulge into the true lumen and ostia of branch vessels, resulting in static or dynamic obstruction.

Static obstruction occurs when the false lumen projects completely into the branch vessel and there is resultant thrombosis. As the name implies, dynamic obstruction is intermittent and is responsible for 80% of the cases of malperfusion syndrome.³ Dynamic obstruction has 2 distinct mechanisms: hypoperfusion through the true lumen due to impaired flow, and prolapse of the false lumen into a branch vessel.

Factors that exacerbate hypoperfusion through the true lumen and make obliteration by the false lumen more likely include large circumference of the dissected aorta, rapid heart rate, and high systolic pressure.⁴ Therefore, it is important to control the heart rate and blood pressure using beta-blockers in cases of aortic dissection with malperfusion syndrome. This treatment may resolve the dynamic obstruction through expansion and resumption of perfusion through the true lumen.⁵

MANAGEMENT OF MALPERFUSION SYNDROME

Aortic dissection can be classified as either Stanford type A (involving the ascending aorta) or type B (involving the descending aorta). Type B dissection associated with malperfusion syndrome is termed “complicated” type B aortic dissection. Our patient had both Stanford type A and complicated type B aortic dissection.

Unlike type A aortic dissection, which requires definitive open surgical repair, complicated type B aortic dissection occasionally responds to medical management alone. A plausible explanation for resolution of limb malperfusion with optimal blood pressure control is expansion of the true lumen and obliteration of the false lumen, as was likely the case in our patient.

In most cases, however, limb malperfusion persists despite optimal medical management. In such patients, endovascular graft stenting or open surgical repair may be needed. Open surgical repair procedures like bypass grafting or surgical fenestration are associated with significant rates of mortality and morbidity.⁵ Therefore, an endovascular approach rather than conventional surgical repair for complicated type B aortic dissection is advocated after optimal medical management.⁶ Endovascular repair also promotes favorable aortic remodeling without the morbidity associated with open surgical repair.

A 40-year-old man with a history of hypertension and alcohol abuse presented with acute onset of mild chest tightness, left leg pain, and increasing agitation, which prevented us from obtaining additional meaningful information from him.

On admission, his heart rate was 120 beats per minute, blood pressure 211/122 mm Hg, respiratory rate 18 per minute, and oxygen saturation 92% on room air. Given his history of alcohol abuse, we checked his blood ethanol level, which was less than 0.01%, well below the legal limit for intoxication.

We gave the patient intravenous lorazepam for possible alcohol withdrawal and started labetalol by intravenous infusion to lower his blood pressure.

On physical examination, his left lower extremity was cold and without pulses, including the femoral pulse. Suspecting acute arterial thrombosis, we ordered immediate computed tomographic (CT) angiography of the abdomen and pelvis with left lower extremity runoff. The images showed dissection of the abdominal aorta with extension to both the left and right common iliac arteries and the origin of the right external iliac artery. There was resultant occlusion of the left external iliac artery (Figure 1).

Immediate CT angiography of the chest was then performed, which revealed dissection of the thoracic aorta as well, starting superior to the aortic valve annulus and involving the ascending aorta, aortic arch, and the entire descending thoracic aorta (Figure 2).

The patient underwent emergency surgical repair of the aortic root, ascending aorta, and aortic arch. Residual dissection of the descending aorta was managed conservatively with blood pressure control using intravenous labetalol initially, which was then switched to oral carvedilol, and the pulses returned in his left lower extremity. He had an unremarkable postoperative recovery and was discharged after 1 week.

AORTIC DISSECTION AND MALPERFUSION SYNDROME

Aortic dissection is most often associated with acute onset of sharp chest pain and upper back pain. On rare occasions, it can have an atypical presentation such as stroke, paraplegia, mesenteric ischemia, or lower limb malperfusion.¹

Extension of aortic dissection into the iliac and femoral arteries can cause impaired or absent blood flow to the lower extremity. These pulse deficits are a part of limb mal­perfusion syndrome. Symptoms of malperfusion syndrome vary greatly and depend on the vessels involved. Malperfusion of the branches of the aortic arch can result in stroke or altered sensorium. Compromise of intra-abdominal vessels due to dissection can involve the mesenteric bed, the renal arteries, or both, resulting in laboratory derangements such as lactic acidosis and renal failure.

How aortic dissection and malperfusion syndrome occur

Over time, shear forces on the aortic wall result in degeneration of the tunica intima and media. Dissection occurs when deterioration of the intima causes propagation of blood through a cleavage plane into the outer portion of the diseased media, forming a false lumen.

Anterograde or retrograde progression of dissection depends on the balance of the pressure gradient between true and false lumens.² With every systolic ventricular contraction, a fluid and pressure wave travels down both lumens (true and false). However, the pressure gradient between the false and true lumens allows the more pliable intimal flap to bulge into the true lumen and ostia of branch vessels, resulting in static or dynamic obstruction.

Static obstruction occurs when the false lumen projects completely into the branch vessel and there is resultant thrombosis. As the name implies, dynamic obstruction is intermittent and is responsible for 80% of the cases of malperfusion syndrome.³ Dynamic obstruction has 2 distinct mechanisms: hypoperfusion through the true lumen due to impaired flow, and prolapse of the false lumen into a branch vessel.

Factors that exacerbate hypoperfusion through the true lumen and make obliteration by the false lumen more likely include large circumference of the dissected aorta, rapid heart rate, and high systolic pressure.⁴ Therefore, it is important to control the heart rate and blood pressure using beta-blockers in cases of aortic dissection with malperfusion syndrome. This treatment may resolve the dynamic obstruction through expansion and resumption of perfusion through the true lumen.⁵

MANAGEMENT OF MALPERFUSION SYNDROME

Aortic dissection can be classified as either Stanford type A (involving the ascending aorta) or type B (involving the descending aorta). Type B dissection associated with malperfusion syndrome is termed “complicated” type B aortic dissection. Our patient had both Stanford type A and complicated type B aortic dissection.

Unlike type A aortic dissection, which requires definitive open surgical repair, complicated type B aortic dissection occasionally responds to medical management alone. A plausible explanation for resolution of limb malperfusion with optimal blood pressure control is expansion of the true lumen and obliteration of the false lumen, as was likely the case in our patient.

In most cases, however, limb malperfusion persists despite optimal medical management. In such patients, endovascular graft stenting or open surgical repair may be needed. Open surgical repair procedures like bypass grafting or surgical fenestration are associated with significant rates of mortality and morbidity.⁵ Therefore, an endovascular approach rather than conventional surgical repair for complicated type B aortic dissection is advocated after optimal medical management.⁶ Endovascular repair also promotes favorable aortic remodeling without the morbidity associated with open surgical repair.

A 40-year-old man with a history of hypertension and alcohol abuse presented with acute onset of mild chest tightness, left leg pain, and increasing agitation, which prevented us from obtaining additional meaningful information from him.

On admission, his heart rate was 120 beats per minute, blood pressure 211/122 mm Hg, respiratory rate 18 per minute, and oxygen saturation 92% on room air. Given his history of alcohol abuse, we checked his blood ethanol level, which was less than 0.01%, well below the legal limit for intoxication.

We gave the patient intravenous lorazepam for possible alcohol withdrawal and started labetalol by intravenous infusion to lower his blood pressure.

On physical examination, his left lower extremity was cold and without pulses, including the femoral pulse. Suspecting acute arterial thrombosis, we ordered immediate computed tomographic (CT) angiography of the abdomen and pelvis with left lower extremity runoff. The images showed dissection of the abdominal aorta with extension to both the left and right common iliac arteries and the origin of the right external iliac artery. There was resultant occlusion of the left external iliac artery (Figure 1).

Immediate CT angiography of the chest was then performed, which revealed dissection of the thoracic aorta as well, starting superior to the aortic valve annulus and involving the ascending aorta, aortic arch, and the entire descending thoracic aorta (Figure 2).

The patient underwent emergency surgical repair of the aortic root, ascending aorta, and aortic arch. Residual dissection of the descending aorta was managed conservatively with blood pressure control using intravenous labetalol initially, which was then switched to oral carvedilol, and the pulses returned in his left lower extremity. He had an unremarkable postoperative recovery and was discharged after 1 week.

AORTIC DISSECTION AND MALPERFUSION SYNDROME

Aortic dissection is most often associated with acute onset of sharp chest pain and upper back pain. On rare occasions, it can have an atypical presentation such as stroke, paraplegia, mesenteric ischemia, or lower limb malperfusion.¹

Extension of aortic dissection into the iliac and femoral arteries can cause impaired or absent blood flow to the lower extremity. These pulse deficits are a part of limb mal­perfusion syndrome. Symptoms of malperfusion syndrome vary greatly and depend on the vessels involved. Malperfusion of the branches of the aortic arch can result in stroke or altered sensorium. Compromise of intra-abdominal vessels due to dissection can involve the mesenteric bed, the renal arteries, or both, resulting in laboratory derangements such as lactic acidosis and renal failure.

How aortic dissection and malperfusion syndrome occur

Over time, shear forces on the aortic wall result in degeneration of the tunica intima and media. Dissection occurs when deterioration of the intima causes propagation of blood through a cleavage plane into the outer portion of the diseased media, forming a false lumen.

Anterograde or retrograde progression of dissection depends on the balance of the pressure gradient between true and false lumens.² With every systolic ventricular contraction, a fluid and pressure wave travels down both lumens (true and false). However, the pressure gradient between the false and true lumens allows the more pliable intimal flap to bulge into the true lumen and ostia of branch vessels, resulting in static or dynamic obstruction.

Static obstruction occurs when the false lumen projects completely into the branch vessel and there is resultant thrombosis. As the name implies, dynamic obstruction is intermittent and is responsible for 80% of the cases of malperfusion syndrome.³ Dynamic obstruction has 2 distinct mechanisms: hypoperfusion through the true lumen due to impaired flow, and prolapse of the false lumen into a branch vessel.

Factors that exacerbate hypoperfusion through the true lumen and make obliteration by the false lumen more likely include large circumference of the dissected aorta, rapid heart rate, and high systolic pressure.⁴ Therefore, it is important to control the heart rate and blood pressure using beta-blockers in cases of aortic dissection with malperfusion syndrome. This treatment may resolve the dynamic obstruction through expansion and resumption of perfusion through the true lumen.⁵

MANAGEMENT OF MALPERFUSION SYNDROME

Aortic dissection can be classified as either Stanford type A (involving the ascending aorta) or type B (involving the descending aorta). Type B dissection associated with malperfusion syndrome is termed “complicated” type B aortic dissection. Our patient had both Stanford type A and complicated type B aortic dissection.

Unlike type A aortic dissection, which requires definitive open surgical repair, complicated type B aortic dissection occasionally responds to medical management alone. A plausible explanation for resolution of limb malperfusion with optimal blood pressure control is expansion of the true lumen and obliteration of the false lumen, as was likely the case in our patient.

In most cases, however, limb malperfusion persists despite optimal medical management. In such patients, endovascular graft stenting or open surgical repair may be needed. Open surgical repair procedures like bypass grafting or surgical fenestration are associated with significant rates of mortality and morbidity.⁵ Therefore, an endovascular approach rather than conventional surgical repair for complicated type B aortic dissection is advocated after optimal medical management.⁶ Endovascular repair also promotes favorable aortic remodeling without the morbidity associated with open surgical repair.

A 59-year-old woman presented with drooling out of the left side of her mouth and inability to close her left eye. She had no ear pain, hearing loss, or skin rash. The facial palsy affected all branches of the left facial nerve. This explained her inability to close her left eyelid and the generalized weakness of the left side of the face, including her forehead and angle of the mouth. No other signs of pontine dysfunction were noted.

See related editorial

The symptoms had begun 2 months earlier, and computed tomography (CT) of the head performed at a nearby clinic 3 days after the onset of symptoms showed no abnormalities. She was given a diagnosis of incomplete Bell palsy and was prescribed prednisolone and valacyclovir. However, her symptoms had not improved after 2 months of treatment, and so she presented to our hospital.

Physical examination revealed moderate nerve dysfunction (House-Brackmann grade III, with grade I normal and grade VI total paralysis) and generalized weakness on the left side of her face including her forehead.¹ She had no loss in facial sensation or hearing and no ataxia or ocular motility disorders.

BELL PALSY

Peripheral facial nerve palsy is classified either as Bell palsy, which is idiopathic, or as secondary facial nerve palsy. Because Bell palsy accounts for 60% to 70% of all cases,² treatment with oral steroids is indicated when no abnormal findings other than lateral peripheral facial nerve palsy are observed. Antiviral drugs may provide added benefit, although academic societies do not currently recommend combined therapy.³ However, 85% of patients with Bell palsy improve within 3 weeks without treatment, and 94% of patients with incomplete Bell palsy—defined by normal to severe dysfunction, ie, not total paralysis, based on House-Brackmann score—eventually achieve complete remission.²

Therefore, although progression of symptoms or lack of improvement at 2 months does not rule out Bell palsy, it should prompt a detailed imaging evaluation to rule out an underlying condition such as tumor (in the pons, cerebellopontine angle, parotid gland, middle ear, or petrosal bone), infection (herpes simplex, varicella zoster, Ramsey-Hunt syndrome, or otitis media), trauma, or systemic disease (diabetes mellitus, multiple sclerosis, sarcoidosis, or systemic lupus erythematosus).⁴

According to a review of common causes of facial nerve palsy, the most common finding in 224 patients misdiagnosed with Bell palsy was tumor (38%).⁵ This indicates the value of magnetic resonance imaging of the head rather than CT when secondary facial nerve palsy is suspected, as CT is not sensitive to brainstem lesions.

A 59-year-old woman presented with drooling out of the left side of her mouth and inability to close her left eye. She had no ear pain, hearing loss, or skin rash. The facial palsy affected all branches of the left facial nerve. This explained her inability to close her left eyelid and the generalized weakness of the left side of the face, including her forehead and angle of the mouth. No other signs of pontine dysfunction were noted.

See related editorial

The symptoms had begun 2 months earlier, and computed tomography (CT) of the head performed at a nearby clinic 3 days after the onset of symptoms showed no abnormalities. She was given a diagnosis of incomplete Bell palsy and was prescribed prednisolone and valacyclovir. However, her symptoms had not improved after 2 months of treatment, and so she presented to our hospital.

Physical examination revealed moderate nerve dysfunction (House-Brackmann grade III, with grade I normal and grade VI total paralysis) and generalized weakness on the left side of her face including her forehead.¹ She had no loss in facial sensation or hearing and no ataxia or ocular motility disorders.

BELL PALSY

Peripheral facial nerve palsy is classified either as Bell palsy, which is idiopathic, or as secondary facial nerve palsy. Because Bell palsy accounts for 60% to 70% of all cases,² treatment with oral steroids is indicated when no abnormal findings other than lateral peripheral facial nerve palsy are observed. Antiviral drugs may provide added benefit, although academic societies do not currently recommend combined therapy.³ However, 85% of patients with Bell palsy improve within 3 weeks without treatment, and 94% of patients with incomplete Bell palsy—defined by normal to severe dysfunction, ie, not total paralysis, based on House-Brackmann score—eventually achieve complete remission.²

Therefore, although progression of symptoms or lack of improvement at 2 months does not rule out Bell palsy, it should prompt a detailed imaging evaluation to rule out an underlying condition such as tumor (in the pons, cerebellopontine angle, parotid gland, middle ear, or petrosal bone), infection (herpes simplex, varicella zoster, Ramsey-Hunt syndrome, or otitis media), trauma, or systemic disease (diabetes mellitus, multiple sclerosis, sarcoidosis, or systemic lupus erythematosus).⁴

According to a review of common causes of facial nerve palsy, the most common finding in 224 patients misdiagnosed with Bell palsy was tumor (38%).⁵ This indicates the value of magnetic resonance imaging of the head rather than CT when secondary facial nerve palsy is suspected, as CT is not sensitive to brainstem lesions.

A 59-year-old woman presented with drooling out of the left side of her mouth and inability to close her left eye. She had no ear pain, hearing loss, or skin rash. The facial palsy affected all branches of the left facial nerve. This explained her inability to close her left eyelid and the generalized weakness of the left side of the face, including her forehead and angle of the mouth. No other signs of pontine dysfunction were noted.

See related editorial

The symptoms had begun 2 months earlier, and computed tomography (CT) of the head performed at a nearby clinic 3 days after the onset of symptoms showed no abnormalities. She was given a diagnosis of incomplete Bell palsy and was prescribed prednisolone and valacyclovir. However, her symptoms had not improved after 2 months of treatment, and so she presented to our hospital.

Physical examination revealed moderate nerve dysfunction (House-Brackmann grade III, with grade I normal and grade VI total paralysis) and generalized weakness on the left side of her face including her forehead.¹ She had no loss in facial sensation or hearing and no ataxia or ocular motility disorders.

BELL PALSY

Peripheral facial nerve palsy is classified either as Bell palsy, which is idiopathic, or as secondary facial nerve palsy. Because Bell palsy accounts for 60% to 70% of all cases,² treatment with oral steroids is indicated when no abnormal findings other than lateral peripheral facial nerve palsy are observed. Antiviral drugs may provide added benefit, although academic societies do not currently recommend combined therapy.³ However, 85% of patients with Bell palsy improve within 3 weeks without treatment, and 94% of patients with incomplete Bell palsy—defined by normal to severe dysfunction, ie, not total paralysis, based on House-Brackmann score—eventually achieve complete remission.²

Therefore, although progression of symptoms or lack of improvement at 2 months does not rule out Bell palsy, it should prompt a detailed imaging evaluation to rule out an underlying condition such as tumor (in the pons, cerebellopontine angle, parotid gland, middle ear, or petrosal bone), infection (herpes simplex, varicella zoster, Ramsey-Hunt syndrome, or otitis media), trauma, or systemic disease (diabetes mellitus, multiple sclerosis, sarcoidosis, or systemic lupus erythematosus).⁴

According to a review of common causes of facial nerve palsy, the most common finding in 224 patients misdiagnosed with Bell palsy was tumor (38%).⁵ This indicates the value of magnetic resonance imaging of the head rather than CT when secondary facial nerve palsy is suspected, as CT is not sensitive to brainstem lesions.

The article in this issue by Shikino et al¹ on a mimic of Bell palsy gives us an opportunity to discuss the question posed by the title of this editorial. The obvious short answer is “no.”

See related article

Any experienced clinician will acknowledge that the extent of the physical examination and the extent of information obtained during the history should be determined by the problem being evaluated at the time and by the setting in which it takes place. The difficulty, of course, is that this relies on the judgment of the clinician, and this may or may not pass the test of hindsight.

Verghese et al² have eloquently emphasized the hazards of an incomplete or inadequate physical examination. Their study was not designed to determine the prevalence of deficient physical examination, either in its extent or its accuracy. Their purpose was to promote the necessity of proper teaching and performance of examination technique.

The neurologic examination is one of the last bastions of physical assessment.³ Despite remarkable advances in imaging and physiologic techniques, the neurologic physical assessment remains critical for diagnosis and management of the neurologic patient. One of my mentors in neurology used to urge residents to examine patients and record the results of the examination as if every patient would subsequently be the subject of a clinicopathologic conference. Anyone who has reviewed a case for a conference or a case report can identify with that sentiment, wishing that some missing piece of information were available. Yet everyone also recognizes the difficulties, if not the impossibility, of achieving that ideal result.

But recording information obtained during the history or physical examination is important even in the course of a daily routine evaluation. I find myself wishing that a previous examiner had commented on whether the muscle stretch reflexes were somewhat hypoactive (eg, “1+”) or on the brisk side (“3+”) rather than “physiologic.” Was the right leg actually globally weak (“4/5”), or was there a discrepancy between proximal and distal muscles or between the physiologic flexors and the extensors?

This can make a big difference in following a patient’s neurologic progress, even over a short time span. It might tell us whether we are dealing with weakness from a peripheral neuromuscular disorder (eg, Guillain-Barré syndrome) or from a myelopathy due to impending spinal cord compression.

It should be mentioned that although Guillain-Barré syndrome is characterized as an ascending paralysis, ie, beginning distally and spreading rostrally, it is one of the few peripheral neuropathies that can present with predominant proximal weakness. It is, in fact, a radiculoneuropathy. But spinal cord (upper motor neuron) disorders preferentially weaken the physiologic flexors of the lower limbs (hamstrings and ankle dorsiflexors), leading to the characteristic extensor posture of the spastic leg. Other findings that can help differential peripheral vs spinal cord disorders include distal sensory loss and hypoactive or absent muscle stretch reflexes in a peripheral neuropathy, compared with dissociated sensory loss (eg, impaired pain and temperature sensation in one leg with reduced vibration perception and proprioception in the other) along with hyperreflexia with cord lesions.

Therefore, a careful neurologic examination may tell us whether magnetic resonance imaging of the spine or an electrodiagnostic study should be the next step.

Shikino et al describe a patient who presented with what looked like idiopathic facial palsy (Bell palsy) but turned out to be the result of a primary central nervous system (CNS) cause. Would a more detailed neurologic examination have identified this as a CNS disorder? Would more specific information about the degree and distribution of facial paresis have facilitated earlier recognition of a progressive process, making idiopathic facial palsy less likely? How much elevation of the eyebrow occurred with voluntary activation, how many millimeters of sclera were visible with gentle eyelid closure? How much space remained between the lips on attempted lip closure?

Upper facial muscle weakness is typically not seen in CNS disorders, although facial nerve or nucleus involvement at the pontine level can impair eyelid and frontalis function. Such lesions would usually be accompanied by “neighborhood” signs such as subtle ipsilateral lateral rectus or abducens palsy, involvement of the vestibular nuclei with vertigo, or facial sensory impairment from disruption of the descending trigeminal nucleus and tract. These would be “pertinent negatives” for excluding a brainstem lesion, and ipsilateral motor, sensory, or “higher cortical” functions would obviously signal a supratentorial CNS disorder.

In the case described by Shikino et al, observation and recording of the amount of facial motor function at the initial visit, 3 days after onset, could facilitate recognition of an aberrant course even a few days later and prompt further investigation at an early follow-up visit (idiopathic palsy is almost invariably maximal by 72 hours). I would assume that no additional clinical information was available to the subsequent examiner in this case, 2 months later, rather than suggesting that such information was omitted for the sake of parsimony.

Would any of this have made a difference? Probably not, but we need all the help we can get in medicine. Remember that every bit of information you obtain from your history or physical examination that you do not record disappears with you and is irretrievably lost.

The article in this issue by Shikino et al¹ on a mimic of Bell palsy gives us an opportunity to discuss the question posed by the title of this editorial. The obvious short answer is “no.”

See related article

Any experienced clinician will acknowledge that the extent of the physical examination and the extent of information obtained during the history should be determined by the problem being evaluated at the time and by the setting in which it takes place. The difficulty, of course, is that this relies on the judgment of the clinician, and this may or may not pass the test of hindsight.

Verghese et al² have eloquently emphasized the hazards of an incomplete or inadequate physical examination. Their study was not designed to determine the prevalence of deficient physical examination, either in its extent or its accuracy. Their purpose was to promote the necessity of proper teaching and performance of examination technique.

The neurologic examination is one of the last bastions of physical assessment.³ Despite remarkable advances in imaging and physiologic techniques, the neurologic physical assessment remains critical for diagnosis and management of the neurologic patient. One of my mentors in neurology used to urge residents to examine patients and record the results of the examination as if every patient would subsequently be the subject of a clinicopathologic conference. Anyone who has reviewed a case for a conference or a case report can identify with that sentiment, wishing that some missing piece of information were available. Yet everyone also recognizes the difficulties, if not the impossibility, of achieving that ideal result.

But recording information obtained during the history or physical examination is important even in the course of a daily routine evaluation. I find myself wishing that a previous examiner had commented on whether the muscle stretch reflexes were somewhat hypoactive (eg, “1+”) or on the brisk side (“3+”) rather than “physiologic.” Was the right leg actually globally weak (“4/5”), or was there a discrepancy between proximal and distal muscles or between the physiologic flexors and the extensors?

This can make a big difference in following a patient’s neurologic progress, even over a short time span. It might tell us whether we are dealing with weakness from a peripheral neuromuscular disorder (eg, Guillain-Barré syndrome) or from a myelopathy due to impending spinal cord compression.

It should be mentioned that although Guillain-Barré syndrome is characterized as an ascending paralysis, ie, beginning distally and spreading rostrally, it is one of the few peripheral neuropathies that can present with predominant proximal weakness. It is, in fact, a radiculoneuropathy. But spinal cord (upper motor neuron) disorders preferentially weaken the physiologic flexors of the lower limbs (hamstrings and ankle dorsiflexors), leading to the characteristic extensor posture of the spastic leg. Other findings that can help differential peripheral vs spinal cord disorders include distal sensory loss and hypoactive or absent muscle stretch reflexes in a peripheral neuropathy, compared with dissociated sensory loss (eg, impaired pain and temperature sensation in one leg with reduced vibration perception and proprioception in the other) along with hyperreflexia with cord lesions.

Therefore, a careful neurologic examination may tell us whether magnetic resonance imaging of the spine or an electrodiagnostic study should be the next step.

Shikino et al describe a patient who presented with what looked like idiopathic facial palsy (Bell palsy) but turned out to be the result of a primary central nervous system (CNS) cause. Would a more detailed neurologic examination have identified this as a CNS disorder? Would more specific information about the degree and distribution of facial paresis have facilitated earlier recognition of a progressive process, making idiopathic facial palsy less likely? How much elevation of the eyebrow occurred with voluntary activation, how many millimeters of sclera were visible with gentle eyelid closure? How much space remained between the lips on attempted lip closure?

Upper facial muscle weakness is typically not seen in CNS disorders, although facial nerve or nucleus involvement at the pontine level can impair eyelid and frontalis function. Such lesions would usually be accompanied by “neighborhood” signs such as subtle ipsilateral lateral rectus or abducens palsy, involvement of the vestibular nuclei with vertigo, or facial sensory impairment from disruption of the descending trigeminal nucleus and tract. These would be “pertinent negatives” for excluding a brainstem lesion, and ipsilateral motor, sensory, or “higher cortical” functions would obviously signal a supratentorial CNS disorder.

In the case described by Shikino et al, observation and recording of the amount of facial motor function at the initial visit, 3 days after onset, could facilitate recognition of an aberrant course even a few days later and prompt further investigation at an early follow-up visit (idiopathic palsy is almost invariably maximal by 72 hours). I would assume that no additional clinical information was available to the subsequent examiner in this case, 2 months later, rather than suggesting that such information was omitted for the sake of parsimony.

Would any of this have made a difference? Probably not, but we need all the help we can get in medicine. Remember that every bit of information you obtain from your history or physical examination that you do not record disappears with you and is irretrievably lost.

The article in this issue by Shikino et al¹ on a mimic of Bell palsy gives us an opportunity to discuss the question posed by the title of this editorial. The obvious short answer is “no.”

See related article

Any experienced clinician will acknowledge that the extent of the physical examination and the extent of information obtained during the history should be determined by the problem being evaluated at the time and by the setting in which it takes place. The difficulty, of course, is that this relies on the judgment of the clinician, and this may or may not pass the test of hindsight.

Verghese et al² have eloquently emphasized the hazards of an incomplete or inadequate physical examination. Their study was not designed to determine the prevalence of deficient physical examination, either in its extent or its accuracy. Their purpose was to promote the necessity of proper teaching and performance of examination technique.

The neurologic examination is one of the last bastions of physical assessment.³ Despite remarkable advances in imaging and physiologic techniques, the neurologic physical assessment remains critical for diagnosis and management of the neurologic patient. One of my mentors in neurology used to urge residents to examine patients and record the results of the examination as if every patient would subsequently be the subject of a clinicopathologic conference. Anyone who has reviewed a case for a conference or a case report can identify with that sentiment, wishing that some missing piece of information were available. Yet everyone also recognizes the difficulties, if not the impossibility, of achieving that ideal result.

But recording information obtained during the history or physical examination is important even in the course of a daily routine evaluation. I find myself wishing that a previous examiner had commented on whether the muscle stretch reflexes were somewhat hypoactive (eg, “1+”) or on the brisk side (“3+”) rather than “physiologic.” Was the right leg actually globally weak (“4/5”), or was there a discrepancy between proximal and distal muscles or between the physiologic flexors and the extensors?

This can make a big difference in following a patient’s neurologic progress, even over a short time span. It might tell us whether we are dealing with weakness from a peripheral neuromuscular disorder (eg, Guillain-Barré syndrome) or from a myelopathy due to impending spinal cord compression.

It should be mentioned that although Guillain-Barré syndrome is characterized as an ascending paralysis, ie, beginning distally and spreading rostrally, it is one of the few peripheral neuropathies that can present with predominant proximal weakness. It is, in fact, a radiculoneuropathy. But spinal cord (upper motor neuron) disorders preferentially weaken the physiologic flexors of the lower limbs (hamstrings and ankle dorsiflexors), leading to the characteristic extensor posture of the spastic leg. Other findings that can help differential peripheral vs spinal cord disorders include distal sensory loss and hypoactive or absent muscle stretch reflexes in a peripheral neuropathy, compared with dissociated sensory loss (eg, impaired pain and temperature sensation in one leg with reduced vibration perception and proprioception in the other) along with hyperreflexia with cord lesions.

Therefore, a careful neurologic examination may tell us whether magnetic resonance imaging of the spine or an electrodiagnostic study should be the next step.

Shikino et al describe a patient who presented with what looked like idiopathic facial palsy (Bell palsy) but turned out to be the result of a primary central nervous system (CNS) cause. Would a more detailed neurologic examination have identified this as a CNS disorder? Would more specific information about the degree and distribution of facial paresis have facilitated earlier recognition of a progressive process, making idiopathic facial palsy less likely? How much elevation of the eyebrow occurred with voluntary activation, how many millimeters of sclera were visible with gentle eyelid closure? How much space remained between the lips on attempted lip closure?

Upper facial muscle weakness is typically not seen in CNS disorders, although facial nerve or nucleus involvement at the pontine level can impair eyelid and frontalis function. Such lesions would usually be accompanied by “neighborhood” signs such as subtle ipsilateral lateral rectus or abducens palsy, involvement of the vestibular nuclei with vertigo, or facial sensory impairment from disruption of the descending trigeminal nucleus and tract. These would be “pertinent negatives” for excluding a brainstem lesion, and ipsilateral motor, sensory, or “higher cortical” functions would obviously signal a supratentorial CNS disorder.

In the case described by Shikino et al, observation and recording of the amount of facial motor function at the initial visit, 3 days after onset, could facilitate recognition of an aberrant course even a few days later and prompt further investigation at an early follow-up visit (idiopathic palsy is almost invariably maximal by 72 hours). I would assume that no additional clinical information was available to the subsequent examiner in this case, 2 months later, rather than suggesting that such information was omitted for the sake of parsimony.

Would any of this have made a difference? Probably not, but we need all the help we can get in medicine. Remember that every bit of information you obtain from your history or physical examination that you do not record disappears with you and is irretrievably lost.

Pulmonary arterial hypertension (PAH) is a hemodynamic disorder that affects small and medium-size pulmonary arteries through cellular proliferation and luminal narrowing.¹ Increased pulmonary vascular resistance causes restricted blood flow in these arteries, leading to elevated pulmonary arterial pressure and afterload on the right ventricle. Despite advances in therapy, death usually occurs as a result of right ventricular failure.

• Group 1—PAH, due to narrowed pulmonary arteries
• Group 2—due to left heart disease
• Group 3—due to lung disease or hypoxia, or both
• Group 4—due to chronic thromboembolism or other pulmonary artery obstruction
• Group 5—due to uncertain or multifactorial causes.

Experts recognize the morbidity and mortality associated with pulmonary hypertension now more than in the past, and they emphasize recognizing it early. Guidelines for its diagnosis and treatment were updated in 2015.¹

Below, we use a case to discuss recommendations for initial evaluation and classification of pulmonary hypertension, particularly PAH.

A PATIENT SUSPECTED OF HAVING PULMONARY HYPERTENSION

A 63-year-old woman with a 25-pack-year history of tobacco use, as well as pulmonary embolism and coronary artery disease, presents to her primary care physician with exertional dyspnea. She had been a clerk at a hardware store and physically active until she took early retirement 8 months ago because of increasing fatigue. She initially felt the fatigue was simply “a sign of getting old.”

Since retiring, she has noticed the slow onset of progressive dyspnea on exertion. She can no longer climb more than 1 flight of stairs or walk more than 1 block. She also complains of mild, fluctuating edema in her lower extremities over the past month. She quit smoking 8 years ago after undergoing placement of a drug-eluting stent in the mid-left circumflex artery. After this, she received clopidogrel and was followed by a cardiologist for 2 years but stopped taking the medication because of bruising. She has not seen her cardiologist in more than 5 years.

She underwent elective right total knee arthroplasty 3 years ago, complicated by acute deep vein thrombosis in the right common femoral vein. Computed tomography (CT) at that time did not reveal pulmonary emboli. She received warfarin therapy for 3 months.

She reports no current cough, chest pain, lightheadedness, or syncope. She has no orthopnea, and she feels normal at rest.

Her family history is unremarkable, and she has had no exposure to illicit substances, environmental toxins, or dietary supplements. She takes aspirin 81 mg daily, metoprolol 25 mg twice daily, lisinopril 10 mg daily, and simvastatin 40 mg at bedtime.

Her primary care physician detects a murmur in the left lower sternal border and sends her for transthoracic echocardiography, which demonstrates mild right ventricular dilation, right atrial dilation, and mildly reduced right ventricular function. The calculated right ventricular systolic pressure is 69 mm Hg. The left ventricle shows mild concentric hypertrophy; the left atrium is normal in size.

DIAGNOSTIC EVALUATION OF SUSPECTED PULMONARY HYPERTENSION

CLINICAL MANIFESTATIONS

Symptoms and signs. As in the patient described above, the first symptoms such as exertional dyspnea, fatigue, and lightheadedness usually arise in situations that call for increased cardiac output.⁴ As right ventricular function worsens, symptoms start to occur at rest, and signs of increased right ventricular preload appear, such as abdominal and lower-extremity edema and pericardial effusion. Syncope is a sign of severe right ventricular dysfunction.⁵

Physical examination. Look for signs of increased right ventricular loading and failure, eg:

• An accentuated intensity and persistent splitting of the second heart sound
• A prominent parasternal heave
• A prominent jugular “a” wave
• A systolic murmur along the left sternal border at the fourth intercostal space, which may worsen with breath-holding
• Pitting lower-extremity edema
• Hepatomegaly
• Hepatojugular reflux
• Hepatic pulsatility.⁶

Many practitioners rely heavily on the estimated right ventricular systolic pressure in diagnosing pulmonary hypertension. In theory, this number should be nearly the same as the pulmonary arterial systolic pressure. However, technical and patient-related aspects of transthoracic echocardiography often limit accurate measurement of the right ventricular systolic pressure, and readings often differ from those measured with right heart catheterization.⁸

Our patient had a markedly elevated right ventricular systolic pressure and signs of right ventricular dysfunction, suggesting a high probability of pulmonary hypertension.

EVALUATING LEFT HEART DISEASE (WHO GROUP 2)

More than 75% of cases of pulmonary hypertension are directly related to left ventricular dysfunction or mitral or aortic valve disease (WHO group 2).¹ Since group 2 differs markedly from group 1 (PAH) in its pathophysiology and treatment, it is important to distinguish between them.

Compared with WHO group 1 patients, those in group 2 tend to be older, more of them are male, and more of them have comorbidities such as metabolic syndrome, hypertension, and coronary artery disease.^1,9 A combination of risk factors and clinical findings should be considered in identifying these patients.¹⁰

Transthoracic echocardiography is used to detect features of systolic and diastolic dysfunction. Left atrial enlargement is a clue that left heart disease may be present. In addition, signs of left ventricular or valvular dysfunction on electrocardiography or chest radiography are often helpful.

When estimated right ventricular systolic pressures are only minimally abnormal and no significant right ventricular dysfunction exists, further diagnostic evaluation is not warranted. However, because no single identifying feature or variable can readily distinguish group 2 from the other WHO groups, further evaluation should be considered if the right ventricular systolic pressure is significantly elevated or right ventricular dysfunction exists.

Our patient had several risk factors for left heart disease, including a history of smoking and coronary artery disease. Nonetheless, findings consistent with severe right ventricular dysfunction necessitated further evaluation for other possible causes of her suspected pulmonary hypertension.

Postcapillary pulmonary hypertension

In patients for whom further evaluation is pursued, the diagnosis of WHO group 2 pulmonary hypertension is ultimately based on findings consistent with postcapillary or “passive” pulmonary hypertension on right heart catheterization. Although mean pulmonary arterial pressures must be at least 25 mm Hg to certify the diagnosis of pulmonary hypertension, a pulmonary artery occlusion pressure greater than 15 mm Hg (normal 6–12) and pulmonary vascular resistance of 3 Wood units or less (normal 0.3–1.6) suggests the pulmonary hypertension is due to elevated left atrial pressure (ie, postcapillary) rather than precapillary pulmonary arterial remodeling.

Mixed pre- and postcapillary pulmonary hypertension

Distinguishing pulmonary venous hypertension from PAH is important, since their management differs. In particular, PAH-specific therapies (ie, prostacyclin analogues, prostaglandin I2 receptor agonists, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and cyclic guanosine monophosphate stimulators) can have a detrimental effect in WHO group 2 patients by causing increased pulmonary capillary leakage with pulmonary edema.^11,12

In some patients, chronic passive congestion in the pulmonary venous circulation causes additional disruption of the homeostatic milieu regulating precapillary smooth muscle and endothelial function. These changes result in structural remodeling of precapillary arterioles and increased precapillary vascular resistance, creating a “mixed” pulmonary hypertension with both pre- and postcapillary abnormalities.

There is controversy over the ideal way to identify these patients but little disagreement that they face a worse prognosis than those without precapillary remodeling.¹³ In light of this, efforts have been made to characterize this cohort.

Historically, mixed pre- and postcapillary pulmonary hypertension was defined as the combination of all of the following:

• Mean pulmonary arterial pressure ≥ 25 mm Hg
• Pulmonary artery occlusion pressure > 15 mm Hg
• Transpulmonary gradient (the mean pulmonary arterial pressure minus the pulmonary artery occlusion pressure) > 12 mm Hg.¹⁴

However, the utility of the transpulmonary gradient for distinguishing mixed pulmonary hypertension has been questioned because of  concerns over its susceptibility to variations in stroke volume and loading conditions.¹⁵

The diastolic pulmonary gradient (the pulmonary arterial diastolic pressure minus the pulmonary artery occlusion pressure) has been proposed as an alternative to the transpulmonary gradient under the theory that it is less sensitive to fluctuation from variations in flow or loading.¹⁵

Current guidelines¹ suggest that a patient who has all of the following should be considered to have mixed pulmonary hypertension:

• A mean pulmonary arterial pressure > 25 mm Hg
• A pulmonary artery occlusion pressure > 15 mm Hg
• A diastolic pulmonary gradient > 7 mm Hg or  a pulmonary vascular resistance > 3 Wood units, or both.

Occult group 2 pulmonary hypertension

Currently, the diagnosis of WHO group 2 pulmonary hypertension is based on elevated resting pulmonary artery occlusion pressure. However, some patients with WHO group 2 pulmonary hypertension and transiently low preload from aggressive diuresis or fasting may have a low pulmonary artery occlusion pressure during right heart catheterization and be misdiagnosed as having WHO group 1 PAH.^12,16

This concern was acknowledged in the 2015 Ambrisentan and Tadalafil in Patients With Pulmonary Arterial Hypertension (AMBITION) study after investigators changed the protocol to exclude patients who technically met the criteria for WHO group 1 PAH, but had borderline-elevated pulmonary artery occlusion pressure and additional risk factors worrisome for left heart disease and occult WHO group 2 pulmonary hypertension.^17,18

Several strategies, including passive leg-raising, fluid challenge, and exercise during diagnostic right heart catheterization, have been proposed to better classify these patients.¹⁹ Unfortunately, due to a lack of standardization of normal values and methodology for executing these maneuvers, consensus is lacking over their routine use, and recommendations for their use have not been provided.¹

All patients with suspected pulmonary hypertension should also be assessed for underlying pulmonary parenchymal or physiologic disease.

WHO group 3 consists of pulmonary disorders that, over an extended time, can lead to pulmonary hypertension. The most common of these disorders include chronic obstructive pulmonary disease, interstitial lung disease, and combined pulmonary fibrosis and emphysema.¹

Pulmonary hypertension in these patients is precapillary, and changes in pulmonary vascular resistance are influenced by multiple factors, the most significant of which is alveolar hypoxia. Hypoxia induces pulmonary artery vasoconstrictionn (in contrast to the reflexive hemodynamics seen in peripheral tissues, where systemic vascular tone is generally lower in states of hypoxia) as a mechanism to divert pulmonary blood flow to well-ventilated portions of the lung and maintain ventilation-perfusion matching.

Repeated chronic hypoxia also alters cellular structure and function of pulmonary vessels and leads to medial hypertrophy and increased vascular tone, thus contributing to the development of pulmonary hypertension in many of these patients.²⁰

Obstructive sleep apnea. Up to 70% of patients with obstructive sleep apnea have pulmonary hypertension.²¹ Chronic repetitive hypoxia throughout the night increases the levels of reactive oxygen species and alters cellular and molecular signaling, thus inducing vascular remodeling. In addition, apneic events during sleep promote catecholamine-driven elevations in systemic blood pressure. Over time, patients are at higher risk of developing left ventricular dysfunction and concomitant postcapillary group 2 pulmonary hypertension.²² Because typical methods of obstructive sleep apnea screening (eg, the Epworth Sleep Scale) have been historically poor at discriminating PAH patients with obstructive sleep apnea from those without, patients diagnosed with PAH should be considered for formal sleep testing.^23,24

Pulmonary function tests, chest imaging

Pulmonary function tests and high-resolution computed tomography are essential to any PAH evaluation and help to exclude WHO group 3 pulmonary hypertension.¹

An abnormal result on CT or spirometry can help point toward parenchymal lung disease. Normal spirometry and lung volumes with an isolated reduction in the diffusing capacity of the lung for carbon monoxide (Dlco) is typical of patients with WHO group 1 PAH.

In our patient, CT of the chest did not show any evidence of parenchymal lung disease, and pulmonary function tests showed no evidence of obstruction or restriction. There was a moderate decrease in Dlco, which did not reach normal limits when adjusted for lung volumes. In this setting, further evaluation of her PAH was warranted.

EVALUATION OF THROMBOEMBOLIC DISEASE (WHO GROUP 4)

Once pulmonary hypertension due to underlying left heart disease or parenchymal lung disease has been excluded, testing for chronic thromboembolic pulmonary hypertension is necessary, even in the absence of prior known pulmonary embolism. Identifying these patients is paramount, as chronic thromboembolic pulmonary hypertension (WHO group 4) is the only type of pulmonary hypertension for which a definitive cure is available.²⁶

Up to 9% of patients who survive acute pulmonary embolism exhibit features of chronic proximal thrombosis and remodeling of distal pulmonary arteries.²⁷

It remains unknown exactly why some patients develop chronic thromboembolic pulmonary hypertension and others do not, but the pathophysiology involves inappropriate thrombus resolution after venous thromboembolic events. Monocyte recruitment (which plays an important role in thrombus resolution) is reduced, angiogenesis is impaired (preventing effective vascular collateralization), and abnormal fibroblast proliferation leads to distal pulmonary vascular wall thickening.²⁸ There is some evidence of increased thrombophilic risk in this population, and approximately 10% to 20% of patients are positive for antiphospholipid antibodies or lupus anticoagulant.^29,30

Patients with chronic thromboembolic pulmonary hypertension usually present with symptoms similar to those of WHO group 1 PAH. Up to one-quarter of patients have no recollection of prior pulmonary embolism.³¹ As the disease progresses, signs and symptoms related to elevated pulmonary vascular resistance and right ventricular dysfunction are common.^32,33

Although thrombi usually resolve quickly, the diagnosis of chronic thromboembolic pulmonary hypertension should be made only after at least 3 months of appropriate anticoagulation to avoid treatment of transient hemodynamic changes often seen after an acute pulmonary embolism.¹

Radiographic changes associated with chronic thromboembolic pulmonary hypertension are distinct from the intraluminal filling defects seen with acute thromboembolism, since chronic thrombi tend to become organized and eccentric. On imaging, one may see features of rapid luminal narrowing or eccentric filling defects rather than the conventional central filling defects of acute pulmonary embolism. These changes are often overlooked by radiologists who are not specifically looking for chronic thromboembolic pulmonary hypertension.³⁴ For this reason, the sensitivity and specificity of identifying chronic thromboembolic disease using radionuclide ventilation-perfusion lung scanning is superior to that of CT angiography.

All patients with suspected PAH should undergo a ventilation-perfusion scan.^1,35 In patients with ventilation-perfusion mismatch on radionuclide scanning, pulmonary angiography can fulfill multiple goals of measuring pulmonary arterial pressures, identifying the extent and location of chronic thromboemboli, and can determine whether surgical thromboendarterectomy is feasible.

If chronic thromboembolic pulmonary hypertension is identified, it is imperative that patients be referred to a center of excellence specializing in its management regardless of symptom severity, as surgery can be curative and may prevent development of progressive right ventricular dysfunction.³⁶

Our patient’s ventilation-perfusion scan was normal, effectively ruling out the possibility of chronic thromboembolism as a cause of her pulmonary hypertension.

Once the above-mentioned conditions have been evaluated, patients with suspected PAH should be referred to a pulmonary hypertension center of excellence to undergo right heart catheterization. If this test reveals PAH, further vasoreactivity testing should be performed if the etiology of the PAH is considered to be idiopathic, heritable, or drug-induced.¹

Vasoreactivity is most commonly tested using 20 ppm of inhaled nitric oxide, but alternative formulations including intravenous epoprostenol, intravenous adenosine, or inhaled iloprost are acceptable. Patients who have a positive vasoreactive test usually respond well to high-dose calcium channel blocker therapy and have a significantly better prognosis than other patients with PAH.³⁷

Patients with WHO group 1 PAH who do not have idiopathic, heritable, or drug-induced PAH have not been shown to have favorable outcomes using calcium channel blockers even if they have a positive vasoreactive response. A positive vasoreactive response is defined as a drop in mean pulmonary arterial pressure of at least 10 mm Hg to an absolute level of 40 mm Hg or less. Cardiac output should be preserved or elevated compared with baseline values during the challenge.¹

In reality, only 10% to 15% of patients with idiopathic PAH have a positive vasoreactive response, and half of these patients stop responding within 1 year.³⁸ Therefore, clinicians should not assume that calcium channel blockers will be successful in the long term in a vasoreactive patient, and these patients should have follow-up right heart catheterization after 3 to 6 months and annually thereafter to ensure continued vasoreactivity.¹

In patients who are no longer vasoreactive or whose functional status is worse than New York Heart Association functional class I or II, conventional PAH-specific therapy should be started.

LOOKING FOR CAUSES OF ‘IDIOPATHIC’ PAH

Pulmonary hypertension is considered the final common pathway of many varied diseases and syndromes, and therefore one cannot say it is idiopathic without making a robust effort to identify features of alternative causes and rule out other contributing factors.
Although the exact etiology of idiopathic PAH is unclear, well-characterized imbalances in vascular homeostasis have been identified. These include processes that promote vasoconstriction, cell proliferation, and thrombosis (thromboxane A2, endothelin-1, and serotonin) and those that suppress prostacyclin, nitric oxide, and vasoactive intestinal peptide-mediated vasodilation.¹ Furthermore, an abnormal angiogenic response to hypoxia and vascular endothelial growth factor has been observed.³⁹

Before considering a diagnosis of idiopathic PAH, a careful history is essential. Other causative agents include appetite-suppressing medications, such as fenfluramine derivatives or stimulants such as amphetamines. Human immunodeficiency virus (HIV) or hepatitis, a history of splenectomy, and prior thyroid or liver disease are also common causes of PAH. Joint pain, myalgias, Raynaud features, or a rash characteristic of connective tissue disease can be identified on history and physical examination. Worldwide, chronic exposure to high-altitude climates and exposure to schistosomiasis are significant causes of PAH, but are rarely seen in developed nations. Confirmatory serum tests for HIV, antinuclear antibody, scleroderma antibody, and thyroid function are essential.¹

Genetic factors

If patients report having relatives with possible or probable PAH, genetic counseling is recommended, particularly for rare but causative gene mutations.

BMPR2, the gene that codes for the bone morphogenetic protein receptor type 2, can carry mutations with variable penetrance over the patient’s lifetime depending on other genetic polymorphisms, concurrent inflammation, and the patient’s sex.⁴⁰

The population carrier estimates of BMPR2 mutations are only 0.001% to 0.01%, but mutations in this gene are identified in approximately 25% of nonfamilial PAH patients and in over 75% of those with a familial inheritance pattern. The BMPR2 protein is a part of the transforming growth factor beta family and is partially responsible for control of vascular cell proliferation. Mutations in this gene lead to PAH at a younger age than in those with mutation-negative idiopathic PAH and to a more severe clinical phenotype in terms of pulmonary vascular resistance and cardiac function.⁴⁰

Other mutations. Although BMPR2 is the most commonly identified gene mutation in patients with PAH, other gene mutations within this family have also been recognized. These include mutations in the genes for activin receptor-like kinase 1 and endoglin, which, although better known for their association with hereditary hemorrhagic telangiectasia, can lead directly to PAH.⁴⁰

More recently, a novel autosomal recessive gene mutation in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) has been identified in patients with pulmonary veno-occlusive disease⁴¹ and pulmonary capillary hemangiomatosis,⁴² which are specific subclasses of WHO group 1 PAH. The mechanistic parallels between EIF2AK4 and these diseases are not clear, but the prevalence of disease in those with a familial inheritance pattern and an EIF2AK4 mutation is nearly 100%.⁴¹ Thus, identification of this mutation has been accepted as a way to confirm pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in patients suspected of PAH with features of these diseases.^43,44

GROUP 5: MISCELLANEOUS FORMS OF PULMONARY HYPERTENSION

WHO group 5 pulmonary hypertension encompasses disorders whose pathophysiology does not fit neatly within the context of the other pulmonary hypertension subtypes. Nonetheless, appreciation of these disorders is important in determining the etiology and appropriate therapy for patients with pulmonary hypertension. The mechanism driving abnormal pulmonary arterial pressures in patients with group 5 pulmonary hypertension is not always clear and may involve intrinsic or extrinsic factors.¹

Diseases within group 5 include those that cause extrinsic compression of the pulmonary arteries (ie, fibrosing mediastinitis) or intrinsic elevations in pulmonary vascular resistance (sarcoidosis, pulmonary Langerhans cell histiocytosis, sickle cell anemia, polycythemia vera, and malignancy).

The most common cause of pulmonary hypertension in this category is sarcoidosis. Current theories suggest that, for most patients, invasion of granulomatous inflammation within the arterial walls induces PAH via fibrotic or inflammatory vascular occlusion. Extrinsic compression due to lymphadenopathy, right or left ventricular dysfunction due to cardiac myocite infiltration, and endothelin-induced pulmonary vasoconstriction are other possible links between the PAH and sarcoidosis.⁴⁵

Cardiac magnetic resonance imaging (MRI) has gained popularity as a noninvasive and reproducible alternative to echocardiography. Image fidelity and characterization of right ventricular function and right ventricular ejection fraction are all more accurate than with echocardiography, and serial MRI has proven valuable in its ability to guide patient prognosis.⁴⁶

However, MRI is more expensive than echocardiography, and some patients cannot tolerate the procedure. In addition, for those who can tolerate it, MRI is not a suitable alternative to right heart catheterization, since it cannot accurately estimate pulmonary artery occlusion pressure or pulmonary arterial pressures.¹ For these reasons, cardiac MRI use varies across pulmonary hypertension centers.

A goal of treatment is to reduce a patient’s risk. While no consensus has been achieved over which PAH-specific therapy to start with, evidence is robust that using more than 1 class of agent is beneficial, capitalizing on multiple therapeutic targets.^17,47

In our patient, right heart catheterization revealed PAH with a mean pulmonary arterial pressure of 44 mm Hg, pulmonary artery occlusion pressure 6 mm Hg, and a cardiac index of 2.1 L/min/m². Ancillary testing for alternative causes of PAH was unrevealing, as was vasoreactivity testing. Our patient could walk only 314 meters on her 6-minute walk test and had an initial NT-proBNP level of 750 ng/L.

Based on these and the findings during her evaluation, she would be classified as having intermediate-risk PAH with an estimated 1-year mortality risk of 5% to 10%.¹ Appropriate therapy and follow-up would be guided by this determination. Specific therapy is beyond the scope of this article but we would start her on dual oral therapy with close follow-up to reassess her 1-year mortality risk. If there were no improvement over a short period of time, we would add further therapy.

Pulmonary arterial hypertension (PAH) is a hemodynamic disorder that affects small and medium-size pulmonary arteries through cellular proliferation and luminal narrowing.¹ Increased pulmonary vascular resistance causes restricted blood flow in these arteries, leading to elevated pulmonary arterial pressure and afterload on the right ventricle. Despite advances in therapy, death usually occurs as a result of right ventricular failure.

• Group 1—PAH, due to narrowed pulmonary arteries
• Group 2—due to left heart disease
• Group 3—due to lung disease or hypoxia, or both
• Group 4—due to chronic thromboembolism or other pulmonary artery obstruction
• Group 5—due to uncertain or multifactorial causes.

Experts recognize the morbidity and mortality associated with pulmonary hypertension now more than in the past, and they emphasize recognizing it early. Guidelines for its diagnosis and treatment were updated in 2015.¹

Below, we use a case to discuss recommendations for initial evaluation and classification of pulmonary hypertension, particularly PAH.

A PATIENT SUSPECTED OF HAVING PULMONARY HYPERTENSION

A 63-year-old woman with a 25-pack-year history of tobacco use, as well as pulmonary embolism and coronary artery disease, presents to her primary care physician with exertional dyspnea. She had been a clerk at a hardware store and physically active until she took early retirement 8 months ago because of increasing fatigue. She initially felt the fatigue was simply “a sign of getting old.”

Since retiring, she has noticed the slow onset of progressive dyspnea on exertion. She can no longer climb more than 1 flight of stairs or walk more than 1 block. She also complains of mild, fluctuating edema in her lower extremities over the past month. She quit smoking 8 years ago after undergoing placement of a drug-eluting stent in the mid-left circumflex artery. After this, she received clopidogrel and was followed by a cardiologist for 2 years but stopped taking the medication because of bruising. She has not seen her cardiologist in more than 5 years.

She underwent elective right total knee arthroplasty 3 years ago, complicated by acute deep vein thrombosis in the right common femoral vein. Computed tomography (CT) at that time did not reveal pulmonary emboli. She received warfarin therapy for 3 months.

She reports no current cough, chest pain, lightheadedness, or syncope. She has no orthopnea, and she feels normal at rest.

Her family history is unremarkable, and she has had no exposure to illicit substances, environmental toxins, or dietary supplements. She takes aspirin 81 mg daily, metoprolol 25 mg twice daily, lisinopril 10 mg daily, and simvastatin 40 mg at bedtime.

Her primary care physician detects a murmur in the left lower sternal border and sends her for transthoracic echocardiography, which demonstrates mild right ventricular dilation, right atrial dilation, and mildly reduced right ventricular function. The calculated right ventricular systolic pressure is 69 mm Hg. The left ventricle shows mild concentric hypertrophy; the left atrium is normal in size.

DIAGNOSTIC EVALUATION OF SUSPECTED PULMONARY HYPERTENSION

CLINICAL MANIFESTATIONS

Symptoms and signs. As in the patient described above, the first symptoms such as exertional dyspnea, fatigue, and lightheadedness usually arise in situations that call for increased cardiac output.⁴ As right ventricular function worsens, symptoms start to occur at rest, and signs of increased right ventricular preload appear, such as abdominal and lower-extremity edema and pericardial effusion. Syncope is a sign of severe right ventricular dysfunction.⁵

Physical examination. Look for signs of increased right ventricular loading and failure, eg:

• An accentuated intensity and persistent splitting of the second heart sound
• A prominent parasternal heave
• A prominent jugular “a” wave
• A systolic murmur along the left sternal border at the fourth intercostal space, which may worsen with breath-holding
• Pitting lower-extremity edema
• Hepatomegaly
• Hepatojugular reflux
• Hepatic pulsatility.⁶

Many practitioners rely heavily on the estimated right ventricular systolic pressure in diagnosing pulmonary hypertension. In theory, this number should be nearly the same as the pulmonary arterial systolic pressure. However, technical and patient-related aspects of transthoracic echocardiography often limit accurate measurement of the right ventricular systolic pressure, and readings often differ from those measured with right heart catheterization.⁸

Our patient had a markedly elevated right ventricular systolic pressure and signs of right ventricular dysfunction, suggesting a high probability of pulmonary hypertension.

EVALUATING LEFT HEART DISEASE (WHO GROUP 2)

More than 75% of cases of pulmonary hypertension are directly related to left ventricular dysfunction or mitral or aortic valve disease (WHO group 2).¹ Since group 2 differs markedly from group 1 (PAH) in its pathophysiology and treatment, it is important to distinguish between them.

Compared with WHO group 1 patients, those in group 2 tend to be older, more of them are male, and more of them have comorbidities such as metabolic syndrome, hypertension, and coronary artery disease.^1,9 A combination of risk factors and clinical findings should be considered in identifying these patients.¹⁰

Transthoracic echocardiography is used to detect features of systolic and diastolic dysfunction. Left atrial enlargement is a clue that left heart disease may be present. In addition, signs of left ventricular or valvular dysfunction on electrocardiography or chest radiography are often helpful.

When estimated right ventricular systolic pressures are only minimally abnormal and no significant right ventricular dysfunction exists, further diagnostic evaluation is not warranted. However, because no single identifying feature or variable can readily distinguish group 2 from the other WHO groups, further evaluation should be considered if the right ventricular systolic pressure is significantly elevated or right ventricular dysfunction exists.

Our patient had several risk factors for left heart disease, including a history of smoking and coronary artery disease. Nonetheless, findings consistent with severe right ventricular dysfunction necessitated further evaluation for other possible causes of her suspected pulmonary hypertension.

Postcapillary pulmonary hypertension

In patients for whom further evaluation is pursued, the diagnosis of WHO group 2 pulmonary hypertension is ultimately based on findings consistent with postcapillary or “passive” pulmonary hypertension on right heart catheterization. Although mean pulmonary arterial pressures must be at least 25 mm Hg to certify the diagnosis of pulmonary hypertension, a pulmonary artery occlusion pressure greater than 15 mm Hg (normal 6–12) and pulmonary vascular resistance of 3 Wood units or less (normal 0.3–1.6) suggests the pulmonary hypertension is due to elevated left atrial pressure (ie, postcapillary) rather than precapillary pulmonary arterial remodeling.

Mixed pre- and postcapillary pulmonary hypertension

Distinguishing pulmonary venous hypertension from PAH is important, since their management differs. In particular, PAH-specific therapies (ie, prostacyclin analogues, prostaglandin I2 receptor agonists, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and cyclic guanosine monophosphate stimulators) can have a detrimental effect in WHO group 2 patients by causing increased pulmonary capillary leakage with pulmonary edema.^11,12

In some patients, chronic passive congestion in the pulmonary venous circulation causes additional disruption of the homeostatic milieu regulating precapillary smooth muscle and endothelial function. These changes result in structural remodeling of precapillary arterioles and increased precapillary vascular resistance, creating a “mixed” pulmonary hypertension with both pre- and postcapillary abnormalities.

There is controversy over the ideal way to identify these patients but little disagreement that they face a worse prognosis than those without precapillary remodeling.¹³ In light of this, efforts have been made to characterize this cohort.

Historically, mixed pre- and postcapillary pulmonary hypertension was defined as the combination of all of the following:

• Mean pulmonary arterial pressure ≥ 25 mm Hg
• Pulmonary artery occlusion pressure > 15 mm Hg
• Transpulmonary gradient (the mean pulmonary arterial pressure minus the pulmonary artery occlusion pressure) > 12 mm Hg.¹⁴

However, the utility of the transpulmonary gradient for distinguishing mixed pulmonary hypertension has been questioned because of  concerns over its susceptibility to variations in stroke volume and loading conditions.¹⁵

The diastolic pulmonary gradient (the pulmonary arterial diastolic pressure minus the pulmonary artery occlusion pressure) has been proposed as an alternative to the transpulmonary gradient under the theory that it is less sensitive to fluctuation from variations in flow or loading.¹⁵

Current guidelines¹ suggest that a patient who has all of the following should be considered to have mixed pulmonary hypertension:

• A mean pulmonary arterial pressure > 25 mm Hg
• A pulmonary artery occlusion pressure > 15 mm Hg
• A diastolic pulmonary gradient > 7 mm Hg or  a pulmonary vascular resistance > 3 Wood units, or both.

Occult group 2 pulmonary hypertension

Currently, the diagnosis of WHO group 2 pulmonary hypertension is based on elevated resting pulmonary artery occlusion pressure. However, some patients with WHO group 2 pulmonary hypertension and transiently low preload from aggressive diuresis or fasting may have a low pulmonary artery occlusion pressure during right heart catheterization and be misdiagnosed as having WHO group 1 PAH.^12,16

This concern was acknowledged in the 2015 Ambrisentan and Tadalafil in Patients With Pulmonary Arterial Hypertension (AMBITION) study after investigators changed the protocol to exclude patients who technically met the criteria for WHO group 1 PAH, but had borderline-elevated pulmonary artery occlusion pressure and additional risk factors worrisome for left heart disease and occult WHO group 2 pulmonary hypertension.^17,18

Several strategies, including passive leg-raising, fluid challenge, and exercise during diagnostic right heart catheterization, have been proposed to better classify these patients.¹⁹ Unfortunately, due to a lack of standardization of normal values and methodology for executing these maneuvers, consensus is lacking over their routine use, and recommendations for their use have not been provided.¹

All patients with suspected pulmonary hypertension should also be assessed for underlying pulmonary parenchymal or physiologic disease.

WHO group 3 consists of pulmonary disorders that, over an extended time, can lead to pulmonary hypertension. The most common of these disorders include chronic obstructive pulmonary disease, interstitial lung disease, and combined pulmonary fibrosis and emphysema.¹

Pulmonary hypertension in these patients is precapillary, and changes in pulmonary vascular resistance are influenced by multiple factors, the most significant of which is alveolar hypoxia. Hypoxia induces pulmonary artery vasoconstrictionn (in contrast to the reflexive hemodynamics seen in peripheral tissues, where systemic vascular tone is generally lower in states of hypoxia) as a mechanism to divert pulmonary blood flow to well-ventilated portions of the lung and maintain ventilation-perfusion matching.

Repeated chronic hypoxia also alters cellular structure and function of pulmonary vessels and leads to medial hypertrophy and increased vascular tone, thus contributing to the development of pulmonary hypertension in many of these patients.²⁰

Obstructive sleep apnea. Up to 70% of patients with obstructive sleep apnea have pulmonary hypertension.²¹ Chronic repetitive hypoxia throughout the night increases the levels of reactive oxygen species and alters cellular and molecular signaling, thus inducing vascular remodeling. In addition, apneic events during sleep promote catecholamine-driven elevations in systemic blood pressure. Over time, patients are at higher risk of developing left ventricular dysfunction and concomitant postcapillary group 2 pulmonary hypertension.²² Because typical methods of obstructive sleep apnea screening (eg, the Epworth Sleep Scale) have been historically poor at discriminating PAH patients with obstructive sleep apnea from those without, patients diagnosed with PAH should be considered for formal sleep testing.^23,24

Pulmonary function tests, chest imaging

Pulmonary function tests and high-resolution computed tomography are essential to any PAH evaluation and help to exclude WHO group 3 pulmonary hypertension.¹

An abnormal result on CT or spirometry can help point toward parenchymal lung disease. Normal spirometry and lung volumes with an isolated reduction in the diffusing capacity of the lung for carbon monoxide (Dlco) is typical of patients with WHO group 1 PAH.

In our patient, CT of the chest did not show any evidence of parenchymal lung disease, and pulmonary function tests showed no evidence of obstruction or restriction. There was a moderate decrease in Dlco, which did not reach normal limits when adjusted for lung volumes. In this setting, further evaluation of her PAH was warranted.

EVALUATION OF THROMBOEMBOLIC DISEASE (WHO GROUP 4)

Once pulmonary hypertension due to underlying left heart disease or parenchymal lung disease has been excluded, testing for chronic thromboembolic pulmonary hypertension is necessary, even in the absence of prior known pulmonary embolism. Identifying these patients is paramount, as chronic thromboembolic pulmonary hypertension (WHO group 4) is the only type of pulmonary hypertension for which a definitive cure is available.²⁶

Up to 9% of patients who survive acute pulmonary embolism exhibit features of chronic proximal thrombosis and remodeling of distal pulmonary arteries.²⁷

It remains unknown exactly why some patients develop chronic thromboembolic pulmonary hypertension and others do not, but the pathophysiology involves inappropriate thrombus resolution after venous thromboembolic events. Monocyte recruitment (which plays an important role in thrombus resolution) is reduced, angiogenesis is impaired (preventing effective vascular collateralization), and abnormal fibroblast proliferation leads to distal pulmonary vascular wall thickening.²⁸ There is some evidence of increased thrombophilic risk in this population, and approximately 10% to 20% of patients are positive for antiphospholipid antibodies or lupus anticoagulant.^29,30

Patients with chronic thromboembolic pulmonary hypertension usually present with symptoms similar to those of WHO group 1 PAH. Up to one-quarter of patients have no recollection of prior pulmonary embolism.³¹ As the disease progresses, signs and symptoms related to elevated pulmonary vascular resistance and right ventricular dysfunction are common.^32,33

Although thrombi usually resolve quickly, the diagnosis of chronic thromboembolic pulmonary hypertension should be made only after at least 3 months of appropriate anticoagulation to avoid treatment of transient hemodynamic changes often seen after an acute pulmonary embolism.¹

Radiographic changes associated with chronic thromboembolic pulmonary hypertension are distinct from the intraluminal filling defects seen with acute thromboembolism, since chronic thrombi tend to become organized and eccentric. On imaging, one may see features of rapid luminal narrowing or eccentric filling defects rather than the conventional central filling defects of acute pulmonary embolism. These changes are often overlooked by radiologists who are not specifically looking for chronic thromboembolic pulmonary hypertension.³⁴ For this reason, the sensitivity and specificity of identifying chronic thromboembolic disease using radionuclide ventilation-perfusion lung scanning is superior to that of CT angiography.

All patients with suspected PAH should undergo a ventilation-perfusion scan.^1,35 In patients with ventilation-perfusion mismatch on radionuclide scanning, pulmonary angiography can fulfill multiple goals of measuring pulmonary arterial pressures, identifying the extent and location of chronic thromboemboli, and can determine whether surgical thromboendarterectomy is feasible.

If chronic thromboembolic pulmonary hypertension is identified, it is imperative that patients be referred to a center of excellence specializing in its management regardless of symptom severity, as surgery can be curative and may prevent development of progressive right ventricular dysfunction.³⁶

Our patient’s ventilation-perfusion scan was normal, effectively ruling out the possibility of chronic thromboembolism as a cause of her pulmonary hypertension.

Once the above-mentioned conditions have been evaluated, patients with suspected PAH should be referred to a pulmonary hypertension center of excellence to undergo right heart catheterization. If this test reveals PAH, further vasoreactivity testing should be performed if the etiology of the PAH is considered to be idiopathic, heritable, or drug-induced.¹

Vasoreactivity is most commonly tested using 20 ppm of inhaled nitric oxide, but alternative formulations including intravenous epoprostenol, intravenous adenosine, or inhaled iloprost are acceptable. Patients who have a positive vasoreactive test usually respond well to high-dose calcium channel blocker therapy and have a significantly better prognosis than other patients with PAH.³⁷

Patients with WHO group 1 PAH who do not have idiopathic, heritable, or drug-induced PAH have not been shown to have favorable outcomes using calcium channel blockers even if they have a positive vasoreactive response. A positive vasoreactive response is defined as a drop in mean pulmonary arterial pressure of at least 10 mm Hg to an absolute level of 40 mm Hg or less. Cardiac output should be preserved or elevated compared with baseline values during the challenge.¹

In reality, only 10% to 15% of patients with idiopathic PAH have a positive vasoreactive response, and half of these patients stop responding within 1 year.³⁸ Therefore, clinicians should not assume that calcium channel blockers will be successful in the long term in a vasoreactive patient, and these patients should have follow-up right heart catheterization after 3 to 6 months and annually thereafter to ensure continued vasoreactivity.¹

In patients who are no longer vasoreactive or whose functional status is worse than New York Heart Association functional class I or II, conventional PAH-specific therapy should be started.

LOOKING FOR CAUSES OF ‘IDIOPATHIC’ PAH

Pulmonary hypertension is considered the final common pathway of many varied diseases and syndromes, and therefore one cannot say it is idiopathic without making a robust effort to identify features of alternative causes and rule out other contributing factors.
Although the exact etiology of idiopathic PAH is unclear, well-characterized imbalances in vascular homeostasis have been identified. These include processes that promote vasoconstriction, cell proliferation, and thrombosis (thromboxane A2, endothelin-1, and serotonin) and those that suppress prostacyclin, nitric oxide, and vasoactive intestinal peptide-mediated vasodilation.¹ Furthermore, an abnormal angiogenic response to hypoxia and vascular endothelial growth factor has been observed.³⁹

Before considering a diagnosis of idiopathic PAH, a careful history is essential. Other causative agents include appetite-suppressing medications, such as fenfluramine derivatives or stimulants such as amphetamines. Human immunodeficiency virus (HIV) or hepatitis, a history of splenectomy, and prior thyroid or liver disease are also common causes of PAH. Joint pain, myalgias, Raynaud features, or a rash characteristic of connective tissue disease can be identified on history and physical examination. Worldwide, chronic exposure to high-altitude climates and exposure to schistosomiasis are significant causes of PAH, but are rarely seen in developed nations. Confirmatory serum tests for HIV, antinuclear antibody, scleroderma antibody, and thyroid function are essential.¹

Genetic factors

If patients report having relatives with possible or probable PAH, genetic counseling is recommended, particularly for rare but causative gene mutations.

BMPR2, the gene that codes for the bone morphogenetic protein receptor type 2, can carry mutations with variable penetrance over the patient’s lifetime depending on other genetic polymorphisms, concurrent inflammation, and the patient’s sex.⁴⁰

The population carrier estimates of BMPR2 mutations are only 0.001% to 0.01%, but mutations in this gene are identified in approximately 25% of nonfamilial PAH patients and in over 75% of those with a familial inheritance pattern. The BMPR2 protein is a part of the transforming growth factor beta family and is partially responsible for control of vascular cell proliferation. Mutations in this gene lead to PAH at a younger age than in those with mutation-negative idiopathic PAH and to a more severe clinical phenotype in terms of pulmonary vascular resistance and cardiac function.⁴⁰

Other mutations. Although BMPR2 is the most commonly identified gene mutation in patients with PAH, other gene mutations within this family have also been recognized. These include mutations in the genes for activin receptor-like kinase 1 and endoglin, which, although better known for their association with hereditary hemorrhagic telangiectasia, can lead directly to PAH.⁴⁰

More recently, a novel autosomal recessive gene mutation in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) has been identified in patients with pulmonary veno-occlusive disease⁴¹ and pulmonary capillary hemangiomatosis,⁴² which are specific subclasses of WHO group 1 PAH. The mechanistic parallels between EIF2AK4 and these diseases are not clear, but the prevalence of disease in those with a familial inheritance pattern and an EIF2AK4 mutation is nearly 100%.⁴¹ Thus, identification of this mutation has been accepted as a way to confirm pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in patients suspected of PAH with features of these diseases.^43,44

GROUP 5: MISCELLANEOUS FORMS OF PULMONARY HYPERTENSION

WHO group 5 pulmonary hypertension encompasses disorders whose pathophysiology does not fit neatly within the context of the other pulmonary hypertension subtypes. Nonetheless, appreciation of these disorders is important in determining the etiology and appropriate therapy for patients with pulmonary hypertension. The mechanism driving abnormal pulmonary arterial pressures in patients with group 5 pulmonary hypertension is not always clear and may involve intrinsic or extrinsic factors.¹

Diseases within group 5 include those that cause extrinsic compression of the pulmonary arteries (ie, fibrosing mediastinitis) or intrinsic elevations in pulmonary vascular resistance (sarcoidosis, pulmonary Langerhans cell histiocytosis, sickle cell anemia, polycythemia vera, and malignancy).

The most common cause of pulmonary hypertension in this category is sarcoidosis. Current theories suggest that, for most patients, invasion of granulomatous inflammation within the arterial walls induces PAH via fibrotic or inflammatory vascular occlusion. Extrinsic compression due to lymphadenopathy, right or left ventricular dysfunction due to cardiac myocite infiltration, and endothelin-induced pulmonary vasoconstriction are other possible links between the PAH and sarcoidosis.⁴⁵

Cardiac magnetic resonance imaging (MRI) has gained popularity as a noninvasive and reproducible alternative to echocardiography. Image fidelity and characterization of right ventricular function and right ventricular ejection fraction are all more accurate than with echocardiography, and serial MRI has proven valuable in its ability to guide patient prognosis.⁴⁶

However, MRI is more expensive than echocardiography, and some patients cannot tolerate the procedure. In addition, for those who can tolerate it, MRI is not a suitable alternative to right heart catheterization, since it cannot accurately estimate pulmonary artery occlusion pressure or pulmonary arterial pressures.¹ For these reasons, cardiac MRI use varies across pulmonary hypertension centers.

A goal of treatment is to reduce a patient’s risk. While no consensus has been achieved over which PAH-specific therapy to start with, evidence is robust that using more than 1 class of agent is beneficial, capitalizing on multiple therapeutic targets.^17,47

In our patient, right heart catheterization revealed PAH with a mean pulmonary arterial pressure of 44 mm Hg, pulmonary artery occlusion pressure 6 mm Hg, and a cardiac index of 2.1 L/min/m². Ancillary testing for alternative causes of PAH was unrevealing, as was vasoreactivity testing. Our patient could walk only 314 meters on her 6-minute walk test and had an initial NT-proBNP level of 750 ng/L.

Based on these and the findings during her evaluation, she would be classified as having intermediate-risk PAH with an estimated 1-year mortality risk of 5% to 10%.¹ Appropriate therapy and follow-up would be guided by this determination. Specific therapy is beyond the scope of this article but we would start her on dual oral therapy with close follow-up to reassess her 1-year mortality risk. If there were no improvement over a short period of time, we would add further therapy.

Pulmonary arterial hypertension (PAH) is a hemodynamic disorder that affects small and medium-size pulmonary arteries through cellular proliferation and luminal narrowing.¹ Increased pulmonary vascular resistance causes restricted blood flow in these arteries, leading to elevated pulmonary arterial pressure and afterload on the right ventricle. Despite advances in therapy, death usually occurs as a result of right ventricular failure.

• Group 1—PAH, due to narrowed pulmonary arteries
• Group 2—due to left heart disease
• Group 3—due to lung disease or hypoxia, or both
• Group 4—due to chronic thromboembolism or other pulmonary artery obstruction
• Group 5—due to uncertain or multifactorial causes.

Experts recognize the morbidity and mortality associated with pulmonary hypertension now more than in the past, and they emphasize recognizing it early. Guidelines for its diagnosis and treatment were updated in 2015.¹

Below, we use a case to discuss recommendations for initial evaluation and classification of pulmonary hypertension, particularly PAH.

A PATIENT SUSPECTED OF HAVING PULMONARY HYPERTENSION

A 63-year-old woman with a 25-pack-year history of tobacco use, as well as pulmonary embolism and coronary artery disease, presents to her primary care physician with exertional dyspnea. She had been a clerk at a hardware store and physically active until she took early retirement 8 months ago because of increasing fatigue. She initially felt the fatigue was simply “a sign of getting old.”

Since retiring, she has noticed the slow onset of progressive dyspnea on exertion. She can no longer climb more than 1 flight of stairs or walk more than 1 block. She also complains of mild, fluctuating edema in her lower extremities over the past month. She quit smoking 8 years ago after undergoing placement of a drug-eluting stent in the mid-left circumflex artery. After this, she received clopidogrel and was followed by a cardiologist for 2 years but stopped taking the medication because of bruising. She has not seen her cardiologist in more than 5 years.

She underwent elective right total knee arthroplasty 3 years ago, complicated by acute deep vein thrombosis in the right common femoral vein. Computed tomography (CT) at that time did not reveal pulmonary emboli. She received warfarin therapy for 3 months.

She reports no current cough, chest pain, lightheadedness, or syncope. She has no orthopnea, and she feels normal at rest.

Her family history is unremarkable, and she has had no exposure to illicit substances, environmental toxins, or dietary supplements. She takes aspirin 81 mg daily, metoprolol 25 mg twice daily, lisinopril 10 mg daily, and simvastatin 40 mg at bedtime.

Her primary care physician detects a murmur in the left lower sternal border and sends her for transthoracic echocardiography, which demonstrates mild right ventricular dilation, right atrial dilation, and mildly reduced right ventricular function. The calculated right ventricular systolic pressure is 69 mm Hg. The left ventricle shows mild concentric hypertrophy; the left atrium is normal in size.

DIAGNOSTIC EVALUATION OF SUSPECTED PULMONARY HYPERTENSION

CLINICAL MANIFESTATIONS

Symptoms and signs. As in the patient described above, the first symptoms such as exertional dyspnea, fatigue, and lightheadedness usually arise in situations that call for increased cardiac output.⁴ As right ventricular function worsens, symptoms start to occur at rest, and signs of increased right ventricular preload appear, such as abdominal and lower-extremity edema and pericardial effusion. Syncope is a sign of severe right ventricular dysfunction.⁵

Physical examination. Look for signs of increased right ventricular loading and failure, eg:

• An accentuated intensity and persistent splitting of the second heart sound
• A prominent parasternal heave
• A prominent jugular “a” wave
• A systolic murmur along the left sternal border at the fourth intercostal space, which may worsen with breath-holding
• Pitting lower-extremity edema
• Hepatomegaly
• Hepatojugular reflux
• Hepatic pulsatility.⁶

Many practitioners rely heavily on the estimated right ventricular systolic pressure in diagnosing pulmonary hypertension. In theory, this number should be nearly the same as the pulmonary arterial systolic pressure. However, technical and patient-related aspects of transthoracic echocardiography often limit accurate measurement of the right ventricular systolic pressure, and readings often differ from those measured with right heart catheterization.⁸

Our patient had a markedly elevated right ventricular systolic pressure and signs of right ventricular dysfunction, suggesting a high probability of pulmonary hypertension.

EVALUATING LEFT HEART DISEASE (WHO GROUP 2)

More than 75% of cases of pulmonary hypertension are directly related to left ventricular dysfunction or mitral or aortic valve disease (WHO group 2).¹ Since group 2 differs markedly from group 1 (PAH) in its pathophysiology and treatment, it is important to distinguish between them.

Compared with WHO group 1 patients, those in group 2 tend to be older, more of them are male, and more of them have comorbidities such as metabolic syndrome, hypertension, and coronary artery disease.^1,9 A combination of risk factors and clinical findings should be considered in identifying these patients.¹⁰

Transthoracic echocardiography is used to detect features of systolic and diastolic dysfunction. Left atrial enlargement is a clue that left heart disease may be present. In addition, signs of left ventricular or valvular dysfunction on electrocardiography or chest radiography are often helpful.

When estimated right ventricular systolic pressures are only minimally abnormal and no significant right ventricular dysfunction exists, further diagnostic evaluation is not warranted. However, because no single identifying feature or variable can readily distinguish group 2 from the other WHO groups, further evaluation should be considered if the right ventricular systolic pressure is significantly elevated or right ventricular dysfunction exists.

Our patient had several risk factors for left heart disease, including a history of smoking and coronary artery disease. Nonetheless, findings consistent with severe right ventricular dysfunction necessitated further evaluation for other possible causes of her suspected pulmonary hypertension.

Postcapillary pulmonary hypertension

In patients for whom further evaluation is pursued, the diagnosis of WHO group 2 pulmonary hypertension is ultimately based on findings consistent with postcapillary or “passive” pulmonary hypertension on right heart catheterization. Although mean pulmonary arterial pressures must be at least 25 mm Hg to certify the diagnosis of pulmonary hypertension, a pulmonary artery occlusion pressure greater than 15 mm Hg (normal 6–12) and pulmonary vascular resistance of 3 Wood units or less (normal 0.3–1.6) suggests the pulmonary hypertension is due to elevated left atrial pressure (ie, postcapillary) rather than precapillary pulmonary arterial remodeling.

Mixed pre- and postcapillary pulmonary hypertension

Distinguishing pulmonary venous hypertension from PAH is important, since their management differs. In particular, PAH-specific therapies (ie, prostacyclin analogues, prostaglandin I2 receptor agonists, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and cyclic guanosine monophosphate stimulators) can have a detrimental effect in WHO group 2 patients by causing increased pulmonary capillary leakage with pulmonary edema.^11,12

In some patients, chronic passive congestion in the pulmonary venous circulation causes additional disruption of the homeostatic milieu regulating precapillary smooth muscle and endothelial function. These changes result in structural remodeling of precapillary arterioles and increased precapillary vascular resistance, creating a “mixed” pulmonary hypertension with both pre- and postcapillary abnormalities.

There is controversy over the ideal way to identify these patients but little disagreement that they face a worse prognosis than those without precapillary remodeling.¹³ In light of this, efforts have been made to characterize this cohort.

Historically, mixed pre- and postcapillary pulmonary hypertension was defined as the combination of all of the following:

• Mean pulmonary arterial pressure ≥ 25 mm Hg
• Pulmonary artery occlusion pressure > 15 mm Hg
• Transpulmonary gradient (the mean pulmonary arterial pressure minus the pulmonary artery occlusion pressure) > 12 mm Hg.¹⁴

However, the utility of the transpulmonary gradient for distinguishing mixed pulmonary hypertension has been questioned because of  concerns over its susceptibility to variations in stroke volume and loading conditions.¹⁵

The diastolic pulmonary gradient (the pulmonary arterial diastolic pressure minus the pulmonary artery occlusion pressure) has been proposed as an alternative to the transpulmonary gradient under the theory that it is less sensitive to fluctuation from variations in flow or loading.¹⁵

Current guidelines¹ suggest that a patient who has all of the following should be considered to have mixed pulmonary hypertension:

• A mean pulmonary arterial pressure > 25 mm Hg
• A pulmonary artery occlusion pressure > 15 mm Hg
• A diastolic pulmonary gradient > 7 mm Hg or  a pulmonary vascular resistance > 3 Wood units, or both.

Occult group 2 pulmonary hypertension

Currently, the diagnosis of WHO group 2 pulmonary hypertension is based on elevated resting pulmonary artery occlusion pressure. However, some patients with WHO group 2 pulmonary hypertension and transiently low preload from aggressive diuresis or fasting may have a low pulmonary artery occlusion pressure during right heart catheterization and be misdiagnosed as having WHO group 1 PAH.^12,16

This concern was acknowledged in the 2015 Ambrisentan and Tadalafil in Patients With Pulmonary Arterial Hypertension (AMBITION) study after investigators changed the protocol to exclude patients who technically met the criteria for WHO group 1 PAH, but had borderline-elevated pulmonary artery occlusion pressure and additional risk factors worrisome for left heart disease and occult WHO group 2 pulmonary hypertension.^17,18

Several strategies, including passive leg-raising, fluid challenge, and exercise during diagnostic right heart catheterization, have been proposed to better classify these patients.¹⁹ Unfortunately, due to a lack of standardization of normal values and methodology for executing these maneuvers, consensus is lacking over their routine use, and recommendations for their use have not been provided.¹

All patients with suspected pulmonary hypertension should also be assessed for underlying pulmonary parenchymal or physiologic disease.

WHO group 3 consists of pulmonary disorders that, over an extended time, can lead to pulmonary hypertension. The most common of these disorders include chronic obstructive pulmonary disease, interstitial lung disease, and combined pulmonary fibrosis and emphysema.¹

Pulmonary hypertension in these patients is precapillary, and changes in pulmonary vascular resistance are influenced by multiple factors, the most significant of which is alveolar hypoxia. Hypoxia induces pulmonary artery vasoconstrictionn (in contrast to the reflexive hemodynamics seen in peripheral tissues, where systemic vascular tone is generally lower in states of hypoxia) as a mechanism to divert pulmonary blood flow to well-ventilated portions of the lung and maintain ventilation-perfusion matching.

Repeated chronic hypoxia also alters cellular structure and function of pulmonary vessels and leads to medial hypertrophy and increased vascular tone, thus contributing to the development of pulmonary hypertension in many of these patients.²⁰

Obstructive sleep apnea. Up to 70% of patients with obstructive sleep apnea have pulmonary hypertension.²¹ Chronic repetitive hypoxia throughout the night increases the levels of reactive oxygen species and alters cellular and molecular signaling, thus inducing vascular remodeling. In addition, apneic events during sleep promote catecholamine-driven elevations in systemic blood pressure. Over time, patients are at higher risk of developing left ventricular dysfunction and concomitant postcapillary group 2 pulmonary hypertension.²² Because typical methods of obstructive sleep apnea screening (eg, the Epworth Sleep Scale) have been historically poor at discriminating PAH patients with obstructive sleep apnea from those without, patients diagnosed with PAH should be considered for formal sleep testing.^23,24

Pulmonary function tests, chest imaging

Pulmonary function tests and high-resolution computed tomography are essential to any PAH evaluation and help to exclude WHO group 3 pulmonary hypertension.¹

An abnormal result on CT or spirometry can help point toward parenchymal lung disease. Normal spirometry and lung volumes with an isolated reduction in the diffusing capacity of the lung for carbon monoxide (Dlco) is typical of patients with WHO group 1 PAH.

In our patient, CT of the chest did not show any evidence of parenchymal lung disease, and pulmonary function tests showed no evidence of obstruction or restriction. There was a moderate decrease in Dlco, which did not reach normal limits when adjusted for lung volumes. In this setting, further evaluation of her PAH was warranted.

EVALUATION OF THROMBOEMBOLIC DISEASE (WHO GROUP 4)

Once pulmonary hypertension due to underlying left heart disease or parenchymal lung disease has been excluded, testing for chronic thromboembolic pulmonary hypertension is necessary, even in the absence of prior known pulmonary embolism. Identifying these patients is paramount, as chronic thromboembolic pulmonary hypertension (WHO group 4) is the only type of pulmonary hypertension for which a definitive cure is available.²⁶

Up to 9% of patients who survive acute pulmonary embolism exhibit features of chronic proximal thrombosis and remodeling of distal pulmonary arteries.²⁷

It remains unknown exactly why some patients develop chronic thromboembolic pulmonary hypertension and others do not, but the pathophysiology involves inappropriate thrombus resolution after venous thromboembolic events. Monocyte recruitment (which plays an important role in thrombus resolution) is reduced, angiogenesis is impaired (preventing effective vascular collateralization), and abnormal fibroblast proliferation leads to distal pulmonary vascular wall thickening.²⁸ There is some evidence of increased thrombophilic risk in this population, and approximately 10% to 20% of patients are positive for antiphospholipid antibodies or lupus anticoagulant.^29,30

Patients with chronic thromboembolic pulmonary hypertension usually present with symptoms similar to those of WHO group 1 PAH. Up to one-quarter of patients have no recollection of prior pulmonary embolism.³¹ As the disease progresses, signs and symptoms related to elevated pulmonary vascular resistance and right ventricular dysfunction are common.^32,33

Although thrombi usually resolve quickly, the diagnosis of chronic thromboembolic pulmonary hypertension should be made only after at least 3 months of appropriate anticoagulation to avoid treatment of transient hemodynamic changes often seen after an acute pulmonary embolism.¹

Radiographic changes associated with chronic thromboembolic pulmonary hypertension are distinct from the intraluminal filling defects seen with acute thromboembolism, since chronic thrombi tend to become organized and eccentric. On imaging, one may see features of rapid luminal narrowing or eccentric filling defects rather than the conventional central filling defects of acute pulmonary embolism. These changes are often overlooked by radiologists who are not specifically looking for chronic thromboembolic pulmonary hypertension.³⁴ For this reason, the sensitivity and specificity of identifying chronic thromboembolic disease using radionuclide ventilation-perfusion lung scanning is superior to that of CT angiography.

All patients with suspected PAH should undergo a ventilation-perfusion scan.^1,35 In patients with ventilation-perfusion mismatch on radionuclide scanning, pulmonary angiography can fulfill multiple goals of measuring pulmonary arterial pressures, identifying the extent and location of chronic thromboemboli, and can determine whether surgical thromboendarterectomy is feasible.

If chronic thromboembolic pulmonary hypertension is identified, it is imperative that patients be referred to a center of excellence specializing in its management regardless of symptom severity, as surgery can be curative and may prevent development of progressive right ventricular dysfunction.³⁶

Our patient’s ventilation-perfusion scan was normal, effectively ruling out the possibility of chronic thromboembolism as a cause of her pulmonary hypertension.

Once the above-mentioned conditions have been evaluated, patients with suspected PAH should be referred to a pulmonary hypertension center of excellence to undergo right heart catheterization. If this test reveals PAH, further vasoreactivity testing should be performed if the etiology of the PAH is considered to be idiopathic, heritable, or drug-induced.¹

Vasoreactivity is most commonly tested using 20 ppm of inhaled nitric oxide, but alternative formulations including intravenous epoprostenol, intravenous adenosine, or inhaled iloprost are acceptable. Patients who have a positive vasoreactive test usually respond well to high-dose calcium channel blocker therapy and have a significantly better prognosis than other patients with PAH.³⁷

Patients with WHO group 1 PAH who do not have idiopathic, heritable, or drug-induced PAH have not been shown to have favorable outcomes using calcium channel blockers even if they have a positive vasoreactive response. A positive vasoreactive response is defined as a drop in mean pulmonary arterial pressure of at least 10 mm Hg to an absolute level of 40 mm Hg or less. Cardiac output should be preserved or elevated compared with baseline values during the challenge.¹

In reality, only 10% to 15% of patients with idiopathic PAH have a positive vasoreactive response, and half of these patients stop responding within 1 year.³⁸ Therefore, clinicians should not assume that calcium channel blockers will be successful in the long term in a vasoreactive patient, and these patients should have follow-up right heart catheterization after 3 to 6 months and annually thereafter to ensure continued vasoreactivity.¹

In patients who are no longer vasoreactive or whose functional status is worse than New York Heart Association functional class I or II, conventional PAH-specific therapy should be started.

LOOKING FOR CAUSES OF ‘IDIOPATHIC’ PAH

Pulmonary hypertension is considered the final common pathway of many varied diseases and syndromes, and therefore one cannot say it is idiopathic without making a robust effort to identify features of alternative causes and rule out other contributing factors.
Although the exact etiology of idiopathic PAH is unclear, well-characterized imbalances in vascular homeostasis have been identified. These include processes that promote vasoconstriction, cell proliferation, and thrombosis (thromboxane A2, endothelin-1, and serotonin) and those that suppress prostacyclin, nitric oxide, and vasoactive intestinal peptide-mediated vasodilation.¹ Furthermore, an abnormal angiogenic response to hypoxia and vascular endothelial growth factor has been observed.³⁹

Before considering a diagnosis of idiopathic PAH, a careful history is essential. Other causative agents include appetite-suppressing medications, such as fenfluramine derivatives or stimulants such as amphetamines. Human immunodeficiency virus (HIV) or hepatitis, a history of splenectomy, and prior thyroid or liver disease are also common causes of PAH. Joint pain, myalgias, Raynaud features, or a rash characteristic of connective tissue disease can be identified on history and physical examination. Worldwide, chronic exposure to high-altitude climates and exposure to schistosomiasis are significant causes of PAH, but are rarely seen in developed nations. Confirmatory serum tests for HIV, antinuclear antibody, scleroderma antibody, and thyroid function are essential.¹

Genetic factors

If patients report having relatives with possible or probable PAH, genetic counseling is recommended, particularly for rare but causative gene mutations.

BMPR2, the gene that codes for the bone morphogenetic protein receptor type 2, can carry mutations with variable penetrance over the patient’s lifetime depending on other genetic polymorphisms, concurrent inflammation, and the patient’s sex.⁴⁰

The population carrier estimates of BMPR2 mutations are only 0.001% to 0.01%, but mutations in this gene are identified in approximately 25% of nonfamilial PAH patients and in over 75% of those with a familial inheritance pattern. The BMPR2 protein is a part of the transforming growth factor beta family and is partially responsible for control of vascular cell proliferation. Mutations in this gene lead to PAH at a younger age than in those with mutation-negative idiopathic PAH and to a more severe clinical phenotype in terms of pulmonary vascular resistance and cardiac function.⁴⁰

Other mutations. Although BMPR2 is the most commonly identified gene mutation in patients with PAH, other gene mutations within this family have also been recognized. These include mutations in the genes for activin receptor-like kinase 1 and endoglin, which, although better known for their association with hereditary hemorrhagic telangiectasia, can lead directly to PAH.⁴⁰

More recently, a novel autosomal recessive gene mutation in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) has been identified in patients with pulmonary veno-occlusive disease⁴¹ and pulmonary capillary hemangiomatosis,⁴² which are specific subclasses of WHO group 1 PAH. The mechanistic parallels between EIF2AK4 and these diseases are not clear, but the prevalence of disease in those with a familial inheritance pattern and an EIF2AK4 mutation is nearly 100%.⁴¹ Thus, identification of this mutation has been accepted as a way to confirm pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in patients suspected of PAH with features of these diseases.^43,44

GROUP 5: MISCELLANEOUS FORMS OF PULMONARY HYPERTENSION

WHO group 5 pulmonary hypertension encompasses disorders whose pathophysiology does not fit neatly within the context of the other pulmonary hypertension subtypes. Nonetheless, appreciation of these disorders is important in determining the etiology and appropriate therapy for patients with pulmonary hypertension. The mechanism driving abnormal pulmonary arterial pressures in patients with group 5 pulmonary hypertension is not always clear and may involve intrinsic or extrinsic factors.¹

Diseases within group 5 include those that cause extrinsic compression of the pulmonary arteries (ie, fibrosing mediastinitis) or intrinsic elevations in pulmonary vascular resistance (sarcoidosis, pulmonary Langerhans cell histiocytosis, sickle cell anemia, polycythemia vera, and malignancy).

The most common cause of pulmonary hypertension in this category is sarcoidosis. Current theories suggest that, for most patients, invasion of granulomatous inflammation within the arterial walls induces PAH via fibrotic or inflammatory vascular occlusion. Extrinsic compression due to lymphadenopathy, right or left ventricular dysfunction due to cardiac myocite infiltration, and endothelin-induced pulmonary vasoconstriction are other possible links between the PAH and sarcoidosis.⁴⁵

Cardiac magnetic resonance imaging (MRI) has gained popularity as a noninvasive and reproducible alternative to echocardiography. Image fidelity and characterization of right ventricular function and right ventricular ejection fraction are all more accurate than with echocardiography, and serial MRI has proven valuable in its ability to guide patient prognosis.⁴⁶

However, MRI is more expensive than echocardiography, and some patients cannot tolerate the procedure. In addition, for those who can tolerate it, MRI is not a suitable alternative to right heart catheterization, since it cannot accurately estimate pulmonary artery occlusion pressure or pulmonary arterial pressures.¹ For these reasons, cardiac MRI use varies across pulmonary hypertension centers.

A goal of treatment is to reduce a patient’s risk. While no consensus has been achieved over which PAH-specific therapy to start with, evidence is robust that using more than 1 class of agent is beneficial, capitalizing on multiple therapeutic targets.^17,47

In our patient, right heart catheterization revealed PAH with a mean pulmonary arterial pressure of 44 mm Hg, pulmonary artery occlusion pressure 6 mm Hg, and a cardiac index of 2.1 L/min/m². Ancillary testing for alternative causes of PAH was unrevealing, as was vasoreactivity testing. Our patient could walk only 314 meters on her 6-minute walk test and had an initial NT-proBNP level of 750 ng/L.

Based on these and the findings during her evaluation, she would be classified as having intermediate-risk PAH with an estimated 1-year mortality risk of 5% to 10%.¹ Appropriate therapy and follow-up would be guided by this determination. Specific therapy is beyond the scope of this article but we would start her on dual oral therapy with close follow-up to reassess her 1-year mortality risk. If there were no improvement over a short period of time, we would add further therapy.

ABSTRACT

Use of mesenchymal stem cells from bone marrow has gained significant popularity. The iliac crest has been determined to be an effective site for harvesting mesenchymal stem cells. Review of the literature reveals that multiple techniques are used to harvest bone marrow aspirate from the iliac crest, but the descriptions are based on the experience of various authors as opposed to studied anatomy. A safe, reliable, and reproducible method for aspiration has yet to be studied and described. We hypothesized that there would be an ideal angle and distance for aspiration that would be the safest, most consistent, and most reliable. Using magnetic resonance imaging (MRI), we reviewed 26 total lumbar spine MRI scans (13 males, 13 females) and found that an angle of 24° should be used when entering the most medial aspect of the posterior superior iliac spine (PSIS) and that this angle did not differ between the sexes. The distance that the trocar can advance after entry before hitting the anterior ilium wall varied significantly between males and females, being 7.53 cm in males and 6.74 cm in females. In addition, the size of the PSIS table was significantly different between males and females (1.20 cm and 0.96 cm, respectively). No other significant differences in the measurements gathered were found. Using the data gleaned from this study, we developed an aspiration technique. This method uses ultrasound to determine the location of the PSIS and the entry point on the PSIS. This contrasts with most techniques that use landmark palpation, which is known to be unreliable and inaccurate. The described technique for aspiration from the PSIS is safe, reliable, reproducible, and substantiated by data.

The iliac crest is an effective site for harvesting bone marrow stem cells. It allows for easy access and is superficial in most individuals, allowing for a relatively quick and simple procedure. Use of mesenchymal stem cells (MSCs) for treatment of orthopedic injuries has grown recently. Whereas overall use has increased, review of the literature reveals very few techniques for iliac crest aspiration,¹ but these are not based on anatomic relationships or studies. Hernigou and colleagues^2,3 attempted to quantitatively evaluate potential “sectors” allowing for safe aspiration using cadaver and computed tomographic reconstruction imaging. We used magnetic resonance imaging (MRI) to analyze aspiration parameters. Owing to the ilium’s anatomy, improper positioning or aspiration technique during aspiration can result in serious injury.^2,4-6 We hypothesized that there is an ideal angle and positioning for bone marrow aspiration from the posterior superior iliac spine (PSIS) that is safe, consistent, and reproducible. Although most aspiration techniques use landmark palpation, this is unreliable and inaccurate, especially when compared with ultrasound-guided injections^7-16 and procedures.^9,12,17-19 We describe our technique using ultrasound to visualize patient anatomy and accurately determine anatomic entry with the trocar.

METHODS

MRI scans of 26 patients (13 males, 13 females) were reviewed to determine average angles and distances. Axial T2-weighted views of the lumbar spine were used in all analyses. The sacroiliac (SI) joint angle was defined as the angle formed between the vector through the midline of the pelvis and the vector that is parallel to the SI joint. The approach angle was defined as the angle formed between the vector of the most medial aspect of the PSIS through the ilium to the anterior wall and the vector through the midline of the pelvis (Figure 1). 

Continue to: For the 13 males, the mean SI joint...

RESULTS

The results are reported in the Table. 

Table. Measurements of Patients Taken on Axial T2-Weighted Views of Lumbosacral MRI Scans^a